Alan F Schatzberg Charles B
Alan F Schatzberg Charles B
Alan F Schatzberg Charles B
TEXTBOOK OF
PSYCHOPHARMACOLOGY
FIFTH EDITION
The American Psychiatric Association Publishing
TEXTBOOK OF
PSYCHOPHARMACOLOGY
FIFTH EDITION
EDITED BY
PART I
Principles of Pharmacology
1 Basic Principles of Molecular Biology and Genomics
Jiang-Zhou Yu, MD., Ph.D.
Mark M. Rasenick, Ph.D.
4 Psychoneuroendocrinology
Roxanne Keynejad, M.A., M.B.B.S., M.R.C.P.
Ania Korszun, Ph.D., M.D., F.R.C.Psych.
Carmine M. Pariante, Ph.D., M.D., F.R.C.Psych.
PART II
Classes of Psychiatric Treatments
10 Fluoxetine
Jerrold F. Rosenbaum, M.D.
Dawn F. Ionescu, M.D.
11 Sertraline
Linda L. Carpenter, M.D.
Alan F. Schatzberg, M.D.
12 Paroxetine
Jonathon R. Howlett, M.D.
Murray B. Stein, M.D., M.P.H.
Charles B. Nemeroff, M.D., Ph.D.
13 Fluvoxamine
Elias Aboujaoude, M.D.
Lorrin M. Koran, M.D.
16 Vortioxetine
Pierre Blier, M.D., Ph.D.
17 Mirtazapine
Alan F. Schatzberg, M.D.
18 Bupropion
David V. Hamilton, M.D., M.A.
Anita H. Clayton, M.D.
19 Venlafaxine and Desvenlafaxine
Michael E. Thase, M.D.
21 Ketamine
David S. Mathai, B.S.
Sanjay J. Mathew, M.D.
22 Benzodiazepines
David V. Sheehan, M.D., M.B.A.
23 Buspirone
Donald S. Robinson, M.D.
Karl Rickels, M.D.
Antipsychotics
24 Classic Antipsychotic Medications
Henry A. Nasrallah, M.D.
Rajiv Tandon, M.D.
25 Clozapine
Stephen R. Marder, M.D.
Yvonne S. Yang, M.D., Ph.D.
26 Olanzapine
Amy L. Silberschmidt, M.D.
Jacob S. Ballon, M.D.
S. Charles Schulz, M.D.
27 Quetiapine
Peter F. Buckley, M.D.
Adriana E. Foster, M.D.
Matthew Byerly, M.D.
30 Ziprasidone
John W. Newcomer, M.D.
Elise Fallucco, M.D.
Martin T. Strassnig, M.D.
31 Asenapine
Leslie L. Citrome, M.D., M.P.H.
32 Iloperidone
Peter F. Buckley, M.D.
Adriana E. Foster, M.D.
Oliver Freudenreich, M.D.
Scott Van Sant, M.D.
33 Lurasidone
Philip D. Harvey, Ph.D.
34 Cariprazine
Sultan Albrahim, M.D.
Joseph H. Henry, M.D.
Charles B. Nemeroff, M.D., Ph.D.
37 Valproate
Charles L. Bowden, M.D.
41 Topiramate
Susan L. McElroy, M.D.
Paul E. Keck Jr., M.D.
Other Agents
42 Agents for Cognitive Disorders
Frank W. Brown, M.D.
43 Sedative-Hypnotics
Seiji Nishino, M.D., Ph.D.
Noriaki Sakai, D.V.M., Ph.D.
Kazuo Mishima, M.D., Ph.D.
Emmanuel Mignot, M.D., Ph.D.
William C. Dement, M.D., Ph.D.
49 Treatment of Schizophrenia
Tsung-Ung W. Woo, M.D., Ph.D.
Carla M. Canuso, M.D.
Joanne D. Wojcik, Ph.D., P.M.H.C.N.S.-B.C.
Douglas Noordsy, M.D.
Mary F. Brunette, M.D.
Alan I. Green, M.D.
53 Treatment of Insomnia
Andrew D. Krystal, M.D., M.S.
Appendix—Psychiatric Medications
Robert H. Chew, Pharm.D.
Index
Contributors
Elias Aboujaoude, M.D.
Clinical Professor, Department of Psychiatry and Behavioral Sciences, Stanford
University School of Medicine, Stanford, California
W. Stewart Agras, M.D.
Professor of Psychiatry Emeritus, Department of Psychiatry and Behavioral
Sciences, Stanford University School of Medicine, Stanford, California
Sultan Albrahim, M.D.
Resident in Psychiatry, Department of Psychiatry and Behavioral Sciences,
University of Miami Miller School of Medicine/Jackson Memorial Hospital,
Miami, Florida
Jacob S. Ballon, M.D., M.P.H.
Clinical Assistant Professor and Director, INSPIRE Clinic, Stanford University
Department of Psychiatry and Behavioral Sciences, Stanford, California
Raman Baweja, M.D.
Assistant Professor, Department of Psychiatry, Penn State College of Medicine
and Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania
Elisabeth B. Binder, M.D., Ph.D.
Director, Department of Translational Research in Psychiatry, Max Planck
Institute of Psychiatry, Munich, Germany; Professor, Department of Psychiatry
and Behavioral Sciences, Department of Human Genetics, Emory University
School of Medicine, Atlanta, Georgia
Pierre Blier, M.D., Ph.D.
Professor, Departments of Psychiatry and Cellular and Molecular Medicine,
University of Ottawa, The Royal Institute of Mental Health Research Institute,
Ottawa, Ontario, Canada
William V. Bobo, M.D., M.P.H.
Associate Professor, Psychiatry and Psychology, Mayo Clinic, Rochester,
Minnesota
Charles L. Bowden, M.D.
Clinical Professor, Departments of Psychiatry and Pharmacology, University of
Texas Health Science Center at San Antonio, San Antonio, Texas
Kathleen T. Brady, M.D., Ph.D.
Distinguished University Professor, Addiction Sciences Division, Department of
Psychiatry and Behavioral Sciences, Medical University of South Carolina; Staff
Psychiatrist, Ralph H. Johnson VA Medical Center, Charleston, South Carolina
Frank W. Brown, M.D.
Associate Chief Quality Officer, Emory University Hospital; Associate Professor
and Vice-Chairman of Clinical Operations, Department of Psychiatry and
Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia
Mary F. Brunette, M.D.
Associate Professor of Psychiatry, Psychiatric Research Center and
Psychopharmacology Research Group, Geisel School of Medicine at Dartmouth,
Concord, New Hampshire
Peter F. Buckley, M.D.
Dean, Medical College of Georgia, Augusta University, Augusta, Georgia
Matthew Byerly, M.D.
Professor of Cell Biology and Neuroscience, Montana State University,
Bozeman, Montana
Joseph R. Calabrese, M.D.
Director, Mood Disorders Program, University Hospitals Case Medical Center,
Bipolar Disorders Research Chair and Professor of Psychiatry, Case Western
Reserve University School of Medicine, Cleveland, Ohio
Carla M. Canuso, M.D.
Senior Director, Neuroscience Clinical Development, Janssen Research and
Development, Titusville, New Jersey
Linda L. Carpenter, M.D.
Professor, Department of Psychiatry and Human Behavior, The Warren Alpert
Medical School of Brown University; Chief, Butler Hospital Mood Disorders
Program; Director, Butler TMS Clinic and Neuromodulation Research Facility,
Providence, Rhode Island
Robert H. Chew, Pharm.D.
Psychiatric Pharmacist Specialist, Sacramento, California
Leslie L. Citrome, M.D., M.P.H.
Clinical Professor of Psychiatry and Behavioral Sciences, New York Medical
College, Valhalla, New York
Anita H. Clayton, M.D.
Chair and David C. Wilson Professor, Department of Psychiatry and
Neurobehavioral Sciences, University of Virginia, Charlottesville, Virginia
Joseph F. Cubells, M.D., Ph.D.
Associate Professor, Department of Psychiatry and Behavioral Sciences,
Departments of Human Genetics and of Psychiatry and Behavioral Sciences,
Emory University School of Medicine, Atlanta, Georgia
Darina Czamara, Ph.D.
Staff Scientist, Department of Translational Research in Psychiatry, Max Planck
Institute of Psychiatry, Munich, Germany
Daniella David, M.D.
Chief, Psychiatry Service, and Medical Director, PTSD Program, Bruce W.
Carter VA Medical Center, Miami, Florida; Professor of Clinical Psychiatry and
Associate Director of Psychiatry Residency Training Program, Department of
Psychiatry and Behavioral Sciences, Miller School of Medicine, University of
Miami, Miami, Florida
Jonathan R.T. Davidson, M.D.
Professor Emeritus, Department of Psychiatry and Behavioral Sciences, Duke
University Medical Center, Durham, North Carolina
Karon Dawkins, M.D.
Associate Professor and Director of General Psychiatry Residency Training
Program, Department of Psychiatry, University of North Carolina School of
Medicine, Chapel Hill, North Carolina
Charles DeBattista, D.M.H., M.D.
Professor of Psychiatry and Behavioral Sciences, Stanford University School of
Medicine, Stanford, California
William C. Dement, M.D., Ph.D.
Lowell W. and Josephine Q. Berry Professor, Department of Psychiatry and
Behavioral Sciences, Stanford University School of Medicine, Stanford, Palo
Alto, California
D.P. Devanand, M.D.
Professor of Psychiatry and Neurology and Director of Geriatric Psychiatry,
Columbia University Medical Center, New York, New York
C. Lindsay DeVane, Pharm.D.
Professor, Department of Psychiatry and Behavioral Sciences, Medical
University of South Carolina, Charleston, South Carolina
Firdaus S. Dhabhar, Ph.D.
Professor, Department of Psychiatry and Behavioral Sciences, Sylvester
Comprehensive Cancer Center, Miller School of Medicine, University of Miami,
Miami, Florida
Barbara D’Orio, M.D., M.P.A.
Associate Professor, Department of Psychiatry and Behavioral Sciences, Emory
University School of Medicine, Atlanta, Georgia
Carolyn M. Drazinic, M.D., Ph.D.
Associate Professor, Department of Psychiatry and Behavioral Sciences,
Leonard M. Miller School of Medicine, University of Miami, Miami, Florida;
Chief Medical Officer of Psychiatry, Jackson Health System, Miami, Florida
Elise Fallucco, M.D.
Director, North Florida Center for Collaborative Care; Adjunct Assistant
Professor, Department of Psychiatry (Child), University of Florida College of
Medicine–Jacksonville, Jacksonville, Florida
Adriana E. Foster, M.D.
Professor and Vice Chair for Clinical and Research Programs, Herbert Wertheim
College of Medicine, Florida International University, Miami, Florida
Oliver Freudenreich, M.D.
Associate Professor of Psychiatry, Harvard Medical School, Boston,
Massachusetts
Mark A. Frye, M.D.
Professor and Chair, Department of Psychiatry and Psychology, Mayo Clinic,
Rochester, Minnesota
Keming Gao, M.D., Ph.D.
Professor of Psychiatry, Department of Psychiatry; Clinical Director, Mood and
Anxiety Clinic in the Mood Disorders Program, University Hospitals Case
Medical Center/Case Western Reserve University School of Medicine,
Cleveland, Ohio
Steven J. Garlow, M.D., Ph.D.
Professor, Department of Psychiatry, University of Wisconsin School of
Medicine and Public Health, Madison, Wisconsin
Alan J. Gelenberg, M.D.
Professor Emeritus of Psychiatry, University of Arizona, Tucson, Arizona
Donald C. Goff, M.D.
Marvin Stern Professor of Psychiatry and Vice Chair for Research, Department
of Psychiatry, NYU Langone Medical Center, New York, New York
Robert N. Golden, M.D.
Dean and Professor of Psychiatry, School of Medicine and Public Health; Vice
Chancellor for Medical Affairs, University of Wisconsin–Madison, Madison,
Wisconsin
Rolando Gonzalez, M.D.
Resident in Psychiatry, Department of Psychiatry and Behavioral Sciences,
University of Miami Miller School of Medicine, Miami, Florida
Todd D. Gould, M.D.
Associate Professor, Departments of Psychiatry, Pharmacology, and Anatomy
and Neurobiology, University of Maryland School of Medicine, Baltimore,
Maryland
Alan I. Green, M.D.
Raymond Sobel Professor of Psychiatry, Professor of Molecular and Systems
Biology, Chairman, Department of Psychiatry, Director, Dartmouth SYNERGY:
The Dartmouth Clinical and Translational Science Institute; Primary Institutional
Affiliation: The Geisel School of Medicine at Dartmouth, Lebanon, New
Hampshire
David V. Hamilton, M.D., M.A.
Assistant Professor, Department of Psychiatry and Neurobehavioral Sciences,
University of Virginia, Charlottesville, Virginia
Ebrahim Haroon, M.D.
Assistant Professor, Department of Psychiatry and Behavioral Sciences, Emory
University School of Medicine, Atlanta, Georgia
Karen J. Hartwell, M.D.
Associate Professor, Addiction Sciences Division, Department of Psychiatry and
Behavioral Sciences, Medical University of South Carolina; Medical Director,
Substance Abuse Treatment Center, Ralph H. Johnson VA Medical Center,
Charleston, South Carolina
Philip D. Harvey, Ph.D.
Leonard M. Miller Professor of Psychiatry and Behavioral Science, University
of Miami Miller School of Medicine, Miami, Florida
Joseph H. Henry, M.D.
Assistant Professor, Department of Psychiatry and Behavioral Sciences,
University of Miami Miller School of Medicine, Miami, Florida
Michele Hill, M.R.C.Psych.
Consultant Psychiatrist, St Michael’s Psychiatric Unit, Mercy University
Hospital, Cork, Ireland
Eric Hollander, M.D.
Clinical Professor of Psychiatry and Behavioral Sciences; Director, Autism and
Obsessive Compulsive Spectrum Program and Anxiety and Depression Program,
Department of Psychiatry and Behavioral Sciences, Albert Einstein College of
Medicine and Montefiore Medical Center, Bronx, New York
Jonathon R. Howlett, M.D.
Associate Physician, Department of Psychiatry, University of California San
Diego, La Jolla, California; Resident Physician, VA San Diego Healthcare
System, San Diego, California
Dawn F. Ionescu, M.D.
Assistant in Psychiatry, Massachusetts General Hospital, and Assistant
Professor, Department of Psychiatry, Harvard Medical School, Boston,
Massachusetts
Ned H. Kalin, M.D.
Hedberg Professor and Chair, Department of Psychiatry; Director,
HealthEmotions Research Institute, University of Wisconsin School of Medicine
and Public Health, Madison, Wisconsin
Masoud Kamali, M.D.
Assistant Professor, Department of Psychiatry, Harvard Medical School, Boston,
Massachusetts
Paul E. Keck Jr., M.D.
Lindner Professor and Executive Vice Chair, Department of Psychiatry and
Neuroscience, University of Cincinnati College of Medicine, Cincinnati, Ohio
David E. Kemp, M.D., M.S.
Associate Professor of Psychiatry, University of Illinois at Chicago; Co-Medical
Director, Behavioral Health Service Line, Advocate Health Care, Downers
Grove, Illinois
Terence A. Ketter, M.D.
Professor of Psychiatry and Behavioral Sciences and Chief, Bipolar Disorders
Clinic, Stanford University School of Medicine, Stanford, California
Jessica Keverne, Ph.D.
Scientist, Department of Translational Research in Psychiatry, Max Planck
Institute of Psychiatry, Munich, Germany
Roxanne Keynejad, M.A., M.B.B.S., M.R.C.P.
Academic Clinical Fellow in General Adult Psychiatry, Institute of Psychiatry,
Psychology and Neuroscience, King’s College London
Lorrin M. Koran, M.D.
Professor (Clinical) of Psychiatry and Behavioral Sciences, Emeritus, Stanford
University School of Medicine, Stanford, California
Ania Korszun, Ph.D., M.D., F.R.C.Psych.
Professor of Psychiatry, Centre for Psychiatry, Wolfson Institute of Preventive
Medicine, Queen Mary University of London, Charterhouse Square, London
Venkatesh Basappa Krishnamurthy, M.D.
Assistant Professor, Department of Psychiatry, Penn State College of Medicine
and Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania
K. Ranga Rama Krishnan, M.D.
Dean, Rush Medical College, Chicago, Illinois
Kurt Kroenke, M.D.
Director of Education and Training Programs, Regenstrief Institute, Inc.;
Professor of Medicine, Indiana University School of Medicine, Indianapolis,
Indiana
Andrew D. Krystal, M.D., M.S.
Professor of Psychiatry and Behavioral Sciences; Director, Brain Stimulation
Program, Sleep Research Laboratory, Insomnia Clinic, and Quantitative EEG
Laboratory, Duke University Medical Center, Durham, North Carolina
Husseini K. Manji, M.D., F.R.C.P.C.
Global Therapeutic Head for Neuroscience, Janssen Pharmaceutical Research
and Development, Johnson & Johnson, Titusville, New Jersey
Stephen R. Marder, M.D.
Professor of Psychiatry, Semel Institute for Neuroscience at UCLA, Los
Angeles, California
David S. Mathai, B.S.
Medical Student, Baylor College of Medicine, Houston, Texas
Sanjay J. Mathew, M.D.
Marjorie Bintliff Johnson and Raleigh White Johnson Jr. Chair for Research in
Psychiatry, Professor of Psychiatry and Behavioral Sciences, Menninger
Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine,
Houston, Texas
Helen Mayberg, M.D.
Professor, Department of Psychiatry, Neurology, and Radiology; Dorothy C.
Fuqua Chair, Psychiatric Neuroimaging and Therapeutics, Emory University
School of Medicine, Atlanta, Georgia
W. Vaughn McCall, M.D., M.S.
Case Distinguished University Chair, Department of Psychiatry and Health
Behavior, Medical College of Georgia at Augusta University, Augusta, Georgia
William M. McDonald, M.D.
J.B. Fuqua Chair for Late-Life Depression and Professor of Psychiatry and
Behavioral Sciences; Vice-Chair for Education; Director, Geriatric Psychiatry
Services and ECT and Neuromodulation Services, Emory University School of
Medicine, Atlanta, Georgia
Susan L. McElroy, M.D.
Professor, Department of Psychiatry and Neuroscience, University of Cincinnati
College of Medicine, Cincinnati, Ohio
Aimee L. McRae-Clark, Pharm.D.
Professor, Addiction Sciences Division, Department of Psychiatry and
Behavioral Sciences, Medical University of South Carolina, Charleston, South
Carolina
Thomas W. Meeks, M.D.
Assistant Professor of Psychiatry, Uniformed Services University of the Health
Sciences, Naval Medical Center San Diego, San Diego, California
Emmanuel Mignot, M.D., Ph.D.
Craig Reynolds Professor of Sleep Medicine; Professor of Psychiatry and
Behavioral Sciences, Stanford University School of Medicine, Palo Alto,
California; Director, Stanford Center for Sleep Sciences and Medicine, Palo
Alto, California
Andrew H. Miller, M.D.
William P. Timmie Professor, Department of Psychiatry and Behavioral
Sciences, Emory University School of Medicine, Atlanta, Georgia
Kazuo Mishima, M.D., Ph.D.
Director, National Institute of Mental Health, National Center of Neurology and
Psychiatry, Kodaira, Tokyo, Japan
Marissa Miyazaki, M.D.
Staff Psychiatrist, Columbia University Student Mental Health Service,
Columbia University Medical Center, New York, New York
Katherine Marshall Moore, M.D.
Assistant Professor, Department of Psychiatry and Psychology, Mayo Clinic,
Rochester, Minnesota
Henry A. Nasrallah, M.D.
Professor and Chairman, Department of Psychiatry and Behavioral
Neuroscience, and Sydney W. Souers Endowed Chair, Saint Louis University
School of Medicine, Saint Louis, Missouri
J. Craig Nelson, M.D.
Leon J. Epstein Professor of Psychiatry and Director of Geriatric Psychiatry,
Department of Psychiatry, University of California–San Francisco, San
Francisco, California
Charles B. Nemeroff, M.D., Ph.D.
Leonard M. Miller Professor and Chairman, Department of Psychiatry and
Behavioral Sciences, University of Miami Miller School of Medicine, University
of Miami, Miami, Florida
John W. Newcomer, M.D.
Vice Dean for Research and Innovation, Charles E. Schmidt College of
Medicine, Florida Atlantic University, Boca Raton, Florida
D. Jeffrey Newport, M.D.
Director, Women’s Reproductive Mental Health; Medical Director, Health and
Recovery Center, Jackson Behavioral Health Hospital; Professor, Departments
of Psychiatry and Behavioral Sciences and of Obstetrics and Gynecology,
University of Miami Miller School of Medicine, Miami, Florida
Linda Nicholas, M.D.
Professor of Psychiatry (retired), University of North Carolina School of
Medicine, Chapel Hill, North Carolina
Seiji Nishino, M.D., Ph.D.
Professor of Psychiatry and Behavioral Sciences, Stanford University School of
Medicine, Stanford, California; Director, Sleep and Circadian Neurobiology
Laboratory, Stanford Sleep Research Center, Palo Alto, California
Douglas Noordsy, M.D.
Clinical Professor, Director of Sports Psychiatry Initiative, Department of
Psychiatry and Behavioral Sciences, Stanford University School of Medicine,
Stanford, California
Sandhaya Norris, M.D.
Assistant Professor, Department of Psychiatry, University of Ottawa; Staff
Psychiatrist, The Royal—Institute of Mental Health Research, Ottawa, Ontario,
Canada
Carmine M. Pariante, Ph.D., M.D., F.R.C.Psych.
Professor of Biological Psychiatry, Institute of Psychiatry, Psychology and
Neuroscience, King’s College London
Steven R. Pliszka, M.D.
Dielmann Distinguished Professor and Chair, Department of Psychiatry,
University of Texas Health Science Center at San Antonio, San Antonio, Texas
Bruce G. Pollock, M.D., Ph.D.
Vice President, Research and Director, Campbell Family Mental Health
Research Institute, Centre for Addiction and Mental Health; Professor of
Psychiatry and Pharmacology and Director, Division of Geriatric Psychiatry,
University of Toronto Faculty of Medicine, Toronto, Ontario, Canada
Robert M. Post, M.D.
Clinical Professor of Psychiatry, George Washington School of Medicine,
Washington, D.C.; Head, Bipolar Collaborative Network, Chevy Chase,
Maryland
Charles L. Raison, M.D.
Professor, Department of Psychiatry, School of Medicine and Public Health,
University of Wisconsin–Madison, Madison, Wisconsin
Mark M. Rasenick, Ph.D.
Distinguished UIC Professor, Departments of Physiology and Biophysics and
Psychiatry, University of Illinois, Chicago, and Jesse Brown VAMC, Chicago,
Illinois
Shona L. Ray-Griffith, M.D.
Assistant Professor, Departments of Psychiatry and of Obstetrics and
Gynecology, University of Arkansas for Medical Sciences, Psychiatric Research
Institute, Little Rock, Arkansas
Karl Rickels, M.D.
Stuart and Emily B.H. Mudd Professor of Behavior and Reproduction in
Psychiatry, Department of Psychiatry, University of Pennsylvania, Philadelphia,
Pennsylvania
Donald S. Robinson, M.D.
Consultant, Worldwide Drug Development, Shelburne, Vermont
Steven P. Roose, M.D.
Professor of Clinical Psychiatry, College of Physicians and Surgeons, Columbia
University; Director, NeuroPsychiatry Research Clinic, New York State
Psychiatric Institute, New York, New York
Patrick H. Roseboom, Ph.D.
Senior Scientist in Psychiatry, University of Wisconsin School of Medicine and
Public Health, Madison, Wisconsin
Jerrold F. Rosenbaum, M.D.
Chief of Psychiatry, Massachusetts General Hospital; Stanley Cobb Professor of
Psychiatry, Harvard
Noriaki Sakai, D.V.M., Ph.D.
Basic Life Science Research Associate, Department of Psychiatry and
Behavioral Sciences, Sleep and Circadian Neurobiology Laboratory, Stanford
University School of Medicine, Palo Alto, California
Carl Salzman, M.D.
Professor of Psychiatry, Harvard Medical School, Beth Israel Deaconess Medical
Center and Massachusetts Mental Health Center, Boston, Massachusetts
Erika F. H. Saunders, M.D.
Associate Professor and Chair, Department of Psychiatry, Penn State College of
Medicine and Penn State Milton S. Hershey Medical Center, Hershey,
Pennsylvania
Alan F. Schatzberg, M.D.
Kenneth T. Norris Jr. Professor, Department of Psychiatry and Behavioral
Sciences, Stanford University School of Medicine, Stanford, California
S. Charles Schulz, M.D.
Emeritus Professor, Department of Psychiatry, University of Minnesota School
of Medicine, Minneapolis; Psychiatrist, PrairieCare Medical Group, Brooklyn
Park, Minnesota
David V. Sheehan, M.D., M.B.A.
Distinguished University Health Professor Emeritus, University of South Florida
College of Medicine, Tampa, Florida
Richard C. Shelton, M.D.
Charles B. Ireland Professor and Vice Chair for Research; Director, Mood
Disorders Program, University of Alabama at Birmingham School of Medicine,
Birmingham, Alabama
Brian J. Sherman, Ph.D.
Postdoctoral Fellow, Addiction Sciences Division, Department of Psychiatry and
Behavioral Sciences, Medical University of South Carolina, Charleston, South
Carolina
Amy L. Silberschmidt, M.D.
Resident, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
Daphne Simeon, M.D.
Associate Professor of Psychiatry; Co-Director, Compulsive and Impulsive
Disorders Research Program; Director, Depersonalization and Dissociation
Research Program; Clinical Director, Center of Excellence for Compulsive and
Impulsive Disorders (CECID), Department of Psychiatry, Mount Sinai School of
Medicine, New York, New York
George M. Simpson, M.D.
Professor of Psychiatry Emeritus, Department of Psychiatry and Behavioral
Sciences, Keck School of Medicine, University of Southern California, Los
Angeles
Joseph K. Stanilla, M.D.
Associate Professor of Psychiatry, Cooper School of Medicine at Rowan
University, Camden, New Jersey
Murray B. Stein, M.D., M.P.H.
Distinguished Professor, Departments of Psychiatry and of Family Medicine and
Public Health, University of California San Diego, La Jolla, California; Staff
Psychiatrist, VA San Diego Healthcare System, San Diego, California
Zachary N. Stowe, M.D.
Professor, Departments of Psychiatry, Obstetrics and Gynecology, and
Pediatrics, University of Arkansas for Medical Sciences, Psychiatric Research
Institute, Little Rock, Arkansas
Martin T. Strassnig, M.D.
Associate Director, Clinical and Translational Research Core; Associate
Professor, Department of Integrated Medical Science, Charles E. Schmidt
College of Medicine, Florida Atlantic University, Boca Raton, Florida
Steven T. Szabo, M.D., Ph.D.
Assistant Professor, Department of Psychiatry and Behavioral Sciences, Duke
University Medical Center, Durham, North Carolina; Attending Psychiatrist,
Mental Health Service Line, Veterans Affairs Medical Center, Durham, North
Carolina
Rajiv Tandon, M.D.
Professor and Executive Vice Chair, Department of Psychiatry, University of
Florida College of Medicine, Gainesville, Florida
Michael E. Thase, M.D.
Professor, Department of Psychiatry, Perelman School of Medicine at the
University of Pennsylvania, Philadelphia, Pennsylvania
Marc L. van der Loos, M.D., Ph.D.
Psychiatrist, Department of Psychiatry, Isala Klinieken, Zwolle, The Netherlands
Scott Van Sant, M.D.
Clinical Assistant Professor, Department of Psychiatry and Health Behavior,
Medical College of Georgia, Augusta University, Augusta, Georgia
Karen Dineen Wagner, M.D., Ph.D.
Titus Harris Chair and Professor and Chair, Department of Psychiatry and
Behavioral Sciences, The University of Texas Medical Branch, Galveston, Texas
Po W. Wang, M.D.
Clinical Professor of Psychiatry and Behavioral Sciences, Stanford University
School of Medicine, Stanford, California
Margaret B. Weigel, M.D.
Assistant Professor, Department of Psychiatry and Behavioral Sciences, Emory
University School of Medicine, Atlanta, Georgia
Joanne D. Wojcik, Ph.D., P.M.H.C.N.S.-B.C.
Associate Director, Commonwealth Research Center, Instructor in Psychiatry,
Harvard Medical School; Beth Israel Deaconess Medical Center Department of
Psychiatry, The Division of Massachusetts Mental Health Center Public
Psychiatry, Boston
Tsung-Ung W. Woo, M.D., Ph.D.
Director, Program in Cellular Neuropathology, Medical Director, Harvard Brain
Tissues Resource Center, McLean Hospital; Assistant Professor of Psychiatry,
Harvard Medical School, Boston, Massachusetts
Yvonne S. Yang, M.D., Ph.D.
Health Sciences Assistant Clinical Professor, Semel Institute for Neuroscience at
UCLA, Los Angeles, California
Jiang-Zhou Yu, M.D., Ph.D.
Research Assistant Professor, Departments of Physiology and Biophysics and of
Surgery, University of Illinois, Chicago
Charles F. Zorumski, M.D.
Samuel B. Guze Professor and Head, Department of Psychiatry; Professor of
Neuroscience; Director, Taylor Family Institute for Innovative Psychiatric
Research, Washington University School of Medicine, St. Louis, Missouri
Disclosure of Interests
The following contributors to this textbook have indicated a financial interest in
or other affiliation with a commercial supporter, manufacturer of a commercial
product, and/or provider of a commercial service as listed below:
Principles of Pharmacology
CHAPTER 1
The nucleus resides in the cell body (the signal processing domain) and
contains the DNA that codes for the genes expressed by neurons. Activation of a
given gene results in the generation of a messenger RNA (mRNA), which is then
translated into a protein (see below). Although such events are common to all
cells, neural cells are unique in some aspects of molecular signaling. Notably, the
variety of gene expression is far greater in the brain than in any other organ or
tissue. Some estimates are that in aggregate, the brain expresses up to 10 times
the number of genes expressed in any other tissue. This does not mean that
individual cells undergo a much greater gene expression. Rather, it suggests an
extraordinary heterogeneity among neurons and glia, which allows for a rich
regulation when those neurons and glia assemble into the elaborate network of
the human brain.
mRNA molecules exported from the nucleus are translated into proteins by
ribosomes in the endoplasmic reticulum. Most of the protein production occurs
in the cell body, although there is some mRNA in the dendrites as well (Steward
and Wallace 1995). This means that newly made proteins must be transported
from that cell body to the axon terminal, a distance as great as 1 meter. These
proteins are often packaged in vesicles, and specialized “motor” molecules
transport packaged proteins down microtubule “tracks” at the cost of adenosine
triphosphate (ATP) hydrolysis (Setou et al. 2000).
DNA Replication
Chromosomal DNA must be replicated to coordinate with cell division.
Replication begins at a sequence called the origin of replication. It involves the
separation of the double helix DNA strands over a short length and the binding
of enzymes, including DNA and RNA polymerases. During DNA replication,
each existing strand of DNA serves as a template for the synthesis of a new
double helix that contains one old strand and one strand that is newly
synthesized but complementary. This process is known as semiconservative
replication. In the process of cell division, each of the 46 double helices is
replicated and folded into chromosomes.
Transcription
Only a fraction of all the genes in a genome are expressed in a given cell or at a
given time. These genes undergo the process of transcription, in which an RNA
molecule complementary to one of the gene’s DNA strands is synthesized in a 5′
to 3′ direction, using nucleotide triphosphates. Transcription can be classified
into three discrete steps: initiation, mRNA chain, elongation, and chain
termination. Transcriptional regulation may occur at any step in the process;
however, initiation appears to be the primary control point because, in a sense, it
is the rate-limiting step. Localization of the transcription start site and regulation
of the rate of transcription are essential to initiation. The cis- and trans-acting
factors described earlier in this section all regulate the initiation of transcription.
Translation
Each mRNA in a cell can code for the primary amino acid sequence of a protein,
using a triplet of nucleotides (codon) to represent each of the amino acids. Some
amino acids are represented by more than one codon, because there are more
triplet codons than there are amino acids. The codons in mRNA do not interact
directly with the amino acids they specify. The translation of the individual
codons of mRNA into protein depends on the presence of another RNA
molecule, tRNA, which has a cloverleaf structure. On the top leaf of the tRNA
structure, three nucleotides form a complementary codon, an anticodon, to each
mRNA nucleotide triplet. Thus, each mRNA nucleotide triplet can code for a
specific amino acid. Each tRNA carries an amino acid corresponding to its
anticodon, and when thus “charged,” the complex is termed aminoacyl-tRNA.
Anticodons of aminoacyl-tRNA bind with mRNA codons in ribosomes.
Ribosomes, a complex of rRNA and enzymes needed for translation, provide the
structure on which tRNA can bind with the codons of mRNA in sequential order.
Initiation of protein synthesis involves the assembly of the components of the
translation system. These components include the two ribosomal subunits, the
mRNA to be translated, the aminoacyl-tRNA specified by the first codon in the
message, guanosine triphosphate (GTP), and initiation factors that facilitate the
assembly of this initiation complex. In eukaryotes, there are at least 12 distinct
translation initiation factors (Roll-Mecak et al. 2000). After the ribosome
recognizes the specific start site on the mRNA sequence, which is always the
codon AUG coding for methionine, it slides along the mRNA molecule strand
and translates the nucleotide sequence one codon at a time, adding amino acids
to the growing end of the polypeptide chain (the elongation process). During
elongation, the ribosome moves from the 5′ end to the 3′ end of the mRNA that
is being translated. The binding of GTP to the elongation factor tu (EFtu)
promotes the binding of aminoacyl-tRNA to the ribosome (Wieden et al. 2002).
When the ribosome finds a stop codon (UAA, UGA, or UAG) in the message
RNA, the mRNA, the tRNA, and the newly synthesized protein are released
from ribosomes with the help of release factors that also bind GTP. The
translation process is stopped, and a nascent protein exists.
It is noteworthy that initiation, elongation, and release factors undergo a
conformational change upon the binding of GTP. In this regard, they are similar
to the G proteins (both heterotrimeric G proteins and small “ras-like” G proteins)
involved in cellular signaling, and regions of amino acid sequence homology in
the GTP-binding domains have been identified (Halliday et al. 1984; Kaziro et
al. 1991).
RNA Polymerases
There are three distinct classes of RNA polymerase—RNA polymerase I (Pol I),
RNA polymerase II (Pol II), and RNA polymerase III (Pol III)—in the nucleus of
eukaryotic cells, and they are designed to carry out transcription. RNA Pol I
synthesizes large rRNA molecules. RNA Pol II is mainly used to yield mRNA
and, subsequently, proteins. RNA Pol III produces small RNA, including rRNA
and tRNA molecules. Each class of RNA polymerase recognizes particular types
of genes. However, RNA polymerases do not bind to DNA directly. Rather, they
are recruited to DNA by other proteins that bind to promoters (Figure 1–2).
mRNA is transcribed from DNA by RNA Pol II, with heterogeneous nuclear
RNA (hnRNA), an intermediate product. The core promoter recognized by Pol II
is the TATA box (Hogness box), a sequence rich in nucleotides A and T, which is
usually located 25–30 bases upstream of the transcription start site. The TATA
box determines the start site of transcription and orients the basal transcription
complex that binds to DNA and recruits RNA Pol II to the TATA box; thus, it
establishes the 5′ to 3′ direction in which Pol II synthesizes RNA. The formation
of the basal transcription complex is promoted by a TATA box binding protein
(TBP) that binds core promoter together with multiple TBP-associated factors
and other general transcription factors. Enhancers are DNA sequences that
increase the rate of initiation of transcription by RNA Pol II through its
interaction with transcription factors, which can be located “upstream” or
“downstream” of the transcription start site. Enhancer elements are important to
cell-specific and stimulus-dependent expression of hnRNA. Some Pol II species,
including those for many genes that are expressed in neurons, lack a TATA box
and possess instead an initiator, a poorly conserved genetic promoter element.
Transcription Factors
Transcription factors act as the key regulators of gene expression. Sequence-
specific transcription factors typically contain physically distinct functional
domains (see Figure 1–2). Numerous transcription factors have been found.
Some of them translocate to the nucleus to bind their cis-regulatory elements in
response to their activation reaction, such as nuclear factor κB (NF-κB).
However, some transcription factors are already bound to their cognate cis-
regulatory elements in the nucleus under basal conditions and are converted into
transcriptional activators by phosphorylation. cAMP (cyclic 3′-5′-adenosine
monophosphate) response element–binding protein (CREB), for example, is
bound to regions of DNA, called cAMP response elements (CREs), before cell
stimulation. CREB can promote transcription when it is phosphorylated on a
serine residue (ser133), because phosphorylated CREB can interact with a
coactivator, CREB-binding protein (CBP), which in turn contacts and activates
the basal transcription complex. Of interest, CBP possesses intrinsic histone
acetyltransferase activity. The activity of most transcription factors is regulated
though second-messenger pathways. CREB can be activated via phosphorylation
at ser133 by second messengers such as cAMP, Ca++, and growth factors
(Kandel 2012) (Figure 1–3).
FIGURE 1–3. Activation of cAMP response element–binding
protein (CREB) via different signal transduction pathways.
Signal cascades are activated by external stimuli, such as hormones or neurotransmitters and
growth factors. Arrows indicate the interaction between pathways. AC=adenylyl cyclase;
C=catalytic subunits of PKA; CA++=calcium; CaMK IV=calmodulin-dependent kinase IV;
cAMP=cyclic 3′-5′-adenosine monophosphate; CBP=CREB-binding protein; Epac=exchange
protein activated by cAMP; ERK=extracellular-regulated kinase; Gαs=α subunit of the
stimulatory G protein; P=phosphorylation; PKA=cAMP-dependent protein kinase;
R=regulatory subunits of PKA; Rap and Ras=small GTPases (small proteins that bind to
guanosine triphosphate [GTP]); RSK2=ribosomal S6 kinase 2.
RNA Editing
RNA editing has been observed in eukaryotes ranging from protozoa to
mammals and is now recognized as a type of RNA process (posttranscriptional
modification of RNA) that differs from the well-known processes of RNA
splicing, 5′ end formation, and 3′ endonucleolytic cleavage and polyadenylation
(DeCerbo and Carmichael 2005; Kable et al. 1997). The conversion of adenosine
to inosine was observed first in yeast tRNA (Grosjean et al. 1996) but has since
been detected in viral RNA transcripts and mammalian cellular RNA (Bass
1997; Simpson and Emeson 1996). The inosine residues generated from
adenosines can alter the coding information of the transcripts, as inosine is
synonymous for guanosine during transcript translation. For example, upon A-
to-I editing the CAC codon for histamine is transformed to CIC, coding for
arginine. RNA editing can have dramatic consequences for the expression of
genetic information, and in a number of cases it has been shown to lead to the
expression of proteins not only with altered amino acid sequences from those
predicted from the DNA sequence but also with altered biological functions
(Bass 2002; Burns et al. 1997).
The enzymes for RNA editing are referred to as adenosine deaminases that
act on RNA (ADARs). ADARs target double-stranded RNA (dsRNA) and
convert adenosines to inosines by catalyzing a hydrolytic deamination at the
adenine base (Bass 2002). Mammals have several ADARs, of which two,
ADAR1 and ADAR2, are expressed in most tissues of the body (Seeburg and
Hartner 2003). RNA editing may also catalyze the conversion of a small number
of adenosines in a transcript to inosines (Stuart and Panigrahi 2002). On the
other hand, RNA editing can convert numerous adenosines to inosines in RNA.
This type of editing is thought to be the result of aberrant production of dsRNA
(DeCerbo and Carmichael 2005) and has been suggested to lead to RNA
degradation (Scadden and Smith 2001), nuclear retention (Zhang and
Carmichael 2001), or even gene silencing (Wang et al. 2005).
The serotonin 5-HT2C receptor is a G protein–coupled receptor that has
variants generated by A-to-I editing (Burns et al. 1997). 5-HT2C receptor
transcripts can be edited at up to five sites, potentially generating 24 different
receptor versions and hence a diverse receptor population. The RNA-edited 5-
HT2C receptor affects ligand affinity and the efficacy of G protein coupling
(Berg et al. 2001; Wang et al. 2000; Yang et al. 2004). The unedited form of the
5-HT2C receptor has the highest affinity to serotonin and exhibits constitutive
activity independent of serotonin or serotonergic agonists. When RNA is edited,
the basal activity of the 5-HT2C receptor is suppressed, and agonist potency and
efficacy are modified.
Non-Coding RNAs
About 2% of the human genome is transcribed into mature protein-coding
RNAs, whereas the large majority, 70%–90%, is transcribed into non-protein-
coding RNAs (ncRNAs). Classes of noncoding transcripts can be divided
between housekeeping noncoding RNAs and regulatory noncoding RNAs.
Housekeeping ncRNAs include rRNA, tRNA, snRNA, and small nucleolar
RNAs and are usually expressed constitutively. Regulatory ncRNAs can be
classified into miRNAs, Piwi-interacting RNAs (piRNAs), small interfering
RNAs (siRNAs), promoter and enhancer RNAs, and long noncoding RNAs
(lncRNAs) (Kaikkonen et al. 2011; Ponting et al. 2009). The majority of the non-
protein-coding transcripts belong to the group of lncRNAs, which are arbitrarily
considered as >200 nucleotides in length (Ponting et al. 2009). However, many
of these lncRNAs can also act as primary transcripts for the production of short
RNAs, making the categorization of this group of ncRNAs ambiguous
(Kaikkonen et al. 2011). The best-known ncRNAs are endogenous siRNAs.
SiRNAs, together with miRNAs and piRNAs, play an instrumental regulatory
and defensive role in organisms. These three classes of small RNAs show
overlap with regard to their structure, synthesis, and biological role. Endogenous
siRNAs are involved in gene regulation and transposon silencing, although the
latter mechanism is still not understood.
Cloning of DNA
The cloning of DNA confers the ability to replicate and amplify individual
pieces of genes. Cloning can be performed with genomic DNA or
complementary DNA (cDNA). cDNA is synthesized artificially from mRNA in
vitro with the aid of reverse transcriptase. Cloned genomic DNA may contain
any stretch of DNA, either intron or exon, whereas cloned cDNA consists only
of exons. For cloning (Figure 1–5 outlines the process), the desired pieces of
DNA (often called “inserts”) are connected with the DNA of genetically
engineered vectors or plasmids and then introduced into hosts such as bacteria or
mammalian cells. A DNA library is a collection of cloned restriction fragments
of the DNA of an organism that consists of random pieces of genomic DNA (i.e.,
genomic library) or cDNA (i.e., cDNA library). Complete cDNA libraries
contain all of the mRNA molecules expressed in a certain tissue. Sometimes
cDNA libraries can be from a specific tissue in a distinct circumstance. For
example, a cDNA library could be made from cerebral cortex in rats with
transient forebrain ischemia (Abe et al. 1993).
FIGURE 1–5. Outline of gene cloning.
See text for details.
Positional Cloning
Disease genes can sometimes be isolated with the aid of positional cloning, a
process also known as reverse genetics (Collins 1995). Positional cloning is the
process used to identify a disease gene based only on knowledge of its
chromosomal location, without any knowledge of the gene’s biological function.
Positional cloning requires a genetic map of unique DNA segments or genes
(genetic markers), with known chromosomal locations, that exist in several
alternative forms (alleles). These allelic variations (polymorphisms) allow
comparisons of the wild type as the “diseased” genotype.
Linkage analysis is a method of localizing one or more genes influencing a
trait to specific chromosomal regions. This is performed by examining the
cosegregation of the phenotype of interest with genetic markers. Relatives who
are phenotypically alike will share common alleles at markers surrounding the
genes influencing the phenotype, whereas relatives who are phenotypically
dissimilar will not share these alleles. To carry out linkage analyses,
investigators need, minimally, a set of families in which phenotypic individuals
have known relationships to one another and the genotypes of these individuals,
including one or more genetic markers.
Once the chromosomal location of the disease gene has been ascertained, the
area of chromosomal DNA can be cloned. Until recently, the process of
positional cloning involved laborious efforts to build a physical map and to
sequence the region. (The sequencing of the human genome has obviated this
step). Physical maps can be produced by isolating and linking together yeast
and/or bacterial artificial chromosomes containing segments of human DNA
from the region. These fragments are then sequenced and ordered, and from
these data, the genomic DNA sequence for the region of the candidate gene is
determined.
Differential Display
The technique of differential display is designed to determine the complement of
genes being expressed (mRNAs) by a tissue or organ at a given point in time.
The establishment of differential display is dependent on the random
amplification and subsequent size separation of cDNA molecules (Liang et al.
1992). With RT-PCR amplification with specific oligo-T primers (one- or two-
base anchored oligo-dT primers, such as oligo-T-XC, oligo-T-XG, oligo-T-XT,
and oligo-T-XA; X=G/A/C), four separate cDNA synthesis reactions are
performed. These cDNA synthesis reactions form the four pools of cDNA for
one original mRNA population. The resulting cDNA molecules from each RT-
PCR reaction are amplified, using the same primer of the reverse transcription
step plus randomly chosen primers. Because the randomly chosen primers will
anneal at various locations upstream of the oligo-T site, many individual cDNA
fragments of different sizes are amplified in each PCR reaction. cDNA
fragments derived from different original mRNA populations are sized and then
separated on parallel gels to analyze the presence of unique bands. The
differentially expressed cDNA fragments can be excised from gels, cloned, and
further characterized by a variety of technologies based on different purposes,
such as in situ hybridization, sequences, and Northern blot analysis.
Differential display is a useful tool for identifying region-specific mRNA
transcripts in brain. The molecular markers for these regions can be found by
screening for gene expression in specific brain regions or nuclei (Mizushima et
al. 2000; Tochitani et al. 2001). In addition, under different stimulation or
behavioral conditions, the changes in gene expression can be explored by
differential display (Hong et al. 2002; Liu et al. 2002; Mello et al. 1997; Tsai et
al. 2002). This technique has even been adapted to indicate the RNA expression
profile of an individual neuron (Eberwine et al. 1992). Many genes related to
ischemia or Alzheimer’s disease in CNS have also been isolated using
differential display (Doyu et al. 2001; Imaizumi et al. 1997; Tanaka et al. 2002).
Genes that are activated in response to chronic drug treatment (e.g., with opiates
or antidepressants) can also be identified this way. Furthermore, as described
later in this chapter, streamlined technologies are now available for this purpose.
Viral Vectors
Several viral vectors with low toxicity, high infection rate, and persistent
expression have extended the methodology of delivery of genes to mammalian
cells. These viruses include DNA viruses, such as adenoviruses and adeno-
associated viruses, herpes simplex viruses, and RNA retroviruses. As a result of
advances in genetic manipulation, adenoviruses and adeno-associated viruses are
now more widely applied to gene transfer. The advantages of the adenoviruses
are 1) the ability to carry large sequences of foreign DNA, 2) the ability to infect
a broad range of cell types, and 3) an almost 100% expression of the foreign
genes in cells.
Human adenovirus is a large DNA virus (containing about 36 kilobase pairs)
composed of early genes (from E1 to E4) and later genes (from L1 to L5). Wild-
type adenovirus cannot be applied to gene transfer because it causes a lytic
infection. Thus, recombinant adenoviruses with defects of some essential viral
genes are used for gene delivery. These adenoviral expression systems are safe,
have the capacity for large DNA inserts, and allow for relatively simple
adenoviral production (Harding et al. 1997; He et al. 1998).
The process of gene transfer into cells (cell lines and primary cells) via
recombinant adenoviruses is simple, but the optimal viral titer, the time of
exposure to virus, and the multiplicity of infection should be optimized for each
cell type. Cell lines and a variety of primary neuronal cells have been infected by
adenoviruses (Barkats et al. 1996; Chen and Lambert 2000; Hughes et al. 2002;
Koshimizu et al. 2002; Slack et al. 1996). In addition, recombinant adenoviruses
containing the desired genes can be delivered to neurons in vivo via intracerebral
injection into particular brain areas (Bemelmans et al. 1999; Benraiss et al. 2001;
Berry et al. 2001; Neve 1993).
Several different “colors” have been developed through mutation of the initial
GFP gene. Depending on the wavelengths of excitation, they can be used to
localize multiple protein species, or fluorescence resonance energy transfer
(FRET) can be used to demonstrate that two target proteins are in close (<10 nm)
proximity. FRET uses two fluors with little spectral overlap and depends on the
emission of one of the fluors exciting the other.
RNA Interference
RNA interference (RNAi) is believed to be a biologically conserved function in a
wide range of eukaryotic species. It may play a role in protection against dsRNA
viruses (Sijen et al. 2001) and genome-invading transposable elements (Provost
et al. 2002; Volpe et al. 2002). Triggered by dsRNA, RNAi identifies and
destroys the mRNA that shares homology with the dsRNA. Thus, the expression
of a particular gene can be suppressed by introducing dsRNA whose antisense
strand sequence matches the mRNA sequence. miRNA and siRNA are central to
RNA interference.
Fire et al. (1998) first described RNAi in the nematode Caenorhabditis
elegans as sequence-specific gene silencing in response to dsRNA. The
mechanism of RNAi is partly understood, and key proteins involved in the
pathway have been identified. In brief, the process of siRNA involves a series of
steps. In a first initiation step, Dicer, an enzyme of the RNase III family, initiates
ATP-dependent fragmentation of long dsRNA into 21- to 25-nucleotide double-
stranded fragments, termed small interfering RNAs (siRNAs). These siRNAs are
specifically characterized by overhanging 3′ ends of two nucleotides and
phosphorylated 5′ ends. The siRNA duplexes bind with Dicer, which facilitates
the formation of an siRNA/multiprotein complex called RISC loading complex
(RLC). The siRNA duplex in RLC then unwinds (which requires the protein
Ago2) to form an active RNA-induced silencing complex (RISC) that contains a
single-stranded RNA (called the guide strand). The RISC recognizes the target
RNA through Watson-Crick base pairing with the guide strand and cleaves the
target RNA. Finally, the RISC releases its cleaved product and goes on to
catalyze a new cycle of target recognition and cleavage (Figure 1–6) (Tomari and
Zamore 2005; Xia et al. 2005).
FIGURE 1–6. A schematic of the mechanism of RNA
interference (RNAi) posttranscriptional knockdown of a gene
product.
The procedure starts with introduction (transfection, electroporation, or injection) of double-
stranded RNA (dsRNA) or small interfering RNA (siRNA) into cells, or expression of small
hairpin RNA (shRNA) in cells with vectors encoding shRNAs. The cellular ribonuclease
(RNase) Dicer recognizes the long dsRNA molecules and shRNA. Subsequently, the dsRNA is
cleaved, resulting in 21-nt RNA duplexes, the siRNAs. These siRNA molecules are then
incorporated into the RNA-induced silencing complex (RISC) multiprotein complex, where
they are unwound by an adenosine triphosphate (ATP)–dependent process, transforming the
complex into an active state. Activated RISC uses one strand of the RNA as a bait to bind
homologous RNA molecules. The target RNA is cleaved and degraded, resulting in gene
silencing. mRNA=messenger RNA; pol III=RNA polymerase III.
miRNAs are formed in a similar manner, from longer RNA precursors, and are
processed in the cytoplasm by Dicer before becoming part of RISC. However,
siRNAs are the products of exogenous dsRNAs that are taken up by cells or that
enter via vectors such as viruses. siRNAs bind to mRNA in the case of complete
complementarity. miRNAs are products of endogenous ncRNA encoded from
genes of the genome. They do not require full complementarity to bind with
target mRNA (e.g., one type of miRNA may regulate many genes, and one gene
may be regulated by several miRNAs) (Carthew and Sontheimer 2009).
Chromatin Immunoprecipitation
The purpose of chromatin immunoprecipitation (ChIP) is to identify genomic
sequence(s) associated with a protein of interest (Solomon et al. 1988). ChIP has
become the technique of choice to determine the genomic enrichment profiles of
transcription factors, posttranslationally modified histones, histone variants, or
chromatin-modifying enzymes. The method comprises three basic steps: 1)
covalent cross-links between proteins and DNA are formed, typically by treating
cells with formaldehyde or another chemical reagent; 2) an antibody specific to
the protein of interest is used to coimmunoprecipitate the protein-bound DNA
fragments that were covalently cross-linked; and 3) the immunoprecipitated
protein-DNA links are reversed. DNA sequences associated with the precipitated
protein can be identified by dot or slot blot, PCR, quantitative PCR (qPCR),
labeling and hybridization to genomewide or tiling DNA microarrays (ChIP–
Chip technique) (Lee et al. 2006), and sequencing technology (Gogol-Döring
and Chen 2012).
Genome-Editing Technologies
Genome-editing technologies based on site-specific DNA nucleases allow
introduction of genetic modifications into almost any cell type and organism. To
date, four major classes of customizable DNA binding proteins have been
engineered for this purpose: meganucleases derived from microbial mobile
genetic elements (Smith et al. 2006), zinc finger nucleases based on eukaryotic
transcription factors (Miller et al. 2007; Urnov et al. 2005), transcription
activator-like effectors from Xanthomonas bacteria (Christian et al. 2010; Miller
et al. 2011), and the RNA-guided DNA endonuclease Cas9 (CRISPR-associated
protein 9) from the type II bacterial adaptive immune system CRISPR (clustered
regularly interspaced short palindromic repeats) (Cong et al. 2013; Mali et al.
2013). The most rapidly developing is the CRISPR/Cas9 system, which can be
targeted to virtually any genomic location of choice via a short RNA guide. The
CRISPR locus is typically composed of a clustered set of CRISPR-associated
(Cas) genes and a series of repeat sequences interspaced by variable sequences
(spacers) corresponding to sequences within foreign genetic elements
(protospacers). A long pre-crRNA transcribed from the spacer-repeat CRISPR
locus is processed into shorter CRISPR RNAs (crRNAs), which direct the
nucleolytic activity of certain Cas enzymes to degrade target nucleic acids
(Brouns et al. 2008; Hale et al. 2009).
Prokaryotes have evolved diverse RNA-mediated systems that use short
crRNAs and Cas proteins to detect and defend against viral DNA elements
(Bhaya et al. 2011; Marraffini and Sontheimer 2008, 2010; Wiedenheft et al.
2012). The guide sequence within these crRNAs can be easily replaced by a
sequence of interest to retarget the Cas9 nuclease. A simple two-component
system—consisting of Cas9 from the bacterial species Streptococcus pyogenes
(Cong et al. 2013; Mali et al. 2013) or Staphylococcus aureus (Ran et al. 2015)
and a fusion of the trans-activating crRNA–crRNA duplex to a single-guide
RNA (sgRNA) (Jinek et al. 2012)—has been engineered for expression in
eukaryotic cells and can achieve DNA cleavage at any genomic locus of interest.
Hence, Cas proteins can be targeted to specific DNA sequences simply by
changing the short specificity-determining part of the guide RNA (gRNA),
which can be easily achieved in one cloning step (Heidenreich and Zhang 2016).
Three variants of the Cas9 nuclease have been adopted to help genome
editing. The first is wild-type Cas9, which can cleave double-stranded DNA at
specific sites to form double-stranded breaks (DSBs). DSBs can be repaired by
the cellular non-homologous end joining (NHEJ) or homology-directed
recombination (HDR) pathway (Burma et al. 2006; Kass et al. 2013; Maruyama
et al. 2015). If a donor template with homology to the targeted locus is supplied,
the DSB may be repaired by HDR. If an exogenous homology repair template is
absent, the DSBs can be repaired by inducing insertion or deletion mutations
(indels) via the NHEJ repair pathway (Bibikova et al. 2002). The second variant
of the Cas9 nuclease is a mutant form, known as Cas9D10A (Cong et al. 2013).
It cleaves only one DNA strand and does not activate NHEJ. Instead, in the
presence of a homologous repair template, DNA repairs are conducted via the
HDR pathway only, resulting in reduced indel mutations (Cong et al. 2013; Jinek
et al. 2012; Qi et al. 2013). The third variant is a nuclease-deficient Cas9 (Qi et
al. 2013). Mutations inactivate cleavage activity but do not prevent DNA binding
(Gasiunas et al. 2012; Jinek et al. 2012). Therefore, this variant can be used
either as a gene silencing or activation tool that “surgically” targets the desired
region of the genome (Gilbert et al. 2013; Hu et al. 2014; Maeder et al. 2013;
Perez-Pinera et al. 2013). It can also be applied to visualize repetitive DNA
sequences with a single sgRNA or nonrepetitive locus using multiple sgRNAs
fused to enhanced green fluorescent protein (Chen et al. 2013). Alterations of
gene sequence or expression induced by the CRISPR/Cas9 system are displayed
in Figure 1–7.
These three mouse models illustrate the usefulness of manipulation of the mouse
genome for the study of human neuropsychiatric disease.
Optogenetics
Optogenetics is a technique for parsing and manipulating specific neural circuits
(Figure 1–9). Optogenetics was developed about 10 years ago and has been
adapted both swiftly and broadly (Deisseroth 2015). Optogenetics makes use of
microbial (bacterial and algal) opsins that have properties of both chromophores
and ion channels. These molecules are unlike the metazoan rhodopsins, which
convert light into an intracellular signal through a G protein–coupled receptor.
Instead, these proteins (channelopsins and bacteriorhodopsin) form ion channels,
and there are naturally occurring molecules that subserve both excitatory (Na+)
and inhibitory (Cl–) functions, as activated by the channels.
FIGURE 1–9. Optogenetic manipulation of neural circuits.
See Plates 2 and 3 to view this figure in color.
(I) Direct stimulation of neuronal cell bodies is achieved by injecting virus at the target region
and then implanting a light-delivery device above the injected region. Even this simple
experiment can provide specificity with viruses that will not transduce afferent axons and
fibers of passage. (II) Additional cell-type specificity is attained either by cell-type-specific
promoters in the viral vector or via a recombinase-dependent virus, injected in a transgenic
animal expressing a recombinase such as Cre in specific cells, leading to specific expression of
the transgene only in defined cell types. (III) Projection (axonal) targeting is achieved by viral
injection at the region harboring cell bodies, followed by implantation of a light-delivery
device above the target region containing neuronal processes from the virally transduced
region; in this way, cell types are targeted by virtue of their projections. (IV) Projection
termination labeling is a more refined version of projection targeting, in which cells are
targeted by virtue of synaptic connectivity to the target region, with likely exclusion of cells
whose axons simply pass through the region. Transcellular labeling using a recombinase-
dependent system is shown. Viruses expressing Cre fused to a transneuronal tracer (lectin) are
delivered at the synaptic target site, and a Cre-dependent virus is injected into the region with
cell bodies. Cells that project to the Cre-injected area express the Cre-dependent virus and
become light sensitive. This can also be achieved with axon terminal–transducing viruses,
although without control over the postsynaptic cell type. (V) Expression of two opsins with
different characteristics in one brain region using a combination of promoter- or Cre-based
approaches. Light delivery to the somata is performed using two different wavelengths
designed to minimize cross-activation. (VI) Projections from two different brain regions are
differentially stimulated with two wavelengths matched to the respective opsins expressed
upstream.
Source. Reprinted from Yizhar O, Fenno LE, Davidson TJ, et al.: “Optogenetics in Neural
Systems.” Neuron 71(1):9–34, 2011. Copyright 2011, Elsevier, Inc. Used with permission.
Conclusion
Rapid advances in the identification of the human genome and in the
methodology for genetic manipulation have combined to open a window into the
brain. We are accumulating knowledge of human gene mutations and their
connection to neurological and psychiatric diseases at a rapid pace. As genes are
being identified, the proteins for which they code are also becoming known. This
knowledge enables the pathogenic mechanism for some of these diseases to
become apparent. Understanding these maladies on the molecular level is likely
to lead to new methods of diagnosis and novel approaches to therapy.
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CHAPTER 2
Neurotransmitters and
Receptors in Psychiatric
Disorders
Carolyn M. Drazinic, M.D., Ph.D.
Steven T. Szabo, M.D., Ph.D.
Todd D. Gould, M.D.
Husseini K. Manji, M.D., F.R.C.P.C.
Receptors
An essential property of any living cell is its ability to recognize and respond to
external stimuli. Cell surface receptors have two major functions: recognition of
specific molecules (neurotransmitters, hormones, growth factors, and even
sensory signals) and activation of “effectors.” Binding of the appropriate agonist
(i.e., neurotransmitter or hormone) externally to the receptor alters the
conformation (shape) of the protein. Cell surface receptors use a variety of
membrane-transducing mechanisms to transform an agonist’s message into
cellular responses. In neuronal systems, the most typical responses ultimately (in
some cases rapidly, in others more slowly) involve changes in transmembrane
voltage and hence neuronal changes in excitability. Collectively, the processes
are referred to as transmembrane signaling or signal transduction mechanisms.
This process is not restricted to neurons. For instance, astrocytes were once
thought to be uninvolved in neurotransmission, but they have since been shown
to possess volume-regulated Cl– anion channels, which work together with gap
junction/hemichannels to permit efflux of amino acids such as taurine,
glutamate, and aspartate in response to swelling due to brain injury (Mulligan
and MacVicar 2006; Ye et al. 2009).
Interestingly, although increasing numbers of potential neuroactive
compounds and receptors continue to be identified, it has become clear that
translation of the extracellular signals (into a form that can be interpreted by the
complex intracellular enzymatic machinery) is achieved through a relatively
small number of cellular mechanisms. Generally speaking, these transmembrane
signaling systems, and the receptors that use them, can be divided into four
major groups (Figure 2–1):
A more extensive and continuously updated synopsis of these and many other
receptors and ligands can be found at the International Union of Basic and
Clinical Pharmacology/British Pharmacological Society Guide to Pharmacology
Web site (www.guidetopharmacology.org) and associated publications
(Alexander et al. 2013a, 2013b, 2013c, 2013d, 2013e, 2013f). We review the
four major groups in the following subsections.
Ionotropic Receptors
The first class of receptors contains in their molecular complex an intrinsic ion
channel. Receptors of this class include those for several amino acids, including
glutamate (e.g., the NMDA [N-methyl-D-aspartate] receptor), GABA (γ-
aminobutyric acid via the GABAA receptor), and the nicotinic acetylcholine
(nACh) receptor and the serotonin type 3 (5-HT3) receptor. Ion channels are
integral membrane proteins that are directly responsible for the electrical activity
of the nervous system by virtue of their regulation of the movement of ions
across membranes. Receptors containing intrinsic ion channels have been called
ionotropic and are generally composed of four or five subunits that open
transiently when a neurotransmitter binds, allowing ions to flow into (e.g., Na+,
Ca2+, Cl–) or out of (e.g., K+) the neuron, thereby generating synaptic potential
(see Figure 2–1).
Often, the ionotropic receptors are composed of different combinations of
various subunits, thereby providing the system with considerable flexibility. For
example, there is extensive research into the potential development of an
anxiolytic that is devoid of sedative effects by targeting GABAA receptor
subunits present in selected brain regions (Salerno et al. 2012; Taliani et al.
2009). In general, neurotransmission that is mediated by ionotropic receptors is
very fast, with ion channels opening and closing within milliseconds, and these
receptors regulate much of the tonic excitatory (e.g., glutamate-mediated) and
inhibitory (e.g., GABA-mediated) activity in the CNS; as we discuss in the
“Neurotransmitter and Neuropeptide Systems” section later in this chapter, many
of the classic neurotransmitters (e.g., monoamines) exert their effects on a
slower time scale and are therefore often considered to be modulatory in their
effects.
G Protein–Coupled Receptors
Most receptors in the CNS do not have intrinsic ionic conductance channels
within their structure but instead regulate cellular activity by the generation of
various “second messengers.” Receptors of this class generally do not interact
directly with the various second-messenger-generating enzymes but transmit
information to the appropriate “effector” by the activation of interposed coupling
proteins. These are the G protein–coupled receptor families, and they provide a
slower onset, but longer duration of signaling, compared with ionotropic
receptors (Squire 2013). The G protein–coupled receptors (GPCRs, which
constitute more than 80% of all known receptors in the body and number about
800 in humans) all span the plasma membrane seven times and have three
intracellular loops and three extracellular loops (see Figure 2–1) (Alexander et
al. 2013b). G proteins are so named because of their ability to bind the guanine
nucleotides guanosine triphosphate and guanosine diphosphate. Receptors
coupled to G proteins include those for dopamine, serotonin, acetylcholine,
various peptides, and even sensory signals such as light and odorants.
GPCRs have increasingly become the focus of extensive research in
psychiatry (Catapano and Manji 2007). The amino terminus is on the outside of
the cell and plays a critical role in recognition of the ligand, which can be a
small molecule, peptide, or large protein; the carboxy terminus and third
intracellular loop are inside the cell and regulate coupling to different G proteins,
“cross-talk” between receptors, and desensitization (see Figure 2–1) (Alexander
et al. 2013b). Although the bimodal model of ligands switching the GPCR “on”
or “off” is appealing, an individual GPCR can actually assume many different
conformations, which influences the nature of the ligand–receptor interaction
and the predominant complex signal generated in a particular cell type; this
concept is called ligand-induced selective signaling (Millar and Newton 2010).
Differential oligomerization, differential phosphorylation, signaling through
molecules other than G proteins, and second-messenger independent signaling
together add even more complexity for future GPCR research (Kandel 2013;
Millar and Newton 2010).
In conclusion, many classes and subtypes of G proteins exist, playing key
roles in amplifying and integrating signals.
Nuclear Receptors
Nuclear receptors are transcription factors that regulate the expression of target
genes in response to steroid hormones and other ligands. Many hormones
(including glucocorticoids, gonadal steroids, and thyroid hormones) are able to
rapidly penetrate into the lipid bilayer membrane because of their lipophilic
composition, and thereby directly interact with these cytoplasmic receptors
inside the cell (see Figure 2–1). On activation by a hormone, the nuclear
receptor–ligand complex translocates to the nucleus, where it binds to specific
DNA sequences referred to as hormone-responsive elements, and subsequently
regulates gene transcription (Mangelsdorf et al. 1995; Truss and Beato 1993).
Nuclear receptors often interact with a variety of coregulators that promote
transcriptional activation when recruited (coactivators) and those that attenuate
promoter activity (corepressors). Numerous nuclear receptors have been
identified, as reviewed elsewhere (Alexander et al. 2013e).
With this broad overview of neurotransmitters and receptor subtypes, we now
turn to a discussion of selected individual neurotransmitters and their receptors.
Serotonergic System
Largely on the basis of the observation that most effective antidepressants and
antipsychotics target these systems, the monoaminergic systems (e.g., serotonin,
norepinephrine, dopamine) have been extensively studied. Serotonin was given
that name because of its activity as an endogenous vasoconstrictor in blood
serum (Rapport et al. 1948). It was later acknowledged as being the same
molecule (secretine) that is found in the intestinal mucosa and that is “secreted”
by chromaffin cells (Brodie 1900). Following these findings, serotonin later was
characterized as a neurotransmitter in the CNS (Bogdanski et al. 1956).
Serotonin-producing cell bodies in the brain are localized to the central gray,
in the surrounding reticular formation, and in cell clusters located in the center,
and thus the name raphe (from Latin, meaning “midline”) was adopted (Figure
2–3A). The dorsal raphe, the largest brain stem serotonin nucleus, contains
approximately 50% of the total serotonin neurons in the mammalian CNS; in
contrast, the medial raphe comprises 5% (Descarries et al. 1982; Wiklund and
Björklund 1980). Serotonergic neurons project widely throughout the CNS
rather than to discrete anatomical locations (as the dopaminergic neurons appear
to do; see Figure 2–4A later in this chapter), leading to the suggestion that
serotonin exerts a major modulatory role throughout the CNS (Reader 1980).
Interestingly, evidence suggests that infralimbic and prelimbic regions of the
ventromedial prefrontal cortex (vmPFC) in rats are responsible for detecting
whether a stressor is under the organism’s control. When a stressor is
controllable, stress-induced activation of the dorsal raphe nucleus is inhibited by
the vmPFC, and the behavioral sequelae of the uncontrollable stress response are
blocked (Amat et al. 2005). The ability to regulate serotonin neuron activity and
function has been a major ongoing focus of psychiatric disorder research and
treatments. Lysergic acid diethylamide, a hallucinogen, has a chemical structure
similar to that of serotonin, and monoamine oxidase (MAO) inhibitors (MAOIs),
which are classic antidepressants, increase the levels of monoamines such as
serotonin in the synapse (Squire 2013).
Serotonin Transporters
As is the case for many classic neurotransmitters, termination of the effects of
serotonin in the synaptic cleft is brought about in large part by an active reuptake
process mediated by the serotonin transporter (5-HTT). Serotonin is taken up
into the presynaptic terminals, where it is metabolized by the enzyme MAO or
sequestered into secretory vesicles by the vesicle monoamine transporter (see
Figure 2–3B). This presumably underlies the mechanism by which MAOIs
initiate their therapeutic effects; that is, the blockade of monoamine breakdown
results in an increase in the available pool for release when an action potential
invades the nerve terminal. It is now well established that many tricyclic
antidepressants and SSRIs exert their initial primary pharmacological effects by
binding to the 5-HTT and blocking serotonin reuptake, thereby increasing the
intrasynaptic levels of serotonin, which initiates a cascade of downstream effects
(see Figure 2–3B for details). It has been hypothesized that the first step in
serotonin transport involves the binding of serotonin to the 5-HTT and then a
cotransport with Na+, and the second step involves the translocation of K+ across
the membrane to the outside of the cell. SSRIs bind to the same site on the
transporter as serotonin itself. Elegant biochemical and mutagenesis experiments
have elucidated a leucine transporter from bacterial species, providing
information that helped unravel the mechanism by which mammalian
transporters couple ions and substrates to mediate neurotransmitter clearance.
The crystal structure for sodium- and chloride-dependent neurotransmitter
transporters (including transporters for serotonin [SERT], dopamine [DAT],
norepinephrine [NET], glycine [GlyT1b], and GABA [GAT1]) with the L-leucine
binding sites for Na+ ions also has been elucidated (Henry et al. 2006; Yamashita
et al. 2005).
In the brain, 5-HTTs have been radiolabeled with [3H]-imipramine (Hrdina et
al. 1985; Langer et al. 1980) and with SSRIs such as [3H]cyanoimipramine
(Wolf and Bobik 1988), [3H]paroxetine (Habert et al. 1985), and [3H]citalopram
(D’Amato et al. 1987). The regional distribution of 5-HTT corresponds to
discrete regions of rat brain known to contain cell bodies of serotonin neurons
and synaptic axon terminals, most notably the cerebral cortex, neostriatum,
thalamus, and limbic areas (Cooper et al. 2003; Hrdina et al. 1985; Madden
2002). The specific cellular localization of 5-HTT in the CNS also has been
accomplished by using site-specific antibodies (Lawrence et al. 1995a).
Immunohistochemical studies that used antibodies against the serotonin carrier
have reported both neuronal and glial staining in areas of the rat brain containing
serotonin somata and terminals (i.e., dorsal raphe and hippocampus) (Lawrence
et al. 1995b). Experimental alterations of 5-HTT in young mice for a brief period
during early development indicate abnormal emotional behavior in the same
mice later in life, similar to the phenotype in mice in which 5-HTT is deficient
throughout life (Ansorge et al. 2004). This suggests the necessity of serotonin
early in emotional development and provides a possible mechanism by which
genetic changes in the 5-HTT system may lead to susceptibility to develop
psychiatric diseases such as depression (Caspi et al. 2003). Furthermore,
serotonin uptake ability has been documented in primary astrocyte cultures
(Kimelberg and Katz 1985) and has been postulated to account for considerable
serotonin uptake in the frontal cortex and periventricular region (Ravid et al.
1992).
Because 5-HTT is transcribed from a single copy gene, abnormalities in
platelet 5-HTT are thought to reflect CNS abnormalities (Owens and Nemeroff
1998). Several studies on platelet 5-HTT density have been undertaken using
[3H]imipramine binding or [3H]paroxetine binding in mood disorders. Although
the results of these studies are not entirely consistent, in total the results suggest
that the receptor density value for platelet serotonin density is significantly lower
in depressed subjects compared with healthy control subjects (Owens and
Nemeroff 1998). The distribution of SERT (5-HTT) in the postmortem human
brain was found to be highest in the thalamus, amygdala, putamen, globus
pallidus externa, lateral geniculate body, hippocampus, and caudate, with the
lowest amounts in the cerebral cortex and minimal levels in the cerebellum and
white matter (Kish et al. 2005).
Numerous studies have examined suicide risk related to individual genetic
polymorphisms in SERT. For example, the serotonin-transporter-linked
polymorphic region (5-HTTLPR) short S allele, which decreases presynaptic 5-
HTT expression and thereby decreases serotonin reuptake and has an interaction
with childhood abuse to increase lifetime depression risk, has nevertheless
yielded contradictory results related to suicide risk, likely because of other
confounding polymorphisms (Purselle and Nemeroff 2003; Ressler et al. 2010).
In patients with major depressive disorder (MDD) who attempted suicide,
positron emission tomographic (PET) scanning with the [11C]N,N-dimethyl-2-
(2-amino-4-cyanophenylthio) benzylamine ([11C]DASB) ligand indicated that
SERT (5-HTT) levels were lower in the midbrain regions (Miller et al. 2013). In
bipolar I patients with depression who completed suicide, a nearly 50% decrease
in serotonin and norepinephrine activity was observed related to the locus
coeruleus in postmortem brain studies, as compared with unipolar depressed
patients who completed suicide and matched control subjects (Wiste et al. 2008).
Three different antidepressants, sertraline (SSRI), citalopram (SSRI), and
venlafaxine (serotonin–norepinephrine reuptake inhibitor), at clinical dosages in
living patients were shown with PET ligand [11C]DASB to have 85% occupancy
of SERT, effectively blocking SERT-mediated reuptake of free serotonin in the
synapse and increasing serotonin synaptic levels (Voineskos et al. 2007). In
summary, multiple mechanisms can lead to insufficient levels of serotonin in
neuronal synapses, which contributes significantly to the risk for depression and
for suicide.
Serotonin Receptors
In 1957, the existence of two separate serotonin receptors was first proposed,
primarily because of the opposing phenomenon this neurotransmitter produces,
in reference to cholinergic mediation of smooth muscle contraction (Gaddum
and Picarelli 1957). Through the use of more precise molecular cloning and
pharmacological and biochemical studies, seven distinct serotonin receptor
families have been identified (5-HT1–7), many of which contain several
subtypes. With the exception of the 5-HT3 receptor, which is an excitatory
ionotropic receptor, all the other serotonin receptors are GPCRs. The 5-
HT1A,B,D,E,F receptors are negatively coupled to adenylyl cyclase; the 5-HT2A,B,C
subtypes are positively coupled to PLC; and the 5-HT4, 5-HT5, 5-HT6, and 5-
HT7 subtypes are positively coupled to adenylyl cyclase (see Figure 2–3B)
(Humphrey et al. 1993; Nestler et al. 2015). When all types and subtypes are
counted, 13 serotonin receptors are identified in humans (Nestler et al. 2015).
G protein Examples of
class Members Effector(s)/functions receptors
αi Gαi1–3, Gαo AC (+) α2, D2, A1, μ, M2, 5-
HT1A
Ligand-type Ca2+ Olfactory signals
channels (+)
Gαz, Gαt1–2 K+ channels (+)
Ca2+ channels (−)a GABAB
cGMP Retinal rods, cones
(rhodopsins)
Phosphodiesterase (+)
(Gαt1–2)
αq Gαq, Gα11, PLC-β (+) TxA2, 5-HT2C, M1,
Gα14, M3, M5, α1
Gα15, Gα16
α12 Gα12, Gα13 RGS domain– TxA2, thrombin
containing rho
exchange factors
βb β (×5) AC type I (−); AC
types II, IV
(potentiation)
PLC (+)
Receptor kinases (+)
Inactivates αs
Dopaminergic System
Dopamine was originally thought to be simply a precursor of norepinephrine and
epinephrine synthesis, but the demonstration that its distribution in the brain was
quite distinct from that of norepinephrine led to extensive research establishing
its role as a critical, unique neurotransmitter. Dopamine synthesis requires
transport of the amino acid L-tyrosine across the blood–brain barrier and into the
cell. Once tyrosine enters the neuron, the rate-limiting step for dopamine
synthesis is conversion of L-tyrosine to L-dihydroxyphenylalanine (L-dopa) by
the enzyme tyrosine hydroxylase; L-dopa is readily converted to dopamine and,
hence, is used as a precursor strategy to correct a dopamine deficiency in the
treatment of Parkinson’s disease (Figure 2–4B). The activity of tyrosine
hydroxylase can be regulated by many factors, including the activity of
catecholamine neurons; furthermore, catecholamines function as end-product
inhibitors of tyrosine hydroxylase by competing with a tetrahydrobiopterin
cofactor (Cooper et al. 2003).
In contrast to the widespread serotonin and norepinephrine projections,
dopamine neurons form more discrete circuits, with the nigrostriatal,
mesolimbic, tuberoinfundibular, and tuberohypophysial pathways constituting
the major CNS dopaminergic circuits (Figure 2–4A). The nigrostriatal circuit is
composed of dopamine neurons from the mesencephalic reticular formation
(region A8) and the pars compacta region of the substantia nigra (region A9) of
the mesencephalon. These neurons give rise to axons that travel via the medial
forebrain bundle to innervate the caudate nucleus and putamen (Andén et al.
1964; Ungerstedt 1971). The dopamine neurons that make up the nigrostriatal
circuit have been assumed to be critical for maintaining normal motor control,
because destruction of these neurons is associated with Parkinson’s disease;
however, it is now clear that these projections subserve a variety of additional
functions. For instance, evidence from human brain imaging studies indicates
that drugs that modulate striatal dopamine receptor activation correlate with the
subject’s ability to choose gradations of rewarding actions during instrumental
learning tasks. This further implies that the dopamine reward pathway in the
brain is likely convergent on many discrete brain circuits and neurotransmitter
alterations and shows that striatal activity can also account for how the human
brain proceeds toward making future decisions based on reward prediction
(Pessiglione et al. 2006).
The mesolimbic dopamine circuit consists of dopamine neurons located in the
midbrain just medial to the A9 cells in an area termed the ventral tegmental area
(VTA) (Cooper et al. 2003; Nestler et al. 2015; Squire 2013). This circuit shares
some similarities to the nigrostriatal circuit in that it is a parallel circuit
consisting of axons that make up the medial forebrain bundle. However, these
axons ascend through the lateral hypothalamus and project to the nucleus
accumbens; olfactory tubercle; bed nucleus of the stria terminalis; lateral
septum; and frontal, cingulate, and entorhinal regions of the cerebral cortex
(Cooper et al. 2003). This circuit innervates many limbic structures known to
play critical roles in motivational, motor, and reward pathways and has therefore
been implicated in a variety of clinical conditions, including psychosis and drug
abuse (Cooper et al. 2003). Data also suggest a potential role of dopamine—and,
in particular, mesolimbic pathways—in the pathophysiology of bipolar mania, as
well as bipolar and unipolar depression (Beaulieu et al. 2004; Dunlop and
Nemeroff 2007; Goodwin et al. 2007; Roybal et al. 2007). It is perhaps
surprising that the role of the dopaminergic system in the pathophysiology of
mood disorders has not received greater study, because it represents a prime
candidate on several theoretical grounds. The motoric changes in bipolar
disorder are perhaps the most defining characteristics of the illness, ranging from
near catatonic immobility to the hyperactivity of manic states. Similarly, loss of
motivation is one of the central features of depression, whereas anhedonia and
“hyperhedonic states” are among the most defining characteristics of bipolar
depression and mania, respectively. In this context, it is noteworthy that the
midbrain dopaminergic system is known to play a critical role in regulating not
only motoric activity but also motivational and reward circuits. It is clear that
motivation and motor function are closely linked and that motivational variables
can influence motor output both qualitatively and quantitatively. Furthermore,
considerable evidence indicates that the mesolimbic dopaminergic pathway
plays a crucial role in the selection and orchestration of goal-directed behaviors,
particularly those elicited by incentive stimuli (Goodwin et al. 2007).
The firing pattern of mesolimbic dopamine neurons appears to be an
important regulatory mechanism; thus, in rats, electrical or glutamatergic
stimulation of medial PFC elicits a burst firing pattern of dopaminergic cells in
the VTA and increases dopamine release in the nucleus accumbens (Murase et al.
1993; Taber and Fibiger 1993). The burst firing of dopamine cell activity elicits
more terminal dopamine release per action potential than the nonbursting,
pacemaker firing pattern (Roth et al. 1987). The phasic, burst firing of dopamine
neurons and accompanying rise in dopamine release normally occur in response
to primary rewards (until they become fully predicted) and reward-predicting
stimuli. Such a role also has been postulated to provide a neural mechanism by
which PFC dysfunction could alter hedonic perceptions and motivated behavior
in mood disorders (Drevets et al. 2002). Studies indicate that the amygdala has
importance in the learning of new cocaine drug-seeking responses and its habit-
forming properties (Lee et al. 2005). The supraphysiological levels of dopamine
induced by cocaine and other drugs of abuse lead to powerful reinforcement of
drug-seeking behavior, by co-opting the dopamine reward circuit of the brain, as
reviewed elsewhere (Volkow and Morales 2015).
Dopamine Transporters
As with serotonin, the dopamine signal in the synaptic cleft is terminated
primarily by reuptake into the presynaptic terminal. The DAT comprises 12
transmembrane domains and is located somatodendritically as well as on
dopamine nerve terminals (see Figure 2–4B). Like other monoamine
transporters, the DAT functions as a Na+/K+ pump to clear dopamine from the
synaptic cleft on its release. However, data suggest that many drugs of abuse are
capable of altering the function of these transporters. Thus, the amphetamines
are thought to mediate their effects, in part, by reversing the direction of the
transporter so that it releases dopamine. Cocaine is capable of blocking the
reuptake of DAT, leading to an increase in dopamine in the synaptic cleft. Of
interest, altered neuronal long-term potentiation in the VTA in response to
chronic cocaine exposure has been linked to drug-associated memory and likely
contributes to the powerful addictive potential of this drug of abuse (Liu et al.
2005). Dopamine in the medial frontal cortex is taken up predominantly by the
norepinephrine transporter, which goes against the dogma of transporters being
able to selectively take up only their respective neurotransmitter. Furthermore,
this provides a mechanism by which norepinephrine reuptake–inhibiting
antidepressants also may increase synaptic levels of dopamine in the frontal
cortex, an effect that may be therapeutically very important. Interestingly, a
meta-analysis of single photon emission computed tomography (SPECT) scans
examining the DAT gene SLC6A3 variable-number tandem repeat (VNTR)
polymorphism did not find significant changes in the levels of the dopamine
transporters in the brains of patients with schizophrenia, attention-
deficit/hyperactivity disorder (ADHD), and even Parkinson’s disease (Costa et
al. 2011). However, another DAT polymorphism of note, a VNTR in the
nontranslated 3′ end of exon 15, causes a 25% decreased density of DAT in
humans with a VNTR of 9 repeats instead of the more common 10 repeats
(Lacerda-Pinheiro et al. 2014). SPECT scanning of the brain with the
presynaptic DAT radioligand is now being used to distinguish Parkinson’s
disease syndromes from other causes of parkinsonism such as antipsychotic-
induced parkinsonism, the latter of which does not show a deficit in DAT
binding in the caudate and putamen (Tatsch and Poepperl 2013).
In patients with MDD and bipolar disorder, SPECT studies showed that DAT
availability is higher—and, by inference, synaptic dopamine is lower—in
patients with depression (Camardese et al. 2014a, 2014b). PET studies identified
decreased binding potential of the DAT PET ligand to the dopamine transporter
in the striatum in MDD patients and more specifically in the caudate in bipolar
patients (Anand et al. 2011; Meyer et al. 2001; Savitz and Drevets 2013).
Postmortem studies in patients with MDD showed lower DAT levels in the
amygdala and higher D2 and D3 receptor levels (no change in D1 receptors),
consistent with similar observations in rats with dopamine depletion (Klimek et
al. 2002).
To treat refractory depression, the new triple transporter reuptake inhibitor
compound BMS-820836, reported by PET studies to specifically inhibit
monoamine transporters DAT, SERT, and NET, was developed for the goal of
increasing synaptic levels of the respective monoamines dopamine, serotonin,
and norepinephrine and thereby decreasing depressive symptoms (Risinger et al.
2014). Moderate to severe MDD or atypical MDD (with reversed
neurovegetative symptoms) was found by PET studies to be associated with
higher levels of MAO-A, an enzyme that catabolizes and thus decreases synaptic
dopamine, serotonin, and norepinephrine, presumably increasing depressive
symptoms (Chiuccariello et al. 2014). Classic MAOIs increase all three
monoamines in the synapse by blocking the catabolizing enzyme MAO (both A
and B enzyme subtypes).
Bupropion is widely believed to increase synaptic dopamine by blocking the
DAT-mediated reuptake, but a PET study showed that it has at most only 22%
occupancy of the DAT (Meyer et al. 2002). Given the observation of a decreased
binding potential of 15% of DAT in patients with MDD, it remains unknown
whether bupropion occupies the same binding site on DAT as the PET ligand,
whether 22% occupancy of DAT is sufficient for bupropion to work (as
compared with 80% binding to SERT for SSRIs), and whether bupropion works
by another uncharacterized mechanism to achieve its antidepressant properties
(Meyer et al. 2001, 2002).
Dopaminergic Receptors
The existence of two subtypes of dopamine receptors, D1 and D2, was initially
established with classic pharmacological techniques in the 1970s (Stoof and
Kebabian 1984). Subsequent molecular biological studies have shown that the
D1 family contains both the D1 and the D5 receptors, whereas the D2 family
contains the D2, D3, and D4 receptors (Cooper et al. 2003). D1 receptor family
members were originally defined solely on the ability to stimulate adenylyl
cyclase, whereas the D2 family inhibited the enzyme. Interestingly, dopamine
receptors complexed with subunits from other subclasses of dopamine receptors
within a receptor family are able to form distinct hetero-oligomeric receptors
also termed kissing cousin receptors. Notably, hetero-oligomeric D1–D2 receptor
complexes in the brain require binding to active sites of both receptor subtypes
to induce activation of the hetero-oligomeric receptor complex. These receptors
have been shown to use traditional D1 receptor intracellular signaling
components of Gq/11 and Ca2+/calmodulin–dependent protein kinase II
(CaMKII) second-messenger activation as seen in the nucleus accumbens
(Rashid et al. 2007). This opens up possibilities for the brain to use different
receptor subunit proportions to further fine-tune brain neurophysiology. Similar
to the DAT exon 15 VNTR, the D2 dopamine receptor gene (DRD2) has a TaqIA
polymorphism (allele A1+) in the 3′ nontranslated region that reduces D2
receptor density (Lacerda-Pinheiro et al. 2014).
Noradrenergic System
Named sympathine because it was initially encountered as being released by
sympathetic nerve terminals, the molecule was later given the name
norepinephrine after meeting the criteria for a neurotransmitter in the CNS
(Cooper et al. 2003). Norepinephrine is produced from the amino acid precursor
L-tyrosine found in neurons in the brain, chromaffin cells, sympathetic nerves,
and ganglia. The enzyme dopamine β-hydroxylase converts dopamine to
norepinephrine, and as is the case for dopamine synthesis, tyrosine hydroxylase
is the rate-limiting enzyme for norepinephrine synthesis (Figure 2–5B). The
dietary depletion of tyrosine and α-methyl-p-tyrosine (a tyrosine hydroxylase
inhibitor) has played an important part in efforts aimed at delineating the role of
catecholamines in the pathophysiology and treatment of mood and anxiety
disorders (Coupland et al. 2001; McCann et al. 1995).
Norepinephrine Transporter
NET, the first of the monoamine transporters to be cloned in humans, transports
norepinephrine from the synaptic cleft back into the neuron (Pacholczyk et al.
1991). Like other monoamine transporters, the NET comprises 12 putative
transmembrane domains, and autoradiography with various norepinephrine
reuptake inhibitors has been used to determine the brain distribution of NET. A
high level of NET is found in the LC, with moderate to high levels found in the
dentate gyrus, raphe nuclei, and hippocampus (Tejani-Butt and Ordway 1992;
Tejani-Butt et al. 1990). This pattern of expression is consistent with the
norepinephrine innervation to these structures. The NET is expressed mainly on
norepinephrine terminals, as shown by a drastic reduction in labeling following
norepinephrine destruction with the neurotoxin 6-hydroxydopamine or N-(2-
chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) (Tejani-Butt and Ordway
1992; Tejani-Butt et al. 1990).
The NET is dependent on extracellular Na+ to mediate norepinephrine
reuptake and the effectiveness of norepinephrine reuptake inhibitors in inhibiting
norepinephrine reuptake (Brüss et al. 1997, 1999; Harder and Bönisch 1985).
The uptake of norepinephrine is chloride dependent, meaning that the
electrogenic process of norepinephrine transport is Na+ and Cl– driven (Harder
and Bönisch 1985). In addition to the electrogenic process, the NET has
properties of a channel-like pore, in that it can transport norepinephrine showing
an infinite stoichiometry that can be blocked by cocaine and desipramine (Galli
et al. 1995, 1996). Several studies suggest that the NET can be regulated by
diverse stimuli, neuronal activity, and peptide hormones, as well as protein
kinases. Indeed, studies have shown that all monoaminergic transporters (5-HTT,
DAT, and NET) are rapidly regulated by direct or receptor-mediated activation of
cellular kinases, particularly PKC (Bauman et al. 2000). PKC activation results
in an activity-dependent transporter phosphorylation and sequestration. Protein
phosphatase–1/2A (PP-1/PP-2A) inhibitors, such as okadaic acid and calyculin
A, also promote monoaminergic transporter phosphorylation and functional
downregulation (Bauman et al. 2000). These phenomena that occur beyond the
receptor level may well be important in the long-term actions of psychotropic
drugs known to regulate protein kinases (Chen et al. 1999; Manji and Lenox
1999). Given that norepinephrine neurons co-localize and release orexins, it is of
interest that these neuropeptides have been implicated in sleep disorders and
hypoglycemia through the glucose-sensing tandem membrane receptor K+
channels (K2P type) affecting coordinated arousal (Scott et al. 2006). It is also
interesting that enkephalin, an endogenous opioid peptide, co-localizes with
NET on the axon terminals of the basolateral amygdala, as indicated by
transmission electron microscopy and immunohistochemistry (Zhang and
McDonald 2016). The latest PET radiotracer developed for human brain NET
showed high uptake in the LC as well as the raphe nucleus, red nucleus, and
thalamus, which could aid in monitoring disease progression of various
conditions with NET dysregulation, including Parkinson’s disease, Alzheimer’s
disease, epilepsy, ADHD, depression, and anxiety (Adhikarla et al. 2016).
Atomoxetine, a selective NET inhibitor and the first nonstimulant medication
approved for the treatment of ADHD in humans, was found to occupy both the
NET and the SERT at clinically relevant doses when tested in rhesus monkeys
(Ding et al. 2014).
Adrenergic Receptors
The α and β catecholamine receptors were first discovered more than 50 years
ago (Ahlquist 1948) and were later subdivided further into α1, α2, β1, β2, and β3
adrenoreceptors—all of which are GPCRs—on the basis of molecular cloning
and pharmacological and biochemical studies (see Figure 2–5B). The crystal
structures of these receptors were subsequently solved, along with those of other
GPCRs, as reviewed elsewhere (Millar and Newton 2010).
α Receptors. The three subtypes of α1 receptors are denoted 1A, 1B, and
1D; they are all positively coupled to PLC and possibly phospholipase A2 (see
Figure 2–5B). The α2 family comprises the 2A/D, 2B, and 2C subtypes, which
couple negatively to adenylyl cyclase and regulate K+ and Ca2+ channels (see
Figure 2–5B). The 2A, 2B, and 2C adrenoceptors correspond to the human genes
ADRA2A, ADRA2B, and ADRA2C, respectively. The bovine, guinea pig, rat, and
mouse α2D adrenoceptor is thought to be a species homologue or variant of the
human α2A adrenoceptor (Bylund et al. 1994) and is often referred to as α2A/D.
The α2 receptors represent autoreceptors for norepinephrine neurons, and
blockade of these autoreceptors results in increased norepinephrine release—a
biochemical effect that has been postulated to play a role in the mechanisms of
action of selected antidepressants (e.g., mianserin, mirtazapine) and
antipsychotics (e.g., clozapine). In the LC, α2-adrenergic receptors converge
onto similar K+ channels as μ opioid receptors, and this convergence has been
postulated to represent a mechanism for the efficacy of clonidine (an α2 agonist)
in attenuating some of the physical symptoms of opioid withdrawal. In addition,
clonidine and another α2 receptor agonist, guanfacine, have both been approved
as nonstimulant medications to treat ADHD (Chan et al. 2016). The α2 receptor
antagonist yohimbine, which robustly increases norepinephrine neuron firing
and norepinephrine release, has been used as a provocative challenge in clinical
studies of anxiety disorders and as an antidepressant-potentiating agent.
Yohimbine also has been used to explore the role of α2 adrenoceptors in
modulating different types of pain in healthy humans given high-frequency
electrical stimulation (Vo and Drummond 2016).
Cholinergic System
Acetylcholine (ACh) is the only major low-molecular-weight neurotransmitter
substance that is not derived from an amino acid (Kandel 2013). ACh is
synthesized from acetyl coenzyme A and choline in nerve terminals via the
enzyme choline acetyltransferase (ChAT). Choline is transported into the brain
by uptake from the bloodstream and enters the neuron via both high-affinity and
low-affinity transport processes (Cooper et al. 2003). In addition to the
“standard” ChAT pathway, ACh can be synthesized by several possible
mechanisms; the precise roles of these additional pathways and their
physiological relevance in the CNS remain to be fully elucidated (Cooper et al.
2003). The highest activity of ChAT is observed in the interpeduncular nucleus,
caudate nucleus, corneal epithelium, retina, and central spinal roots. In contrast
to the other transmitters discussed thus far (which are most dependent on
reuptake mechanisms), ACh has its signal terminated primarily by the enzyme
ACh esterase, which degrades ACh (Figure 2–6B). Not surprisingly, therapeutic
strategies to increase synaptic ACh levels (e.g., for the treatment of Alzheimer’s
disease) have focused on inhibiting the activity of cholinesterases (Nestler et al.
2015).
FIGURE 2–6. The cholinergic system.
See Plate 9 to view this figure in color.
This figure depicts the cholinergic pathways in the brain (A) and various regulatory processes
involved in cholinergic neurotransmission (B). Choline crosses the blood–brain barrier to enter
the brain and is actively transported into cholinergic presynaptic terminals by an active uptake
mechanism (requiring adenosine triphosphate [ATP]). This neurotransmitter is produced by a
single enzymatic reaction in which acetyl coenzyme A (AcCoA) donates its acetyl group to
choline by means of the enzyme choline acetyltransferase (ChAT). AcCoA is primarily
synthesized in the mitochondria of neurons. Upon its formation, acetylcholine (ACh) is
sequestered into secretory vesicles by vesicle ACh transporters (VATs), where it is stored.
Vesamicol effectively blocks the transport of ACh into vesicles. An agent such as β-
bungarotoxin or AF64A is capable of increasing synaptic concentration of ACh by acting as a
releaser or a noncompetitive reuptake inhibitor, respectively. In turn, agents such as botulinum
toxin are able to attenuate ACh release from nerve terminals. Once released from the
presynaptic terminals, ACh can interact with a variety of presynaptic and postsynaptic
receptors. In contrast to many other monoaminergic neurotransmitters, the ACh signal is
terminated primarily by degradation by the enzyme acetylcholinesterase (AChE) rather than
by reuptake. Interestingly, AChE is present on both presynaptic and postsynaptic membranes
and can be inhibited by physostigmine (reversible) and soman (irreversible). Currently, AChE
inhibitors such as donepezil and galantamine are the only classes of agents that are FDA
approved for the treatment of Alzheimer’s disease. ACh receptors are of two types: muscarinic
(G protein–coupled) and nicotinic (ionotropic). Presynaptic regulation of ACh neuron firing
activity and release occurs through somatodendritic (not shown) and nerve terminal M2
autoreceptors, respectively. The binding of ACh to G protein–coupled muscarinic receptors
that are negatively coupled to adenylyl cyclase (AC) or coupled to phosphoinositol hydrolysis
produces a cascade of second-messenger and cellular effects (see diagram). ACh also activates
ionotropic nicotinic acetylcholine (nACh) receptors. ACh has its action terminated in the
synapse through rapid degradation by AChE, which liberates free choline to be taken back into
the presynaptic neuron through choline transporters (CTs). Once inside the neuron, it can be
reused for the synthesis of ACh, can be repackaged into vesicles for reuse, or undergoes
enzymatic degradation. There are some relatively new agents that selectively antagonize the
muscarinic receptors, such as CI-1017 for M1, methoctramine for M2, 4-DAMP for M3, PD-
102807 for M4, and scopolamine (hardly a new agent) for M5 (although it also has affinity for
the M3 receptor). Nicotine receptors (or nACh receptors) are activated by nicotine and the
specific alpha(4)beta(2*) agonist metanicotine. Mecamylamine is an ACh receptor antagonist.
cAMP=cyclic adenosine monophosphate; DAG=diacylglycerol; IP3=inositol-1,4,5-
triphosphate; PLC=phospholipase C.
Source. Adapted from Cooper JR, Bloom FE, Roth RH: The Biochemical Basis of
Neuropharmacology, 8th Edition. New York, Oxford University Press, 2001. Copyright 1970,
1974, 1978, 1982, 1986, 1991, 1996, 2001 by Oxford University Press, Inc. Used by
permission of Oxford University Press, Inc. Modified from Nestler et al. 2001.
Cholinergic Receptors
The two major distinct classes of cholinergic receptors are the muscarinic and
nicotinic receptors. Five muscarinic receptors (M1 through M5) have been cloned
(Kandel 2013). These receptors are G protein–coupled and act either by
regulating ion channels (in particular, K+ or Ca2+) or through being linked to
second-messenger systems. Generally speaking, M1, M3, and M5 are coupled to
phosphoinositol hydrolysis, whereas M2 and M4 are coupled to inhibition of
adenylyl cyclase and regulation of K+ and Ca2+ channels (Cooper et al. 2003)
(see Figure 2–6B). M1, M3, and M4 receptors are located in the cerebral cortex
and hippocampus, with the M1 and M4 receptors concentrated in the striatal
motor and reward circuits; the M5 receptors are expressed widely at low levels;
and the M2 presynaptic autoreceptors (which decrease ACh release into the
synapse) are located in the basal forebrain (Cannon et al. 2011; Nestler et al.
2015). Many older medications such as chlorpromazine (antipsychotic),
benztropine (used for EPS), tricyclic antidepressants, and antihistamines also are
antagonists of muscarinic receptors, and they cause common side effects such as
dry mouth and constipation. One older muscarinic antagonist, scopolamine,
commonly known to help with seasickness, more recently was found in humans
to have rapid antidepressant properties, and in rats, a single dose reversed
chronic unpredictable stress anhedonia, potentially through a burst increase in
glutamate, mTORC1 (mechanistic target of rapamycin complex 1), and synaptic
spines in the medial PFC (Drevets et al. 2013; Navarria et al. 2015).
Furthermore, one study showed that a TT homozygous polymorphism rs324650
in the fifth intron of the presynaptic M2 autoreceptor gene (CHRM2) resulted in
more severe illness, including increased risk for suicide, that was potentially
related to the observed reduced total volume of distribution (VT) of M2 receptors
in the cingulate cortex of depressed bipolar patients, as measured by the high-
affinity PET ligand M2 receptor agonist [18F]FP-TZTP (Cannon et al. 2011). A
conflicting postmortem observation detected no difference between bipolar
patients and control subjects with the M2/M4 receptor antagonist [3H]AFDX
(Smith and Jakobsen 2009). This negative result with [3H]AFDX, as compared
with the positive result with [18F]FP-TZTP, was potentially explained by a
difference in the binding properties of the two radioligands (Cannon et al. 2011).
By contrast, the nicotinic receptors are ionotropic receptors, and at least 12
different functional receptors (based on different subunit composition) have been
identified (Nestler et al. 2015). Biochemical and biophysical data indicate that
the nicotinic receptors in the muscle are formed from five protein subunits
around a central pore, with the stoichiometry of α2βγδ (Kandel 2013). The
binding of ACh molecules on the α subunit is necessary for channel activation.
By contrast, neuronal nicotinic receptors contain only two types of subunits (α
and β), with the α occurring in at least eight different forms and the β in three
(Cooper et al. 2003; Nestler et al. 2015). The most common nicotinic receptor
subtypes are α4β2-nACh and α7-nACh (Horti et al. 2013). Nicotinic receptors
are the targets of considerable cross-talk, as a variety of kinases (including PKA,
PKC, and tyrosine kinases) are able to regulate the sensitivity of this receptor.
Several regulatory mechanisms exist. For example, the mammalian prototoxin
lynx1 acts as an allosteric modulator of the nicotinic receptor (Miwa et al. 2006).
Curare (a poisonous full nicotinic receptor antagonist used in poison-tipped
arrows and so forth) and succinylcholine (a weak partial nicotinic receptor
agonist and routine surgical muscle relaxant) are two examples of compounds
affecting nicotinic receptors (Nestler et al. 2015).
From a clinical standpoint, a long-standing observation is that patients with
schizophrenia have a rate of nicotine use disorder that is substantially higher
than that in the general population, in both the prevalence (~90%) and the
quantity of cigarettes smoked (chain smoking). This observation has led to
numerous studies of medication targeting nicotinic receptors to try to alleviate
symptoms of psychosis, including the use of nicotine replacement, but the results
have been disappointing in terms of treating psychosis even though the nicotine
replacement maintains cognitive functioning (AhnAllen et al. 2015). One report
(Freedman et al. 1997) determined that in a cohort of patients with
schizophrenia, abnormal P50 auditory evoked potentials were linked to a
susceptibility locus for this disease on chromosome 15. Notably, this is where a
nicotinic receptor subunit is found, providing indirect genetic and phenotypic
support for the long-standing contention that the high rates of cigarette smoking
in patients with schizophrenia may represent some attempt by patients to self-
medicate for their underlying nicotinic receptor defect. Varenicline, a partial
agonist at the α4β2-nACh receptor subtype developed for smoking cessation,
helped patients with schizophrenia quit smoking but did not help them with their
psychotic symptoms or cognitive deficits (Smith et al. 2016).
Although the PET radioactive ligand [11C]nicotine was one of the earliest
human radioligands developed, it had problematic qualities as a PET ligand
because of poor specificity and fast metabolism; the latest generation nicotinic
ligand [18F]AZAN has some of the highest specific activity observed for the
α4β2-nACh receptor, and it was shown to be only partially blocked in the human
brain by nicotine gum or secondhand smoke but completely blocked by the
specific agonist varenicline (Horti et al. 2013). Despite the well-publicized long-
term negative health consequences of smoking, tobacco products that contain
nicotine remain one of the most widely used addictive legal substances in the
world.
Glutamatergic System
Glutamate and aspartate are the two major excitatory amino acids in the CNS
and are present in high concentrations (Nestler et al. 2015; Squire 2013). As the
principal mediators of excitatory synaptic transmission in the mammalian brain,
they participate in wide-ranging aspects of both normal and abnormal CNS
function. Physiologically, glutamate appears to play a prominent role in synaptic
plasticity, learning, and memory. However, glutamate can also be a neuronal
excitotoxin under a variety of experimental conditions, triggering either rapid or
delayed neuronal death. Unlike the monoamines, which require transport of
amino acids through the blood–brain barrier, glutamate and aspartate cannot
adequately penetrate into the brain from the periphery and are produced locally
by specialized brain machinery. The metabolic and synthetic enzymes
responsible for the formation of these nonessential amino acids are located in
glial cells and neurons (Squire 2013).
The major metabolic pathway in the production of glutamate is derived from
glucose and the transamination of α-ketoglutarate; however, a small proportion
of glutamate is formed directly from glutamine. The latter is actually synthesized
in glia, via an active process (requiring adenosine triphosphate [ATP]), and is
then transported to neurons, where glutaminase is able to convert this precursor
to glutamate (Figure 2–7). Following release, the concentration of glutamate in
the extracellular space is highly regulated and controlled, primarily by a Na+-
dependent reuptake mechanism involving several transporter proteins.
FIGURE 2–7. The glutamatergic system.
See Plate 10 to view this figure in color.
This figure depicts the various regulatory processes involved in glutamatergic
neurotransmission. The biosynthetic pathway for glutamate involves synthesis from glucose
and the transamination of α-ketoglutarate; however, a small proportion of glutamate is formed
more directly from glutamine by glutamine synthetase. The latter is actually synthesized in
glia and, via an active process (requiring adenosine triphosphate [ATP]), is transported to
neurons, where in the mitochondria glutaminase is able to convert this precursor to glutamate.
Furthermore, in astrocytes glutamine can undergo oxidation to yield α-ketoglutarate, which
can also be transported to neurons and participate in glutamate synthesis. Glutamate is either
metabolized or sequestered and stored in secretory vesicles by vesicle glutamate transporters
(VGluTs). Glutamate can then be released by a calcium-dependent excitotoxic process. Once
released from the presynaptic terminal, glutamate is able to bind to numerous excitatory amino
acid (EAA) receptors, including both ionotropic (e.g., NMDA [N-methyl-D-aspartate]) and
metabotropic (mGlu) receptors. Presynaptic regulation of glutamate release occurs through
metabotropic glutamate receptors (mGlu2 and mGlu3), which subserve the function of
autoreceptors; however, these receptors are also located on the postsynaptic element.
Glutamate has its action terminated in the synapse by reuptake mechanisms utilizing distinct
glutamate transporters that exist on not only presynaptic nerve terminals but also astrocytes;
indeed, current data suggest that astrocytic glutamate uptake may be more important for
clearing excess glutamate, raising the possibility that astrocytic loss (as has been documented
in mood disorders) may contribute to deleterious glutamate signaling, but more so by
astrocytes. It is now known that a number of important intracellular proteins are able to alter
the function of glutamate receptors (see diagram). Also, growth factors such as glial-derived
neurotrophic factor (GDNF) and S100β secreted from glia have been demonstrated to exert a
tremendous influence on glutamatergic neurons and synapse formation. Of note, serotonin1A
(5-HT1A) receptors have been documented to be regulated by antidepressant agents; this
receptor is also able to modulate the release of S100β. AKAP=A kinase anchoring protein;
AMPA=α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid;
CaMKII=Ca2+/calmodulin–dependent protein kinase II; ERK=extracellular response kinase;
H-ras=Harvey rat sarcoma proto-oncogene; GKAP=guanylate kinase–associated protein;
Glu=glutamate; Gly=glycine; GTg=glutamate transporter glial; GTn=glutamate transporter
neuronal; Hsp70=heat shock protein 70; MEK=mitogen-activated protein kinase/ERK;
mGluR=metabotropic glutamate receptor; MyoV=myosin V; NMDAR=NMDA receptor;
nNOS=neuronal nitric oxide synthase; PKA=phosphokinase A; PKC=phosphokinase C; PP1,
PP2A, PP2B=protein phosphatases; PSD-95=an abundant postsynaptic density (PSD) protein
that forms a two-dimensional lattice immediately under the postsynaptic membrane; PTP1D=a
protein tyrosine phosphatase; PYK2=protein tyrosine kinase 2; Rac1=Ras-related C3
botulinum toxin substrate 1; Raf=Raf-1 proto-oncogene, serine/threonine kinase; Rap2=related
to AP2 domain protein; RSK=ribosomal S6 kinase; SHP2=src homology 2 (SH2) domain–
containing tyrosine phosphatase; Src=SRC proto-oncogene, non–receptor tyrosine kinase;
SynGAP=synaptic Ras-GTPase activating protein.
Source. Adapted from Cooper JR, Bloom FE, Roth RH: The Biochemical Basis of
Neuropharmacology, 8th Edition. New York, Oxford University Press, 2001. Copyright 1970,
1974, 1978, 1982, 1986, 1991, 1996, 2001 by Oxford University Press, Inc. Used by
permission of Oxford University Press, Inc. Table modified from Nestler et al. 2015.
The major glutamate transporter proteins found in the CNS, all of which clear
the released glutamate from synapses, include the Na+-dependent excitatory
amino acid transporters (EAATs): the “faster turnover” EAATs—EAAT1 (or
GLAST), EAAT2 (or GLT-1), and EAAT3 (or EAAC1); and the “slower
turnover” EAATs—EAAT4 and EAAT5 (Robinson and Jackson 2016). The
corresponding human gene names are SLC1A3, 2, 1, 6, and 7, respectively
(Robinson and Jackson 2016). Additionally, these transporters are differentially
expressed in specific cell types, with EAAT1 and EAAT2 being found primarily
in glial cells, responsible for most of the glutamate reuptake, and EAAT3 being
localized on both excitatory and inhibitory neurons and oligodendrocytes
(Robinson and Jackson 2016). EAAT2 is the most predominantly expressed form
in the forebrain; EAAT4 is mainly localized in Purkinje cells of the cerebellum
but also found elsewhere; EAAT5 is on the presynaptic termini of bipolar
neuronal cells of the retina (Robinson and Jackson 2016; Squire 2013). Evidence
indicates that phosphorylation of the transporters by protein kinases
differentially regulates glutamate transporters and therefore glutamate reuptake
(Casado et al. 1993; Conradt and Stoffel 1997; Pisano et al. 1996). Glutamate
concentrations have been shown to rise to excitotoxic levels within minutes
following traumatic or ischemic injury, and evidence indicates that the function
of the glutamate transporters becomes impaired under these excitotoxic
conditions (Faden et al. 1989). It is surprising that the glutamatergic system has
only recently undergone extensive investigation with regard to its possible
involvement in the pathophysiology of major mental illnesses, because it is the
major excitatory neurotransmitter in the CNS and is known to play a role in
regulating the threshold for excitation of most other neurotransmitter systems.
After decades of research exploring the classic dopamine dysfunction hypothesis
as the pathophysiological basis for schizophrenia, the glutamate dysfunction
hypothesis became an equally vigorous research effort on the basis of initial
observations of the psychotogenic properties of phencyclidine (PCP) and
ketamine. Both are NMDA receptor antagonists that acutely increase glutamate
levels in the synapses, causing many of the core features of schizophrenia
(psychosis, thought disorder, negative symptoms, and executive cognitive
deficits) to emerge from otherwise healthy human subjects (Moghaddam and
Krystal 2012). However, the enthusiasm for the use of ketamine-induced
psychosis as a model for schizophrenia has dampened because of the lack of
efficacy of haloperidol (a D2 receptor antagonist) and group II metabotropic
glutamate receptor (mGlu2/3) agonists in ameliorating ketamine-induced
psychosis and the lack of genetic and postmortem data to support NMDA
receptor dysfunction in schizophrenia (Moghaddam and Krystal 2012).
It is now clear that modification of the levels of synaptic AMPA-type
glutamate receptors—in particular, by receptor subunit trafficking, insertion, and
internalization—is a critically important mechanism for regulating various forms
of synaptic plasticity and behavior. Studies have identified region-specific
alterations in expression levels of AMPA and NMDA glutamate receptor
subunits in patients with mood disorders (Beneyto et al. 2007). Supporting the
suggestion that abnormalities in glutamate signaling may be involved in mood
pathophysiology, AMPA receptors have been shown to regulate affectivelike
behaviors in rodents. AMPA receptor antagonists have been found to attenuate
amphetamine- and cocaine-induced hyperactivity and psychostimulant-induced
sensitization and hedonic behavior (Goodwin et al. 2007). Patients with
treatment-resistant unipolar and bipolar depression given one intravenous dose
of ketamine had strong relief of their depressive symptoms (Berman et al. 2000;
Diazgranados et al. 2010; Zarate et al. 2006a). Ketamine antidepressant efficacy
typically has been assumed to depend on direct glutamate NMDA receptor
inhibition, which is how it works as an anesthetic (Leung and Baillie 1986).
However, the results of human treatment trials indicate that alternative NMDA
receptor antagonists lack the strong, rapid, or sustained antidepressant properties
of ketamine (Newport et al. 2015). It has recently been shown that the
metabolism of ketamine to one of its major metabolites, (2S,6S;2R,6R)-
hydroxynorketamine, is essential for its antidepressant effects in mice (Zanos et
al. 2016). These antidepressant actions are NMDA receptor inhibition
independent, which requires activation of a different subtype of glutamate
receptors, the AMPA receptors (Zanos et al. 2016).
Glutamatergic Receptors
The many subtypes of glutamatergic receptors in the CNS can be classified into
two major subtypes: ionotropic and metabotropic receptors (see Figure 2–7).
Kainate receptors. The KA receptor has pre- and postsynaptic roles, sharing
some properties with AMPA receptors. It is composed of the combination of the
GluK1, GluK2, and GluK3 low-affinity subunits co-assembling with the GluK4
or GluK5 high-affinity subunits (formerly called the GluR5, GluR6, GluR7,
KA1, and KA2 subunits, respectively) to form a dimer of dimers (tetrameric
complex) (see Figure 2–7) (Møllerud et al. 2017). The crystal structures suggest
that the pore remains closed even with glutamate bound to it, indicating that an
additional mechanism is required to induce conformational change to open the
pore (Møllerud et al. 2017). The precise role of KA receptors in the mature CNS
is unknown, although the activity of the receptors clearly plays a role in synaptic
function in many brain areas. Increasing data suggest the involvement of
aberrant synaptic plasticity in the pathophysiology of bipolar disorder. KA
receptors contribute to synaptic plasticity in different brain regions involved in
mood regulation, including PFC, hippocampus, and amygdala. GluK2 (formerly
called GluR6; the gene name continues to be GRIK2) is a subtype of KA
receptor whose chromosomal loci of 6q16.3–q21 was identified as potentially
harboring genetic polymorphism(s) contributing to the increased risk of mood
disorders. The role of GluK2 in modulation of animal behaviors correlated with
mood symptoms was investigated with GluK2 knockout mice and wild-type
mice (Shaltiel et al. 2007). GluK2 knockout mice appeared to attain normal
growth and lacked neurological abnormalities. The GluK2 knockout mice
showed increased basal- or amphetamine-induced activity, were extremely
aggressive, took more risks, and consumed more saccharin (a measure of
hedonic drive). Notably, most of these aberrant behaviors responded to chronic
lithium administration. These results suggest that abnormalities in KA receptor
throughput generated by GluK2 gene disruption may lead to the concurrent
appearance of a constellation of behaviors related to manic symptoms, including
persistent hyperactivity, escalated irritability and aggression, risk taking, and
hyperhedonia.
KA receptors play an important role in the hippocampus with place cell
activity patterns and working memory (Sihra and Rodríguez-Moreno 2013). KA
receptors modulate glutamate release between the mossy fibers of the granular
cells of the dentate gyrus and the principal cells of the CA3 region, and there is
high expression of KA receptors at those mossy fiber–CA3 synapses (Sihra and
Rodríguez-Moreno 2013). KA receptors both prevent excessive glutamate
release and facilitate increased glutamate release when the levels of glutamate
are low in those same synapses (Sihra and Rodríguez-Moreno 2013). Recovery
of the synapses with KA receptors is long and slow compared with the fast
NMDA receptors, which may assist with memory formation (Sihra and
Rodríguez-Moreno 2013). The CA3 may be more prone to develop seizures as a
result of the KA receptors facilitating glutamate release (Sihra and Rodríguez-
Moreno 2013).
Glycine
Glycine is a nonessential amino acid that also functions as a neurotransmitter in
the CNS, serving as a co-agonist for NMDA receptor activation. Glycine may be
produced in the CNS by two distinct pathways. First, glycine is produced from
serine by the enzyme serine-trans-hydroxymethylase in a reversible, folate-
dependent reaction (Cooper et al. 2003; Nestler et al. 2015; Squire 2013).
Second, a smaller proportion of glycine also may be produced from glyoxylate
by the enzyme D-glycerate dehydrogenase. Glycine is found in higher
concentrations in the spinal cord than in the rest of the CNS, and it acts as an
inhibitory neurotransmitter predominantly in the brain stem and spinal cord
(Nestler et al. 2015). As discussed earlier, a very important role that glycine also
plays is to augment the NMDA-mediated frequency of NMDA receptor channel
opening. This effect is strychnine-insensitive and pharmacologically suggests
that the actions of glycine on NMDA receptor function are different from its
effect on the spinal cord, where glycine’s inhibitory effect is blocked by
strychnine (Cooper et al. 2003). The allosteric modulation of NMDA receptors
via a glycine site is further underscored by receptor binding experiments
yielding an anatomical distribution similar to that of NMDA receptors.
Functionally, it has been postulated that glycine is able to augment the NMDA-
mediated responses by speeding up the recovery process of the NMDA receptor
(Cooper et al. 2003).
Glycine receptors, similar to GABAA receptors, contain a chloride channel,
and are composed of a combination of three α subunits containing the glycine
binding site and two β subunits, which associate with gephyrin, a cytoplasmic
protein (Nestler et al. 2015). Glycine receptors are bound by the compounds
strychnine, a selective glycine receptor antagonist, and picrotoxin, a
noncompetitive inhibitor, which block the chloride channel pore and cause
seizures (Nestler et al. 2015). Synaptic glycine is removed mostly through the
glycine transporter GlyT1. Ligands to GlyT1 are being explored as potential
candidates for the treatment of schizophrenia, and a specific PET ligand,
[18F]MK6577, recently has been developed (Xia et al. 2015). The endogenous
ligands for the glycine receptor are actually D-serine and D-cycloserine (Labrie
and Roder 2010). Glycine receptor agonism (D-serine) or GlyT antagonism
(sarcosine) effectively increases glycine in the synapse, causing an increase in
NMDA GluN1 receptor activation, which may ameliorate symptoms of
schizophrenia, and clinical trials have suggested that these compounds may be
helpful as augmentation agents together with other antipsychotics (Labrie and
Roder 2010).
GABAergic System
GABA—the major inhibitory neurotransmitter system in the CNS—is one of the
most abundant neurotransmitters, and GABA-containing neurons are located in
virtually every area of the brain. Unlike the monoamines, GABA occurs in the
brain in high concentrations on the order of micromoles per milligrams (about
1,000-fold higher than concentrations of monoamines) (Cooper et al. 2003;
Nestler et al. 2015; Squire 2013). GABA is produced when glucose is converted
to α-ketoglutarate, which is then transaminated to glutamate by GABA α-
oxoglutarate transaminase (GABA-T). Glutamic acid is decarboxylated by
glutamic acid decarboxylase, which leads to the formation of GABA (Figure 2–
8). Indeed, the neurotransmitter and the rate-limiting enzyme are localized
together in the brain and at approximately the same concentration. Catabolism of
GABA occurs via GABA-T, which is also important in the synthesis of this
transmitter.
FIGURE 2–8. The GABAergic system.
See Plate 11 to view this figure in color.
This figure depicts the various regulatory processes involved in GABAergic
neurotransmission. The amino acid (and neurotransmitter) glutamate serves as the precursor
for the biosynthesis of γ-aminobutyric acid (GABA). The rate-limiting enzyme for the process
is glutamic acid decarboxylase (GAD), which utilizes pyridoxal phosphate as an important
cofactor. Furthermore, agents such as L-glutamine-γ-hydrazide and allylglycine inhibit this
enzyme and, thus, the production of GABA. Once released from the presynaptic terminal,
GABA can interact with a variety of presynaptic and postsynaptic receptors. Presynaptic
regulation of GABA neuron firing activity and release occurs through somatodendritic (not
shown) and nerve-terminal GABAB receptors, respectively. Baclofen is a GABAB receptor
agonist. The binding of GABA to ionotropic GABAA receptors and metabotropic GABAB
receptors mediates the effects of this receptor. The GABAB receptors are thought to mediate
their actions by being coupled to Ca2+ or K+ channels via second-messenger systems. Many
agents are able to modulate GABAA receptor function. Benzodiazepines, such as diazepam,
increase Cl– permeability, and there are numerous available antagonists directed against this
site. There is also a distinctive barbiturate binding site on GABAA receptors, and many
psychotropic agents are capable of influencing the function of this receptor (see blown-up
diagram). GABA is taken back into presynaptic nerve endings by a high-affinity GABA
uptake transporter (GABAT) similar to that of the monoamines. Once inside the neuron,
GABA can be broken down by GABA transaminase (GABA-T), which is localized in the
mitochondria; GABA that is not degraded is sequestered and stored in secretory vesicles by
vesicular GABA transporters (VGATs), which differ from vesicular monoamine transporters
(VMATs) in their bioenergetic dependence. The metabolic pathway that produces GABA,
mostly from glucose, is referred to as the GABA shunt. The conversion of α-ketoglutarate into
glutamate by the action of GABA-T and GAD catalyzes the decarboxylation of glutamic acid
to produce GABA. GABA can undergo numerous transformations, of which the simplest is the
reduction of succinic semialdehyde (SS) to γ-hydroxybutyrate (GHB). On the other hand,
when SS is oxidized by succinic semialdehyde dehydrogenase (SSADH), the production of
succinic acid (SA) occurs. GHB has received attention because it regulates narcoleptic
episodes and may produce amnestic effects. The mood stabilizer and antiepileptic drug
valproic acid is reported to inhibit SSADH and GABA-T. AC=adenylyl cyclase; TBPS=t-
butylbicyclophosphorothionate.
Source. Adapted from Cooper JR, Bloom FE, Roth RH: The Biochemical Basis of
Neuropharmacology, 8th Edition. New York, Oxford University Press, 2001. Copyright 1970,
1974, 1978, 1982, 1986, 1991, 1996, 2001 by Oxford University Press, Inc. Used by
permission of Oxford University Press, Inc.
Peptidergic Neurotransmission
Neuropeptides have garnered increasing attention as critical modulators of CNS
function. In general, peptide transmitters are released from neurons when they
are stimulated at higher frequencies than those required to facilitate release of
traditional neurotransmitters but can also be co-localized and co-released
together with other neurotransmitters (Cooper et al. 2003; Nestler et al. 2015).
Modulation of the firing rate pattern of neurons and subsequent release of
neurotransmitters and peptides in a circumscribed fashion are likely important in
the basal functioning of the brain, as well as response to specific stimuli.
Interestingly, cannabinoids, an example of a neuropeptide neurotransmitter, do
not alter firing rates of hippocampal neurons but change temporal coordination,
an effect that correlates with memory deficits in individuals (Soltesz and Staley
2006). Localization of brain stem cannabinoid receptors (CB1 and CB2) provided
clues to how cannabinoids regulate brain function (Van Sickle et al. 2005).
Virtually every known mammalian bioactive peptide is synthesized first as a
precursor protein in which product peptides are flanked by cleavage sites.
Neuropeptides are generally found in large dense-core vesicles, whereas other
neurotransmitters, such as the monoamines, are packaged in small synaptic
vesicles (approximately 50 nm) and are usually half the size of their peptidergic
counterparts (Kandel 2013; Squire 2013).
Space limitations preclude an extensive discussion of the diverse array of
neuropeptides known to exist in the mammalian brain. Table 2–2 highlights
some of the major neuropeptides that may be of particular psychiatric relevance.
In the remainder of this section, we highlight the basic aspects of peptidergic
transmission vis-à-vis an overview of opioidergic neurotransmission. We briefly
discuss selected neuropeptides here; a general review of neuropeptides as
potential drug targets can be found elsewhere (Hoyer and Bartfai 2012).
Corticotropin-Releasing Factor
Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis may relate to the
pathophysiology of mental illness. Corticotropin-releasing factor (CRF) is a key
neuropeptide controlling the HPA axis with a 41–amino acid sequence that is
identical in humans and in rats (Montecucchi et al. 1980). CRF is produced in
the paraventricular nucleus (PVN) of the hypothalamus, and once secreted into
pituitary portal blood, it binds to Gs-coupled receptors on cells in the pituitary to
increase adenylate cyclase, cAMP-dependent protein kinase, and cytosolic
calcium concentrations (Lovejoy et al. 2014). CRF is also capable of activating
Gq-, Gi-, Go-, and Gz-coupled receptors (Grammatopoulos et al. 2001). CRF
receptors are classified into CRF1 and CRF2 (Chen et al. 1993; Liaw et al. 1996;
Lovejoy et al. 2014). The CRF1A receptor is the dominant subtype in the brain
and peripheral tissue, whereas the CRF1D receptor is thought to play a
competing role against CRF1A, with CRF1B and CRF1C also being identified
(Hillhouse and Grammatopoulos 2006). Although CRF2 receptors and their
spliced variants CRF2A, CRF2B, and CRF2C are localized in the brain, they
exist to a greater degree in peripheral tissue (Hillhouse and Grammatopoulos
2006).
Stressful life events and chronic stress can induce brain circuit changes that
are thought to relate to the pathophysiology of some anxiety disorders and
PTSD. Increased CRF secretion from the hypothalamus and adrenocorticotropic
hormone (ACTH) from the anterior pituitary gland are associated with aberrant
cortisol responses to stress. Depressed patients and suicide victims have
elevations of CRF concentrations in the CSF, increased cerebrocortical CRF
immunoreactivity, and decreased CRF1 receptor binding; furthermore, decreased
CRF1 mRNA expression has been reported in postmortem brain tissue of suicide
victims (Sanders and Nemeroff 2016). Although probes of HPA function, such as
the dexamethasone/CRF suppression tests, indicate hyperactivity of the axis in
depressed patients, it is largely a nonspecific finding and can occur in other
psychiatric illnesses.
Opiates
Opioids are a family of peptides that occur endogenously in the brain
(endorphins), as botanicals, or as drugs. POMC is a precursor protein
characterized in the 1980s that gives rise to ACTH and a class of endogenous
opiates called endorphins. POMC, proenkephalin-derived peptides, and
prodynorphin-derived peptides yield opioid peptides on cleavage. Three opioid
peptide families exist: enkephalins, endorphins, and dynorphins. POMC gene
expression occurs in various areas of the brain and in other tissues. POMC has
tissue- and cell-specific regulatory factors at every step from gene transcription
to its posttranslational processing. Opioid peptides are stored in large dense-core
vesicles and are co-released from neurons that usually contain a classic
neurotransmitter agent (e.g., glutamate and norepinephrine). Opiorphin, an
endogenously derived enkephalin that inactivates zinc ectopeptidase, has been
described as equal to morphine in the perception of pain (Wisner et al. 2006).
Although opiates are widely associated with and used therapeutically in pain
modulation, evidence indicates that dynorphin can actually activate bradykinin
receptors and contribute to neuropathic pain (Altier and Zamponi 2006).
Opioids activate a variety of signal transduction processes, and different
mechanisms in their regulation are in place for different cell types. The opioid
receptors are GPCRs and exert their cellular effects by inhibiting adenylyl
cyclase and regulating K+ and Ca2+ channels, via activation of Gi/Go. There are
three types of opioid receptors—μ, δ, and κ, each of which is further
subclassified—in addition to opioid receptor like–1 (ORL1) receptor. These
receptors are 7-transmembrane-spanning proteins that couple to inhibitory G-
proteins or form homo- and heterodimeric complexes. They also alter calcium
signaling through dissociation of Gβγ subunits and by reducing sensitivity to L-
type, N-type, and P/Q-type channels. Also, numerous mechanisms have been
described that allow opiates and synthetic opiate agents (i.e., morphine, fentanyl)
to regulate receptor signaling, which can occur from the receptor being
phosphorylated, desensitized, and internalized. Once the receptor is
phosphorylated, recruitment of arrestins to the receptor occurs and can prime for
sequestration. Interestingly, arrestin-3–deficient mice have tolerance to morphine
and other μ opioid receptor agents, whereas polymorphisms in OPRM1 have
been associated with opioid dependency. Intracellular cascades associated with
opioid dependence and withdrawal have documented changes in mitogen-
activated protein kinase (MAPK) and extracellular signal-regulated kinase 1/2
(ERK1/2) cascades, as well as changes in transcription factors such as
phosphorylated cAMP response element-binding protein (pCREB) and
DeltaFosB, which have been linked to changes in the reward system (Al-Hasani
and Bruchas 2011).
The continued study of the opioid system and the second-messenger changes
brought about by the chronic administration of opioids has greatly facilitated our
understanding of the molecular and cellular effects of drugs of abuse and the
potential to develop novel therapeutics (Nestler et al. 2015). In response to the
worldwide heroin epidemic, the medication buprenorphine, a partial agonist of
the μ opioid receptor and an antagonist of the δ and κ opioid receptors, has
become one of the most widely prescribed medications in the world to treat
opioid use disorders, perhaps because it can be prescribed from an outpatient
office setting.
Conclusion
We have provided an overview of some fundamental aspects of
neurotransmitters and brain receptor classes. For most psychiatrists, molecular
and cellular biology have not traditionally played a major role in day-to-day
clinical practice. However, new insights into the molecular and cellular basis of
disease and drug action are being generated at an ever-increasing rate and will
ultimately result in a transformation of our understanding and management of
diseases. The “molecular medicine revolution” has used the power of
sophisticated cellular and molecular biological methodologies to tackle many of
society’s most devastating illnesses. The rate of progress has been exciting
indeed, and hundreds of GPCRs and their effectors have now been identified and
characterized at the molecular and cellular levels. These efforts have allowed the
study of a variety of human diseases that are caused by abnormalities in cell-to-
cell communication. Studies of such diseases are offering unique insights into
the physiological and pathophysiological functioning of many cellular
transmembrane signaling pathways.
Psychiatry, like much of the rest of medicine, has entered a new and exciting
age demarcated by the rapid advances and the promise of molecular and cellular
biology and neuroimaging. There is a growing appreciation that severe
psychiatric disorders arise from abnormalities in cellular plasticity cascades,
leading to aberrant information processing in synapses and circuits mediating
affective, cognitive, motoric, and neurovegetative functions. Thus, these
illnesses can be best conceptualized as genetically influenced disorders of
synapses and circuits rather than simply as deficits or excesses in individual
neurotransmitters. Furthermore, many of these pathways play critical roles not
only in synaptic and behavioral plasticity but also in long-term atrophic
processes. Targeting these pathways in treatment may stabilize the underlying
disease process by reducing the frequency and severity of the profound mood
cycling that contributes to morbidity and mortality.
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CHAPTER 3
Twin studies have firmly established important genetic contributions for all
psychiatric disorders, with heritability estimates (i.e., the proportion of risk for a
disorder attributable to the additive effects of genes) ranging from 30% to 80%
for most common psychiatric disorders (Table 3–1).
N in meta-
Disorder Heritability analysis References
Autism spectrum >0.80 — Bailey et al.
disorder 1995; Rutter
2000
Schizophrenia 0.81 (0.73–0.90) 12 studies Sullivan et al.
(Sweden, 2003 (meta-
United States, analysis)
England,
Norway,
Denmark,
Finland,
Germany), N
not available
Bipolar disorder 0.79–0.85 — Kendler et al.
1995b;
McGuffin et
al. 2003
Major depressive 0.37 (0.31–0.42) 5 studies (United Sullivan et al.
disorder Kingdom, 2000 (meta-
Sweden, analysis)
United States),
N>21,000
Panic disorder 0.43 (0.32–0.53) 3 studies, Hettema et al.
N>9,000 2001 (meta-
analysis)
Generalized 0.32 (0.24–0.39) 2 studies, Hettema et al.
anxiety N>12,000 2001 (meta-
disorder analysis)
Specific phobia 0.25–0.35 — Kendler et al.
1992, 2001b
Social phobia 0.20–0.30 — Kendler et al.
(social anxiety 1992, 2001b
disorder)
Agoraphobia 0.37–0.39 — Kendler et al.
1992, 2001b
Obsessive- 0.45–0.65 — van Grootheest
compulsive (children) et al. 2005
disorder 0.27–0.47 (review)
(adults)
Anorexia 0.56 (0.00–0.86) Swedish twin Bulik et al. 2006
nervosa registry,
N>30,000
Bulimia nervosa 0.28–0.83 — Bulik et al. 2000
(review)
Alcohol 0.48–0.73 (men) — Tyndale 2003
dependence 0.51–0.65 (review)
(women)
Nicotine 0.40–0.70 — Li 2003; Tyndale
addiction 2003
(reviews)
Antisocial 0.32 51 studies, N not Rhee and
personality available Waldman
disorder 2002 (meta-
analysis)
In more recent research, twin studies are being used to investigate the
influence of epigenetics. Epigenetics refers to the chemical modification of
genes without alteration of the genome sequence. These modifications determine
whether a given gene is expressed (switched on) or not expressed (switched off)
and are driven by the DNA sequence together with environmental stimuli. Large-
scale twin studies are helping to reveal the contribution of epigenetic alterations
in psychiatric disorders by allowing investigators to disentangle genetic versus
environmental contributions in MZ and DZ twins.
Genetic epidemiology also can contribute to exploration of more complex
questions, such as whether genetic risk factors are shared among different
psychiatric disorders and between sexes and whether these genetic risk factors
can moderate the effects of environmental risk factors (Kendler 2001) and can
therefore lead the design of follow-up molecular genetic studies. For example, a
twin study has suggested that genetic risk factors for major depressive disorder
could in part act by increasing vulnerability to stressful life events (Kendler
1995). This suggestion has been corroborated by findings from a number of gene
× environment (G×E) interaction studies, including studies confirming the
interaction of functional alleles of the locus encoding the serotonin transporter
protein with stressful life events to predict risk of depression (Caspi et al. 2003;
Karg et al. 2011; Kaufman et al. 2004; Kendler et al. 2005; Sjöberg et al. 2006;
Surtees et al. 2006; Wilhelm et al. 2006) and the interaction of genetic
polymorphisms at the gene for FK506 binding protein 5 (FKBP5) with
childhood abuse to predict risk of posttraumatic stress disorder (PTSD; Zannas
et al. 2016). Genetic epidemiological studies—and, more specifically, twin
studies—therefore have been an important foundation of psychiatric genetics
and are likely to continue to contribute more elaborate disease models for future
molecular genetic analysis. The major limitation of these studies, however, is
that the estimated heritability with twin studies is only an estimate of the
aggregate genetic effect. Heritability does not give any information about the
contributions of specific genes to risk for a disorder. The answers to those
questions, which will require deployment of an array of molecular genetic
techniques, will ultimately shed light on the developmental neurobiology
underlying psychiatric illness.
From the cumulative evidence of psychiatric genetic studies thus far, one can
conclude that psychiatric disorders deviate from the “common disease, common
variant” hypothesis and instead fit a polygenic mode of inheritance, with many
polymorphic loci contributing to these disorders (Cross-Disorder Group of the
Psychiatric Genomics Consortium 2013; Geschwind and Flint 2015; Smoller
2016; Sullivan et al. 2012), as has been found in studies of unipolar depression
(i.e., major depressive disorder) (Johansson et al. 2001; Kendler et al. 2006;
Ripke et al. 2013b), bipolar disorder (Blackwood and Muir 2001; Psychiatric
GWAS Consortium Bipolar Disorder Working Group 2011; Ruderfer et al.
2014), schizophrenia (S.H. Lee et al. 2012; Purcell et al. 2009; Ripke et al.
2013a; Ruderfer et al. 2014), and autism spectrum disorder (Carayol et al. 2014;
Folstein and Rosen-Sheidley 2001; Gillis and Rouleau 2011). For example, the
largest genomewide association analysis to date identified 108 schizophrenia loci
(Ruderfer et al. 2014), supporting the hypothesis that locus heterogeneity is an
important factor in schizophrenia. Thus, Bleuler (1951) appears to have been
correct when he referred to dementia praecox as “the group of schizophrenias.”
As already noted, susceptibility genes are likely to interact with environment,
gender, and other genes, making the search for “genes for psychiatric disorders”
even more complex (Kendler and Greenspan 2006). Twin studies have produced
evidence that genetic interactions with stressful life events predict major
depressive disorder (Kendler et al. 1995a) and that genetic interactions with
early rearing environment predict schizophrenia, conduct disorder, and drug
abuse (Cadoret et al. 1995a, 1995b; Tienari et al. 2004). A key series of studies
by Caspi and Moffitt (2006) enriched our understanding of G×E interactions and
led to increased momentum in research. Although most G×E studies look into
detrimental environmental factors, their scope also should encompass positive or
protective environmental factors (Klengel and Binder 2015). Furthermore,
gender-specific predisposing genes for psychiatric disorders are likely. Data
from twin studies suggest that the combined genetic factors conferring risk for
major depressive disorder, phobias, and alcoholism may differ in some respects
for men and women (Kendler and Prescott 1999; Kendler and Walsh 1995;
Kendler et al. 2001a, 2002, 2006; Prescott and Kendler 2000; Prescott et al.
2000), and this theory has been supported in molecular genetic studies by the
identification of gender-specific loci for anxiety and major depressive disorder,
for example (Quast et al. 2014; Unschuld et al. 2010). Finally, gene–gene
interactions also may be relevant for these disorders (Risch 1990) but have not
been studied in detail thus far.
Translocations
Karyotypic examination and other cytogenetic techniques such as fluorescent in
situ hybridization (FISH) can detect additional large-scale chromosomal
abnormalities, such as translocations, deletions, or duplications of large regions
of chromosomes. In a large Scottish pedigree, a balanced translocation between
chromosomes 1 and 11 appears to be causally linked to a series of major
psychiatric disorders, including schizophrenia, bipolar disorder, recurrent major
depressive disorder, and conduct disorder (St Clair et al. 1990). This balanced
translocation (which exchanged parts of chromosome 1 with parts of
chromosome 11 to produce two abnormal chromosomes but no net loss of
chromosomal material) disrupts two genes at the translocation breakpoint on
chromosome 1, termed disrupted in schizophrenia (DISC) 1 and 2 (Millar et al.
2000, 2001). Subsequent molecular analysis has provided strong evidence that
variation in DISC1 can alter the risk for schizophrenia (Porteous et al. 2006).
Although most still consider the DISC1 translocation to be a confirmed
schizophrenia risk factor (Porteous et al. 2014), this is hotly debated because of
concerns about the standard of the evidence (Sullivan 2013).
Deletions
Microdeletions occurring on the long arm of chromosome 22 have received
considerable attention as cytogenetic risk factors for the development of
schizophrenia (Karayiorgou and Gogos 2004). The 22q11 deletion syndrome, in
which 1.5–3.0 million base pairs (bp) of DNA are missing on one copy of 22q,
includes a spectrum of disorders affecting structures associated with
development of the fourth branchial arch and migration of neural crest cells
(e.g., the great vessels of the heart, the oropharynx, the facial midline, the
thymus, the parathyroid glands). Originally described as distinct disease
syndromes prior to the elucidation of their common molecular etiology, 22q11
deletion syndrome includes velocardiofacial syndrome (VCFS), DiGeorge
syndrome, and conotruncal anomaly face syndrome. Following an initial report
of early-onset psychosis in patients with VCFS (Shprintzen et al. 1992), Pulver
et al. (1994) examined psychiatric symptoms in adults with VCFS and in a
cohort of patients ascertained for schizophrenia (Karayiorgou et al. 1995). The
latter study identified two previously undiagnosed cases in 200 patients, verified
by FISH to carry 22q11 deletions (Karayiorgou et al. 1995). There is a reported
10–20 times higher prevalence of the 22q11 deletion in patients with
schizophrenia (Rees et al. 2014b), and duplications of 22q11.2 might prove
protective (Rees et al. 2014a). The deletion is thought to be one of the strongest
risk factors for psychosis (Schneider et al. 2014), with early cognitive decline
being a strong indicator of subsequent psychosis development (Vorstman et al.
2015).
Duplications
Duplications of the long arm of chromosome 15 (15q11–13) are the most
frequent cytogenetic anomalies in autism spectrum disorder, occurring in
approximately 1%–2% of cases (Cook 2001). This duplication syndrome cannot
be clinically differentiated from idiopathic autism (Veenstra-VanderWeele and
Cook 2004), indicating that a complete workup of autism spectrum disorder
should include testing for this cytogenetic abnormality as well as several others
(Martin and Ledbetter 2007). Interestingly, deletion of this same region of 15q is
associated with Angelman syndrome when the deletion occurs on the maternal
copy of chromosome 15 and with Prader-Willi syndrome when the deletion
occurs on the paternal chromosome (or, more rarely, when two maternal copies
of chromosome 15 are present and the paternal chromosome is missing entirely,
a condition known as maternal disomy). Both syndromes manifest as quite
distinct but dramatic neurobehavioral disorders (Nicholls and Knepper 2001;
Vogels and Fryns 2002). Induced pluripotent stem cells are now being used to
model copy number variations for individual patients. These models have the
potential to help explain the underlying mechanisms of psychopathologies. For
example, induced pluripotent stem cells taken from patients with 15q11 copy
deletion show deficits in adherens junctions and apical polarity. The study
pinpointed a haploinsufficiency at CYFIP1, one of the genes within the larger
deletion (Yoon et al. 2014).
Insertion/Deletion Polymorphisms
Microscopic insertions and deletions (much smaller than CNVs—on the order of
one to hundreds of bp) are another important type of genetic variation. The most
famous insertion/deletion polymorphism in psychiatric genetics is a common
functional polymorphism in the promoter region of the serotonin transporter
gene SLC6A4, referred to as the serotonin transporter–linked promoter region
(5HTTLPR). It consists of a repetitive region containing 16 imperfect repeat
units of 22 bp, located approximately 1,000 bp upstream of the transcriptional
start site (Heils et al. 1996; Lesch et al. 1996). The 5HTTLPR is polymorphic
because of the insertion/deletion of the repeat units 6–8 (of the 16 repeats),
which produces a short (S) allele that is 44 bp shorter than the long (L) allele.
Although the 5HTTLPR was originally described as biallelic, rare (<5%) very-
long and extra-long alleles have been described in Japanese and African
Americans (Gelernter et al. 1999). Numerous additional variants within the
repetitive region also occur (Nakamura et al. 2000). Thus, although most studies
continue to treat this complex region as biallelic, this is an oversimplification
that may be hiding additional genetic information.
The 5HTTLPR has been associated with altered basal activity of the
transporter, most likely related to differential transcriptional activity (Heils et al.
1996; Lesch et al. 1996). The long variant (L allele) of this polymorphism has
been shown to lead to a higher serotonin reuptake by the transporter in vitro. It is
also noteworthy that the function of this insertion/deletion polymorphism may be
influenced by a single nucleotide polymorphism (SNP) that occurs with the L
allele (Hu et al. 2006). However, a positron emission tomography (PET) study
was unable to identify differences in serotonin transporter binding potential by
the 5HTTLPR genotype, even when including the information of the additional
SNP, in healthy control subjects or patients with major depressive disorder
(Parsey et al. 2006). This polymorphism has shown associations with a multitude
of psychiatric disorders and related phenotypes. The best-established
associations are with response to SSRI antidepressants (Porcelli et al. 2012;
Serretti et al. 2007) and with moderation of the influence of life events on risk of
depression (Caspi et al. 2003), although the latter finding remains controversial
(Karg et al. 2011; Kaufman et al. 2004; Kendler et al. 2005; Munafò et al. 2009;
Risch et al. 2009; Surtees et al. 2006; Wilhelm et al. 2006; Zalsman et al. 2006).
Cytogenetic Studies
Disruption of chromosomal integrity by rare events such as balanced
translocations has facilitated gene discovery in a variety of diseases and holds
significant promise for similar applications in psychiatric illness (Pickard et al.
2005). Advances in techniques such as chromosome painting, high-resolution
FISH, and, most recently, genomewide analysis of CNVs using microarrays have
made it possible to identify disruptions in chromosomal architecture to single-
base resolution, thus facilitating identification of specific genes in families
cosegregating mental illness and cytogenetic abnormalities. Such data then may
be used to generate testable hypotheses about the role of a particular gene in
disease pathophysiology. The DISC1 and DISC2 genes provide clear examples
of specific genes implicated in mental illness following their discovery through
careful molecular analysis of a cytogenetic anomaly. Because much more work
has been published on DISC1, we focus on that locus here.
As noted previously, DISC1 was initially identified by cytogenetic studies in
which a large Scottish family with numerous relatives affected by major
psychiatric illness were shown to carry a balanced (1;11) (q42;q14.3)
translocation that cosegregates with the presence of psychiatric illness. Linkage
analysis using the psychiatric diagnosis as a phenotype and the translocation as a
genetic marker yielded highly significant evidence supporting linkage of the
translocation to psychiatric illness, and particularly to schizophrenia (Blackwood
et al. 2001; St Clair et al. 1990). The translocation was shown to disrupt DISC1
and DISC2 on chromosome 1 (Millar et al. 2000, 2001), whereas no known
genes were disrupted on chromosome 11. DISC1 was shown to encode a novel
protein, with no known related proteins, that subsequently has been shown to
play important roles in several key neuronal functions, including axonal
transport and regulation of G-protein-mediated intracellular signaling (Porteous
et al. 2006, 2014). Studies in induced pluripotent stem cell–derived forebrain
neurons suggest that DISC1 mutations are associated with disrupted synaptic
vesicle release (Wen et al. 2014).
Linkage Studies
In the 1980s and 1990s, many genes for Mendelian disorders were successfully
identified with linkage analysis in large families. Linkage relies on the principle
that, on average, chromosomes from parents differ from those of offspring by
only one meiotic crossover event. During meiosis, the cell divisions that produce
gametes by reducing the diploid genome (i.e., two chromosomes of each pair per
cell) to a haploid genome (one copy of each chromosome per spermatocyte or
ooctye), homologous grandparental chromosomes (i.e., paternal and maternal to
the parents of the offspring of interest), make physical contact and exchange
homologous regions (referred to as crossing over) to give rise to a new set of
chromosomes in which each gametic chromosome is a mix of grandparental
sequences. This crossing-over process produces recombination that can then be
tracked with molecular markers to delineate the ancestral origin of each
chromosomal region in the offspring.
Classically, linkage studies use from several hundred to a few thousand
microsatellite markers, evenly spaced across the genome. These markers are then
genotyped in large families in which the disease of interest is common. To
identify positions in the genome that may be involved in the disease, one tracks
whether marker alleles are inherited by affected relatives more often than would
be expected by chance (i.e., linkage tests whether a particular chromosomal
region cosegregates with the disease). A quantitative measure of the likelihood
of a particular pattern of marker–disease cosegregation is the logarithm of odds
(LOD) score. As the name implies, the LOD score is logarithmic, with LOD=1
corresponding to 1:10 odds, LOD=2 to 1:100 odds, and so forth. Because of the
high a priori probability that a given region is not linked to a given phenotype, a
LOD score of 3.3 or greater is usually required before significant linkage is
accepted (Lander and Schork 1994). The results of linkage analyses are usually
presented as plots of LOD scores at each marker, which are arranged in their
known order across individual chromosomes or the entire genome. These plots
show a pattern of peaks and valleys. Linkage peaks identify chromosomal
regions (i.e., loci) where the LOD score is high, suggesting a high probability
that a disease-linked variant resides nearby. Because of the spacing of the
markers and their multiallelic properties, the identified regions are usually large,
comprising up to tens of mega bases and harboring dozens of genes (which are
then referred to as positional candidates because they reside under the linkage
peak). Linkage peaks need to be followed up with additional fine mapping using
denser marker maps, including SNPs, to hone in on the candidate gene(s) of
interest.
Classical linkage approaches have been very successful in identifying
monogenic diseases that follow clear, simple patterns of inheritance, but they
have been far less successful in complex psychiatric disease. Parametric linkage
analysis requires specification of an inheritance model (e.g., recessive or
dominant), information we do not have for psychiatric disorders, as they clearly
do not follow Mendelian inheritance. In addition, each family may have a
different pattern of inheritance, so that specifying one model for several
pedigrees may decrease the power to detect a signal in some of the families.
Nonparametric linkage analyses that are mode-of-inheritance independent have
been developed to address this problem. Also, linkage analysis requires that each
person in a pedigree be designated as either affected or unaffected, so one must
decide, for example, in which category to place individuals with a single major
depressive episode in a bipolar pedigree. Linkage analysis studies therefore often
run several different models and also may use different definitions of affected
status and then report the best LOD score, but here the threshold for significance
also has to be adjusted for additional multiple testing, so that even higher LOD
scores are required for statistical significance. Linkage analyses in psychiatric
disorders are further complicated by the fact that they explore complex
psychiatric diseases, with likely multiple (possibly additive or interacting)
susceptibility genes and a strong environmental component, all of which cannot
be modeled easily in these analyses. It is therefore not surprising that linkage
analyses have yielded inconsistent results in the past.
Association Studies
Association studies are usually performed in case–control studies of unrelated
individuals. In such studies, allele frequencies of markers are compared between
a case and a control population. Association has been shown to have more power
than linkage studies to detect susceptibility genes that exert only a small effect
on disease risk (Risch and Merikangas 1996). Considering the strong evidence
supporting complex inheritance for most psychiatric disorders, it appears that
association studies are the optimal study design to identify and/or test candidate
genes for these disorders. To help interpret genetic association studies, we first
want to introduce several key concepts, which are important for the design and
understanding of association studies.
Linkage Disequilibrium
Association studies rely on the principle that even unrelated individuals share
very small stretches of chromosomal DNA derived from a distant common
ancestor. In the case of a disease-predisposing mutation, some proportion of ill
individuals will share that mutation arising from an original common ancestor.
As the variant is passed down from generation to generation, meiotic
recombination events will shrink the size of the initial piece of ancestral
chromosome that is inherited together with the disease mutation. On these small
ancestral stretches of chromosome (perhaps several thousand to several hundred
thousand bp in length), nonfunctional “marker” polymorphisms close to the
disease mutation will “ride” through generations together with the disease
variant. Such markers (SNPs, for example) thus can serve as surrogate “tags” for
the disease mutation. Note, however, that as generations pass and individuals
become ever more distant relatives (to a point when social/cultural “memory” of
genetic relationship is usually lost), different families will produce
recombination events at different points near the disease mutation. Therefore, at
a population level, unrelated individuals carrying the disease marker will carry
variable lengths of DNA on which markers linked to the disease variant ride.
Stated another way, unrelated individuals carrying the disease variant will carry
haplotypes that become more similar to one another as the boundaries of the
haplotypes are moved closer to the disease variant. Thus, the closer a marker is
to the disease variant, the more likely it is to be originally linked to the variant.
When a marker is close enough to a disease marker that the number of
recombination events in the population has not yet completely randomized, and
the odds are high that it is on the same ancestral stretch of DNA (haplotype) as
the disease variant, the marker and the disease variant are correlated and are said
to be in linkage disequilibrium (LD). Knowing the allele of a marker variant in
LD with a disease variant can therefore allow one to predict the allele of the
disease variant (i.e., the marker and the disease variant are not statistically
independent).
Several factors influence the length of DNA over which LD occurs. The most
important are the geographic origins of the population from which an individual
is drawn and the history of that population. For example, sub-Saharan African
populations are ancient and reflect the greatest proportions of the total human
pool of variation, because most of the human species’ history predates migration
of humans out of Africa. Therefore, on average, sub-Saharan African
populations have undergone the greatest number of recombination events since a
given pair of unrelated individuals shared a common ancestor. Those individuals
thus share only short stretches of ancestral chromosomes (which are said to be
identical by descent, or IBD). Non-African populations all derive from a
relatively small number of migrants who left Africa within approximately the
last 100,000 years. Thus, Europeans, Eastern Asians, or Native Americans share
longer stretches of DNA IBD within their respective continental groups than do
sub-Saharan Africans (Daly et al. 2001; Gabriel et al. 2002; Patil et al. 2001;
Reich et al. 2001). On the other extreme, individuals from reproductively
isolated populations, in which a small recent founder population has expanded
with little admixture (i.e., introduction of outside individuals into the mating
pool), share longer blocks of ancestral chromosomes IBD (Shifman and Darvasi
2001). An example of such an isolate is the Icelandic population, which derives
almost exclusively from a small number of migrants who arrived on the island
only several hundred years ago (Helgason et al. 2003).
Another factor contributing to the complexity of patterns of LD is the fact that
recombination events do not occur with the same likelihood across all parts of
the genome (Phillips et al. 2003; Reich et al. 2002). In addition to a general
pattern in which more telomeric regions of chromosomes are more likely to
recombine than centromeric regions, specific “hot spots” of recombination have
been identified that are spaced unevenly along chromosomes. This variation
across the genome in the likelihood of recombination results in the observation
that certain stretches in the genome (sometimes referred to as blocks) have
undergone relatively little recombination over the generations and therefore
show strong LD among SNPs in the region. Such regions of high LD can span
millions of bases, whereas other regions in the same population have recombined
more frequently, resulting in very short blocks of LD (e.g., <5,000 bp). It is
important to note that the observed haplotypes formed by the SNPs within a
given stretch of chromosome usually represent only a small proportion of all
possible haplotypes (for SNPs, the number of possible haplotypes=2n, where
n=the number of SNPs defining the haplotype). For this reason, such regions of
high LD are also called haplotype blocks (Daly et al. 2001; Gabriel et al. 2002;
Patil et al. 2001; Reich et al. 2001).
Population Stratification
Frequencies of specific alleles can vary to a large degree among different
populations. The frequency of the S allele of the 5HTTLPR, for example, is
approximately 40%–50% in European, approximately 70%–80% in East Asian,
and approximately 25% in African populations (Gelernter et al. 1999). Spurious
associations can thus be found if subjects for a genetic association study are
sampled from genetically different subpopulations (with different marker allele
frequencies) in different proportions in case and control participants, for
example. False-positive associations can also result if an outcome is more
prevalent in one subpopulation, perhaps because of different environmental
exposure, so that individuals from this subpopulation will be represented more
frequently in the case as opposed to the control group. Differences in allele
frequencies between comparison groups can thus result from differences in the
population structure of the sample alone, without any causal relationship to the
outcome of interest. This problem is called population stratification and is
exemplified by the hypothetical example of the “chopsticks gene” (Hamer and
Sirota 2000).
Several methods have been developed to address population stratification in
genetic association studies. Family-based approaches to genetic association
studies, such as the transmission disequilibrium test (TDT; Spielman et al. 1993)
and the haplotype–relative risk (HRR) method (Knapp et al. 1993), are robust to
population stratification. In the TDT, rather than comparing allele frequencies
between case and control subjects, genotypes are determined in probands
(individuals who serve as the starting point for the study) and their parents. To be
informative, at least one parent must be heterozygous at the marker of interest
(this is one of the disadvantages of the method in its original form: in some
cases, not all families can be used). The allele transmitted to the proband from
each parent is recorded, as well as the nontransmitted allele. Under the null
hypothesis of no linkage or association, the expected chance of each allele’s
transmission is 50%. Significant deviations from that chance provide evidence
for association (and linkage) between the trait and the marker. The HRR method
is similar, except that the frequency of the nontransmitted alleles is compared
with that of the transmitted alleles over a large number of families. Each family
thus provides its own control, and because the proband is always matched for the
population background of the parents, population stratification cannot arise.
Methods based on the TDT have been developed to allow transmission
disequilibrium testing in larger family groups. Such family-based association
tests offer the advantage of using more of the available genetic information from
each family (Horvath et al. 2001). The major disadvantage of the family-based
methods is that it is often impractical to gather families, especially in disorders
such as schizophrenia or substance use disorder, which are often associated with
familial estrangement, or in age-related disorders such as Alzheimer’s disease, in
which surviving relatives (especially parents) may not be available. An
additional problem with family-based association studies is that they generally
have less statistical power than case–control studies (Risch and Merikangas
1996).
To control for population stratification in case–control studies, several
methods have been suggested. One approach is to estimate, and then correct for,
the expected degree of stratification by typing a series of unlinked markers
across the genome (Devlin and Roeder 1999; Pritchard et al. 2000). The method
of genomic control (Devlin and Roeder 1999) derives an inflation factor, the so-
called λ value, by comparing observed with expected test statistics. This value is
then used to rescale association results. One disadvantage of this approach is that
λ, and hence inflation, is assumed to be constant across the genome.
Structured association (Rosenberg et al. 2002) involves the use of a clustering
algorithm to assign samples to subpopulations. Association statistics are
computed stratified by cluster.
Principal components analysis is another widely used method of detecting and
correcting for spurious associations resulting from population stratification
(Price et al. 2006). In this approach, the main axes of variation, also called
principal components, are plotted against each other to identify possible
population outliers or clusters. These main (principal) components are also
included as covariates in subsequent association analyses to correct for
population admixture.
How many SNPs? The presence of LD in the human genome allows the
investigator to evaluate a large extent of the common genetic variation with
selected markers. Estimates of the number of SNPs necessary to account for
most of the common sequence variation across the genome (e.g., to account for
SNPs with minor allele frequencies of 1% or greater) have varied over time, with
estimates ranging from as few as 10,000–100,000 to more than a million SNPs.
Thanks to the HapMap, 1,000 Genomes, and ENCyclopedia Of DNA Elements
(ENCODE) resequencing projects (Altshuler et al. 2010; www.hapmap.org), we
can efficiently cover the entire genome using SNP assays. Even though the cost
for next-generation sequencing has decreased dramatically in the last decade,
and the $1,000 genome was made available in January 2014 by Illumina, array-
based methods are still much more cost and time efficient, especially given the
enormous sample sizes (10,000 cases and greater) required to identify disease
loci in psychiatric traits. These massive genotyping and resequencing projects
have confirmed the segments of long LD in the genome and thus the possibility
of using tag SNPs (see discussion in “Linkage Disequilibrium” earlier in this
chapter) for each of these segments. Using the data from several hundred
thousand SNPs should be sufficient to cover most common variants in
Caucasians; more SNPs will be necessary in African populations with shorter
LD distances (for a review, see Hirschhorn and Daly 2005).
Certainly to date, genomewide association studies (GWAS) that use arrays
have been the most common approach to identifying disease associations across
the whole genome. However, next-generation sequencing methods are the most
comprehensive, able to interrogate all 3.2 billion bases of the human genome,
including rare and private mutations. This unbiased detection of changes at bp
resolution makes next-generation sequencing attractive (Precone et al. 2015).
Cost of sequencing depends on both the length of the genome and the depth of
sequencing (i.e., the coverage, defined as the number of times a genomic region
is read in the sequencing process). Next-generation sequencing typically allows
deeper sequencing (i.e., at a coverage of >10×).
Reduced cost for more focused approaches can be achieved by preselecting
(i.e., targeting) only parts of the genome. The most common targeted next-
generation sequencing method is whole-exome sequencing. The exome makes up
less than 2% of the genome but contains many known disease-causing rare
variants (Tennessen et al. 2012). This narrower focus makes whole-exome
sequencing a cost-effective targeted method with high coverage. The higher
coverage possible with whole-exome sequencing allows identification of rare
variants that currently would be too expensive with whole-genome sequencing.
The last few years have yielded a profusion of published studies in which
whole-exome sequencing was used, some of which apply to psychiatry; for
comprehensive reviews, the reader is referred to Kato (2015) and Schreiber et al.
(2013). Some of the most notable findings in psychiatric research from whole-
exome sequencing have been in autism spectrum disorder (Chapman et al. 2015;
Toma et al. 2014). It should be noted that in the future, communicating the
results of whole-genome sequencing to patients will almost certainly raise
ethical questions (Biesecker and Peay 2013), given that information beyond
genetic risk for the interrogated disease will be available.
A major drawback of whole-genome LD-based approaches to association
testing, such as those just outlined, is that most sequence variation in the genome
is rare, with minor allele frequencies too small to be detected with any power by
even very dense maps of SNPs. Thus, to the degree that the genetic
underpinnings of complex disease deviate from the “common disease, common
variant” hypothesis, whole-genome SNP scans will be inadequate to detect
associated genes (Zwick et al. 2000). This concern is not merely theoretical.
Thus, it is abundantly clear that in Mendelian diseases, such as cystic fibrosis, in
which variation at only one locus accounts for the disease, a multitude of very
rare sequence variants are causal in different families. Rare variation also clearly
contributes to complex disease—most notably, autism spectrum disorder (Levy
et al. 2011; Merikangas et al. 2015; Sanders et al. 2011). In all likelihood,
complex disorders will represent a mixture of contributions from rare and
common variants, so that methods appropriate for both types of variation will
need to be developed and implemented.
How many individuals? Genomewide associations require massive
correction for multiple testing so that genomewide significant P values less than
5×10–8 can be achieved. These necessarily low alpha levels, together with the
expected low odds ratios (ORs) associated with identified susceptibility variants,
require large sample sizes for adequate power. When one surveys genomewide
association discoveries over time, it can be seen that the larger the sample size,
the more genomewide association hits are found (see Figure 2 in Visscher et al.
2012; available at:
www.ncbi.nlm.nih.gov/pmc/articles/PMC3257326/figure/fig2).
Power (i.e., the probability of obtaining a true positive result) is determined by
sample size, allele frequency, effect size, and significance level. For example, to
detect the effect of a susceptibility allele that has a frequency of 20% and an OR
of 1.3 with a power of at least 80% and an even more liberal alpha level of 10–6,
more than 2,500 cases are necessary. If the allele is rarer (e.g., 10% carriers), at
least 6,000 cases would be required (Wang et al. 2005). Considering a
quantitative trait and setting the alpha level to 5×10–8, to detect a variant that
explains 0.2% of the variance with a power of at least 80%, more than 10,000
individuals would be needed (Visscher 2008). Often, these high sample sizes can
be reached only within consortia that combine samples from many different
studies and meta-analyze them together.
Although the initial years for GWAS in psychiatry were fraught with
disappointment, they brought the realization that only very large numbers can
yield reliable associations. This realization led to establishment of the
international Psychiatric Genomics Consortium (PGC; www.med.unc.edu/pgc)
in 2007 that leads the way on GWAS in psychiatry as a result of its very large
clinical cohorts (Sullivan 2010). The PGC involves more than 800 scientists
worldwide and currently has samples from more than 900,000 individuals.
The largest molecular study ever to focus on schizophrenia, carried out by the
PGC, was published in 2014 (Schizophrenia Working Group of the Psychiatric
Genomics Consortium 2014). This groundbreaking study analyzed 36,989 case
participants and 113,075 control participants and found 108 independent loci that
met genomewide significance (see Figure 3–3). Through this effort, the
explained variance of schizophrenia by genetic variation has increased from 3%
(in GWAS from 2009) to close to 20% (as of 2014). This study has truly changed
the view of genetics in psychiatry, cementing its role unquestionably in the
etiology of schizophrenia at least (Flint and Munafò 2014a, 2014b; Need and
Goldstein 2014). From the 108 loci identified, the authors estimated more than
600 genes to be involved. Notably, they highlighted the region encoding the
extended major histocompatibility complex (MHC). The MHC had already been
identified in several previous studies (Purcell et al. 2009) as playing an
important role in schizophrenia. Perhaps unsurprisingly, the locus corresponding
to the DRD2 gene also has been implicated. This gene encodes the D2 dopamine
receptor, a target of many antipsychotic medications. Other interesting genes
implicated in the 108 loci include calcium channel subunits and proteins
involved in synaptic plasticity. These findings tie in well (Hall et al. 2015) with
the findings of another recent GWAS that implicated calcium signaling (Ripke et
al. 2013a) as well as with the findings of studies on de novo mutations in
schizophrenia, which also identified synaptic networks (Fromer et al. 2014),
voltage-gated calcium ion channels, and the signaling complex formed by the
activity-regulated cytoskeleton-associated scaffold protein of the postsynaptic
density (Purcell et al. 2014).
Although it has been established that genetics plays an important role in the
development of depression (twin studies estimate a heritability of 0.4–0.5), no
GWAS to date have been able to conclusively find a consistent genetic
association (Dunn et al. 2015). It has been suggested that the reasons for this
limited success are either the highly heterogeneous nature of depression or the
failure to take the environmental contributions into account. The PGC has a
working group for depression, and in 2013 they published a “mega-analysis” of
GWAS for depression (Ripke et al. 2013b). The authors stated that although this
study was the largest case–control GWAS of depression ever to be carried out
(with 9,240 case participants and 9,519 control participants), it nonetheless had
insufficient power to detect effects seen in complex disorders, so no SNP
reached genomewide significance. The PGC now has GWAS data on more than
60,000 individuals.
The CHARGE (Cohorts for Heart and Aging Research in Genomic
Epidemiology) Consortium carried out a GWAS meta-analysis with a discovery
sample of 34,549 (Hek et al. 2013). In this study, the investigators examined
current depressive symptoms as opposed to lifetime diagnosis of depression.
Again, no SNP reached genomewide significance. The authors estimated that a
sample of more than 50,000 subjects would be necessary to gain sufficient
power. Indeed, when the discovery sample was combined with the replication
sample (N=51,258), one SNP reached genomewide significance. This association
was band 5q21.
The CONVERGE (China, Oxford, and Virginia Commonwealth University
Experimental Research on Genetic Epidemiology) Consortium aimed to address
the issue of heterogeneity by using a large, homogeneous cohort of patients
(CONVERGE Consortium 2015). In 2015, the consortium reported two loci that
reached genomewide significance: SIRT1 and LHPP. The cohort consisted of
5,303 Han Chinese women with recurrent depression. When the investigators
restricted cases to those with the more severe subtype, melancholia, the SIRT1
association became even stronger (CONVERGE Consortium 2015).
Whole-genome SNP association studies have been more successful in bipolar
disorder, and polymorphisms in the genes encoding ankyrin G (ANK3) and the
alpha 1C subunit of the L-type voltage-gated calcium channel (CACNA1C) have
emerged as new candidates for this disorder from data combining several large
samples (Ferreira et al. 2008; Kloiber et al. 2012; Schulze et al. 2008). The
CACNA1 gene family also may be of relevance in schizophrenia (Moskvina et
al. 2009). Interestingly, the independent samples (Baum et al. 2008a, 2008b;
Craddock et al. 2010; Sklar et al. 2008; Wellcome Trust Case Control
Consortium 2007) mostly yielded no genomewide significant associations or
could not be replicated in single association studies, showing the importance of
large sample sizes for these studies.
The ever-growing sets of GWAS data in psychiatric genetics are providing
new insights into the genetics of psychiatric disorders. Although promising,
these data raise several important issues:
Polygenic analysis of GWAS data. Over the past decade, there have
been many attempts to identify genes associated with psychiatric disorders using
SNP markers. Although GWAS have successfully identified some variants, it is
becoming clear that in complex disorders, genetic risk is determined both by
many common variants of small effect and by rare and de novo variants of large
effect. This dilemma again illustrates the inadequacy of the “common disease,
common variant” model and the limitations of GWAS. As a result, it has been
proposed that between these two extremes, there is a middle ground in which
moderately penetrant but somewhat rarer variants are being missed (Maher
2008). These missing variants might be unearthed if a single polygenic risk score
(PGRS) could be calculated. Polygenic analysis examines the extent to which
heritability is due to the additive effects of many common loci variants that
individually are of little effect (Dudbridge 2013). By using all SNPs to examine
the net effect on disease risk, a composite score can be calculated, thus providing
significant predictive ability. The PGRS is composed of many true but
subthreshold variants that GWAS initially might have missed as a result of being
underpowered to detect them at the conventional alpha level of P=5×10–8
(Gratten et al. 2014). PGRSs can be calculated with bioinformatics software
such as PRSice (http://prsice.info). Polygenic risk profiling from GWAS can
predict case–control status in independent samples. Recent research has
suggested that adjustment for LD can improve the predictive performance of
PGRSs (Vilhjálmsson et al. 2015).
This new polygenic analysis approach addresses the genetic complexity of
psychiatric disorders because their underlying genetic architecture is highly
polygenic. In the context of a particular disease, the term genetic architecture
refers to “the number, frequency, and effect sizes of genetic risk alleles and the
way in which they combine together” (Wray and Visscher 2010, p. 14). The
PGRS also can be analyzed in relation to the clinical phenotype and against
quantitative traits related to the disorder.
The recent polygenic analysis study in schizophrenia (Schizophrenia Working
Group of the Psychiatric Genomics Consortium 2014) validated the polygenic
analysis approach. PGRSs can predict schizophrenia case–control status, albeit
with varying sensitivity and specificity, possibly because of differing sampling
strategies (Meier et al. 2016). In contrast to twin and family studies, the
polygenic heritability approach provides information on the frequency of the
alleles underlying the phenotype.
By supplementing PGRSs with family history, risk prediction can be
significantly improved. This strategy has yet to be used in the field of psychiatry
but has been successful in improving the predictive performance of PGRSs in
other disorders (Chatterjee et al. 2013).
In schizophrenia at least, PGRSs may improve future clinical decision making
and may even inform prevention strategies. Evaluation of the clinical efficacy of
a PGRS can be carried out via the receiver operating characteristic curve. The
area under this curve expresses the accuracy with which high- and low-risk
groups can be distinguished (Janssens et al. 2007). PGRSs may be able to
personalize genomics in psychiatry in the future (Smoller 2014).
Cross-Disorder Studies
The traditional view that psychiatric disorders are distinct in nature is being
challenged by evidence emerging from studies looking at the genetic landscape
(Cross-Disorder Group of the Psychiatric Genomics Consortium 2013). Some
disorders clearly share genetic risks. The genetic architecture correlation
calculated with common SNPs was r=0.68 for bipolar disorder and
schizophrenia, r=0.47 for bipolar disorder and depression, and r=0.43 for
schizophrenia and depression (Cross-Disorder Group of the Psychiatric
Genomics Consortium 2013).
An attempt has been made to identify the underlying molecular source of the
cross-disorder overlap. The Cross-Disorder Group of the Psychiatric Genomics
Consortium (2013) examined the five PGC disorders: schizophrenia, depression,
bipolar disorder, autism spectrum disorder, and ADHD (S.H. Lee et al. 2013).
They looked for SNPs in a GWAS of samples from 33,332 case participants and
27,888 control participants. Findings from these cross-disorder studies seem to
confirm the biological overlap of psychiatric traits. Four SNPs with genomewide
significance on cross-disorder risk were found: AS3MT, ITIH3, and the L-type
voltage-gated calcium channel subunits CACNB2 and CACNA1C. These
findings again implicate calcium channels in psychopathology.
Conclusion
Taken together, epidemiological, cytogenetic, linkage, and association studies in
psychiatric genetics to date paint a picture of highly complex genetic influences
on psychiatric disorders. As Kendler (2005) pointed out more than a decade ago,
the phrase “a gene for...” will not apply to psychiatric genetics. As Kendler
(2005, p. 1243) went on to note: “the impact of individual genes on risk for
psychiatric illness is small, often nonspecific, and embedded in a complex causal
pathway.” We suggest that the field adopt strategies that are tailored to the most
likely disease models. Three main strategies for addressing this issue are
proposed.
First, we may need to reconsider how we define cases or the phenotype of
interest. Our current classification schemes are not likely directly reflective of
the underlying biology—and thus the genetic determinants—of psychiatric
disease. The currently used diagnostic algorithms (DSM-5 [American
Psychiatric Association 2013] and ICD-10 [World Health Organization 1992])
group diagnoses by symptoms and clinical course, which may not reflect a
common biology but rather a final common pathway of several different
pathophysiological disturbances. That recognition has led some to propose the
use of intermediate phenotypes, including neurophysiological, biochemical,
cognitive, and endocrine measures (Gottesman and Gould 2003; Hasler et al.
2004; Insel 2014), in psychiatric genetic studies in order to create biologically
more homogeneous subgroups of patients and thus to increase the power to
detect case–control associations. Another important consideration is that some
symptoms are common to several different diagnoses, and the genetic
susceptibility to develop these symptoms may be common across disorders
(Doherty and Owen 2014). In fact, evidence indicates that the major psychiatric
disorders may share susceptibility genes (Cross-Disorder Group of the
Psychiatric Genomics Consortium 2013).
Second, environmental measures should be included more consistently in
genetic studies, including whole-genome association studies. Epidemiological
(Kendler 1995) as well as molecular genetic studies have now repeatedly shown
the importance of G×E interactions in psychiatric disease (Klengel and Binder
2015). Genetic effects may be obscured by unmeasured environmental effects, so
that different environmental exposures in replication samples may be one source
of nonreplication of genetic association.
Third, one should not forget that SNPs are simply the most common and
convenient type of genetic variant, not the only type. Other types of variation,
such as CNVs, are equally important (Zarrei et al. 2015; Sebat et al. 2004).
Thanks to ever-advancing technologies, genetics and genomics are entering a
new and exciting era. Progress will no doubt advance rapidly, bringing with it
the potential to redefine psychiatry.
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11701635
CHAPTER 4
Psychoneuroendocrinology
Roxanne Keynejad, M.A., M.B.B.S., M.R.C.P.
Ania Korszun, Ph.D., M.D., F.R.C.Psych.
Carmine M. Pariante, Ph.D., M.D., F.R.C.Psych.
The HPA axis regulates peripheral body functions, including metabolism and
immune response, as well as brain function. For example, glucocorticoids have
well-established effects on carbohydrate metabolism, modulating pancreatic
insulin release and hepatic and nonhepatic responses to insulin. Glucocorticoids
have a wide range of enhancing and suppressive actions on both innate and
adaptive immune responses, including upregulation of phagocytosis by
neutrophils and macrophages; suppression of cytokine release by type 1 T helper
(Th1) cells; and selective enhancement of type 2 T helper (Th2) cells
(Franchimont 2004). Centrally, glucocorticoids regulate neuronal survival,
neurogenesis, the acquisition of new memories, and the emotional appraisal of
events, as well as the sizes of complex anatomical structures such as the
hippocampus (Herbert et al. 2006).
Stressful stimuli activate all levels of the HPA axis, causing increases in CRH,
ACTH, and cortisol secretion. However, these increases are superimposed on an
intrinsic circadian pattern of HPA activity driven by the suprachiasmatic nucleus.
HPA axis hormone secretion is pulsatile in nature, with the trough of integrated
secretion occurring in the evening and early nighttime and the peak of secretion
occurring just before awakening; active secretion continues throughout the
morning and early afternoon. Under normal conditions, the pulsatile secretion of
glucocorticoids causes continuous mineralocorticoid receptor (MR) activation
and phasic and short-acting glucocorticoid receptor (GR) activation after each
endogenous pulse (Conway-Campbell et al. 2007). The synergy of MR and GR
activation is key to mediating glucocorticoid feedback inhibition. The pulsatile
or “ultradian” pattern of HPA axis hormone secretion is essential for optimal
transcription as well as for maintenance of neuroendocrine and behavioral
responsiveness to stress. Recent research suggests that chronic (e.g., obstructive
sleep apnea) and acute disease states (e.g., cardiac surgery) are associated with
disruptions of the dynamic changes in adrenocortical steroid-producing cells that
are required to maintain the normal ultradian pattern (Spiga and Lightman 2015).
Psychosis
HPA axis abnormalities likewise have been demonstrated in patients with
psychosis. Studying patients who are experiencing their first psychotic episode
has been considered the preferred approach to avoid confounding by illness and
treatment duration. A recent systematic review (Borges et al. 2013) reported
evidence of HPA axis hyperactivity in first-episode psychosis, with higher
baseline cortisol levels and blunted cortisol awakening responses in patients
compared with control participants. Studies of patients at ultrahigh risk of
developing psychosis have reported associations between higher cortisol levels
and prodromal and psychotic symptoms (Corcoran et al. 2012; Mittal and
Walker 2011), and pituitary gland enlargement at baseline has been shown to
predict future psychotic illness (Garner et al. 2005). The association of HPA axis
abnormalities with psychosis-like symptoms has also been found in patients with
schizotypal personality disorder (Mittal et al. 2007) and in healthy participants
scoring high on measures of schizotypal traits (Hori et al. 2011). Elevated ACTH
responses to stress (Brunelin et al. 2008) and raised cortisol at baseline and
following stress (Collip et al. 2011) have been demonstrated in healthy relatives
of patients with psychosis. Pituitary gland enlargement also has been reported in
first-degree relatives of people with schizophrenia compared with healthy
controls (Mondelli et al. 2008). Borges et al. (2013) suggested that these studies
point to the presence of a familial, potentially genetic, vulnerability to HPA axis
hyperactivity in individuals who develop schizophrenia. It is noteworthy that
studies in two independent samples have identified enlarged pituitary gland
volumes—one study in the context of psychotic depression, psychotic mania,
and schizophrenia (Pariante et al. 2004) and the other study in the context of the
pre-psychosis prodromal phase (Garner et al. 2005). A possible mechanism for
the pituitary gland enlargement seen in these studies may be ineffective negative
feedback by circulating glucocorticoid hormones, leading to proliferation and
expansion of the pituitary cells that produce ACTH.
Posttraumatic Stress Disorder
Although there is evidence that HPA axis abnormalities are present in PTSD,
methodological difficulties initially made some of the literature challenging to
interpret, with evidence of both increased and decreased HPA axis activity based
on comorbidity with depression, type of trauma, and other sociodemographic
features of the sample. For example, in a study of combat veterans with a
diagnosis of PTSD, both low cortisol and enhanced cortisol suppression in
response to dexamethasone were reported, irrespective of comorbid MDD
(Yehuda 2002). However, that sample included only male combat veterans,
whereas in community samples, women are more likely to experience PTSD
(Frans et al. 2005; Kessler et al. 1995). Furthermore, studies of PTSD in veteran
populations are subject to significant confounding with current and past alcohol
and substance use disorders. Additional evidence of elevated CSF CRH levels
and blunted ACTH responses to CRH suggests that pituitary CRH receptors are
downregulated in PTSD (Bremner et al. 1997). A study using serial CSF
sampling over a period of 6 hours demonstrated elevated CRH despite normal
free urinary cortisol in war veterans diagnosed with PTSD compared with
veterans without PTSD and healthy controls (Baker et al. 1999). PTSD studies
generally report comorbid depression in participants, and depression studies
often fail to measure and report trauma histories. As a result, documented
depression confounds much of literature on the HPA axis in PTSD, and
undocumented trauma and abuse may confound some of the literature on the
HPA axis in depression.
These problems were avoided by Heim et al. (2001) in their studies on
childhood abuse and MDD, which examined multiple HPA axis challenges in the
same participants. The authors found an effect of early abuse (with comorbid
PTSD in 11 of 13 participants) and MDD on stress reactivity, documenting both
increased ACTH and increased cortisol response to the stressor in depressed
patients with a history of childhood abuse compared with either healthy controls
or depressed patients without a history of childhood abuse. In this same cohort,
patients with MDD showed a blunted response to CRH challenge irrespective of
the presence or absence of an abuse history, whereas patients with a history of
childhood abuse who were not depressed showed a heightened response to CRH
challenge. Thus, childhood abuse produced an increased pituitary response with
adaptive adrenal compensation, a change compatible with low or normal basal
cortisol levels. Furthermore, lower cortisol levels and greater CRH suppression
in the low-dose dexamethasone suppression test were found in women with a
history of abuse who developed depression but not in those without depression
(Newport et al. 2004), irrespective of PTSD features.
A meta-analysis of 37 studies of basal cortisol levels in adults with current
PTSD compared with adults without psychiatric disorders (Meewisse et al.
2007) examined data from 828 patients and 800 control participants. Although
the authors found no significant differences in basal cortisol between the two
groups, significantly lower serum cortisol was observed in studies that included
only female participants, in studies that investigated physical or sexual abuse,
and in studies that used afternoon cortisol sampling. A second meta-analysis of
47 studies comparing patients with PTSD, patients with PTSD and comorbid
MDD, and control subjects with and without trauma exposure (Morris et al.
2012) found that cortisol levels were lower for the PTSD and the PTSD + MDD
groups than for the no-trauma control group (which did not differ significantly
from the trauma-exposed control group). Cortisol levels in response to
dexamethasone suppression testing were lower in the PTSD group, the PTSD +
MDD group, and the trauma-exposed control group relative to the no-trauma
control group, with effect sizes moderated by age, time since traumatic event,
and age at traumatic experience. The authors proposed that whereas lower daily
cortisol may represent a marker of PTSD, increased HPA axis response to
dexamethasone suppression testing may represent a marker of trauma exposure
more generally.
Studies demonstrating increased GR binding and function in patients with
PTSD have given rise to the suggestion that hypocortisolism may result from
hypersensitivity of negative feedback inhibition (Yehuda 2006). Indeed,
prospective studies have found evidence that the presence of hypocortisolism
prior to traumatic experiences may predict vulnerability to PTSD (Yehuda et al.
1998), prompting the hypothesis that low baseline cortisol could represent a risk
factor for abnormal stress response (Sherin and Nemeroff 2011). Furthermore,
some studies report that PTSD can be averted by hydrocortisone treatment
following trauma (de Quervain 2008), while others suggest that treatment aimed
at replicating the normal cortisol secretion pattern is effective (Aerni et al. 2004).
A possible explanation for hypocortisolism in PTSD is that cortisol may interfere
with traumatic memory retrieval (de Quervain and Margraf 2008). A recent
intriguing study of intergenerational transmission of susceptibility to PTSD
reported differential effects of paternal and maternal PTSD on the offspring of
Holocaust survivors (Yehuda et al. 2014). Offspring with paternal PTSD but no
maternal PTSD showed higher methylation of the exon 1F promoter of the
glucocorticoid receptor (GR-1F) gene (NR3C1), whereas offspring with both
maternal and paternal PTSD showed lower methylation.
Hypothalamic-Pituitary-Thyroid Axis
Despite the well-recognized importance of the hypothalamic-pituitary-thyroid
(HPT) axis in clinical psychiatry, it has been far less researched in recent times
than the HPA axis. In this important hormonal system, hypothalamic secretion of
thyrotropin-releasing hormone (TRH) stimulates the anterior pituitary gland to
release thyroid-stimulating hormone (TSH). TSH in turn stimulates thyroid
secretion of triiodothyronine (T3) and thyroxine (T4), which exert negative
feedback on the pituitary gland and hypothalamus. There is a well-known
association between hypothyroidism and mood disorders, including depression
and rapid-cycling bipolar disorder, and between hyperthyroidism and symptoms
of anxiety and dysphoria (Hendrick et al. 1998). Studies of depressed patients
have found evidence of changes in the TSH response to TRH, higher levels of
antithyroid antibodies, and elevated concentrations of TRH in the CSF
(Musselman and Nemeroff 1996). However, despite these promising findings, a
double-blind randomized, placebo-controlled trial of T3 augmentation of
sertraline treatment in patients with MDD found no added benefit from
combining T3 with sertraline (Garlow et al. 2012).
Studies examining the relationship between HPT axis abnormalities and PTSD
have been limited, but there is some evidence of thyroid abnormalities in combat
veterans. Elevated T3 and T4 were reported in Vietnam veterans diagnosed with
PTSD (Prange 1999), whereas in World War II veterans with more chronic
PTSD diagnoses, T3 was elevated but T4 levels were normal (Wang and Mason
1999).
Prolactin
Prolactin is secreted by the anterior pituitary gland in 14 pulses over 24 hours in
a circadian pattern consisting of increased pulsation at the time of sleep onset,
with the peak level occurring halfway through the sleep period and the trough
level occurring on awakening. Prolactin trough levels are higher during the luteal
phase of the menstrual cycle. Dopamine acts at anterior pituitary D2 receptors to
inhibit prolactin secretion, whereas serotonin exerts a stimulatory effect. Studies
using serotonin-challenge agents to examine basal prolactin in patients with
depression have yielded mixed findings, likely attributable to issues such as
methodological difficulties, the complexity of the serotonin system, and the
multifactorial nature of depression itself (Nicholas et al. 1998). A study in
antipsychotic-naïve adults identified hyperprolactinemia (which is frequently
attributed to iatrogenic causes) in more than 30% of individuals diagnosed as
being at risk for psychosis (n=43) and more than 20% of those experiencing a
first psychotic episode (n=26) (Aston et al. 2010).
Hypothalamic-Pituitary-Gonadal Axis
In contrast to the HPT and HPS axes, the hypothalamic-pituitary-gonadal (HPG)
axis has been far more widely investigated in relation to mental health. Secretion
of the principal gonadal steroids, estrogen and progesterone, is governed by
cyclic changes in ovarian follicular and corpus luteum development over the
course of the menstrual cycle. Critical to the proper functioning and timing of
the monthly hormonal cycle is the pulsatile secretion of gonadotropin-releasing
hormone (GnRH). GnRH secretion from the hypothalamus drives the secretion
of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from
pituitary gonadotropes.
The pulsatile secretion of GnRH is driven by a pulse generator in the arcuate
nucleus of the hypothalamus. This pulsatile pattern is critical for the control of
serum LH, FSH, and ovulation. LH secretory pulses in the peripheral circulation
are used as the marker of GnRH secretory pulses. In humans, the follicular phase
of the menstrual cycle is characterized by LH pulses of relatively constant
amplitude every 1–2 hours (Reame et al. 1984).
It has been established that an increased incidence of depression in women
(Weissman and Klerman 1977) extends from adolescence until menopause
(Kessler et al. 1993), suggesting a potential role for ovarian steroids in the
etiology of depressive disorders. This hypothesis is supported by evidence that in
women with a history of depression, times of rapidly changing gonadal steroid
concentrations, such as those occurring premenstrually or postpartum, constitute
periods of particular vulnerability to depressive symptoms. Several studies have
shown that a history of depression increases the risk of both postpartum “blues”
and postpartum MDD (O’Hara 1986; O’Hara et al. 1991) and that premenstrual
hormonal changes may affect mood (Halbreich et al. 1984). Other studies found
a relationship between elevated estrogen and testosterone levels and the rising
incidence of depression in girls during adolescence (Angold et al. 1999).
Premenstrual syndrome (PMS) is one of the best-studied depressive disorders
in terms of the effects of ovarian steroids on mood. Studies of follicular, mid-
luteal, and late-luteal phases of the menstrual cycle found no significant
differences between healthy controls and women diagnosed with PMS (Reame et
al. 1984). The hypothesis that PMS symptoms are related to delayed effects of
progesterone on mood prompted several studies of RU486, a progesterone
antagonist. Schmidt et al. (1991) found no reduction in mood symptoms
following RU486 creation of an artificial follicular phase during the second half
of the menstrual cycle. Furthermore, human chorionic gonadotropin did not
reduce mood symptoms; progesterone blockade caused early menses without
preventing depression. A subsequent 6-month randomized double-blind,
placebo-controlled crossover study also showed no benefit of RU486 on
depressive symptoms (Chan et al. 1994). Rubinow and Schmidt (1989) proposed
that PMS is a cyclical mood disorder “entrained” to the menstrual cycle, rather
than a disorder caused by changes in ovarian steroids.
Because of the documented increased incidence of depression at critical
hormonal transition phases (e.g., postpartum, perimenopause), much speculation
has focused on estrogen’s role as a precipitant. Two epidemiological cohort
studies (Cohen et al. 2006; Freeman et al. 2006) also identified an increased
incidence of depressive symptoms and MDD during the menopausal transition.
Both high and low estrogen levels were associated with depression (Freeman et
al. 2004, 2006), suggesting that estrogen levels may drive depression, and
women who showed rapid changes in estrogen (from high to low levels and vice
versa) tended to develop depressive symptoms during the perimenopause
transition. Schmidt and Rubinow (2009) proposed that in some women,
menopausal changes in estrogen secretion may trigger CNS effects that
predispose to depression. These authors pointed to evidence that perimenopausal
depressive episodes tend to occur during the late menopausal transition
(Steinberg et al. 2008), a phase of estradiol withdrawal (Santoro et al. 1996).
Furthermore, double-blind, placebo-controlled trials of estradiol therapy in
perimenopausal women diagnosed with depression have shown significant
improvement in symptoms after 3 weeks of treatment (Schmidt et al. 2000;
Soares et al. 2001). Finally, a randomized double-blind, placebo-controlled trial
of the effect of estradiol withdrawal on mood in women with a history of
perimenopausal depression documented a recurrence of depressive symptoms
during blinded hormone withdrawal (Schmidt et al. 2015).
Another time of increased vulnerability to depression in women is pregnancy
and the postpartum period. Although it is known that this period coincides with a
sudden drop in progesterone and estradiol levels, there is limited evidence on
how this drop relates to depression onset. A recent systematic review of risk
factors for antenatal and postnatal depression identified a wide range of
biological, psychological, and social factors in both high- and low-income
countries (Howard et al. 2014). Studies of both animals and humans provide
evidence of a subtype of depression associated with 1) sensitivity to reproductive
hormone changes; 2) higher rates of depression premenstrually, postnatally, and
perimenopausally (Craig 2013; Schiller et al. 2015); and 3) a personal or family
history of postnatal depression (Cooper and Murray 1995; Forty et al. 2006).
Although some studies have reported elevated CRH (Yim et al. 2009),
glucocorticoid, and CRH receptor polymorphisms (Engineer et al. 2013) and
raised leptin levels (Skalkidou et al. 2009) as risk factors during pregnancy, the
relative paucity of literature addressing this clinically significant area
underscores the need for replication studies and further research.
In their review of perinatal bipolar disorder, affective psychosis, and
schizophrenia, Jones et al. (2014) concluded that most of the evidence
supporting a role for hormones in these disorders has been circumstantial (Bloch
et al. 2003). The reviewers suggested that rather than indicating abnormal
hormone levels, postpartum psychotic disorders may indicate abnormal
responses to normal perinatal hormone changes (Bloch et al. 2000).
Furthermore, Jones et al. (2014) pointed to evidence of a dysregulated immune–
neuroendocrine set point in postpartum psychosis, including monocyte and
macrophage overactivity (Bergink et al. 2013; Weigelt et al. 2013), a finding that
requires further investigation.
Effects of the Hypothalamic-Pituitary-
Adrenal Axis on the Hypothalamic-Pituitary-
Gonadal Axis
Stress has long been known to inhibit the HPG axis, and there is a well-
established association between infertility and high population density. Shortly
after the isolation and sequencing of the CRH gene, it was demonstrated in rats
that CRH inhibited LH secretion (Rivier and Vale 1984) and GnRH secretion
(Petraglia et al. 1987), and further primate studies showed inhibition of LH
secretion by injection of CRH (Olster and Ferin 1987).
Studies in ewes found that LH secretory amplitude was inhibited by stress,
that the effects of stress were reversed by metyrapone inhibition of cortisol
synthesis, and that infusion of stress levels of cortisol could produce inhibition
of LH pulse amplitude but not frequency (Breen et al. 2004; Debus et al. 2002).
These data suggest that cortisol, in addition to central CRH, may play a role in
LH disruption.
Human studies have linked HPG axis abnormalities to HPA axis activation in
anorexia nervosa, exercise-induced amenorrhea, and hypothalamic amenorrhea.
In all three syndromes, hypercortisolemia has been observed, indicating
overactivity of the HPA axis (Berga et al. 1989; Casanueva et al. 1987; Hohtari
et al. 1988; Loucks et al. 1989; Suh et al. 1988; Villanueva et al. 1986). In all
three conditions, exogenous CRH challenge elicits diminished ACTH or cortisol
responses, suggesting that high baseline cortisol exerts negative feedback on
hormonal effects of CRH (Berger et al. 1983; Biller et al. 1990; Gold et al. 1986;
Hohtari et al. 1991). In anorexia nervosa, the hormonal abnormalities in the HPA
and HPG axes are secondary to the weight loss. Weight restriction and low body
weight are also observed in exercise-induced amenorrhea, and low body weight
has been reported in hypothalamic amenorrhea. Even relatively mild degrees of
weight loss in normal-weight or obese patients can lead to disturbances in both
of these axes, as manifested by resistance to dexamethasone and by disturbances
in menstrual cycle regularity or amenorrhea (Berger et al. 1983; Edelstein et al.
1983; Pirke et al. 1985). In anorexia nervosa, LH secretory patterns may revert
to prepubertal levels of low nonpulsatile secretion or to a pubertal pattern of
entrainment of LH secretion to the sleep cycle. Studies by Reame et al. (1985) in
women with hypothalamic amenorrhea demonstrated that LH secretion during
the follicular phase was slowed to the rate normally observed during the luteal
phase.
Conclusion
In this chapter, we have sought to provide an overview of the established
findings and the most promising developments in the dynamic field of
psychoneuroendocrinology. Following a resurgence of research in this area, the
interrelationships among early stressful life events, HPA axis dysregulation,
altered immune function, vulnerability to psychiatric disorders, and inadequate
response to treatment have become increasingly well characterized, although
many findings remain correlational in nature. The growing clinical recognition
of the burden of postpartum psychopathology and the associations between
reproductive hormone changes and psychiatric disorders has provided further
impetus for academic progress in this area. Stressful life events are strongly
associated with depression, psychosis, and PTSD, but the relative contributions
of genetic, developmental, and environmental factors to an individual’s
vulnerability have yet to be fully understood.
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11377437
CHAPTER 5
Brain–Immune System
Interactions
Evidence suggests that depression, like chronic stress, may impair T cell
function in ways that are relevant to disease vulnerability. For example, one
study reported that patients with major depressive disorder have a marked
decrease in the ability to generate lymphocytes that respond to the herpes zoster
virus (Irwin et al. 1998). Also consistent with impaired T cell function in
depression is the observation that depressed patients, especially those with
melancholia, demonstrate impaired cell-mediated immunity (CMI), as measured
by the delayed-type hypersensitivity response (Hickie et al. 1993, 1995).
A growing database suggests that depression in both medically healthy and
medically ill patients is associated with increased immunopathological
proinflammatory responses (Andrei et al. 2007; Kim et al. 2007; Lespérance et
al. 2004; Maes 1999; Miller and Raison 2016; Musselman et al. 2001b; Raison
et al. 2006). Findings consistent with inflammatory activation in depression
include increased plasma and cerebrospinal fluid (CSF) concentrations of
inflammatory cytokines, increased in vitro production of proinflammatory
cytokines from stimulated peripheral blood mononuclear cells, increased acute-
phase proteins (and decreased negative acute-phase proteins), increased
chemokines and adhesion molecules, and increased production of prostaglandins
(Kim et al. 2007; Maes 1999; Raison et al. 2006).
On the basis of meta-analyses, increases in peripheral blood IL-6 and C-
reactive protein are two of the most reliable inflammatory biomarkers associated
with depression (Zorrilla et al. 2001). Indeed, careful studies examining IL-6
across the circadian cycle have found that in comparison with control subjects,
depressed patients show a reverse circadian pattern of IL-6, with markedly
elevated levels of this cytokine during the morning hours (Alesci et al. 2005). Of
interest, given the role of IL-6 and C-reactive protein in predicting disease
outcome in both cardiovascular disorders and diabetes (Ridker et al. 2000a,
2000b), as well as data indicating that inflammation may play a role in cancer
(Aggarwal et al. 2006), the relationship between depression and activation of the
proinflammatory response may provide a mechanism that explains the negative
impact of depression on a number of illnesses (Evans et al. 2005). Moreover,
immune activation in major depressive disorder may be involved in several of
the pathophysiological changes that are common in the context of depression,
including bone loss, insulin resistance, cachexia, increased body temperature,
and hippocampal volume loss (Raison et al. 2006).
It is important to recognize that in the absence of chronic infection, cancer, or
immunodeficiency disease, modest elevations in anti-inflammatory cytokines
may exert salubrious or health-protective effects by mediating the resolution of
inflammatory processes and preventing or antagonizing the damaging effects of
prolonged inflammation. In contrast to the attention focused on proinflammatory
cytokines, considerably less attention has been accorded to the potential role of
anti-inflammatory/immunomodulatory cytokines such as IL-10 in depression. In
healthy individuals, there is a regulated balance between pro- and anti-
inflammatory cytokines: for example, IL-6 mediates the early phase of the
inflammatory process and induces the release of IL-10, which exerts
immunoregulatory effects and resolves inflammation (Daftarian et al. 1996;
Fang et al. 2008; Ogawa et al. 2008). The net result of such regulatory
relationships is that the immune system can quickly respond to a challenge and
subsequently return to homeostasis once the challenge has ended. Short-term
inflammatory reactions in response to immune challenges such as wounding or
infection are adaptive and essential for survival, but chronic inflammation is
harmful. Interestingly, depression is associated with numerous disorders that are
thought to involve chronic inflammation (Dantzer et al. 2008; Evans et al. 2005;
Kiecolt-Glaser and Glaser 2002). These include cardiovascular disease (Frasure-
Smith et al. 2007; McCaffery et al. 2006; Musselman and Nemeroff 2000;
Whooley et al. 2007), obesity (Onyike et al. 2003), rheumatoid arthritis (Bruce
2008; Zautra et al. 2004), multiple sclerosis (Triantafyllou et al. 2008), and
cancer (Currier and Nemeroff 2014).
A number of potential factors may contribute to increased proinflammatory
responses in depressed patients. One factor that has received special attention is
body mass index (BMI). BMI has been reliably correlated with peripheral
markers of inflammation, including IL-6, in part related to the capacity of
adipocytes to produce inflammatory cytokines (Schäffler et al. 2007). Of
relevance in this regard, an analysis of data from the Third National Health and
Nutrition Examination Survey revealed that after adjustment for a multitude of
variables, including BMI, there was a strong association between major
depressive disorder and elevated levels of C-reactive protein in men but not in
women (Ford and Erlinger 2004). Early life stress is another factor that may be
involved. For example, males with current major depressive disorder and a
history of high early life stress exhibited significantly greater increases in IL-6
and nuclear factor (NF)–κB DNA binding following a psychosocial stressor
compared with nondepressed male control subjects (Pace et al. 2006).
It has been suggested that an important and relatively underappreciated
mechanism for the link between depression and inflammatory disorders may be
disruption of the immunoregulatory balance between pro- and anti-inflammatory
cytokines (Dhabhar et al. 2009). The cytokine balance can be tilted toward a
proinflammatory milieu because of elevated concentrations of proinflammatory
cytokines such as IL-6, lowered concentrations of anti-
inflammatory/immunomodulatory cytokines such as IL-10, or a combination of
the two. Therefore, in addition to the absolute concentrations of these cytokines,
the relative concentrations of pro- and anti-inflammatory cytokines can provide a
useful index of the net inflammatory milieu and of immune dysregulation. In
keeping with this hypothesis, it has been demonstrated that in comparison with
control subjects, depressed subjects manifest significantly lower serum IL-10
concentrations, nonsignificantly higher IL-6 concentrations, and significantly
higher IL-6 to IL-10 ratios (Dhabhar et al. 2009). Furthermore, higher levels of
depressive symptoms were significantly related to lower IL-10 concentrations
and tended to be related to higher IL-6 to IL-10 ratios but were not significantly
related to IL-6 concentrations across the total sample of participants (Dhabhar et
al. 2009). Moreover, control subjects showed a strong positive correlation
between serum IL-6 and IL-10 concentrations, which was completely absent
(near-zero effect size) in depressed subjects. Although depressed subjects had
significantly higher BMIs than did the controls, covarying for BMI (or
controlling for BMI) did not alter this finding (Dhabhar et al. 2009).
Given the anti-inflammatory properties of glucocorticoids (Rhen and
Cidlowski 2005), it might be expected that patients with depression who have
decreased glucocorticoid sensitivity, as manifested by nonsuppression of cortisol
on the dexamethasone suppression test (DST), would be especially likely to
show signs of immune activation. Some evidence suggests that this is indeed the
case. Compared with patients with depression who have normal in vivo
glucocorticoid sensitivity, patients who are DST nonsuppressors show increased
plasma concentrations of the acute-phase reactant α1-glycoprotein, as well as
increased in vitro mitogen-stimulated IL-6 production (Sluzewska 1999).
Glucocorticoid resistance, as assessed by the DST, has been associated with poor
response to antidepressant treatment (Holsboer 2000). Of interest in light of the
relationship between DST nonsuppression and increased inflammatory activity,
study findings suggest that patients with treatment-resistant depression are more
likely than patients whose depression is responsive to treatment to show
evidence of increased inflammatory activity, including increased plasma
concentrations of acute-phase proteins, IL-6, and the soluble receptor for IL-6
(sIL-6r), which synergistically enhances IL-6 activity (Raison et al. 2006;
Sluzewska 1999). Moreover, depressed patients who show reductions in
unstimulated tumor necrosis factor alpha (TNF-α) during antidepressant
treatment are more likely to respond than those whose TNF-α remains elevated
(Lanquillon et al. 2000).
Mediating Pathways
Underlying the ability of the central nervous system (CNS) to affect the immune
system is a host of connections between autonomic nervous system (ANS) and
neuroendocrine pathways and immune system elements. Immune cells are able
to directly respond to brain outflow pathways via receptors for small-molecule
neurotransmitters, adrenal and gonadal steroids, hypothalamic-releasing factors,
and other neuropeptides (Raison et al. 2002). Specific receptor densities vary
among immune cell types, and these variations correlate with cell sensitivity to a
given ligand.
Hypothalamic-Pituitary-Adrenal Axis
In concert with the ANS, the HPA axis serves as a central component of the
mammalian stress response system. Although glucocorticoids, which represent
the final product of HPA axis activation, have long been viewed as
immunosuppressive because of their well-documented ability to suppress
inflammation (largely through protein–protein interactions between the
glucocorticoid receptor and NF-κB) (Rhen and Cidlowski 2005), it is
increasingly recognized that HPA axis effects on immunity are complex
(Dhabhar 2009a, 2009b, 2014; Dhabhar et al. 1995). This complexity arises from
the fact that HPA axis effects on the immune system depend on numerous
factors, including the immune compartment that is being assessed, the element
of the HPA axis being evaluated (i.e., CRH vs. cortisol), and the duration and
timing relative to the immune response and stressor application. Thus, for
example, glucocorticoids are known to mediate immune cell redistribution in the
body (Dhabhar et al. 1996, 2012) and to enhance CMI in vivo (Dhabhar and
McEwen 1996) through their effects on lymphocyte trafficking (Dhabhar 1998,
2009_, 2014). Moreover, different HPA axis elements demonstrate divergent
immune system effects. For example, the end result of CRH-induced HPA axis
activation is proinflammatory cytokine suppression, yet studies demonstrate that
the direct effect of CRH on proinflammatory cytokine production may be
stimulatory (Labeur et al. 1995; Paez Pereda et al. 1995).
Finally, the effect of glucocorticoids on naturalistic measures of immunity,
such as cutaneous CMI, depends on both the concentration and the duration of
glucocorticoids within the immune compartment under consideration. Thus, low
doses of glucocorticoids applied for brief periods have been shown in rodents to
stimulate CMI, whereas higher (or more protracted) glucocorticoid exposure
suppresses CMI (Dhabhar 2009a, 2009b, 2014; Dhabhar and McEwen 1999).
CRH applied within the CNS suppresses several measures of immunity,
including splenic NKCA, mitogen-stimulated lymphocyte proliferation, and in
vivo and in vitro antibody formation, as well as T cell responses to T cell
receptor antibody (Caroleo et al. 1993; Irwin et al. 1988; Labeur et al. 1995;
Rassnick et al. 1994). CRH-overproducing mice demonstrate a profound
decrease in the number of B cells and severely diminished primary and memory
antibody responses (Stenzel-Poore et al. 1994). These immunosuppressive
effects appear to be mediated by stress response outflow pathways activated by
CRH, given that blockade of the sympathetic nervous system abolishes CRH
effects on NKCA and adrenalectomy obviates CRH effects on lymphocyte
proliferation (Irwin et al. 1988; Labeur et al. 1995). In addition, the B cell
decreases in CRH-overproducing mice are consistent with the marked reduction
in rodent B cells observed after chronic glucocorticoid exposure (Miller et al.
1994).
In contrast to its immunosuppressive properties, CRH has also been shown to
enhance proinflammatory cytokine production in rodents and humans when
administered peripherally or within the CNS. Chronic intracerebroventricular
administration of CRH to rats leads to induction of IL-1β messenger RNA
(mRNA) in splenocytes, and acute intravenous administration in humans has
been reported to cause a fourfold increase in the induction of IL-1α (Labeur et al.
1995; Schulte et al. 1994). Similarly, the addition of CRH to in vitro
mononuclear cell preparations induces the release of IL-1 and IL-6 (Leu and
Singh 1992; Paez Pereda et al. 1995). Both chronic and acute CRH infusion have
also been reported to increase production of the immunoregulatory cytokine IL-2
in humans and rodents (Labeur et al. 1995; Schulte et al. 1994). In addition to
potential proinflammatory activities of CRH within the CNS, peripheral
production of CRH has been demonstrated in inflammatory diseases such as
ulcerative colitis and arthritis, in which it appears to act as a local
proinflammatory agent (Karalis et al. 1997; Nishioka et al. 1996).
Of all neurotransmitters or hormones known to modulate immune functioning,
the actions of glucocorticoids, although complicated, are probably the best
understood (Raison et al. 2002). Identified effects of glucocorticoids on the
immune (and inflammatory) system include the following:
Once proinflammatory cytokines have gained access to the CNS through any
of the routes outlined in Table 5–2, the inflammatory signal appears to be
amplified by a cytokine network within the brain itself (Quan et al. 1999). It has
already been noted that cytokines produced in the periphery stimulate the
production of proinflammatory cytokines, such as IL-1, IL-6, and TNF-α, in a
number of brain regions (Dantzer and Kelley 2007; Gatti and Bartfai 1993; Layé
et al. 1994; Quan 2006, 2014; Quan et al. 1999). Receptors for proinflammatory
cytokines are found in the brain, especially in areas of particular importance to
homeostatic and emotional regulation, such as the hypothalamus and
hippocampus (Benveniste 1998). Among neural cells, activated microglia are
capable of producing significant numbers of proinflammatory cytokines, which
in turn are potent activators of glial cells (Schöbitz et al. 1994). Of interest,
growing evidence suggests that nonimmunological stressors can induce cytokine
expression in the brain, an effect likely mediated by stress-induced activation of
microglia (Frank et al. 2007). These data suggest that CNS cytokine pathways
may participate in an organism’s response to a wide variety of environmental
perturbations. Consistent with this finding, proinflammatory cytokines have been
implicated in the modulation of circadian functioning, especially the sleep–wake
cycle (Hohagen et al. 1993; Opp 2005).
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CHAPTER 6
Principles of Pharmacokinetics
and Pharmacodynamics
C. Lindsay DeVane, Pharm.D.
Pharmacokinetics
The mathematical models and their accompanying differential equations that
describe the time course of drugs and metabolites in the body were developed in
the late 1960s and 1970s (Gibaldi and Perrier 1975; Wagner 1971). These
models were used to explain observational data as chromatographic techniques
became available to measure nanogram quantities of drugs in animals and
humans. Unfortunately, the mathematical expertise required for development of
these models makes them incomprehensible to most clinicians treating patients
with drugs. The principles in this chapter have been validated with substantial
experimental and observational data. However, these principles continue to be
reexamined and refined. At the time pharmacokinetic models were first
conceived, there was no knowledge of drug transporters. This rapidly evolving
area of research is reshaping many of the tenets of drug disposition.
Significance of Drug Transporters
Since the last update of this chapter, advances in the understanding of
pharmacokinetics and pharmacodynamics of drugs have led to an investigative
focus on the role of membrane-bound transporters in influencing drug
distribution to various tissues (Giacomini et al. 2010). It is now recognized that
multiple transporters present in the cerebral capillaries that form the blood–brain
barrier (BBB) influence drug access to and accumulation in the central nervous
system (CNS). Initial studies focused on the ABCB1 gene product P-
glycoprotein (P-gp) and revealed a role for this protein in altering the efflux of
its substrates through the gastrointestinal tract, the BBB, and the placenta and in
influencing drug elimination through the biliary tract and renal tubules. The
amount of drug in various tissues correlated with the presence of transporters
and their genetically determined activity. It soon became apparent that multiple
transporters functioned at these sites, opposing each other in direction of
transport and having overlapping substrate specificity. This complexity became
problematic for discerning the role of any single transporter in regulating CNS
drug concentration. Much as with the genes that influence disease expression, it
is unlikely that any single transporter polymorphism will be identified that could
serve as a biomarker for pharmacokinetic/pharmacodynamic predictability.
Other transporters in the brain capillary endothelial cells contributing to the
function of the BBB include the uptake transporters organic anion transporting
polypeptides 1A2 and 2B1 (OATP1A2, OATP2B1) and the efflux pumps P-gp,
breast cancer resistance protein (BCRP), and multidrug resistance proteins 4 and
5 (MRP4, MRP5) (Nigam 2015).
Some provocative results have stimulated this field of research. When P-gp
activity was lowered through use of a specific inhibitor, risperidone was found to
have an increased drug concentration in the brain of rats that correlated with
enhanced pharmacological effects that were surrogates for antipsychotic activity
(Pacchioni et al. 2010). The translational application of this research is the
possibility that use of specific inhibitors might increase CNS drug concentration
and enhance central effects without causing an increase in peripheral drug
concentration that relates to the development of adverse effects. The research
supporting these types of investigations is built on a foundation of basic
pharmacokinetic principles. The fundamental description of drug disposition
begins with studies of single drug doses.
Presystemic Elimination
Many drugs undergo extensive metabolism as they move from the
gastrointestinal tract to the systemic circulation (i.e., as they pass through the
gastrointestinal membranes and hepatic circulation during absorption). This
process is known as the first-pass effect or presystemic elimination and is an
important determinant of drug bioavailability after oral administration. Several
factors are potentially important in influencing the degree of first-pass effect.
Food has been mentioned previously as one factor. A first-pass effect is usually
indicated by either a decreased amount of parent drug reaching the systemic
circulation or an increased quantity of metabolites after oral administration
compared with parenteral dosing. This process is important in the formation of
active metabolites for psychoactive drugs and is a major source of
pharmacokinetic variability (George et al. 1982).
Presystemic metabolism of drugs is extensively accomplished by cytochrome
P450 (CYP) enzymes located both in the liver and in the luminal epithelium of
the small intestine (Kolars et al. 1992). CYP3A4 represents approximately 70%
of total CYP in the human intestine. Many useful psychopharmacological drugs
are CYP3A4 substrates, inhibitors, and/or inducers. The liver contains about
two- to fivefold greater amounts of CYP3A protein (nmol/mg protein) compared
with the intestine (de Waziers et al. 1990). Nevertheless, intestinal CYP3A4 has
a profound effect on presystemic drug metabolism. Up to 43% of orally
administered midazolam, for example, is metabolized as it passes through the
intestinal mucosa (Paine et al. 1996). The exposure of drugs to gut CYP3A4 is
not limited by binding to plasma proteins, as can occur with hepatic metabolism.
Slower blood flow may also contribute to intestinal metabolism, thereby
compensating for the lower quantity of CYP3A4 in the gut compared with the
liver.
Certain foods, such as grapefruit juice, can substantially alter the
bioavailability of some drugs. Components in grapefruit juice—which contains a
variety of suspect candidates, including naringin, other flavonoids, bergamottin,
and other furanocoumarins—inhibit intestinal CYP3A4-mediated first-pass
metabolism (Paine et al. 2005). The maximal effect can occur within 30 minutes
of ingestion of juice. Grapefruit juice may also inhibit the efflux transport of
drugs by P-gp and MRP2. In the gut, P-gp works in concert with CYP3A4 to
limit the intestinal absorption of drugs that are common substrates for both
proteins. Efflux transporters minimize drug absorption by recycling drug that has
escaped metabolism back to the gastrointestinal tract for further exposure to
enzymatic elimination before absorption. Current research aims to develop
nonabsorbable inhibitors of drug transporters to increase drug bioavailability.
Such compounds would be useful for coadministration with drugs having poor
bioavailability or excessive costs.
Changing the route of administration to avoid presystemic metabolism can
have a therapeutic advantage. When given orally, selegiline, an irreversible
inhibitor of monoamine oxidase (MAO), is substantially converted to several
metabolites through extensive first-pass metabolism. Transdermal dosing with
drug contained in a removable patch adhering to the skin results in higher
systemic exposure to selegiline and lower exposure to metabolites. This allows
greater CNS exposure to selegiline from a given dose to inhibit MAO relative to
the required dose from oral administration (Azzaro et al. 2007).
In summary, an important pharmacokinetic principle is that the choice of drug
formulation and the route of administration can determine the rate at which the
drug and metabolites appear in the systemic circulation. This rate may be
manipulated to retard the magnitude of the peak plasma drug concentration when
a high peak concentration is related to the occurrence of adverse effects. For
example, slow-release formulations of lithium and paroxetine reduce
gastrointestinal side effects (DeVane 2003). Alternatively, rapid absorption may
be desirable to achieve immediate pharmacological effects.
Distribution
Drug distribution to tissues begins almost simultaneously with absorption into
the systemic circulation. The rate at which distribution occurs will partially
influence the onset of pharmacological response. Access to effect sites depends
on membrane permeability, the patient’s state of hydration, regional blood flow,
and other physiological variables. Physicochemical properties influencing the
rate of drug distribution to effect sites include lipid solubility, ionizability, and
affinity for plasma proteins and tissue components. Diazepam is highly
lipophilic, and its onset of effect is rapid as a result of its entry into the brain
within minutes after oral administration (Greenblatt et al. 1980). The
concentration of diazepam at its effect site may fall so precipitously as a result of
redistribution that diazepam’s duration of action after an initial dose is shorter
than would be expected based on its elimination half-life.
Frequently, the intensity and duration of the pharmacological effect of a
second drug dose, taken immediately after cessation of the effect of the first
dose, are greater and longer, respectively, than the intensity and duration of the
effect of the first dose. This is known as the second-dose effect in
pharmacokinetics (DeVane and Liston 2001). When dosing is repeated before
the previous dose has been eliminated from the body, the second and subsequent
doses produce a greater effect than the initial dose, but the relative intensity of
subsequent doses diminishes. This second-dose effect occurs, regardless of the
half-life of the drug, when dosing is repeated in response to the observed effect.
Common examples of this phenomenon include the self-administration of
caffeine and the administration of certain anesthetics.
The predicted time course of drug concentration in plasma and in tissue
following a single intravenous drug injection is shown in Figure 6–3. Drug
concentration in plasma rapidly declines in a manner consistent with the
extensive distribution of the compound out of the systemic circulation. Drug
concentration in tissue rapidly increases during this time. Pharmacological
effects may not occur immediately but may be delayed until the tissue
concentration at the effect site rises above an MEC. An equilibrium eventually
occurs between drug in plasma and drug in tissue. Concentrations from this time
forth decline in parallel during a terminal elimination phase.
Elimination
Drugs are eliminated or cleared from the body through renal excretion in an
unchanged or conjugated form; through biotransformation, primarily in the liver,
to polar metabolites; or through both of these mechanisms (see Figure 6–1).
Clearance is defined as the volume of blood or other fluid from which drug is
irreversibly removed per unit of time. Thus, clearance units are volume per time.
Drug clearance is analogous to creatinine clearance by the kidney. From the
blood that delivers drug to the liver, or any other eliminating organ, an extraction
occurs as blood travels through the organ. Because drug extraction by the liver
and other organs is rarely 100%, the portion that escapes presystemic elimination
reaches the systemic circulation intact. Plasma protein binding, as mentioned
above, can restrict the organ extraction process, depending on the specific drug.
If a drug were to be completely extracted, then clearance would equal the blood
flow to the organ. An average hepatic blood flow is 1,500 mL/minute. When
drug is eliminated by additional organs, the total clearance is an additive
function of all the individual organ clearances. Clearance values in excess of
1,500 mL/minute reported for many psychopharmacological drugs are reflective
of presystemic elimination (DeVane 1994). When the drug dose and
bioavailability are constant, then clearance is the pharmacokinetic parameter that
determines the extent of drug accumulation in the body to a steady state. By
contrast, elimination half-life is useful to reflect the rate, but not the extent, of
drug accumulation.
Elimination half-life is defined as the time required for the amount of drug in
the body, or drug concentration, to decline by 50%. This parameter is commonly
determined after a single-dose pharmacokinetic study or after drug
discontinuation in a multiple-dose study. In either situation, drug concentration
decline in plasma can be followed by multiple (serial) blood sampling. Half-life
is easily determined by graphical means or by inspection, as long as data are
used from the terminal log-linear portion of the elimination curve (see Figures
6–2 and 6–3). Knowledge of a drug’s elimination half-life is particularly useful
for designing multiple-dosing regimens.
The term steady state is a misnomer in that a true drug steady state occurs
only with a constant-rate intravenous infusion. Because of the concurrent
processes of drug absorption, distribution, and elimination, drug concentration is
constantly changing in plasma and tissues during an oral dosing regimen. A peak
and a trough concentration occur within each dosage interval. The average
steady-state concentration occurs somewhere between these extremes and is
determined by the daily dosage and the drug’s total body clearance for that
individual.
On reaching a steady-state concentration, the average concentration and the
magnitude of the peaks and troughs may be manipulated according to
established pharmacokinetic principles. Figure 6–6 shows the predicted plasma
concentration changes based on drug doses given every 24 hours. The selected
dose does not produce a high enough average steady-state concentration to reach
the desired concentration range between an MEC and a concentration threshold
associated with an increased risk of toxicity. When the dose is doubled and the
dosage interval is kept constant, the average steady-state concentration increases,
but the magnitude of the peak and trough concentration difference also increases.
These changes are consistent with the pharmacokinetic principles of
superposition and linearity (Gibaldi and Perrier 1975).
FIGURE 6–6. Predicted plasma concentration changes from
administering either a selected dose (D) every 24 hours (D
q24h), twice the dose every 24 hours (2D q24h), or the original
dose every 12 hours (D q12h).
MEC=minimal effective concentration.
Pharmacodynamics
Pharmacodynamic variability may exceed pharmacokinetic variability (see
Figure 6–1). The drug dosage or concentration that produces a pharmacological
effect differs widely among patients. Similarly, pharmacological effects can vary
widely among patients with comparable plasma concentrations of drug.
The principles of dosage regimen design discussed above rely heavily on the
existence of a functional relationship between the concentration at an effect site
and the intensity of the response produced. Many observed processes in nature
behave according to the sigmoid relationship shown in Figure 6–7. At a low
dosage or concentration, only a marginal effect is produced. As drug dosage or
concentration increases, the intensity of effect (E) increases until a maximum
effect (Emax) is achieved. This response is observed as a plateau in the sigmoid
dose–effect curve (see Figure 6–7). Further dosage increases do not produce a
greater effect.
FIGURE 6–7. The sigmoid maximum effect (Emax)
pharmacodynamic model relates concentration (C) to intensity
of effect (E).
EC50 is the concentration that produces half of the Emax, and n is an exponent that relates to
the shape of the curve.
In Figure 6–9B, the response has begun to diminish with time before
concentration begins to decline. This type of plot is known as a clockwise
hysteresis curve. The observed effect may be explained by the development of
tolerance. The time course of tolerance to psychoactive drug effects varies from
minutes to weeks. Acute tolerance to some euphoric effects of cocaine can occur
following a single dose (Foltin and Fischman 1991). Tolerance to the sedative
effects of various drugs may take weeks. The mechanisms operative in the
development of tolerance include acute depletion of a neurotransmitter or
cofactor, homeostatic changes in receptor sensitivity from blockade of various
transporters, and receptor agonist or antagonist effects. Ultimately, cellular
responses to chronic treatment with drugs can alter gene transcription factors as
mediators of physical and psychological aspects of tolerance (Nestler 1993).
A time delay in response occurs when effects are increasing and are
maintained despite decreasing plasma drug concentration (see Figure 6–9C).
This results in a counterclockwise hysteresis curve. A pharmacokinetic
explanation of this lag in response may involve a delay in reaching the critical
drug MEC at the effect site until the plasma concentration has already begun to
decline. Alternatively, response may depend on multiple “downstream” receptor
effects. Response may increase despite a decreasing drug concentration when a
metabolite contributes to the observed effects. To overcome these complications,
kinetic dynamic models can incorporate an “effect” compartment (see Figure 6–
1). The effect site equilibrates with plasma after a finite time, which can be
assigned a half-life.
Active Metabolites
With the exceptions of lithium and gabapentin, which are renally excreted, drugs
used in clinical psychopharmacology are cleared partially or completely by
metabolism, primarily in the liver. A general characteristic of highly lipid-
soluble drugs is a likelihood of elimination involving metabolism, whereas
water-soluble drugs will undergo some degree of clearance from the body by
renal elimination in an unchanged form. Many psychoactive drugs produce
pharmacologically active metabolites that distribute to the effect sites (see Figure
6–1). Like their precursors, metabolites may have multiple pharmacological
effects that may be similar to or different from those of the parent drug.
When pharmacotherapy is being switched from one drug or drug class to
another, the presence of any active metabolites should be considered.
Norfluoxetine, for example, has an average half-life of 8–9 days, much longer
than the average of 2–3 days for fluoxetine, its parent drug (DeVane 1994), and
it is an equipotent serotonin reuptake inhibitor. It may take several weeks for this
metabolite to clear the body after discontinuation of fluoxetine (Pato et al. 1991).
A similar situation applies to aripiprazole and its active metabolite
dehydroaripiprazole, which have elimination half-lives approaching 75 hours
and 94 hours, respectively.
Metabolites will accumulate to a steady state in the body in relation to their
own elimination half-lives and not those of their parent drugs. For a drug that is
nearly completely metabolized in the liver, a characteristic of numerous
psychoactive drugs, the metabolites will always have an elimination half-life that
is equal to or longer than the half-life of the parent drug. This is a logical
conclusion of considering that a metabolite cannot be eliminated faster than it is
formed. Of course, administration of the metabolite as a separate molecular
entity apart from the parent drug would produce a drug concentration–time curve
independent of any influence of the metabolite being formed from a precursor in
vivo. For some drugs, the full expression of direct pharmacological effects may
not be expected until both the drug and any important active metabolites have all
attained their steady-state concentration. For drugs producing indirect effects,
when the response depends on second messengers or a cascade of receptor
actions, the waiting period for fully expressed effects may be even longer.
Stereochemistry
Stereochemistry or chirality of drug molecules is an important consideration in
pharmacokinetics. Many psychoactive drugs exist as two or more stereoisomers
or enantiomers with distinctly different biological properties and are marketed as
the racemic (i.e., 50:50) mixtures of both isomers. Although enantiomers have
identical physicochemical properties, they are often recognized as distinct
entities by biological systems and may bind to transport proteins, drug-
metabolizing enzymes, and pharmacological effect sites with different affinities.
As a result, one enantiomer may possess a significant pharmacological effect,
whereas the other stereoisomer may lack that effect or produce different effects.
Enantiomers may also differ in their absorption, metabolism, protein binding,
and excretion, leading to substantial differences in pharmacokinetic properties
(Darwish et al. 2009; DeVane and Boulton 2002). Furthermore, one isomer may
modify the effects of the other. Motivation for development of individual
enantiomers has been stimulated by reports that some enantiomers may
antagonize or counteract the activity of the other stereoisomer.
The development of single-isomer drugs may offer advantages over use of the
racemic mixture. Potential advantages include a less complex and more selective
pharmacological profile, a possibly improved therapeutic index, a more
simplified pharmacokinetic profile, a reduced propensity for complex drug
interactions, and a more definable relationship between plasma drug
concentration and effect. Examples of racemic mixtures in current use include
methadone, methylphenidate, bupropion, venlafaxine, fluoxetine, and
citalopram. Clearly, each drug needs to be considered individually with regard to
its development as a single stereoisomer formulation. Recent examples of
successful switches to single isomers include escitalopram, dexmethylphenidate,
and armodafinil.
Pharmacogenomics
Inheritance accounts for a large part of the variations observed in the ability to
eliminate drugs (see Figure 6–1) among individuals. This forms the basis of
pharmacogenetics, which is defined as the study of the genetic contribution to
the variability in drug response (Kalow et al. 1986; Price Evans 1993). This term
was originally applied to the effect on pharmacokinetics, whereas
pharmacogenomics dealt specifically with genes mediating drug response. More
recently, the terms have been used interchangeably. Numerous association
studies have investigated genetic polymorphisms of molecular targets as
predictors of disease susceptibility, specific drug response, and drug tolerability.
Recent pharmacogenomic studies have yielded advances in five areas: 1) the role
of serotonin pharmacogenomic targets in predicting response to antidepressants
(Lekman et al. 2008; Liu et al. 2007; Serretti et al. 2007; Yatham et al. 1999); 2)
the role of potential pharmacogenomic targets in predicting response to
prophylactic lithium in bipolar disorder (Masui et al. 2006; Serrenti et al. 2002);
3) the relationship between polymorphisms in serotonin, dopamine, and
glutamate receptor genes and antipsychotic response in schizophrenia (Arranz et
al. 1998; Bishop et al. 2005); 4) the relationship between the pharmacogenomics
of the μ-opioid receptor and treatment response to naltrexone in alcohol use
disorder (Oslin et al. 2003); and 5) the role of pharmacogenomics in the
occurrence of adverse effects from psychopharmacotherapy (Murphy et al. 2003,
2004). Specific pharmacogenomic data are discussed elsewhere in this volume
(see Chapter 1, “Basic Principles of Molecular Biology and Genomics,” by Yu
and Rasenick).
The genetic differences in pharmacokinetics that have been identified apply
mostly to drug metabolism. Renal clearance of drugs appears to be similar in
age- and weight-matched healthy subjects with no defined genetic
polymorphisms. Genetic polymorphisms have been identified and defined for
some drug transporters and several hepatic enzymes important in the cellular
transport and metabolism of many drugs used in psychopharmacology.
P-gp, as the most thoroughly studied drug transporter, appears to be
significantly involved in the disposition of a variety of psychoactive drugs
(Mahar Doan et al. 2002). More than 70 polymorphisms have been reported in
the ABCB1 gene that encodes for P-gp, and three single-nucleotide
polymorphisms (SNPs) of P-gp have been associated with functional changes in
P-gp activity. The majority of SNP-related reports focus on the silent C3435T
SNP of exon 26, which has been associated with changes in expression resulting
in increased serum concentrations of digoxin and fexofenadine (Hoffmeyer et al.
2000; Kurata et al. 2002). There is emerging evidence that haplotypes of P-gp
SNPs may influence drug-resistant epilepsy (Siddiqui et al. 2003), access of
drugs to the brain (Brunner et al. 2005), and placental transfer of psychoactive
drugs (Rahi et al. 2007). Theoretically, P-gp substrates may act as competitive
inhibitors of P-gp, so that drug–drug interactions may also involve P-gp (Wang
et al. 2006).
Basic research describing the functional capacity of P-gp to influence the
distribution of drug substrates in several tissues, including access to the brain,
has led to translational studies that demonstrated ABCB1 genetic effects on
antidepressant outcomes. In 297 depressed patients treated for 6 weeks with
antidepressants, several ABCB1 polymorphisms from 95 genotyped SNPs were
associated with remission. A relationship between genotype and remission was
found in patients receiving antidepressants that were P-gp substrates but not in
patients receiving non–P-gp substrates (Uhr et al. 2008). This seminal
observation led to a prospective study in which ABCB1 gene test results from 58
depressed inpatients were incorporated into the clinical decision-making process
(Breitenstein et al. 2014). Either increasing the drug dosage or switching to
another antidepressant when patient-specific genotyping was available resulted
in higher remission rates in patients whose ABCB1 genotype was available
during the hospital stay. The largest trial to date to test the value of ABCB1
genotyping was performed as part of the prospective multicenter iSPOT
antidepressant trial (Schatzberg et al. 2015). In this intent-to-treat sample of 683
depressed patients, a specific variant, rs10245483, was found to be closely
correlated with medication-specific antidepressant efficacy and adverse events.
Considered together, this research affirms that drug transporters influence
pharmacodynamic effects by active transport to sites containing molecular
targets. Further research will define the principal polymorphisms of value for
therapeutic decision making.
Genetic polymorphism in a drug-metabolizing enzyme or transporter can
result in subpopulations of people who may deviate substantially from the
population mean in their ability to metabolize substrates of the affected enzyme.
People who are poor metabolizers constitute at least 1% of the population, but
the majority of people are normal or rapid metabolizers, and some are identified
as ultrarapid metabolizers due to duplicate or multiple genes. Genetic
polymorphisms that define poor metabolizers have been identified for major
drug-metabolizing enzymes, including CYP2D6, CYP2C9, and CYP2C19.
Studies employing either single drugs or mixtures of drugs as probe compounds
have been used to calculate an individual’s metabolic ratio (MR)—an index of
relative ability to metabolize substrates of a particular enzyme—thereby
providing a phenotype identity. The MR is equal to the concentration of parent
drug divided by the concentration of the major metabolite determined in the
urine excreted during a timed interval following an oral dose.
Many pharmacogenetic studies yield results similar to the frequency
distribution histograms shown in Figure 6–10. The frequency in Figure 6–10A is
expected when enzyme activity is distributed normally within a population
without genetic polymorphisms. The range of values for the MR may be broad,
which reflects a large variability in oxidation reaction capacity in the study
population. Thus, vastly different dosages are required for many patients. The
bimodal distribution in Figure 6–10B is a typical finding for an enzyme that has
a genetic polymorphism. Values above the antimode for the reference (or
“probe”) drug define poor metabolizers, who are clearly differentiated from
normal or extensive metabolizers. The probe drug need not be metabolized by
only one enzyme (as is exemplified by the use of caffeine for phenotyping the
enzyme activity of N-acetyltransferase and CYP1A2), but the overlap of other
enzymes should be minimal in order to produce the specific metabolite of
interest (Denaro et al. 1996). Comparisons of MRs across many patients of
different ethnic origins have yielded measures of variability in enzyme activity
in the population (Lin et al. 1996). The widespread availability of a commercial
microarray chip for genotyping a small group of CYP enzymes has eliminated
the need to perform phenotyping procedures in most circumstances. Although a
genotypical extensive metabolizer may be phenotypically a poor metabolizer, the
opposite situation does not occur.
FIGURE 6–10. Theoretical frequency histograms of the
distribution of the metabolic ratio of a model substrate showing a
unimodal distribution among a population of normal or extensive
metabolizers (A) and a bimodal distribution among a population
including poor metabolizers and ultrarapid metabolizers (B).
Drug Interactions
Drugs are frequently coadministered to achieve therapeutic effects from the
combined actions at effect sites or to treat the adverse effects caused by one drug
with another. Drug combinations routinely used include hypnotics with
antidepressants, anticholinergic–antiparkinsonian drugs with antipsychotics,
benzodiazepines with selective serotonin reuptake inhibitors (SSRIs), and mood
stabilizers with antipsychotics. The use of more than one antidepressant or
antipsychotic in combination for specific patients is increasingly encountered in
clinical practice. When more than one drug is administered concurrently to a
patient, the drugs may interact either in a positive manner or in a negative or
undesired way because of either pharmacodynamic or pharmacokinetic
mechanisms.
Pharmacodynamic interactions are likely to occur when an MAO inhibitor is
combined with an SSRI (producing a serotonin syndrome) and when ethanol is
combined with a benzodiazepine (leading to psychomotor impairment). Two
drugs may have affinity for the same receptor sites in the brain and produce
additive or synergistic effects, or their actions may oppose each other through
antagonistic interactions at receptor sites. Most often, pharmacodynamic
mechanisms are not such obvious causes of drug interactions and are less easily
determined and investigated than pharmacokinetic interactions.
The kinetics of drug interactions has been extensively described and is a
routine focus of clinical investigations as part of drug development (Rowland
and Matin 1973). Two major mechanisms of drug interactions involve an
alteration of metabolism through either induction or inhibition of hepatic CYP
enzymes. Major differences exist in the pharmacokinetic consequences of these
interactions. The expected changes are illustrated in Figures 6–11 and 6–12. In
Figure 6–11, the steady-state plasma concentration of drug A following
continuous intermittent dosing is altered by the addition of an enzyme inducer.
After the inducer is started, the effects on the steady-state concentration of drug
A do not occur for several days while additional enzyme that metabolizes drug A
is synthesized. Ultimately, an increase in the metabolic clearance of drug A
accompanied by a decrease in its steady-state plasma concentration occurs. The
degree to which clearance is increased will depend on the relative importance of
the particular induced enzymes in the overall elimination of drug A and the dose
and potency of the inducer. A clinically significant example of this type of
interaction is the loss of oral contraceptive effect as a consequence of
carbamazepine induction of CYP3A4. The time required for a new steady state
of drug A to occur following enzyme induction and the extent to which plasma
concentrations decrease will depend on how marked a change in clearance
occurs and the resulting change in drug half-life.
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CHAPTER 7
Brain Imaging in
Psychopharmacology
Ebrahim Haroon, M.D.
Helen Mayberg, M.D.
Neuroimaging Techniques
Neuroimaging is a generic term encompassing a number of techniques and
methods aimed at detecting meaningful information through the acquisition of
brain images of different kinds. A first classification of these techniques may be
technology based, as follows:
Most FDG uptake studies are based on the assumption that glucose uptake and
neural activity at the synaptic level might be coupled. A caveat must be borne in
mind when evaluating studies using FDG-PET. Glutamate, the main excitatory
neurotransmitter in the brain, is removed from the synapse through a process of
uptake by astroglial tissues, thereby terminating neural activation (Magistretti
and Pellerin 1999a, 1999b). However, studies have shown that uptake of
glutamate by astroglia can by itself stimulate glucose (and FDG) uptake
(Magistretti 2006; Magistretti and Pellerin 1999a). In fact, deactivation might
actually be coupled with increased glucose uptake in a variety of conditions
(Magistretti 2006). Thus, the same problems that accompany studies of fMRI—
i.e., whether the signal is actively excitatory versus actively inhibitory—are
present in FDG-PET studies as well. Notwithstanding these limitations, PET
studies have provided important information that helps to identify which patient
will respond best to which treatment.
Other
targets
PET [11C] carfentanil, Opioid receptors Pain perception and
[11C] placebo response
diprenorphine, Probe type: opioid
[11C] receptors
LY2795050
PET [11C] PK11195, Microglial Pain perception and
[11C] PBR28, labeling: TSPO placebo response
[18F] FEPPA, binding site Probe type: opioid
[18F] PBR06, receptors
[18F] PBR111
PET [11C] OMAR, Cannabinoid Pain perception and
[18F] MK9470 receptors placebo response
Probe type:
cannabinoid type 1
receptors
Note. 5-HT=serotonin (5-hydroxytryptamine); GABA=γ-aminobutyric acid;
MRS=magnetic resonance spectroscopy; PET=positron emission tomography;
SERT=serotonin transporter; SPECT=single photon emission computed
tomography; TSPO=translocator protein.
Method of
Type of imaging Technique analysis Purpose
Structural MRI Voxel-based Automated Measure volumes of
(sMRI)— T1 morphometry brain regions in
based (VBM) brain disorders
and ischemic
lesions
(hyperintensities)
sMRI—T2 Region of Manual/automated Measure volumes of
based interest (ROI) brain regions in
analysis brain disorders
and ischemic
lesions
(hyperintensities)
Functional MRI BOLD Computerized Measure area of
(fMRI) technique algorithm activation in
(described in response to
text) cognitive/affective
challenge
Functional Resting-state Computerized Reveal connectivity
connectivity activity, algorithms, between different
analysis independent statistical components of
component models neural network
analysis during various
(ICA), mental states
structural
equation
modeling
Diffusion-based Diffusion- Computerized Assess tissue
MRI weighted, algorithms integrity by
perfusion- imaging water
weighted, diffusion in
diffusion restricted and free
tensor space; used in
imaging diagnosis of
(DTI) stroke and
neurodegeneration
Perfusion- Blood flow– Computerized Measure neural
weighted based imaging algorithms tissue response to
imaging with using activation or
arterial spin magnetic pharmacological
labeling resonance challenge
labeling paradigms
approaches
Magnetic Detection of Automated and Detect neuronal and
resonance concentrations voxel based glial metabolic
spectroscopy of specific (manual) abnormalities in
metabolites in localized (single)
cerebral or distributed
regions (multiple) brain
regions or voxels
Innovative in vivo magnetic resonance approaches
Machine Identification of Advanced Identify consistent
learning minor but machine- patterns of brain
consistent learning changes across
patterns of algorithms disease states;
changes in often used for
structural subtyping
and/or
functional
imaging data
Multimodality Combination of EEG/MEG + Reveal structural and
imaging data from fMRI + functional
multiple tractography connection
modalities to changes in mental
obtain disorders
meaningful
conclusions
Connectomics Application of Computerized Identify nodal and
graph theory approaches connectivity
to changes in brain
connectivity architecture in
analysis different contexts
Hyperscanning Online linkage Web based Reveal cerebral
of two fMRI activation changes
scanners in during social
different interactions
locations (social
neuroscience
technique)
Note. BOLD=blood oxygenation level–dependent; EEG=electroencephalography;
MEG=magnetoencephalography.
The rate at which the scanner can acquire images is influenced by the desired
resolution. Generally, the more slices and the finer the resolution within each
slice, the longer a whole-brain acquisition takes. Whereas an individual slice can
be acquired in as little as 60 milliseconds, whole-brain imaging usually requires
about 2–3 seconds. In contrast to the ease with which fMRI measurements can
be performed, there are specific limitations with BOLD imaging:
Spatial errors. The BOLD effect originates from venous vessels (capillaries,
venules, and veins), so the signal is not exactly collocated either with the
locus of neural activity or with the arterial supply. This spatial error may,
however, be negligible for brain-mapping studies employing a standard spatial
resolution (voxel size ∼50 mm3).
Bulk head motion and physiological pulsation (heart pulse, respiration)
artifacts. To reduce motion, head movement should be restrained while
maintaining a comfortable situation for the subject.
Susceptibility artifacts. The fact that BOLD detects local changes in magnetic
susceptibility (due to the variation in deoxyhemoglobin concentration) renders
it vulnerable to the large discontinuity that exists at the interfaces between
bone/air and bone/liquid. In these regions, the steep variations in tissue
density cause a distortion of the local magnetic field, resulting in both a spatial
distortion of the image and a drop in the BOLD signal. These spatial
distortions make it difficult to detect the small changes associated with
deoxyhemoglobin variations. The problematic regions are notably the
orbitofrontal cortex and the inferior part of the temporal lobes, which
unfortunately are the loci of many interesting neuropsychological processes.
Conclusion
Contemporary brain-imaging methods provide a variety of strategies to probe
structural, functional, and chemical abnormalities in specific neural circuits
relevant to psychiatric illness. Such studies are having a considerable impact on
our conceptualization of these disorders, with potential impacts on diagnosis
(Mayberg 2003a), clinical management (monitoring occupancy or PIB changes
with treatment [Klunk et al. 2004]), and novel treatment development (Mayberg
2009). Brain-imaging studies in psychopharmacology can be categorized both by
the scanning technology employed (e.g., MRI, PET, EEG) and by the type of
measurement obtained (e.g., activation, resting state, behavioral, biochemical,
receptor mapping). Receptor-mapping studies have clearly added to our ability to
understand mechanisms of action of psychopharmacological agents and their
side-effect profiles. Activation studies, which indirectly measure neuronal
activity vis-à-vis changes in CBF, have become widely used with fMRI
technology, providing new insights into behaviorally specific subcircuits.
Structural MRI studies have also begun to yield considerable data, enabling a
better understanding of how the disease processes are regionally localized,
where to target for functional imaging, and where to obtain specimens for
postmortem histopathological analysis. Multimodal imaging through a
combination of fMRI, PET, structural MRI, MRS, and electromagnetic
measurement (EEG, MEG) offers the promise of identifying both neuronal and
chemical changes related to brain function.
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_____________
The authors wish to acknowledge the significant contribution made by Christine
Heim, Ph.D., Guiseppe Pagnoni, Ph.D., and Greg Berns, M.D., Ph.D., in the
preparation of the chapter in the previous edition of this Textbook.
Portions of this chapter are reprinted from Berns GS: “Functional
Neuroimaging.” Life Sciences 65(24):2531–2540, 1999. Copyright 1999,
Elsevier Science. Used with permission.
PART II
Monoamine Oxidase
A and B Isoenzymes
MAO is widely distributed in mammals. Two isoenzymes, MAO-A and MAO-B,
are of special interest (Cesura and Pletscher 1992). Both are present in the
central nervous system (CNS) and in some peripheral organs. For example,
MAO-A is present in the liver, heart, and pancreas, and MAO-B is present in the
liver, posterior pituitary, renal tubules, and endocrine pancreas (Saura et al.
1992). Both MAO-A and MAO-B are present in discrete cell populations within
the CNS. MAO-A is present in both dopamine (DA) and norepinephrine (NE)
neurons, whereas MAO-B is present to a greater extent in serotonin (5-HT)–
containing neurons. Both are also present in nonaminergic neurons in various
subcortical regions of the brain. Glial cells also express MAO-A and MAO-B
(Cesura and Pletscher 1992).
The physiological functions of these two isoenzymes have not been fully
elucidated. The main substrates for MAO-A are epinephrine, NE, and 5-HT. The
main substrates for MAO-B are phenylethylamine, phenylethanolamine,
tyramine, and benzylamine. DA and tryptamine are metabolized by both
isoenzymes. The localization of the MAO subtypes does not fully correspond to
the neurons containing the substrates. The reason for this discrepancy is
unknown. The occurrence of the MAO-B form in 5-HT neurons may actually
protect these neurons from amines (other than 5-HT) that could be toxic to them
(Cesura and Pletscher 1992).
The primary structures of MAO-A and MAO-B have been fully described.
MAO-A has 527 amino acids, and MAO-B has 520 amino acids. About 70% of
the amino acid sequence of the two forms is homologous. The genes for both
isoenzymes are located on the short arm of the human X chromosome. MAO-A
and MAO-B are linked and have been located in the XP11.23–P11 and XP22.1
regions, respectively. The genes span about 70 kilobases (kb) and consist of
about 15 exons and 14 introns. MAO-A has two messenger RNA (mRNA)
transcripts of 2.1 and 5.0 kb in length. MAO-B has a 3-kb mRNA single
transcript (Cesura and Pletscher 1992). A rare inherited disorder, Norrie’s
disease, is characterized by deletion of both genes; patients with this disorder
have very severe mental retardation and blindness. Another rare inherited
disorder is Brunner syndrome, caused by a mutation in the MAO-A gene. It is
characterized by impulsive aggressiveness and mild mental retardation (Brunner
et al. 1993).
The subunit composition of MAO is unknown. The enzyme is primarily found
in the outer mitochondrial membrane; flavin adenine dinucleotide is a cofactor
for both MAO-A and MAO-B.
Because the cofactor domain is the same for both of the MAO isoenzymes, the
structural differences responsible for substrate specificity are believed to lie in
regions of the protein that bind to the hydrophobic moiety of the substrate.
Although DA is considered to be a mixed substrate for both MAO-A and MAO-
B, the breakdown of DA in the striatal regions of the brain is preferentially by
MAO-B. In other regions, MAO-A may be more important. There may be
regional differences as to which isoenzyme is responsible for the metabolism of
other biogenic amines that are substrates for both forms of MAO (Cesura and
Pletscher 1992).
Enzyme Kinetics
The enzyme kinetics of MAO-A have not been well studied. The enzyme
kinetics for MAO-B, for which more information is available, depend on the
nature of the substrate. Some substrates (e.g., tyramine) go through ping-pong
mechanisms characterized by oxidation of the amine to the imine form, which is
subsequently released from the reduced enzyme before reoxidation occurs. Other
substrates (e.g., benzylamine) involve formation of a tertiary complex with the
enzyme and oxygen (Husain et al. 1982; Pearce and Roth 1985; Ramsay and
Singer 1991).
Mechanism of Action
The target function of MAOIs is regulation of the monoamine content within the
nervous system. Because MAO is bound to the outer surface of the plasma
membrane of the mitochondria, in neurons MAO is unable to deaminate amines
that are present inside stored vesicles and can metabolize only amines that are
present in the cytoplasm. As a result, MAO maintains a low cytoplasmic
concentration of amines within the cells. Inhibition of neuronal MAO produces
an increase in the amine content in the cytoplasm. Initially, it was believed that
the therapeutic action of MAOIs was a result of this amine accumulation
(Finberg and Youdim 1984; Murphy et al. 1984, 1987). More recently, it has
been suggested that secondary adaptive mechanisms may be important for the
antidepressant action of these agents.
After several weeks of treatment, MAOIs produce effects such as a reduction
in the number of β-adrenoceptors, α1- and α2-adrenoreceptors, and serotonin
type 1 (5-HT1) and serotonin type 2 (5-HT2) receptors. These changes are
similar to those produced by the chronic use of tricyclic antidepressants (TCAs)
and other antidepressant treatment (DaPrada et al. 1984, 1989).
MAOIs can be subdivided on the basis of not only the particular type of
enzyme inhibition but also the type of inhibition they produce (reversible or
irreversible). The reversible MAOIs are basically chemically inert substrate
analogs. MAOIs are recognized as substrates by the enzyme and are converted
into intermediates by the normal mechanism. These converted compounds react
to the inactive site of the enzyme and form a stable bound enzyme. This effect
occurs gradually, and there is usually a correlation between the plasma
concentration of the reversible inhibitors and pharmacological action.
Pharmacological Profile
The classic MAOIs inhibit both forms of the enzyme and are divided into two
main subtypes: hydrazine and nonhydrazine derivatives (Figure 8–1). The
hydrazine derivatives, two of which are currently available (phenelzine and
isocarboxazid), are related to iproniazid. One nonhydrazine derivative,
tranylcypromine, is commercially available.
Among the selective MAOIs, clorgyline (which was never marketed in the
United States) is an example of an irreversible inhibitor of MAO-A, whereas
selegiline is an irreversible inhibitor of MAO-B. Moclobemide is the only
reversible inhibitor of MAO-A on the market (available in the United Kingdom
and Australia, but not in the United States).
Three classic MAOIs (i.e., phenelzine, isocarboxazid, and tranylcypromine)
are of clinical interest. Clinicians must recognize that these drugs not only
inhibit MAO but also exert other actions that may be clinically relevant. Thus,
these compounds can block MAO uptake—tranylcypromine more than
isocarboxazid or phenelzine. In addition, because tranylcypromine is structurally
similar to amphetamine, it is believed to exert stimulant-like actions in the brain.
Many issues are common to all three of these MAOIs.
Irreversible MAOIs
Panic Disorder
Both single- and double-blind studies have demonstrated the efficacy of
phenelzine and iproniazid in treating panic disorder (Lydiard et al. 1989; Quitkin
et al. 1990; Tyrer et al. 1973). About 50%–60% of patients with panic disorder
respond to irreversible MAOIs. In the early stages of treatment, patients may
have a worsening of symptoms. This is reduced in clinical practice by combining
the MAOI with a benzodiazepine for the initial phase of the study. It has been
suggested that in addition to having an antipanic effect, phenelzine has an
antiphobic action (Kelly et al. 1971). The time course of effect and the dose used
are similar to those for major depressive disorder.
Social Phobia
Liebowitz et al. (1992) reported that phenelzine is effective in treating social
phobia. In an open-label study, Versiani et al. (1988) suggested that
tranylcypromine is effective. Versiani et al. (1992) also demonstrated the
efficacy of the reversible MAOI moclobemide in a double-blind study. About
50% of patients respond to MAOIs, and the onset of response is gradual (usually
about 2–3 weeks) (Liebowitz et al. 1992).
A Cochrane review of pharmacotherapy for social phobia noted that whereas
classic irreversible MAOIs were comparable in efficacy to SSRIs, reversible
MAOIs were less efficacious (Stein et al. 2004).
Obsessive-Compulsive Disorder
Although initial case reports suggested that irreversible MAOIs may be effective
in treating obsessive-compulsive disorder (Jenike 1981), no double-blind studies
conducted have indicated efficacy (Jenike et al. 1997).
Bulimia Nervosa
Both phenelzine and isocarboxazid have been shown to be effective in treating
some symptoms of bulimia nervosa (Kennedy et al. 1988; McElroy et al. 1989;
Walsh et al. 1985, 1987).
Premenstrual Dysphoria
Preliminary studies and clinical experience suggest that MAOIs may be effective
in the treatment of premenstrual dysphoria (Glick et al. 1991).
Chronic Pain
MAOIs are believed to be effective in the treatment of atypical facial pain and
other chronic pain syndromes. However, only limited data on these conditions
are available.
Neurological Diseases
The classic MAOIs have not been found to be effective for treating neurological
disorders such as Parkinson’s disease and Alzheimer’s dementia. However, the
MAO-B inhibitor selegiline has been shown to be effective in slowing the
progression of Parkinson’s disease (Cesura and Pletscher 1992), although the
mechanism underlying this effect is unknown.
Drug–Drug Interactions
Drug–drug interactions are also extremely important concerns in patients taking
irreversible MAOIs. The extensive inhibition of MAO enzymes by MAOIs
raises the potential for a number of interactions with other drugs (Table 8–4). Of
particular importance, many over-the-counter medications can interact with
MAOIs. These medications include cough syrups containing sympathomimetic
agents, which in the presence of an MAOI can precipitate a hypertensive crisis.
Another area of caution is the use of MAOIs in patients who need surgery.
Potential interactions include those with narcotic drugs, especially meperidine.
Meperidine administered with MAOIs can produce a syndrome characterized by
coma, hyperpyrexia, and hypertension. This syndrome has been reported
primarily with phenelzine; however, it has also been reported with
tranylcypromine (Mendelson 1979; Stack et al. 1988). Stack et al. (1988) noted
that this syndrome is most likely to occur with meperidine and that it may be
related to that drug’s serotonergic properties (similar to serotonin syndrome).
Similar reactions have not been reported to any significant extent with other
narcotic analgesics such as morphine and codeine. In fact, many patients
probably receive these medications without problems. Only a small fraction of
patients may have this interaction, and it could reflect a serotonin toxicity effect.
In general, current opinion favors the use of morphine when intra- or
postoperative narcotics are needed in patients taking MAOIs.
The issue of whether directly acting sympathomimetic amines interact with
MAOIs is more controversial. Intravenous administration of sympathomimetic
amines to patients receiving MAOIs does not provoke hypertension. When a
bolus infusion of any of various catecholamines is given to healthy volunteer
subjects who have been taking phenelzine or tranylcypromine for 1 week, a
potentiation of the pressor effect of phenylephrine occurs, but no clinically
significant potentiation of cardiovascular effects of NE, epinephrine, or
isoproterenol occurs (Wells 1989).
In general, direct sympathomimetic amine–MAOI interactions do not appear
to produce significant cardiovascular problems. However, there is a low
incidence of hypertensive episodes in the presence of indirect
sympathomimetics. Ideally, these compounds should not be used in patients who
are receiving MAOIs. A direct-acting compound is preferable to an indirect-
acting compound.
Caution should be exercised when using MAOIs in patients with
pheochromocytoma or with cardiovascular, cerebrovascular, or hepatic disease.
Because phenelzine tablets contain gluten, they should not be given to patients
with celiac disease.
Each patient should be given a card indicating that he or she is taking an
MAOI and instructed to carry the card at all times. A medical bracelet indicating
that the wearer takes an MAOI is also a good idea.
Phenelzine
Phenelzine, a hydrazine derivative, is a potent irreversible MAOI and is the best
studied of the MAOIs.
Pharmacokinetics
Phenelzine is a substrate as well as an inhibitor of MAO. Major identified
metabolites of phenelzine include phenylacetic acid and p-hydroxyphenylacetic
acid. Phenelzine undergoes acetylation, and therefore drug levels are lower in
fast acetylators than in slow acetylators. However, because phenelzine is an
irreversible inhibitor, plasma concentrations are not relevant. The antidepressant
effect, the degree of inhibition of MAO, and the amount of free phenelzine
excreted in the urine are all significantly greater in slow acetylators than in fast
acetylators (Baker et al. 1999).
Indications
Phenelzine is useful in the treatment of major depressive disorder, atypical
depression, panic disorder, social phobia, and atypical facial pain (see section
“Indications and Efficacy” earlier in this chapter).
Side Effects
The primary side effects of phenelzine are similar to those of other MAOIs.
Hepatitis secondary to phenelzine may occur in rare cases (<1 in 30,000). The
most difficult side effect, often leading to discontinuation, is postural
hypotension.
Contraindications
The contraindications to phenelzine include known sensitivity to the drug,
pheochromocytoma, congestive heart failure, and history of liver disease. (In
addition, see sections “Dietary Interactions” and “Drug–Drug Interactions”
earlier in this chapter.)
Isocarboxazid
Isocarboxazid is an irreversible MAOI of the hydrazine type.
Pharmacokinetics
Isocarboxazid is rapidly absorbed from the gastrointestinal tract and is
metabolized in the liver. It is primarily excreted as hippuric acid. Its half-life is
of little interest because it is an irreversible MAOI. Chemically, isocarboxazid is
5-methyl-3-isoxazolecarboxylic acid 2-benzylhydrazide. Isocarboxazid is a
colorless crystalline substance with very little taste.
Indications
Isocarboxazid is the least studied of the MAOIs. It is indicated for the treatment
of depression.
Side Effects
The side effects of isocarboxazid are similar to those of phenelzine, described
earlier in this section. Postural hypotension is the most common problem.
Contraindications
The contraindications to isocarboxazid are similar to those of phenelzine,
described earlier in this section.
Tranylcypromine
Tranylcypromine, a nonhydrazine irreversible MAOI, increases the
concentration of NE, epinephrine, and 5-HT in the CNS. Tranylcypromine has a
mild stimulant effect.
Pharmacokinetics
Limited data exist on the pharmacokinetics of tranylcypromine. The drug is
excreted within 24 hours. The dynamic effect lasts for up to 5 days after
withdrawal. There is considerable debate about whether tranylcypromine is
metabolized to amphetamine; most studies in the literature indicate that this does
not occur.
Indications
Tranylcypromine is indicated for the treatment of major depressive disorder
without melancholia.
Side Effects
The side effects of tranylcypromine are similar to those of other MAOIs. In
addition, problems with physical dependence on tranylcypromine have been
reported. Thus, withdrawal symptoms, such as anxiety, restlessness, depression,
and headache, may occur. Syndrome of inappropriate antidiuretic hormone
(SIADH) has been reported with tranylcypromine. Rare cases of toxic hepatitis
have also been reported. Tranylcypromine can lead to increased agitation,
insomnia, and restlessness, compared with phenelzine.
Contraindications
The contraindications to tranylcypromine are the same as those for phenelzine,
described earlier in this section. In addition, in view of the greater potential for
hypertensive episodes, tranylcypromine should be used with particular caution in
patients with cerebrovascular or cardiovascular disease.
Moclobemide
Moclobemide, a reversible inhibitor of MAO-A enzyme (Amrein et al. 1989),
has a higher potency in vivo than in vitro. Therefore, it has been suggested that
moclobemide is a prodrug and that it is metabolized to a form with higher
affinity for MAO-A than the parent compound. After single- or repeated-dose
administration of moclobemide, the recovery of MAO-A activity is much
quicker than that seen with other MAOIs. One of the metabolites of
moclobemide does inhibit MAO-B; however, this action is minimally significant
in humans. When administered to rats, moclobemide increases the concentration
of 5-HT, NE, epinephrine, and DA in rat brain (Haefely et al. 1992). These
effects are short lasting, and they parallel the time course of MAO-A inhibition.
In addition, unlike with irreversible inhibitors, repeated administration does not
increase the inhibition.
Moclobemide only partially potentiates the blood pressor effect of oral
tyramine (DaPrada et al. 1989). This is because it is a reversible inhibitor with a
low affinity for the MAO isoenzymes and is easily displaced by the pressor
amines ingested in food. On the basis of these studies, moclobemide is thought
to be safer than irreversible MAOIs.
Pharmacokinetics
After oral administration of moclobemide, peak plasma concentrations are
reached within 1 hour. The drug is about 50% bound to plasma proteins and is
extensively metabolized; only 1% of the compound is excreted (unchanged) in
the urine. The half-life of the compound is approximately 12 hours.
Moclobemide is extensively metabolized; 95% of the administered dose is
excreted in the urine. The metabolites are pharmacologically inactive. The
presence of food reduces the rate (but not the extent) of moclobemide
absorption.
Indications
Moclobemide has been studied in all types of depressive disorders (Gabelic and
Kuhn 1990; Larsen et al. 1991; Rossel and Moll 1990). Controlled trials have
found that it is superior to placebo. In addition, moclobemide has been found to
be as effective as imipramine, desipramine, clomipramine, and amitriptyline in
the treatment of depression. The dosage required is 300–600 mg/day.
Unlike the classic MAOIs, moclobemide has been found to be effective in
treating both endogenous and nonendogenous depression. In addition, in
combination with antipsychotics, the drug seems to be effective in treating
psychotic depression (Amrein et al. 1989). Moclobemide has also been effective
in treating bipolar endogenous depression.
Versiani et al. (1992) compared phenelzine, moclobemide, and placebo and
reported that both phenelzine and moclobemide were superior to placebo in
treating patients with social phobia. Given the efficacy of classic MAOIs in the
treatment of other psychiatric disorders, such as bulimia, panic disorder, and
PTSD, it is likely that patients with such disorders would also respond to a
reversible MAOI. Additional trials of moclobemide are required to confirm its
utility in other psychiatric disorders.
Side Effects
Nausea was the only side effect noted to be greater in patients taking
moclobemide than in patients taking placebo. Thus, the profile of moclobemide
seems to be ideal in that it causes few or no major side effects. Case reports have
shown no toxicity after overdoses of up to 20 g (Amrein et al. 1989).
Dietary Interactions
Intravenous tyramine pressor tests indicate that a single dose of moclobemide
increases tyramine sensitivity (Cusson et al. 1991). However, this increase is
marginal, compared with the increase associated with other MAOIs. Under most
conditions, there appears to be limited drug–food interaction. However, to
minimize even mild tyramine pressor effects, the recommended action is to
administer moclobemide after a meal rather than before it. In a study in which
tyramine was administered in doses up to 100 mg, inpatients pretreated with
moclobemide had no significant changes in blood pressure. The drug also has
minimal effect on cognitive performance and no effect on body weight or
hematological parameters (Wesnes et al. 1989; Youdim et al. 1987).
Drug–Drug Interactions
Several studies have examined potential drug–drug interactions with
moclobemide (Amrein et al. 1992). No drug interaction with lithium has been
reported. No interactions with benzodiazepines or antipsychotics have been
reported (Amrein et al. 1992). Parallel data suggest that moclobemide can
potentiate the effects of meperidine; therefore, the narcotic–MAOI interaction
may occur. Combination with other antidepressants (including SSRIs) is best
avoided in view of potential serotonin toxicity. Until proven otherwise, it would
be prudent to avoid the combination of moclobemide with opiates like
meperidine. A pharmacokinetic interaction has been observed with cimetidine
that requires the reduction of the moclobemide dose because cimetidine reduces
the clearance of moclobemide.
Selegiline Hydrochloride
Selegiline hydrochloride is an irreversible MAO-B inhibitor (Cesura and
Pletscher 1992). Its primary use is in the treatment of Parkinson’s disease, as an
adjunct to L-dopa and carbidopa. The average dosage for Parkinson’s disease is
5–10 mg/day. The exact mechanism of action of MAO-B in Parkinson’s disease
is unknown (Gerlach et al. 1996; Hagan et al. 1997; Lyytinen et al. 1997).
Pharmacokinetics
Selegiline is metabolized to levoamphetamine, methamphetamine, and N-
desmethylselegiline. Selegiline hydrochloride undergoes significant first-pass
metabolism following oral administration. Transdermal delivery avoids the first-
pass effect and provides greater levels of unchanged drug and reduced levels of
metabolites compared with the oral regimen. The time to reach the peak is less
than 1 hour. The elimination half-life of selegiline is about 1.5 hours. There is at
least a threefold increase in the area under the curve (AUC) of selegiline with
food (Mahmood 1997).
Side Effects
The few side effects that have been noted with selegiline include nausea,
dizziness, and light-headedness. When the drug is abruptly discontinued, nausea,
hallucinations, and confusion have been reported.
Dietary Interactions
Because MAO-B is not involved in the intestinal tyramine interaction, dietary
interaction with selegiline (at low dosages of 5–10 mg/day) would probably be
minimal. An interaction between selegiline and narcotics has been reported and
should be kept in mind.
Drug–Drug Interactions
Selegiline’s potential drug interactions are similar to those of other MAOIs, and
there is a risk for serotonin syndrome if selegiline is combined with other drugs
(including SSRIs) that can increase serotonin.
Side Effects
The main side effects with STS are diarrhea, skin irritation, and insomnia.
Drug–Drug Interactions
Potential drug–drug interactions for STS are the same as for other MAOIs.
Conclusion
Various MAOIs have been shown to be effective in treating a wide variety of
psychiatric disorders, including depression, panic disorder, social phobia, and
PTSD. The classic MAOIs are currently used only rarely as first-line medication
because of potential dietary interactions and other long-term side effects. The
reversible inhibitors of MAO-A enzyme, such as moclobemide, which have
fewer side effects and no dietary restrictions compared with classic MAOIs, are
unlikely to be introduced in the United States. In fact, the risk–benefit ratio for
these compounds is highly favorable compared with other antidepressants. The
MAO-B inhibitor selegiline is used to reduce the progression of Parkinson’s
disease. Its utility in treating other degenerative disorders is currently being
assessed. STS reduces dietary interactions when used at low doses and is now
approved for the treatment of major depressive disorder. New applications and a
wider use of these compounds may be found in the near future.
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CHAPTER 9
Structure–Activity Relations
Tricyclic and tetracyclic compounds are categorized on the basis of their
chemical structure (Figure 9–1). The tricyclics have a central three-ring
structure, hence the name. The tertiary-amine tricyclics, such as amitriptyline
and imipramine, have two methyl groups at the end of the side chain. These
compounds can be demethylated to secondary amines, such as desipramine and
nortriptyline. The tetracyclic compound maprotiline has a four-ring central
structure. Five tertiary amines have been marketed in the United States—
amitriptyline, clomipramine, doxepin, imipramine, and trimipramine. The three
secondary-amine compounds are desipramine, nortriptyline, and protriptyline.
All of these compounds, in addition to amoxapine and maprotiline, have been
approved for use in major depressive disorder with the exception of
clomipramine, which in the United States is approved for use only in obsessive-
compulsive disorder (OCD).
FIGURE 9–1. Chemical structures of tricyclic and tetracyclic
antidepressants.
The nature of the side chain appears to be important for the tricyclics’
function. The tertiary tricyclic agents—amitriptyline, imipramine, and
clomipramine—are more potent in blocking the serotonin transporter. The
secondary tricyclics are much more potent in blocking the norepinephrine
transporter (Table 9–1) (Bolden-Watson and Richelson 1993; Tatsumi et al.
1997).
Drug 5-HT NE DA α1 α2 H1
Amitriptyline 4.3 35 3,250 27 940 1.1 18
Amoxapine 58.0 16 4,310 50 2,600 25 1,000
Clomipramine 0.28 38 2,190 38 3,200 31 37
Desipramine 17.6 0.83 3,190 130 7,200 110 198
Doxepin 68.0 29.5 12,100 24 1,100 0.24 80
Imipramine 1.4 37 8,500 90 3,200 11 90
Maprotiline 5,800.0 11.1 1,000 90 9,400 2 570
Nortriptyline 18.0 4.37 1,140 60 2,500 10 150
Protriptyline 19.6 1.41 2,100 130 6,600 25 25
Trimipramine 149.0 2,450 3,780 24 680 0.27 58
Reference
Pentolamine 15
Yohimbine 1.6
D- 15
Chlorpheniramine
Atropine 2.4
Serotonin
Ketanserin
Note. Affinity and potency=equilibrium dissociation constants in molarity. α1=α
adrenergic; DA=dopamine; 5-HT=serotonin; 5-HT1A=serotonin1A; 5-HT2=serotonin
M1=muscarinic1; NE=norepinephrine.
Source. Potency uptake data adapted from Tatsumi et al. 1997. Receptor affinity data adapted from Richelson and Nelson 198
The structure of amoxapine differs from the structures of the other tricyclics.
With a central three-ring structure and a side chain unlike those of the tricyclics,
amoxapine is structurally closer to the antipsychotic loxapine, from which it is
derived. Similar to the secondary tricyclics, it is a potent norepinephrine
reuptake inhibitor. Unlike all of the other compounds in this group, amoxapine,
and particularly its metabolite 7-hydroxyamoxapine, blocks postsynaptic
dopamine receptors (Coupet et al. 1979). As a result, it is the only compound in
the group that has antipsychotic activity in addition to antidepressant effects.
Maprotiline also differs from the others in this group. Although maprotiline is
tetracyclic, its side chain is identical to that in desipramine, nortriptyline, and
protriptyline. As would be predicted from this similarity, maprotiline is most
potent in blocking the norepinephrine transporter (Randrup and Braestrup 1977).
Pharmacological Profile
Reuptake Blockade
Early in the history of the tricyclic and tetracyclic antidepressants, the ability of
these compounds to block the transporter site for norepinephrine was described
(Axelrod et al. 1961) (see Table 9–1). The tertiary amines have greater affinity
for the serotonin transporter, whereas the secondary amines are relatively more
potent at the norepinephrine transporter. During the administration of
amitriptyline, imipramine, or clomipramine, these tertiary amines are
demethylated to secondary amines; thus, both serotonergic and noradrenergic
effects occur. In addition, because dopamine is inactivated by norepinephrine
transporters in the frontal cortex (Bymaster et al. 2002), norepinephrine reuptake
inhibitors would be expected to increase dopamine concentrations in that region.
Secondary Effects
The tricyclic and tetracyclic compounds have a variety of additional actions
mediated by other receptors (Cusack et al. 1994; Richelson and Nelson 1984)
(see Table 9–1). For example, these compounds block muscarinic receptors,
producing anticholinergic effects. Although these anticholinergic effects have
generally been thought to mediate the adverse effects of tricyclics and
tetracyclics, a double-blind randomized crossover study in 19 subjects with
major depressive disorder found that the anticholinergic drug scopolamine had a
beneficial effect on depressive and anxious symptoms (Furey and Drevets 2006).
Consistent with this finding, donepezil, a cholinergic drug (a cholinesterase
inhibitor), when given as an adjunct to an SSRI, increased the risk of depression
relapse in older adults (Reynolds et al. 2011). The tricyclics also block
histamine1 (H1) receptors and α1- and α2-adrenergic receptors, resulting in a
variety of other effects (as discussed in the next section). Tricyclics act on
voltage-gated sodium channels, which explains their adverse cardiac effects;
however, these same actions may contribute to the beneficial effects of tricyclics
on pain (Liang et al. 2014; Priest and Kaczorowski 2007). The potency of
secondary effects of the tricyclics and tetracyclics varies considerably. Among
the tricyclics, amitriptyline is the most anticholinergic and desipramine the least
anticholinergic. Doxepin is the most potent H1 antagonist among the tricyclics,
but mirtazapine is even more potent. The consequences of these secondary
effects are discussed below.
Volume of Distribution
The tricyclic and tetracyclic compounds are basic lipophilic amines and are
concentrated in a variety of tissues throughout the body. As a result, they have a
high volume of distribution. For example, concentrations of these drugs in
cardiac tissue exceed concentrations in plasma.
First-Pass Metabolism
Following absorption, the tricyclics are taken up in the circulation but pass first
through the liver, and metabolism of the drug begins—the so-called first-pass
effect. As a result, the amount of the compound that enters the systemic
circulation is reduced.
Hepatic Metabolism
Hepatic metabolism is the principal method of clearance for the tricyclic and
tetracyclic compounds. Only a small portion of drug is eliminated by the
kidneys. Rates of hepatic metabolism vary widely from person to person,
resulting in dramatic differences in steady-state plasma concentrations.
Elimination half-lives for most of the tricyclic and tetracyclic compounds
average about 24 hours or longer; thus, the drugs can be given once a day (Table
9–2). Amoxapine has a shorter half-life than the other tricyclics and is an
exception.
Tertiary tricyclics
Amitriptyline 5–45 20–70 150–300
Clomipramine 15–60 20–120 150–300 >150a
Doxepin 10–25 40–60 150–300
Imipramine 5–30 30–100 150–300 >200a
Trimipramine 15–40 40–105
Secondary tricyclics
Desipramine 10–30 80–170 75–300 >125
Nortriptyline 20–55 15–80 50–150 50–
150
Protriptyline 55–200 5–25 15–60
Tetracyclics
Amoxapine 5–10 225–275 150–300
Maprotiline 25–50 15–35 100–225
a
Total concentration of the parent compound and the desmethyl metabolite.
Source. Adapted from Nelson JC: “Tricyclic and Tetracyclic Drugs,” in Comprehensive Textbook of
Psychiatry/VII, 7th Edition. Edited by Kaplan HI, Sadock BJ. Baltimore, MD, Lippincott Williams &
Wilkins, 2000, p. 2494. Copyright 2000, Lippincott Williams & Wilkins. Used with permission.
Steady-State Concentrations
Steady state is the point on a fixed dose at which plasma concentrations of the
drug reach a plateau. Steady state is achieved after five half-lives. If blood level
monitoring is employed, a sample is drawn immediately before the next dose is
scheduled to be given, usually in the morning, after the patient’s level has
reached steady state. Steady-state drug concentrations should remain relatively
stable as long as the dosage is constant, the patient is adherent to the medication
regimen, and no interactive drugs are added. If only one sample is drawn, the
clinician should bear in mind that even if the laboratory error is low, there will
be moderate biological variability (±10%–15%). Single blood level samples are
better viewed as estimates than as precise measures.
When the drug concentration is measured, the total of both the free and bound
drug is reported. Drug concentrations in the cerebrospinal fluid are proportional
to the free levels. The free concentration is dependent on dose and hepatic
clearance but is not affected by plasma protein binding (Greenblatt et al. 1998).
Factors that affect plasma proteins—malnutrition, inflammation—may lead to
changes in the bound fraction, but the absolute free concentration is unaffected.
Linear Kinetics
Most of the tricyclics have linear kinetics; that is, concentration increases in
proportion to dose within the therapeutic range. There are exceptions.
Desipramine, for example, has nonlinear kinetics at the usual dosage range
(Nelson and Jatlow 1987). In cases of overdose, nonlinear changes are more
likely to occur, and the clinician cannot assume that usual rates of drug
elimination will be maintained.
Effects of Aging
Changes in the pharmacodynamics and pharmacokinetics of medications occur
with aging, yet some are relatively unimportant (Greenblatt et al. 1998). The
ratio of fat to lean body mass increases, and cardiac output and hepatic blood
flow decrease. There may be further changes associated with medical illness.
But the clinical importance of these changes is usually relatively minor because
of the dramatic variability of hepatic metabolism. The activity of the CYP3A4
pathway does slow with age (von Moltke et al. 1995), and concentrations of the
tertiary amines are increased somewhat in older individuals (Abernethy et al.
1985). Alternatively, most studies of nortriptyline (Katz et al. 1989; Young et al.
1984) and desipramine (Abernethy et al. 1985; Nelson et al. 1985, 1995) indicate
that ratios of blood level to dosage of these drugs are relatively unaffected by
aging, suggesting that the 2D6 isoenzyme is not similarly affected. Renal
clearance of the hydroxy metabolites does decrease with age (Nelson et al.
1988a; Young et al. 1984). As a result, concentrations of hydroxynortriptyline
may be substantially elevated in older patients.
In children, the clearance of tricyclic compounds is increased. Half-lives of
imipramine are shorter, and ratios of desmethylimipramine to imipramine are
higher, consistent with more rapid metabolism (Geller 1991; Rapoport and Potter
1981). Alternatively, a study of desipramine in children found that the clearance
of both desipramine and hydroxydesipramine was increased, so that hydroxy
metabolite–parent compound ratios were not elevated (Wilens et al. 1992).
Bipolar Depression
Forty years ago, it was suggested that the MAOI antidepressants might be more
effective than the tricyclics in treating bipolar depression (Himmelhoch et al.
1972). Later, Himmelhoch et al. (1991) demonstrated in a double-blind study
that tranylcypromine was more effective than imipramine for bipolar depression.
Because tricyclics are more likely than other agents to induce mania (Wehr and
Goodwin 1987), they are not recommended for monotherapy of bipolar
depression.
Late-Life Depression
Gerson et al. (1988) reviewed studies of tricyclic antidepressants in older
patients reported prior to 1986. They found 13 placebo-controlled trials but
noted several methodological problems. Although tricyclics were effective,
overall response rates in older patients appeared to be lower than rates in
nonelderly patients (Agency for Health Care Policy and Research 1993). Katz et
al. (1990) performed one of the first placebo-controlled trials of nortriptyline in
the treatment of patients older than 80 years living in a residential care facility.
Nortriptyline was more effective than placebo. The doses employed and levels
achieved were similar to those in younger subjects. This study remains the only
study to date showing an advantage for an antidepressant over placebo in
depressed nursing home patients.
Depression in Children
In children and adolescents, the tricyclic antidepressants have not demonstrated
superiority over placebo (Ryan 1992).
Panic Disorder
Although none of the tricyclic or tetracyclic drugs is approved for use in panic
disorder, imipramine was the first drug described for use in this disorder (Klein
1964). The efficacy of both tertiary and secondary tricyclics has been
demonstrated in controlled trials (Jobson et al. 1978; Munjack et al. 1988; Zitrin
et al. 1980). In treating this disorder, the drug is initiated at a low dose to avoid
exacerbation of panic symptoms.
Obsessive-Compulsive Disorder
Unlike depression, which responds to a variety of antidepressant agents, OCD
appears to require treatment with a serotonergic agent. Clomipramine, the most
serotonergic of the tricyclics, is approved by the FDA for use in OCD, and its
efficacy in this disorder is well established (Greist et al. 1995). Studies
comparing its effectiveness with that of noradrenergic agents such as
desipramine found that clomipramine was substantially superior (Leonard et al.
1989). Although the SSRIs are effective in treating OCD, there is a suggestion
that clomipramine may be superior (Greist et al. 1995). Whether this suggested
superiority is due to the dual mechanism of clomipramine or to other factors is
unclear.
Attention-Deficit/Hyperactivity Disorder
The efficacy of the stimulant drugs in treating attention-deficit/hyperactivity
disorder (ADHD) is well established. The tricyclics, especially desipramine, also
appear to be of value. In one study, desipramine, given at dosages greater than 4
mg/kg for 3–4 weeks, was effective in two-thirds of the children, whereas
placebo was effective in only 10% (Biederman et al. 1989). Desipramine was
also found to be more effective than placebo in adults with ADHD (Wilens et al.
1996). One of the advantages of desipramine is its low potential for abuse.
Unfortunately, five cases of sudden death were reported in the early 1990s in
children being treated with desipramine (Riddle et al. 1991, 1993). All were
under the age of 12 years. As a result, desipramine is contraindicated in children
younger than 12 years (discussed in greater detail below; see section “Side
Effects and Toxicology”). Given that tricyclics as a group share the same adverse
cardiac effects, there is reason to be concerned that other tricyclics might also
have safety issues in young children (see also Chapter 55, “Treatment of Child
and Adolescent Disorders”).
Pain Syndromes
The tricyclics and the tetracyclic maprotiline have been widely used in various
chronic pain syndromes. In a review of the literature, O’Malley et al. (1999)
identified 56 controlled studies involving tricyclic antidepressant therapy for
various pain syndromes, including headache (21 studies), fibromyalgia (18
studies), functional gastrointestinal syndromes (11 studies), idiopathic pain (8
studies), and tinnitus (2 studies); and Salerno et al. (2002) identified 7 more
placebo-controlled trials of tricyclics or maprotiline used for chronic back pain.
These agents were quite effective; the mean effect size (0.87) and the drug–
placebo difference in response rates (32%) in the pain trials were more robust
than those usually observed in placebo-controlled studies in depression. The
analgesic effects of these compounds were not simply the result of their
antidepressant effects.
The mechanism of these agents’ analgesic effects appears to differ from that of
their antidepressant effects. The antinociceptive actions of the antidepressants
result from actions on descending norepinephrine and serotonin pathways in the
spinal cord (Yoshimura and Furue 2006). In animals, the antinociceptive effects
of norepinephrine reuptake inhibitors and combined norepinephrine–serotonin
reuptake inhibitors appear to be more potent than those of SSRIs (Mochizucki
2004). In humans, there is some evidence that the combined-action agents
amitriptyline and clomipramine are more effective than the SSRI fluoxetine
(Max et al. 1992) or the norepinephrine-selective agents maprotiline (Eberhard
et al. 1988) and nortriptyline (Panerai et al. 1990). In humans, antidepressant
dosing and timing of effects for pain differ from those for depression. For
example, usual dosages of amitriptyline required for pain management (≤75
mg/day) are lower than those required to treat depression (15–300 mg/day), and
response occurs more quickly, usually within the first 1 or 2 weeks.
Other Indications
Imipramine has been used for treatment of nocturnal enuresis in children, with
FDA approval, and controlled trials indicate efficacy (Rapoport et al. 1980). The
dose of imipramine is usually 25–50 mg at bedtime. Amitriptyline and
nortriptyline also appear to be useful for this indication, although they are not
FDA approved for use in the disorder. The mechanism of action is unclear but
may in part be anticholinergic. Given the serious cardiac risks attached to
desipramine’s use in children younger than 12 years (discussed in earlier
subsection “Attention-Deficit/Hyperactivity Disorder”), concerns have been
raised regarding whether tricyclics other than desipramine might also pose safety
risks in this population. However, the low doses used in imipramine treatment of
pediatric nocturnal enuresis may reduce this risk.
Tricyclic antidepressant drugs have been extensively studied in patients with
schizophrenia. However, in the absence of a major depressive episode, these
agents appear to be of limited value (Siris et al. 1978).
The more sedating tricyclics have been used to treat insomnia, and doxepin
(as Silenor) is FDA approved for this indication. Because of its antihistaminic
effects, doxepin has also been used for pruritis and is FDA indicated (as
Zonalon) for short-term management of moderate pruritus in atopic dermatitis
and lichen simplex chronicus.
Anticholinergic Effects
The tricyclics block muscarinic receptors and can cause a variety of
anticholinergic side effects, such as dry mouth, constipation, blurred vision, and
urinary hesitancy. These effects can precipitate an ocular crisis in patients with
narrow-angle glaucoma. The tricyclic and tetracyclic compounds vary
substantially in their muscarinic potency (see Table 9–1). Amitriptyline is the
most potent, and desipramine is the least anticholinergic. Amoxapine and
maprotiline also have minimal anticholinergic effects. Anticholinergic effects
can contribute to tachycardia, but tachycardia also occurs as a result of
stimulation of β-adrenergic receptors in the heart. Thus, tachycardia also occurs
in patients receiving desipramine, which is minimally anticholinergic
(Rosenstein and Nelson 1991).
Although anticholinergic effects are annoying, they are usually not serious.
They can, however, become severe. An ocular crisis in patients with narrow-
angle glaucoma is an acute condition associated with severe pain. Urinary
retention can be associated with stretch injuries to the bladder. Constipation can
progress to severe obstipation. (Paralytic ileus has been described but is rare.) In
these conditions, medication must be discontinued and appropriate supportive
measures instituted. Elderly patients are at greatest risk for severe adverse
consequences. The incidence of severe anticholinergic adverse reactions is
increased by concomitant administration of other anticholinergic agents. Use of a
tricyclic with weak anticholinergic properties, such as nortriptyline or
desipramine, can help to reduce the likelihood of these problems.
Anticholinergic side effects may benefit from other interventions. Bethanechol
(Urecholine) at a dosage of 25 mg three or four times a day may be helpful in
patients with urinary hesitancy. The regular use of stool softeners helps to
manage constipation. Patients with narrow-angle glaucoma who are receiving
pilocarpine eye drops regularly can be treated with a tricyclic, as can those who
have had an iridectomy. Tricyclic agents do not affect patients with chronic
open-angle glaucoma.
Antihistaminic Effects
Several of the tricyclic compounds and maprotiline have clinically significant
antihistaminic effects. Doxepin, the most potent H1 receptor antagonist among
the tricyclics, is more potent than diphenhydramine but less potent than
mirtazapine. Central H1 receptor blockade can contribute to sedation and
delirium and also appears to be related to the increased appetite and associated
weight gain that patients may develop with chronic treatment. Because of their
sedating effects, the tricyclic antidepressants, especially amitriptyline, have been
used as hypnotics. Given their cardiac effects and lethality in overdose, this
practice should be discouraged.
Cardiovascular Effects
Orthostatic hypotension is one of the most common reasons for discontinuation
of tricyclic antidepressant treatment (Glassman et al. 1979). It can occur with all
of the tricyclics but appears to be less pronounced with nortriptyline (Roose et
al. 1981; Thayssen et al. 1981). The α1-adrenergic blockade associated with the
tricyclics contributes to orthostatic hypotension; however, it is the postural reflex
that is primarily affected. Resting supine blood pressure may be unaffected or
can even be elevated (Walsh et al. 1992). Orthostatic hypotension is most likely
to occur or is most severe in patients who have preexisting orthostatic
hypotension (Glassman et al. 1979). It is also aggravated by concurrent
antihypertensive medications, especially volume-depleting diuretic agents. The
elderly are more likely to have preexisting hypotension and are also more
vulnerable to the consequences of orthostatic hypotension, such as falls and hip
fractures.
Orthostatic hypotension often occurs at low medication blood levels. Gradual
dosage adjustment may allow accommodation to the subjective experience of
light-headedness, but the actual orthostatic blood pressure changes do not
accommodate within a reasonable period of time (e.g., 4 weeks) (Roose et al.
1998). As a consequence, patients who experience serious symptomatic
orthostatic hypotension may not be treatable with a tricyclic antidepressant.
Fludrocortisone (Florinef) has been used to raise blood pressure, but in this
author’s experience it is not very effective. If patients are receiving
antihypertensives, it may be possible and helpful to reduce the dosage of these
agents.
Desipramine has been reported to raise supine blood pressure in young
women (ages 18–45 years), although it is not clear that this effect is limited to
that age group (Walsh et al. 1992). The elevation in blood pressure may be
similar to that reported for venlafaxine.
Tachycardia occurs with all of the tricyclics, not just the more anticholinergic
agents. Both supine and postural pulse changes can occur, and the standing pulse
can be markedly elevated. A study of nortriptyline, dosed to a therapeutic plasma
concentration, found a mean pulse increase of 11% (8 beats per minute) (Roose
et al. 1998). Patients do not accommodate to the pulse rise, which can persist for
months. Tachycardia is more prominent in young patients, who appear to be
more sensitive to sympathomimetic effects, and is one of the most common
reasons for drug discontinuation in adolescents. A persistent pulse rise, however,
increases cardiac work and may be clinically significant in patients with
ischemic heart disease.
The effect of tricyclic antidepressants on cardiac conduction has been a
subject of great interest. Cardiac arrhythmia is the principal cause of death
following tricyclic overdose (Spiker et al. 1975). Apparently, through inhibition
of sodium/potassium (Na+/K+) adenosine triphosphatase (ATPase), the tricyclics
stabilize electrically excitable membranes and delay conduction, particularly His
ventricular conduction. Consequently, the tricyclics have type I antiarrhythmic
qualities or quinidine-like effects.
At therapeutic blood levels, the tricyclics can have beneficial effects on
ventricular excitability. In patients with preexisting conduction delay, however,
the tricyclic antidepressants can cause heart block (Glassman and Bigger 1981;
Roose et al. 1987b). A pretreatment QTc interval of 450 milliseconds or greater
indicates that conduction is already delayed and that the patient is not a
candidate for tricyclic antidepressant treatment. High drug plasma levels (e.g.,
imipramine plasma concentrations >350 ng/mL) increase the risk of first-degree
atrioventricular heart block (Preskorn and Irwin 1982). The tricyclic
antidepressants do not reduce cardiac contractility or cardiac output (Roose et al.
1987a).
Glassman et al. (1993), noting that the type I antiarrhythmic drugs routinely
given following myocardial infarction actually increase the risk of sudden death,
suggested that the tricyclics may pose similar risks. The risk of sudden death is
also increased when heart rate variability is reduced, and the tricyclics reduce
heart rate variability (Roose et al. 1998).
As mentioned earlier (see subsection “Attention-Deficit/Hyperactivity
Disorder”), five cases of sudden death were reported in children younger than 12
years who were receiving desipramine (Riddle et al. 1991, 1993). It was
suggested that the immature conduction system in some children might render
them more vulnerable to the cardiac effects of desipramine. However, no cardiac
abnormalities were observed in a study of 71 children with 24-hour cardiac
monitoring (Biederman et al. 1993). These findings suggest that cardiac events
in children are not dose dependent and that electrocardiogram monitoring is not
likely to identify those at risk.
Hepatic Effects
Acute hepatitis has been associated with use of imipramine (Horst et al. 1980;
Moskovitz et al. 1982; Weaver et al. 1977) or desipramine (Powell et al. 1968;
Price et al. 1983). Mild increases in liver enzymes (less than three times normal)
are not uncommon and usually can be monitored safely over a period of days or
weeks. Enzyme changes do not appear to be related to drug concentrations (Price
et al. 1984). Acute hepatitis is relatively uncommon but can occur. The etiology
is not well established, but in some cases the condition appears to represent a
hypersensitivity reaction. Tricyclic-induced acute hepatitis is characterized by
very high enzyme levels (e.g., aspartate aminotransferase [AST] levels >800),
which develop within days. The enzyme pattern can be either hepatocellular or
cholestatic. Enzyme changes may precede clinical symptoms, especially in the
hepatocellular form. If a random blood test indicates mildly elevated liver
enzymes, enzyme levels can be followed for a few days. Because of the rapid
rise in liver enzyme levels in acute hepatitis, that condition will become evident
quickly and will be easily distinguished from mild, persistent enzyme level
elevations.
Acute hepatitis is a dangerous and potentially fatal condition. If it develops,
the antidepressant must be discontinued and should not be introduced again,
because the next reaction may be more severe.
Overdose
Because antidepressants are used by depressed patients who are at risk for
overdose, the lethality of antidepressant drugs in overdose is of great concern. A
tricyclic overdose of 10 times the total daily dosage can be fatal (Gram 1990;
Rudorfer and Robins 1982). Death most commonly results from cardiac
arrhythmia. However, seizures, CNS depression, and respiratory depression also
can occur. Although the use of tricyclics in depression has declined,
amitriptyline remains widely used for other indications, such as pain. The total
number of amitriptyline-associated deaths reported to U.S. poison control
centers is more than twice the number of deaths associated with all other
tricyclics and tetracyclics combined (Mowry et al. 2014). All of the tricyclic and
tetracyclic compounds can be dangerous in overdose; however, two reports
found that the ratio of deaths to number of prescriptions written was relatively
low for clomipramine compared with that for other tricyclics (Cassidy and
Henry 1987; Farmer and Pinder 1989).
Teratogenicity
The long history of tricyclic use without observation of birth defects argues for
the safety of these agents. Of course, the patient must be informed of the
possible risks and benefits of taking the drug and the risks of discontinuing
treatment before making a decision. The risk of recurrence is particularly high
during or following pregnancy for patients with a prior history of depression.
If tricyclics are continued during pregnancy, dosage adjustment may be
required because of metabolic changes (Altshuler and Hendrick 1996). Drug
withdrawal following delivery can occur in the infant and is characterized by
tachypnea, cyanosis, irritability, and poor sucking reflex. Drugs in this class
should be discontinued 1 week prior to delivery if possible. The tricyclics are
excreted in breast milk at concentrations similar to those in plasma, but the
actual quantity delivered is very small, so that drug levels in the infant are
usually undetectable (Rudorfer and Potter 1997; also see Chapter 57,
“Psychopharmacology During Pregnancy and Lactation”).
Drug–Drug Interactions
Both pharmacodynamic and pharmacokinetic drug interactions should be
considered.
Pharmacodynamic Interactions
Serious pharmacodynamic interactions can occur between the tricyclics and the
MAOIs. The most dangerous scenario—administration of a large dose of a
tricyclic to a patient who is already taking an MAOI—could result in a sudden
increase in catecholamines and a potentially fatal hypertensive reaction.
Tricyclics and MAOIs have been used together to treat patients with refractory
depression (Goldberg and Thornton 1978; Schuckit et al. 1971). When used in
combination, treatment is begun with lower dosages, and either the two
compounds are started together or the tricyclic is started first.
The most common pharmacodynamic interaction involving tricyclics occurs
when they are added to other sedating agents, resulting in increased sedation. By
blocking the norepinephrine transporters, the tricyclics block the uptake and thus
interfere with the actions of guanethidine and tyramine. Desipramine and the
other tricyclics reduce the effect of clonidine.
Quinidine is an example of a drug with a potential for dynamic and kinetic
interaction with tricyclics. Because the tricyclics have quinidine-like effects, the
effects of tricyclics and quinidine on cardiac conduction are potentially additive.
In addition, quinidine is a potent CYP2D6 isoenzyme inhibitor that can raise
tricyclic levels, further adding to the problem.
Pharmacokinetic Interactions
A number of drugs can block the metabolic pathways of the tricyclics, resulting
in higher and potentially toxic blood levels of drug. Desipramine has been of
particular interest because it is metabolized via the CYP2D6 isoenzyme and
there are no major alternative pathways. Inhibition of CYP2D6 can result in very
high desipramine plasma levels, and toxicity can occur (Preskorn et al. 1990).
Quinidine, mentioned above, is a very potent CYP2D6 inhibitor. Fluoxetine and
paroxetine, duloxetine, bupropion, and some antipsychotics also inhibit
CYP2D6. Fluoxetine and paroxetine at usual dosages raise desipramine levels,
on average, three- to fourfold in individuals who are extensive metabolizers
(Preskorn et al. 1994). CYP2D6 inhibitors would be expected to block
nortriptyline metabolism, but the magnitude of this interaction has not been well
studied.
Because the tertiary tricyclics are metabolized by several pathways (CYP1A2,
3A4, 2C19), a selective inhibitor of one pathway would be unlikely to have a
significant effect on their plasma levels. Although numerous drug interactions
have been described, many are of doubtful clinical significance (for
comprehensive reviews, see Nemeroff et al. 1996; Pollock 1997).
Enzyme induction can also occur, which may render the tricyclic acted upon
ineffective. Unlike enzyme inhibition, which occurs quickly, enzyme induction
requires synthesis of new enzyme, and the full effect may take 2–3 weeks to
develop. Barbiturates and carbamazepine are potent inducers of CYP3A4;
induction by phenytoin appears to be less pronounced. Although CYP2D6 is a
noninducible isoenzyme, phenobarbital reduces the availability of desipramine
substantially. Apparently when CYP3A4 is induced, it becomes an important
metabolic pathway for desipramine and the other tricyclics. In this author’s
experience, it can be difficult to attain an effective blood level of desipramine in
the presence of a barbiturate.
Nicotine induces the CYP1A2 pathway and may lower concentrations of the
tertiary tricyclics, but the secondary tricyclics (e.g., desipramine, nortriptyline)
are less affected.
Acute ingestion of alcohol can reduce first-pass metabolism, resulting in
higher tricyclic levels. Because tricyclic overdose is often associated with
alcohol ingestion, this is an important consideration. Alternatively, chronic use
of alcohol appears to induce hepatic isoenzymes and may lower tricyclic levels
(Shoaf and Linnoila 1991).
The tricyclics themselves appear to be weak enzyme inhibitors, and few
clinically significant interactions have been described. The tertiary tricyclics
compete with warfarin for some metabolic enzymes (e.g., CYP1A2) and may
raise warfarin levels.
Conclusion
The tricyclic drugs were the mainstay of treatment for depression for three
decades. Although the second-generation antidepressants appear to be better
tolerated, no new agent has been shown to be more effective than the tricyclics,
and if anything, there has been concern that the new agents may be less
effective. The tricyclics were “dirty” drugs; that is, they had multiple actions.
Although their side effects have been emphasized, these multiple actions may
contribute to their efficacy. Not only does amitriptyline block uptake of 5-HT,
but its metabolite blocks uptake of norepinephrine, and in addition, amitriptyline
is a 5-HT2 antagonist. Furthermore, the anticholinergic effects of amitriptyline
may contribute to antidepressant activity. The principal drawback of this class of
agents is the risk of serious cardiac adverse effects. Tricyclics can aggravate
arrhythmia in patients with preexisting conduction delay. They also may increase
the risk of sudden death in children and in patients with ischemic heart disease.
Moreover, a week’s supply of medication taken in overdose can be fatal.
Because of these adverse effects, it is unlikely that there will be a resurgence of
interest in the tricyclics. Nevertheless, the efficacy of these agents across a range
of disorders, including pain, illustrates the potential advantages of antidepressant
drugs that have multiple actions.
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6101535
CHAPTER 10
Fluoxetine
Jerrold F. Rosenbaum, M.D.
Dawn F. Ionescu, M.D.
Structure–Activity Relations
Drugs that inhibit 5-HT reuptake vary in their selectivity. Despite the tendency to
lump the contemporary SSRIs into the same class designation, significant
structural and activity differences exist. Their chemical structures help illustrate
this diversity (Figure 10–1). In contrast to paroxetine and sertraline, which exist
as single isomers, fluoxetine, like citalopram, is a racemate. The family of SSRIs
manifests diverse structural and activity relations. Such data are in vitro and thus
subject to methodological variability (Thomas et al. 1987). Fluoxetine is less
potent than paroxetine in vitro and less selective for 5-HT reuptake inhibition
(relative to norepinephrine) than citalopram. However, note that in vitro potency
does not necessarily equate with in vivo dosing experience, clinical efficacy, or
adverse-event profile.
FIGURE 10–1. Chemical structures of selective serotonin
reuptake inhibitors and selected tricyclic antidepressants.
Pharmacological Profile
Serotonin
The action of any SSRI extends beyond the inhibition of 5-HT reuptake. At least
14 different 5-HT receptor subtypes reside at pre- and postsynaptic locations
(Fuller 1996). Serotonin1A (5-HT1A) binding sites include both somatodendritic
and presynaptic auto-receptors (which inhibit 5-HT firing) and postsynaptic
receptors. The latter are predominantly hippocampal, and their sensitivity is
increased after chronic antidepressant exposure (Aghajanian et al. 1988; Castro
et al. 2003).
After chronic administration, many antidepressants downregulate or reduce
the density of serotonin2 (5-HT2) binding sites in rat frontal cortex (Peroutka and
Snyder 1980). Some, but not all, SSRIs have been associated with this effect
(Fraser et al. 1988), and fluoxetine has been demonstrated to normalize 5-HT1A
density in rats (Sodero et al. 2006). SSRIs, as a drug class, have been reported to
normalize both 5-HT1A and 5-HT2 receptor density among patients with
depression (Leonard 1992).
The mechanisms by which fluoxetine and other SSRIs interact with the human
serotonin transporter (SERT) are not fully understood. Some evidence suggests
that fluoxetine’s effect on SERT is partially based on SERT promoter
polymorphism; it can lead to increased or decreased SERT expression,
depending on an individual’s genotype (Little et al. 2006). Further studies have
shown that SERT may also be inhibited at the posttranslational stage, likely
through multiple binding sites on the SERT molecule itself (Henry et al. 2006;
Iceta et al. 2007).
Fluoxetine transiently inhibits dorsal raphe firing, decreases terminal
autoreceptor function, and ultimately increases net 5-HT synaptic transmission
within CA3 pyramidal cells in the hippocampus (Blier et al. 1988).
Electrophysiological studies indicate that most antidepressants enhance net 5-HT
transmission after chronic administration (Blier et al. 1990), albeit at different
loci: the TCAs via enhanced sensitivity of postsynaptic 5-HT1A receptors, and
the SSRIs (and MAO inhibitors [MAOIs]) via reduced sensitivity of
somatodendritic (5-HT1A) and terminal (serotonin1D [5-HT1D]) autoreceptors.
SSRIs and TCAs also exert an inhibitory effect on serotonin3 (5-HT3) receptors
in a noncompetitive fashion (Eisensamer et al. 2003). These observations of
different mechanisms may help to explain why certain depressive symptoms that
do not respond to one class of antidepressant will respond to another class and
may also explain the enhanced response reported when combinations of
antidepressant agents are used.
Norepinephrine
Chronic administration of most somatic treatments for depression downregulates
or reduces the density of β-adrenergic binding sites in the brain (Bergstrom and
Kellar 1979). These treatments include traditional norepinephrine-specific and
mixed uptake inhibitors (Charney et al. 1981). However, results with the SSRIs
have been less consistent (Johnson 1991). Despite its in vitro 5-HT selectivity,
fluoxetine has been observed, with autoradiography, to induce β-adrenergic
receptor downregulation. It has also been shown in at least one study to increase
extracellular norepinephrine concentrations in rat prefrontal cortex after acute
systemic administration; this effect was not observed with other SSRIs tested
(Bymaster et al. 2002). Fluoxetine has also been demonstrated to potentiate the
noradrenergic effects of bupropion (Li et al. 2002).
Most studies with SSRIs have not shown a consistent change in β-adrenergic
binding or β-adrenergic-stimulated cyclic adenosine monophosphate (cAMP)
production. However, Baron et al. (1988) reported that fluoxetine, when it was
coadministered with desipramine, augmented the reduction in cortical β-
adrenergic receptors expected with desipramine alone. In contrast, investigations
with fluvoxamine, paroxetine, and citalopram have not yielded consistent results.
In general, the greater the 5-HT selectivity of a compound, the less in vitro
evidence for β-adrenergic downregulation has been seen. Thus, β-adrenergic
downregulation may not be essential for clinical efficacy.
Current data do not support a significant effect on α-adrenergic receptor
affinity or density by the SSRIs. Studies using radiolabeling to investigate
fluoxetine (Wong et al. 1985) have shown relative inactivity at this site.
Fluoxetine has been reported to reduce desipramine-induced release of growth
hormone after 4 weeks of treatment (O’Flynn et al. 1991). This effect suggests
possible indirect activity at the α2-adrenergic receptor.
In summary, although relative differences in adrenoreceptor affinity exist
across the SSRI class, and fluoxetine may have more adrenergic activity than
some of the other SSRIs, the clinical significance of these differences appears to
be negligible.
Dopamine
Animal studies provide evidence that the serotonergic system may exert tonic
inhibition on the central dopaminergic system. Serotonin has also been shown to
decrease the generation of dopaminergic cells from mesencephalic precursors in
rats, an effect mediated by serotonin4 (5-HT4) and serotonin7 (5-HT7) receptors
found on glial cells (Parga et al. 2007). Thus, fluoxetine might diminish
dopaminergic transmission, consistent with anecdotes of extrapyramidal side
effects (EPS) occurring during fluoxetine therapy (Bouchard et al. 1989). 5-HT
agonists, however, also exert a facilitatory influence on dopamine release
(Benloucif and Galloway 1991), which can be antagonized by the 5-HT1 blocker
pindolol, and evidence suggests that SSRIs may actually sensitize mesolimbic
dopamine receptors (Arnt et al. 1984a, 1984b). Furthermore, repeated
administration of fluoxetine, citalopram, or paroxetine to rats increased
spontaneous dopaminergic neuronal activity (Sekine et al. 2007), and chronic
fluoxetine treatment also increased brain-derived neurotrophic factor (BDNF)
expression within rat dopaminergic regions (Molteni et al. 2006).
Mechanism of Action
In the absence of pharmacological manipulation, the reuptake of 5-HT into the
presynaptic nerve terminal typically leads to its inactivation. Fluoxetine, through
blockade of the reuptake process, acutely enhances serotonergic
neurotransmission by permitting 5-HT to act for an extended period of time at
synaptic binding sites. A net result is an acute increase in synaptic 5-HT. One
difference separating SSRIs from direct-acting agonists is that SSRIs are
dependent on neuronal release of 5-HT for their action—that is, SSRIs can be
considered augmenters of basal physiological signals, but they are not direct
stimulators of postsynaptic receptor function, and they are dependent on
presynaptic neuronal integrity. These pharmacodynamic features might explain
SSRI nonresponse. If the release of 5-HT from presynaptic neuronal storage sites
is substantially compromised and, in turn, if net synaptic 5-HT concentration is
negligible, a clinically meaningful response to an SSRI would not be expected.
Serotonin receptors also include a family of presynaptic autoreceptors that
suppresses the further release of 5-HT, thus limiting the degree of postsynaptic
receptor stimulation that can be achieved. de Montigny et al. (1989) investigated
the mechanism of action of several SSRIs and suggested that the enhanced
efficacy of serotonergic synaptic transmission is not the result of increased
postsynaptic sensitivity. Rather, longer-term SSRI treatment induced a
desensitization of somatodendritic and terminal 5-HT autoreceptors. This
desensitization would permit 5-HT neurons to reestablish a normal rate of firing,
despite sustained reuptake blockade. These neurons could then release a greater
amount of 5-HT (per impulse) into the synaptic cleft. This modification
reportedly occurs over a time course that is compatible with the antidepressant
response.
Panic Disorder
SSRIs are the drugs of choice in the prevention of panic attacks and in the
treatment of panic disorder. Positive results from double-blind, placebo-
controlled trials in patients with panic disorder are available for fluoxetine
(Michelson et al. 2001). In general, patients with panic disorder need a low
initial dose of fluoxetine (e.g., 10 mg); however, often usual antidepressant
dosing for optimal response (e.g., 20–80 mg) is required. The initial low dose
serves to minimize early side effects in anxious patients who are particularly
sensitive to somatic symptoms of anxiety, and it sets the stage for long-term
compliance. The recurrent and chronic nature of panic disorder requires
individual medication regimens that may include multiple agents as well as
variable dosages.
Eating Disorders
Manipulation of central 5-HT results in significantly altered feeding behaviors
(e.g., an increased satiety response) (Carruba et al. 1986). Blundell (1986)
reported that pharmacological enhancement of 5-HT reduced meal size, rate of
eating, and body weight. The predominant locus of this 5-HT effect is likely
within the hypothalamus and may be mediated through gene expression of
neuropeptide Y (NPY) and pro-opiomelanocortin (POMC) (Myung et al. 2005).
In general, the ability of an antidepressant to diminish appetite and, in turn, to
reduce weight is related to its ability to block 5-HT uptake (Angel et al. 1988).
Bulimia Nervosa
Agents with at least some degree of 5-HT uptake inhibition have been useful in
bulimia nervosa (see Brewerton et al. 1990). Clinical trials with fluoxetine have
found a positive treatment effect on binge eating and purging behaviors
(Goldstein et al. 1995). In a large placebo-controlled trial, Enas et al. (1989)
studied dosing of 20 mg versus 60 mg of fluoxetine in 382 female outpatients
with bulimia. A clinical benefit was observed in binge frequency, purging, mood,
and carbohydrate craving. In a smaller study of 91 female patients in a primary
care setting, women assigned to receive fluoxetine kept more physician
appointments, exhibited greater reductions in binge eating and vomiting, and had
a greater improvement in psychological symptoms than those assigned to receive
placebo (Walsh et al. 2004). Continued treatment with fluoxetine is associated
with improvement and decreased risk of relapse (Romano et al. 2002).
Anorexia Nervosa
Pharmacological trials with SSRIs in patients with anorexia nervosa have been
relatively sparse. Kaye et al. (1991) suggested that fluoxetine may help maintain
body weight in patients with anorexia nervosa who have gained weight. This
group also completed a similar study with fluoxetine under controlled
conditions, suggesting some benefit for fluoxetine in improving outcome and
preventing relapse (Kaye et al. 2001). On the other hand, Walsh et al. (2006)
found no benefit for continued treatment with fluoxetine after weight restoration
in a randomized, double-blind, placebo-controlled trial of 93 patients. Efficacy
of SSRIs has been linked to the food obsessions of many patients with eating
disorders.
Pain Syndromes
Fluoxetine has shown efficacy in reducing pain associated with diabetic
neuropathy (Max et al. 1992). Fluoxetine (20 mg/day) improved scores on
measures of pain and discomfort in subjects with fibromyalgia, compared with
subjects on placebo (Arnold et al. 2002; Goldenberg et al. 1996). The effect of
fluoxetine combined with amitriptyline was superior to the effect of either agent
used alone. Fluoxetine reduced the number of attacks in patients with migraine
headaches (Saper et al. 1994). More recent work has demonstrated that
antidepressants that also affect the norepinephrine system (i.e., serotonin–
norepinephrine reuptake inhibitors [SNRIs]) are more effective than the SSRIs in
treating neuropathic pain (Mochizucki 2004; Pedersen et al. 2005). In fact, the
SNRI duloxetine has received FDA approval for the treatment of neuropathic
pain.
Obesity
SSRIs have been extensively investigated for an effect on food consumption.
This interest stems from evidence that perturbation of 5-HT receptors modifies
animal feeding behavior (Garattini et al. 1986). This modification appears to be
independent of a local gastrointestinal effect (e.g., the perception of nausea). 5-
HT innervation to the hypothalamus influences satiety and may selectively affect
carbohydrate consumption (Wurtman et al. 1981). In one large trial, 458 patients
were treated for 52 weeks with fluoxetine (60 mg/day) or placebo (Goldstein et
al. 1994). Weight loss was significantly greater in the fluoxetine-treated group at
28 weeks, but not at 52 weeks. Long-term benefits may be better sustained when
fluoxetine is combined with behavior modification (Marcus et al. 1990).
The broad involvement of the serotonergic system in modulating behavior and
cognition supports the wide potential utility of SSRIs.
Specific Issues
Suicidality
Evidence implicating 5-HT in suicide or violence is compelling. Reduced
cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) concentrations
correlate highly with completed suicides in patients with depression (Edman et
al. 1986; Ninan et al. 1984). In vitro binding assays have shown an increased
density (Bmax) of 5-HT2 receptors in individuals with depression and suicidal
tendencies (Pandey et al. 1990). Both observations are consistent with a relative
state of 5-HT depletion among subjects with suicidal tendencies. The American
College of Neuropsychopharmacology (1992) reviewed evidence showing that
antidepressants result in substantial improvement or remission of suicidal
ideation and impulses in the vast majority of patients; SSRIs were thought to
potentially “carry a lower risk for suicide than older tricyclic antidepressants” (p.
181) when taken in overdose. Furthermore, the task force stated that no evidence
indicated that SSRIs triggered emergent suicidal ideation above base rates
associated with depression. In addition, Warshaw and Keller (1996) determined
that fluoxetine use did not increase the rate of suicide in a group of 654 patients
with anxiety disorders. In a large retrospective review of patients receiving one
or more of 10 antidepressants (including fluoxetine), Jick et al. (1995) concluded
that the risk for suicide was similar among all agents.
Concern about suicidality surged in 2003 after the industry alerted the FDA
that there might be an increased risk of suicide-related adverse events in children
being treated with paroxetine. The FDA’s review of available data found that
approximately 4% of children taking SSRI medications reported or exhibited
suicidal thinking or behavior (including suicide attempts)—twice the rate of
those taking placebo. No completed suicides occurred among nearly 2,200
children treated with SSRIs, however.
The FDA’s review was followed by a number of other studies examining this
issue, including a meta-analysis of 24 pediatric trials of nine antidepressant
drugs by Hammad et al. (2006). These authors found a modestly increased risk
of suicidality (risk ratio=1.66) for SSRIs in depression trials (95% confidence
interval=1.02–2.68). This risk must be balanced against the benefit—in the form
of general improvement in mood and overall functioning—experienced by most
depressed patients when they are placed on antidepressant therapy. In most
cases, the therapeutic benefit of SSRIs will outweigh the risk of increased
suicidal thoughts or behaviors (Bridge et al. 2007).
Overdose
A major advantage of SSRIs, relative to other antidepressants, has been their
superior therapeutic index (Cooper 1988; Pedersen et al. 1982). The number of
deaths per 1 million prescriptions, across several SSRIs (0–6), is substantially
lower than that for conventional TCAs (8–53) or MAOIs (0–61) (Leonard 1992).
Borys et al. (1992) reported on 234 cases of fluoxetine overdose (serum
level=232–1,390 ng/mL) obtained in a prospective multicenter study. Fluoxetine
was the sole ingestant in 87 cases; in the remaining 147 cases, it was taken in
combination with alcohol and/or other drugs. Common symptoms included
tachycardia, sedation, tremor, nausea, and emesis. The authors concluded that
the emergent symptoms were minor and of short duration; thus, aggressive
supportive care “is the only intervention necessary” (Borys et al. 1992, p. 115).
Drug–Drug Interactions
Although the potential for significant interactions exists, SSRIs are unlikely to
be associated with many of the conventional problems seen with the earlier
antidepressants. These problems include the cumulative CNS-depressant effects
with alcohol, anticholinergic agents, or antihistaminic compounds. The structural
differences among SSRIs offer a basis for some intraclass differences. Lithium
concentrations are generally unaffected.
One potential for clinically relevant antidepressant pharmacokinetic
interactions is based on the drug effect on the CYP family of enzymes (Brøsen
and Gram 1989). For example, SSRIs are both substrates for and inhibitors of
oxidation via CYP2D6. Crewe et al. (1992) ranked the potency of CYP2D6
inhibition for serotonergic antidepressants, revealing the most clinically relevant
effects on 2D6 for paroxetine and fluoxetine and less relevant effects for
sertraline, fluvoxamine, citalopram, clomipramine, and amitriptyline.
Through inhibition of CYP2D6, fluoxetine may elevate the concentration of
concomitantly administered drugs that rely on this enzyme for metabolism. This
has particular clinical relevance when the second agent has a narrow therapeutic
index. Examples of such agents include flecainide, quinidine, carbamazepine,
propafenone, TCAs, and several antipsychotics (Rudorfer and Potter 1989). The
clinical consequence of such an interaction may either enhance or impair
efficacy and/or heighten the adverse-event profile.
The data with respect to fluoxetine’s inhibition of other CYP enzymes, such as
3A3/4, 2C9, and 2C19, are less consistent, but the potential for such interaction
exists.
Conclusion
Fluoxetine has been shown to be a safe and effective drug that has proved to be
better tolerated than TCAs and to have a superior safety profile in overdose for
patients with comorbid medical illness. Evidence suggests a broad utilitarian role
for fluoxetine across a spectrum of psychopathology.
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22751539
CHAPTER 11
Sertraline
Linda L. Carpenter, M.D.
Alan F. Schatzberg, M.D.
Structure–Activity Relations
Sertraline [(+)-cis-(1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-
1-naphthylamine] (Figure 11–1) specifically blocks the reuptake of 5-HT in the
soma and terminal regions of serotonergic neurons. The ability of sertraline to
inhibit 5-HT reuptake is approximately 20-fold higher than its capacity to inhibit
uptake of either norepinephrine or dopamine (Heym and Koe 1988). However,
sertraline is more potent at blocking dopamine receptor uptake than are other
selective serotonin reuptake inhibitors (SSRIs) and TCAs (Hiemke and Härtter
2000; Richelson 1994).
Pharmacological Profile
Among the various antidepressant agents that block the 5-HTT, sertraline is
second only to paroxetine in potency for 5-HT reuptake blockade, as
demonstrated in animal models (Hiemke and Härtter 2000; Owens et al. 2001;
Richelson 1994). The selectivity of sertraline for norepinephrine follows that of
escitalopram (Hiemke and Härtter 2000; Owens et al. 2001), although other
work suggests greater selectivity for fluvoxamine than for sertraline (Richelson
1994). The relative selectivity for the 5-HTT, compared with the dopamine
transporter (DAT), is lowest for sertraline (Owens et al. 2001).
Sertraline exhibits inhibitory activity on several cytochrome P450 (CYP)
enzymes. The ability of the compound to slightly elevate dextromethorphan and
desipramine supports modest inhibition of CYP2D6 (Hiemke and Härtter 2000;
Ozdemir et al. 1998; Preskorn 1996). It has little appreciable inhibition of
CYP1A2, even when used at higher dosages (Ozdemir et al. 1998). A very mild
elevation of CYP2C9/10 substrates has been found in several studies (Preskorn
1996). Sertraline has complex effects on the CYP3A3/4 enzyme system: it
initially shows slight inhibition, but it also induces this system, albeit modestly,
over time (Preskorn 1996).
Pharmacokinetics and Disposition
Sertraline is absorbed slowly via the gastrointestinal tract, with peak plasma
levels occurring between 6 and 8 hours after ingestion (Warrington 1991). The
delay may be the result of enterohepatic circulation (Hiemke and Härtter 2000;
van Harten 1993). When sertraline is taken with food, the peak plasma level
occurs earlier, at about 5.5 hours (Pfizer 2016). The medication is more than
95% protein bound; however, because it binds weakly to α1-glycoproteins, it
does not cause substantial displacement of other protein-bound drugs (Preskorn
1996).
The volume of distribution (Vd) of sertraline is large, exceeding 20 L/kg. The
distribution is larger in young females than in young males (Warrington 1991).
In animal models, the concentration of sertraline is 40 times higher in brain than
in plasma (Hiemke and Härtter 2000).
The elimination half-life of sertraline is 26–32 hours, and steady-state levels
are achieved after 7 days. Sertraline shows linear pharmacokinetics within a
range of 50–200 mg/day (Warrington 1991) and does not appear to inhibit or
induce its own metabolism. Peak plasma levels are somewhat lower in young
males than in young females, older females, or older males (Pfizer 2016;
Ronfeld et al. 1997; Warrington 1991), and the elimination rate constant is
higher in young males than in young females, older females, or older males
(0.031/hour in young males, 0.022/hour in young females, and 0.019/hour in
older males and females). Maximal plasma concentrations of sertraline may be
significantly reduced following a gastric bypass procedure (Roerig et al. 2012).
In children between the ages of 6 and 17 years, weight-corrected metabolism
is more rapid. The maximum concentration and area under the curve (AUC) are
22% lower in children than in adults. Despite this relatively more efficient
metabolism, the smaller body mass of most children suggests that lower dosages
of sertraline should be used in pediatric populations (Pfizer 2016).
Sertraline is metabolized in the liver via oxidative metabolism; the
concentration of the primary metabolite, desmethylsertraline, is up to threefold
higher than that of the parent compound (Hiemke et al. 1991; Ronfeld et al.
1997; Warrington 1991). Desmethylsertraline levels are also lower in young
males than in young females, elderly females, or elderly males. The peak
concentration (tmax) of desmethylsertraline is attained more quickly in young
females than in young males, older females, and older males (6 hours in young
females vs. 9 hours in young males, 8 hours in older females, and 14 hours in
older males) (Warrington 1991). The half-life of desmethylsertraline is 1.6–2.0
times that of the parent compound (Warrington 1991).
Whereas desmethylsertraline is the major metabolite of sertraline, other minor
metabolites include a ketone and an alcohol compound (Warrington 1991). Less
than 0.2% of an oral dose of sertraline is excreted unchanged in urine, whereas
approximately 50% is found in feces. The enzymes involved in metabolism of
sertraline to desmethylsertraline remain unclear (Greenblatt et al. 1999).
Although six different CYP enzymes have the capacity to catalyze this reaction,
none accounts for more than 25% of sertraline’s clearance. The contribution of
each CYP enzyme is dependent not only on the protein’s activity on the
substrate, as evidenced through in vitro models, but also on the abundance of the
enzyme. Given these properties, one computer model identified 2C9 as the
greatest contributor (~23%) to sertraline demethylation, with 3A4 and 2C19 each
contributing about 15%, 2D6 adding 5%, and 2B6 contributing 2% to the
process (Greenblatt et al. 1999; Lee et al. 1999). These percentages can vary
across individuals, depending on the amount of enzyme that is available or
enzyme inhibition that occurs. Because multiple CYP enzymes are involved in
sertraline’s metabolism, concurrent use of medications with specific CYP
inhibition is unlikely to substantially impair the process (Greenblatt et al. 1999).
However, increased CYP2B activity was seen in mice as a consequence of
sertraline coadministration with bupropion (Molnari et al. 2012).
Patients with liver disease experience decreased sertraline metabolism
(Hiemke and Härtter 2000). For individuals with mild liver impairment, the half-
life of the drug may be increased threefold (Pfizer 2016), and concentrations are
likely to be greater in patients with severe impairment. Although renal
impairment does not appreciably influence the metabolism of sertraline (Hiemke
and Härtter 2000), hemodialysis patients with severe end-stage renal disease do
not appear to tolerate sertraline 25 mg/day without risk of significant toxicity
(Chander et al. 2011).
Mechanism of Action
The means by which all antidepressants exert their therapeutic action is largely
unknown, although some of the properties noted above have been related to
hypothetical mechanisms (Blier 2001; Blier et al. 1990). As previously
mentioned, the immediate effect of sertraline is to decrease neuronal firing rates.
This is followed by normalization and an increase in firing rates, as
autoreceptors are desensitized. As activity in the presynaptic neuron increases,
noradrenergic neurons are stimulated by postsynaptic 5-HT receptors located on
noradrenergic nerve terminals, leading to eventual downregulation of β-
adrenergic receptors, an effect produced by many, but not all, antidepressant
agents (Frazer and Scott 1994; Guthrie 1991).
Not inconsistent with the above are findings suggesting that SSRI treatment
decreases production of 5-HT1B messenger RNA (mRNA), the message for a
regulatory autoreceptor on dorsal raphe neurons that controls the amount of 5-
HT released with each impulse (Anthony et al. 2000). Again, the decrease in
mRNA production coincides temporally with the time frame for SSRI
therapeutic effects. In addition to inhibition of 5-HT reuptake, preclinical
research demonstrated that sertraline inhibits hippocampal presynaptic sodium
channels to control neurotransmitter release (Aldana and Sitges 2012), and
sertraline’s ability to increase extracellular dopamine concentration in nucleus
accumbens and striatum differentiated it from other SSRIs (Kitaichi et al. 2010).
Panic Disorder
Sertraline’s efficacy in the treatment of panic disorder has been demonstrated in
several studies. In a 12-week randomized, placebo-controlled, flexible-dose
multicenter trial in outpatients with panic disorder (with and without
agoraphobia) but without depression (Pohl et al. 1998), sertraline was superior to
placebo on a number of efficacy measures. One hundred sixty-eight patients
meeting diagnostic criteria for panic disorder without depression were randomly
assigned to receive sertraline or placebo after a 2-week single-blind lead-in. The
mean sertraline dosage at endpoint was 126 mg/day (SD=62 mg/day), and the
reduction in frequency of panic attacks was significantly greater for the
sertraline group (77% vs. 51% for the placebo group), with significantly fewer
panic symptom episodes occurring in that group. Similar results supporting
sertraline’s efficacy for panic disorder were reported by Pollack et al. (1998),
who randomly assigned 178 patients to sertraline or placebo.
A fixed-dosage study of sertraline (50 mg/day, 100 mg/day, or 200 mg/day) or
placebo for 12 weeks (Londborg et al. 1998) demonstrated sertraline’s
superiority over placebo in numerous trial outcomes, including number of panic
attacks and limited-symptom attacks, severity of anticipatory anxiety,
dimensional anxiety measures, and global measures of improvement. Pooled
sertraline data indicated a 65% reduction in the number of panic attacks,
compared with a 39% decrease in the placebo group. Effect sizes, reflecting the
magnitude of difference between the two treatments, for the three different
sertraline dosages tested were 0.58 (50 mg/day), 0.41 (100 mg/day), and 0.60
(200 mg/day), but response rates did not differ significantly among dosage
groups. In the panic studies described above, the authors reported a low
incidence of attrition secondary to sertraline adverse events, concluding that
sertraline is a safe and effective treatment for patients with panic disorder.
Sertraline’s beneficial effects in panic disorder may be further enhanced when
the drug is used in combination with self-administered CBT (Koszycki et al.
2011).
Obsessive-Compulsive Disorder in Adults
Several multicenter trials found benefit for sertraline over placebo in the acute-
and maintenance-phase treatment of OCD in adults. One study failed to show
superiority of sertraline over placebo, perhaps because of the limited sample size
(n=19) or the treatment-resistant characteristics of the cohort (Jenike et al. 1990).
Larger-scale studies with diverse patients had differing results. By week 3 of a
12-week flexible-dose study in 167 patients (Kronig et al. 1999), sertraline
(mean 165 mg/day) differentiated from placebo. At study endpoint, 41% of
patients receiving sertraline and 23% of those receiving placebo had achieved a
CGI–Improvement scale (CGI-I) score of 1 or 2.
A fixed-dose study (Greist et al. 1995) also found superior results with three
different daily dosages (50, 100, or 200 mg) of sertraline, compared with
placebo, over 1 year of treatment in a multisite trial. OCD patients (n=325) were
randomly assigned to 12 weeks of double-blind treatment after a 1-week
washout period. Responders (40% of sertraline-treated patients and 26% of
placebo-treated patients) were offered enrollment in an additional 40 weeks of
continuation treatment. Over the 52 weeks of the study, sertraline-treated
subjects demonstrated significantly greater improvement than did subjects given
placebo.
Some evidence suggests that higher daily dosages of sertraline may be helpful
for patients whose symptoms do not respond to standard dosages. In one study,
66 patients with OCD that was unresponsive to sertraline therapy at dosages of
200 mg/day after 16 weeks of treatment were randomly assigned to continue on
the same dosage for an additional 12 weeks or to increase their dosage to 250–
400 mg/day (Ninan et al. 2006). At the end of the trial, those receiving higher
dosages had greater improvement in Yale-Brown Obsessive Compulsive Scale
(Y-BOCS) scores, although rates of response were similar for the two groups.
Other studies supporting the utility of sertraline in OCD have included head-
to-head comparisons with other antidepressants (Bergeron et al. 2002; Bisserbe
et al. 1997; Hoehn-Saric et al. 2000). In a comparison of lower-dosage sertraline
with cognitive-behavioral group therapy, both treatments were shown to be
efficacious, although OCD patients treated with group therapy had greater
reductions in symptoms (Sousa et al. 2006). Continuation of CBT versus
sertraline initiation in children and adolescents with OCD who had not
responded to an initial trial of CBT resulted in similar efficacy (Skarphedinsson
et al. 2015).
Depression in Cancer
Sertraline has been studied in patients with cancer and depression. A 12-week
open-label, flexible-dose trial of sertraline in patients undergoing chemotherapy
demonstrated positive effects on depressed mood (Torta et al. 2008), but in a
controlled trial of almost 200 patients with advanced disease who did not have
MDD, sertraline had no mood benefit over placebo (Stockler et al. 2007).
Vasomotor Symptoms
Another proposed off-label use for sertraline is the alleviation of hot flashes
associated with menopause (Aedo et al. 2011; Gordon et al. 2006; Grady et al.
2007) or with tamoxifen treatment for breast cancer (Kimmick et al. 2006) in
women, as well as in men following medical castration for advanced prostate
cancer (Roth and Scher 1998). One study suggested that a positive response to
sertraline for hot flashes is related to activity level, education, and menopausal
status (Kerwin et al. 2007).
Sertraline was superior to placebo in a study that examined its potential for
controlling hot flashes in women with or at high risk of breast cancer, for whom
hormone therapy was not recommended (Wu et al. 2009).
Other Uses
There has been some research investigating sertraline’s potential benefit in a
variety of other conditions.
Sertraline has been used successfully in the treatment of children and
adolescents with MDD and dysthymic disorder (Ambrosini et al. 1999; Nixon et
al. 2001), and it has demonstrated some utility in the treatment of depression in
patients with schizophrenia (Addington et al. 2002; Kirli and Caliskan 1998;
Mulholland et al. 2003). One study in patients with MDD showed that sertraline
increased adaptive traits associated with psychopathic personality (social charm
and interpersonal and physical boldness) and reduced maladaptive traits
associated with psychopathy (dysregulated impulsivity and externalization),
independent of its antidepressant effects (Dunlop et al. 2011).
Sertraline has also shown some benefit in the treatment of generalized anxiety
disorder (GAD). Two randomized GAD trials showed that sertraline had
superiority over placebo (Allgulander et al. 2004; Brawman-Mintzer et al. 2006)
and efficacy similar to that of paroxetine (Ball et al. 2005). In a placebo-
controlled trial (Rynn et al. 2001), sertraline was both effective and safe in
children with GAD.
Results from some investigations suggest a role for sertraline in the treatment
of various eating disorders, including anorexia nervosa (Santonastaso et al.
2001), bulimia nervosa (Milano et al. 2004), binge-eating disorder (Leombruni
et al. 2006; McElroy et al. 2000), and night-eating syndrome (O’Reardon et al.
2006).
Several studies have reported sertraline’s benefit in treating premature
ejaculation (Arafa and Shamloul 2006; Biri et al. 1998).
Trials of sertraline for DSM-IV impulse-control disorders have yielded mixed
results; positive outcomes were observed in a trichotillomania sample
(Dougherty et al. 2006), but no therapeutic effect was demonstrated for gambling
disorders (Saiz-Ruiz et al. 2005).
A number of studies have highlighted the effective use of sertraline in treating
aggressive and self-harming behaviors (Buck 1995; Feder 1999), specifically in
patients with personality disorders (Kavoussi et al. 1994), patients with
Huntington’s disease (Ranen et al. 1996), and adults with intellectual disability
or autism spectrum disorder (Hellings et al. 1996; McDougle et al. 1998).
Sertraline has proved useful in preventing dialysis-induced hypotension, a
condition that can be exacerbated by other antidepressive agents (Perazella
2001). Sertraline also has been of benefit in treating pruritus associated with
cholestatic liver disease (Mayo et al. 2007). Finally, it has been shown to reduce
symptom severity in refractory tinnitus (Zöger et al. 2006).
Side Effects and Toxicology
Sertraline has been demonstrated to have a low incidence of anticholinergic,
sedative, and cardiovascular effects because of its low affinity for adrenergic,
cholinergic, histaminergic, and benzodiazepine receptors. However, in
premarketing evaluations, sertraline was associated with a number of adverse
effects. The most commonly reported side effects were gastrointestinal
disturbance (nausea, 27%; diarrhea/loose stools, 21%), sleep disturbance
(insomnia, 22%; somnolence, 14%), headache (26%), dry mouth (15%), and
sexual dysfunction (ejaculation failure, 14%; decreased libido, 6%). Other side
effects reported by subjects and described as frequent (i.e., occurring in at least 1
of 100 subjects) in premarketing pooled data from clinical trials included
impotence, palpitations, chest pain, hypertonia, hypoesthesia, increased appetite,
back pain, asthenia, malaise, weight gain, myalgia, yawning, rhinitis, and
tinnitus (Pfizer 2016).
Hyponatremia
Sertraline and other SSRIs have been associated with cases of hyponatremia, as
well as with the syndrome of inappropriate antidiuretic hormone (SIADH)
secretion (see Bouman et al. 1997; Bradley et al. 1996; Catalano et al. 1996;
Goldstein et al. 1996; Kessler and Samuels 1996). Bradley et al. (1996), in a
review of the literature, noted that the average age of patients experiencing
SIADH was greater than 70 years, suggesting that the elderly may be more
vulnerable to age-related changes in water balance, which may make them more
susceptible to developing SIADH with an SSRI.
Sexual Dysfunction
Sexual dysfunction is a well-known side effect of SSRIs, including sertraline. A
Cochrane Database review noted that although limited evidence is available,
some trials have suggested that the addition of sildenafil or bupropion can reduce
antidepressant-induced erectile dysfunction in men (Rudkin et al. 2004).
Discontinuation Syndrome
Sertraline has been associated with a discontinuation syndrome. Leiter et al.
(1995) described two cases in which patients experienced alterations in mood,
cognition, energy, gait, and equilibrium, in addition to gastrointestinal
symptoms, headaches, and paresthesias. Elsewhere there have been reports of
insomnia, impaired short-term memory, myalgias, dyspnea, and chills without
fevers (Louie et al. 1994). In a systematic 28-week study in patients with panic
disorder (Rapaport et al. 2001), abrupt discontinuation of sertraline was
primarily associated only with insomnia (15.7% of patients randomly assigned to
placebo vs. 4.3% continuing on sertraline) and dizziness (4.3% of patients
continuing to take sertraline and 16.4% switched to placebo). There was no
statistically significant increase in headache or in general malaise in patients
randomly assigned to switch to placebo.
Drug–Drug Interactions
Sertraline has a number of potential drug–drug interactions. Because the drug is
tightly bound to plasma proteins, caution should be employed when sertraline is
used in combination with pharmaceuticals possessing similar characteristics,
such as warfarin, and prothrombin time should be monitored when sertraline and
warfarin are used concurrently (Pfizer 2016). The potential for serotonin
syndrome may be increased when sertraline is used in combination with other
SSRls, serotonin-norepinephrine reuptake inhibitors, or triptans prescribed for
the acute treatment of migraines. Coadministration of sertraline with an MAOI is
contraindicated because of the significant risk of serotonin syndrome with this
combination.
The degree of sertraline’s inhibition of the CYP system, most significantly
CYP2D6, is relatively minor in comparison with that of other SSRIs, such as
fluoxetine and paroxetine (Preskorn et al. 2007), although mouse data have
shown a mild pharmacokinetic drug–drug interaction between bupropion and
sertraline that leads to a small elevation in bupropion metabolism (Molnari et al.
2012). Because TCAs are substrates of CYP2D6, drug levels and dosages need
to be closely monitored when TCAs are used in combination with sertraline.
Sertraline, in common with its fellow SSRIs citalopram and escitalopram, is
also metabolized by the CYP2C19 isoenzyme, which is inhibited by proton
pump inhibitors (PPIs). In a study examining the effect of PPIs on serum
concentrations of SSRIs, coadministration of the PPI esomeprazole led to
significant elevations (+38.5%; P=0.0014) in sertraline blood levels but caused
an almost twofold increase (+81.8%; P<0.001) in escitalopram blood levels
(Gjestad et al. 2015).
Conclusion
Controlled clinical trials support sertraline’s efficacy in the treatment of a variety
of psychiatric conditions, including depressive and anxiety disorders, and
uncontrolled studies suggest an expanded role for sertraline in a number of other
conditions. Sertraline’s safety profile is superior to that of older antidepressant
agents, thus increasing the potential target population of patients in whom
sertraline treatment can be beneficial.
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CHAPTER 12
Paroxetine
Jonathon R. Howlett, M.D.
Murray B. Stein, M.D., M.P.H.
Charles B. Nemeroff, M.D., Ph.D.
Mechanism of Action
Paroxetine and all of the other SSRIs cause immediate elevations in extracellular
5-HT concentrations in serotonergic synapses, resulting from the decreased 5-HT
clearance associated with 5-HTT inhibition (Wagstaff et al. 2002). Paroxetine
initially causes a paradoxical decrease in 5-HT neurotransmission, likely due to
activation of a negative feedback system mediated by increased 5-HT binding to
the 5-HT1A autoreceptor and subsequent diminution in serotonergic neural
activity (Blier et al. 1990). After 2 weeks of paroxetine treatment, the 5-HT1A
autoreceptors are desensitized, and there is an associated increase in serotonergic
neurotransmission (Chaput et al. 1991). The delayed changes in 5-HT1A receptor
sensitivity and 5-HT neurotransmission seen after long-term daily paroxetine use
are temporally associated with clinical improvement, hinting at a possible
mechanistic link.
Pindolol, a nonselective β-adrenergic receptor antagonist/5-HT1A receptor
antagonist, has been studied as a novel approach to accelerate the therapeutic
response to SSRIs, as well as to convert SSRI nonresponders to responders. It
was hypothesized that blockade of the presynaptic 5-HT1A autoreceptor might
prevent the initial reduction in serotonergic transmission that occurs with SSRIs,
leading to a more rapid and robust clinical response (Pérez et al. 1999).
This hypothesis was supported by results from open studies and from several
double-blind, placebo-controlled trials indicating that the addition of pindolol
(2.5–5.0 mg three times a day) to paroxetine in the early phase of treatment for
major depressive disorder increased the rapidity of clinical improvement
(Artigas et al. 1994; Blier and Bergeron 1995). However, data on augmentation
of clinical efficacy with pindolol were not compelling, especially in individuals
with depression refractory to paroxetine monotherapy (Bordet et al. 1998; Pérez
et al. 1999; Tome et al. 1997; Zanardi et al. 1997). In another study, paroxetine
with pindolol augmentation was found to be most efficacious in patients with
depression who were drug naive and in patients with bipolar depression
(Geretsegger et al. 2008). It may be that the dosages of pindolol previously
studied were inadequate to obtain a response (Martinez et al. 2000).
Paroxetine has also been shown to have an effect on the hypothalamic-
pituitary-adrenal (HPA) axis. It is well established that many individuals with
depression have HPA axis hyperactivity and hypersecretion of corticotropin-
releasing factor (CRF) from the hypothalamic and extrahypothalamic circuits
(Heim and Nemeroff 1999). Early life stress is associated with hyperactivity of
the HPA axis and increased CRF messenger RNA (mRNA) expression
(Nemeroff 1996; Newport et al. 2002). In adult animals, these effects are
reversed by chronic—but not acute—paroxetine treatment.
Other agents. Paroxetine has also been compared with a variety of other
agents in the treatment of depression. Nefazodone and paroxetine were shown to
possess similar efficacy and tolerability (Baldwin et al. 1996), and mirtazapine
and paroxetine were found to be equivalent in terms of efficacy and tolerability
(Benkert et al. 2000). However, a Cochrane review concluded that mirtazapine
may be superior to paroxetine, whereas paroxetine may be superior to the
norepinephrine reuptake inhibitor reboxetine in terms of early response to
treatment (1–4 weeks) (Purgato et al. 2014). A post hoc analysis of a clinical trial
determined that paroxetine CR was superior to bupropion extended release (XL)
in reducing a “psychic depression” symptom cluster that was correlated with
suicidal ideation (Grunebaum et al. 2013).
In a meta-analysis of the venlafaxine worldwide database, the SNRI
venlafaxine showed a slight statistically significant advantage in efficacy over
SSRIs as a class, although no such advantage was demonstrated for venlafaxine
over paroxetine (Nemeroff et al. 2003). A study comparing venlafaxine XR and
paroxetine in the maintenance treatment of depression found higher rates of
remission with venlafaxine (Shelton et al. 2005). In patients with treatment-
resistant depression (defined as inadequate response to appropriate courses of at
least two different antidepressants), venlafaxine (200–300 mg/day) was shown to
be superior to paroxetine (30–40 mg/day) in bringing about remission (Poirier
and Boyer 1999).
In contrast, a study in Chinese patients with treatment-resistant depression
showed no significant differences among paroxetine, mirtazapine, and
venlafaxine XR (Fang et al. 2010). A study comparing paroxetine with the SNRI
duloxetine (40–80 mg/day) suggested a higher probability of remission with
duloxetine 80 mg/day than with paroxetine (Goldstein et al. 2004). Another
study in Chinese patients found a nonsignificantly higher remission rate with
paroxetine compared with duloxetine 40–60 mg/day (Wang et al. 2015). A study
comparing paroxetine with the SNRI milnacipran in Japanese patients showed
no difference in efficacy (Kamijima et al. 2013). In evaluating studies comparing
paroxetine with SNRI agents, it is important to take into account the dosages
used for paroxetine, because paroxetine 20 mg/day is too low to exhibit any NET
blockade.
Paroxetine has also been compared with investigational agents such as
substance P (NK1) receptor antagonists. In the Merck-sponsored NK1 receptor
antagonist trials in major depressive disorder, paroxetine 20 mg/day was superior
to both placebo and the novel agent (Cutler et al. 2000).
Panic Disorder
Paroxetine was the first SSRI to be granted FDA approval for the treatment of
panic disorder. Paroxetine and clomipramine have been shown to be equally
efficacious in the treatment of panic attacks, and a faster onset of action was
noted with paroxetine (Lecrubier et al. 1997a). Paroxetine’s long-term efficacy
and tolerability have also been demonstrated in patients with panic disorder
(Lecrubier et al. 1997b; Nardi et al. 2012). The combination of cognitive-
behavioral therapy and paroxetine is more effective in the treatment of panic
disorder than cognitive-behavioral therapy alone (Bakker et al. 1999; Oehrberg
et al. 1995).
In general, patients with panic disorder should be treated initially with a low
dosage of paroxetine (e.g., 10 mg/day), with gradual increases in dosage as
clinically indicated. The data that led to FDA approval suggested that 40 mg/day
was the minimum effective dosage for this condition; however, clinical
experience has shown that lower dosages may be sufficient in some patients and
higher dosages may be required in other patients (Ballenger et al. 1998). The
standard duration of treatment ranges from 6 to 12 months; however, rates of
relapse for panic disorder appear to be greater than those for major depressive
disorder, suggesting that panic disorder may require an indefinite course of
treatment (Hirschfeld 1996).
Obsessive-Compulsive Disorder
Currently, the SSRIs fluvoxamine, fluoxetine, sertraline, and paroxetine are FDA
approved for the treatment of OCD in adults. Although two meta-analyses
assessing the efficacy and tolerability of the TCA clomipramine and SSRIs in
OCD seemed to favor clomipramine in terms of overall effectiveness (Greist et
al. 1995; Piccinelli et al. 1995), the only placebo-controlled multicenter study to
compare clomipramine directly against an SSRI (paroxetine) revealed equal
efficacy, with greater tolerability for paroxetine (Zohar and Judge 1996).
Paroxetine also has demonstrated efficacy in pediatric OCD. In a randomized,
double-blind, placebo-controlled multicenter trial (Geller et al. 2004), paroxetine
was found to be an effective and generally well-tolerated treatment for OCD in
children and adolescents. Patients with comorbid major depressive disorder were
excluded from this study, and only one incident of treatment-emergent suicidal
behavior or ideation was reported.
In adults, paroxetine daily dosages of ≥60 mg are usually required for optimal
efficacy in OCD. Although patients usually respond to treatment within 3–4
weeks, clinical improvement may not be discernible until 10–12 weeks;
therefore, a standard trial of up to 12 weeks should be conducted before an
alternative medication is considered (Rasmussen et al. 1993).
Suicidality
As previously discussed (see “Depression in Children and Adolescents”
subsection earlier in this chapter), in 2004 the FDA ordered pharmaceutical
companies to place a black box warning on the package insert for all
antidepressants, stating that suicidal behavior might increase in children and
adolescents taking these medications. Concerns about a link between
antidepressant usage and suicidal ideation led FDA regulators to request that
antidepressant manufacturers examine their databases for similar findings in
adults. GlaxoSmithKline conducted a meta-analysis of its clinical data
comparing suicidality with paroxetine (Paxil/Seroxat) versus placebo. Among
depressed patients taking paroxetine, 0.32% (11 of 3,455) attempted suicide,
compared with 0.05% (1 of 1,978) of depressed patients taking placebo, an odds
ratio of 6.7 (GlaxoSmithKline 2006). Cases of completed suicide in both
samples were exceedingly rare, with one reported in the paroxetine sample
versus none reported with placebo. GlaxoSmithKline further examined the data
to identify clinical features of those patients who developed suicidal behavior
(Kraus et al. 2010). Common features among these patients included some
improvement in depressive symptoms, younger age (<30 years old),
psychosocial stressor preceding the attempt, and no identified suicidality at the
prior study visit (Kraus et al. 2010).
Another analysis of both published and unpublished data on paroxetine in the
treatment of depression evaluated suicidality as a secondary outcome (Barbui et
al. 2008), finding an odds ratio of 2.55, with a number needed to harm of 142.
The authors noted that whereas suicidality is exceedingly rare, the data are also
variably recorded, making it difficult to track this outcome through retrospective
reports (Barbui et al. 2008). As noted earlier, a recent reanalysis of a published
GlaxoSmithKline study of paroxetine treatment of child and adolescent
depression (Keller et al. 2001) concluded that the risk of suicidal ideation and
suicidal behavior associated with paroxetine was greater than had initially been
reported (Le Noury et al. 2015).
A retrospective cohort study of 36,842 children and adolescents ages 6–18
years initiating treatment with an antidepressant found no differences in risk of
suicide attempts among commonly prescribed SNRIs and SSRIs, including
paroxetine (Cooper et al. 2014). Another cohort study of 287,543 adult residents
of British Columbia ages 18 years and older who were receiving antidepressants
(Schneeweiss et al. 2010b) found no significant differences in suicidality risk
among individual SSRIs (fluoxetine, citalopram, fluvoxamine, paroxetine, and
sertraline). As in the study of children and adolescents mentioned earlier
(Schneeweiss et al. 2010a; see the subsection “Depression in Children and
Adolescents”), most of the suicidal events occurred during the first 6 months of
treatment (Schneeweiss et al. 2010b). A retrospective study of 502,179 U.S.
Department of Veterans Affairs patients with depression diagnoses who initiated
antidepressant treatment found evidence suggesting a lower risk of suicide death
with fluoxetine and sertraline compared with paroxetine, although the authors
noted that this finding differed according to which data analysis technique was
used (Valenstein et al. 2012).
A limitation of findings regarding the link between paroxetine and suicidality
is that the placebo-controlled studies included in meta-analyses did not have
suicidal ideation and self-harming behaviors as main outcome measures.
Procedures for assessing suicidality have not, until recently, been standardized
and are based largely on unsolicited and unstructured reports and observations.
Also, depression is a risk factor for suicidal behavior, and suicide is a potential
complication of the disease. Transient suicidal thinking must be considered in
the context of the overall risk–benefit analysis of paroxetine in the treatment of
adults with major depressive disorder.
Nevertheless, in late 2006, an FDA advisory panel extended the black box
warning to cover young adults up to their mid-20s (U.S. Food and Drug
Administration 2007). The advisory panel reported that in patients 18–24 years
of age, antidepressant use was associated with 4 cases of suicidal ideation per
1,000 patients treated, that there was no evidence of increased risk in adults
older than 24 years, and that antidepressant treatment was unequivocally
protective against suicidality in patients 65 years and older.
Clinicians should inform their patients about the possible risks and should
monitor depressed patients closely when paroxetine or any other antidepressant
is prescribed, particularly during the early phase of treatment. The FDA advisory
committee has made it clear that the black box warning should not dissuade
physicians from prescribing antidepressants to patients in need (U.S. Food and
Drug Administration 2007).
Medical Safety
Paroxetine treatment in clinical trials has not been associated with any
significant abnormalities in standard laboratory tests, including hematological
indices and chemistry panels, electroencephalogram (EEG), or
electrocardiogram (ECG). One possible concern regarding paroxetine had been
its potential for decreasing heart rate variability, which is a significant risk factor
for myocardial infarction and cardiovascular mortality (Carney et al. 2005).
Other norepinephrine reuptake–inhibiting antidepressants have been shown to
cause decreases in this electrophysiological variable (Rechlin 1994), and
depressed patients have been shown to exhibit lower heart rate variability than
nondepressed persons (Gorman and Sloan 2000); however, paroxetine does not
exhibit this effect. A review of the literature also determined that paroxetine may
have the lowest risk of QT prolongation among the SSRIs (Funk and Bostwick
2013).
Paroxetine and other SSRIs have been implicated in precipitation of the
syndrome of inappropriate antidiuretic hormone (SIADH), particularly in elderly
individuals; symptoms resolve on discontinuation of the medication (Strachan
and Shepherd 1998). One study demonstrated that hyponatremia (defined as
plasma sodium levels <135 mEq/L) occurred in 12% (9 of 75) of subjects,
typically within the first 10 days of paroxetine treatment (Fabian et al. 2004).
Risk factors for developing hyponatremia were low body mass index and low
baseline plasma sodium levels.
Discontinuation Syndrome
With abrupt discontinuation or treatment interruption, patients may develop what
has become known as the SSRI discontinuation syndrome. Symptoms (such as
dizziness, paresthesias, agitation, anxiety, nausea, and sweating) occur as early
as the second day after a missed dose and may persist for several days. A
comparison of SSRI postmarketing safety data found that withdrawal-related
events occurred more frequently in paroxetine-treated patients than in patients
treated with sertraline, fluvoxamine, or fluoxetine and that these events had a
mean duration of 10.2 days (Price et al. 1996); similar results were reported by
other groups (Michelson et al. 2000; Montgomery et al. 2004; Rosenbaum et al.
1998). Studies examining the effect of shorter SSRI treatment interruptions (3–5
days)—similar to what a patient would experience if he or she missed just a few
medication doses—found that whereas paroxetine-treated patients develop
significant discontinuation-emergent effects, fluoxetine-treated patients do not, a
disparity likely due to differences in the half-lives of these medications (Judge et
al. 2002; Michelson et al. 2000).
To prevent the emergence of withdrawal symptoms, practitioners are advised
to gradually taper the dosage when discontinuing paroxetine in their patients.
Despite the potential for withdrawal reactions after abrupt discontinuation of
paroxetine, there is no clinical evidence of dosage escalation, craving, or drug-
seeking behavior associated with dependence or addiction (Inman et al. 1993;
Johnson et al. 1998; Sharma et al. 2000).
Overdose
Overdoses with paroxetine are rarely associated with morbidity or mortality,
which is in sharp contrast to the situation with the TCAs or venlafaxine (Cheeta
et al. 2004; Whyte et al. 2003). In the clinical trials program prior to FDA
registration of paroxetine, 16 patients had ingested an overdose (doses of up to
850 mg of paroxetine); all patients recovered uneventfully (Jenner 1992). An
extensive review of the literature (including adverse events databases) revealed a
total of 28 fatalities involving paroxetine overdoses; however, in nearly all cases,
either coingestants were involved or causality could not be ascertained (Barbey
and Roose 1998).
Drug–Drug Interactions
As noted previously (see “Pharmacokinetics and Disposition” section earlier in
chapter), paroxetine is dependent primarily on the CYP2D6 hepatic enzyme for
conversion into its inactive metabolites (Hiemke and Härtter 2000). Paroxetine is
not only a substrate of this system but also an inhibitor; therefore, other drugs
that are metabolized by CYP2D6 are potentially subject to decreased clearance
and subsequent increased plasma concentrations (Sindrup et al. 1992b). Concern
is greatest for potential drug–drug interactions when the medication in question
has a low therapeutic index. (Table 12–1 lists potentially important drug–drug
interactions involving paroxetine.)
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CHAPTER 13
Fluvoxamine
Elias Aboujaoude, M.D.
Lorrin M. Koran, M.D.
Structure–Activity Relations
Fluvoxamine belongs to the 2-aminoethyl oxime ethers of the aralkyl ketones
(Figure 13–1) and is chemically identified as 5-methoxy-4′-(trifluoromethyl)
valerophenone-(E)-O-(2-aminoethyl) oxime maleate (1:1). Fluvoxamine’s
empirical formula is C15H21O2N2F3.C4H4O4, and it does not have a chiral center
or exist in stereoisomers. Because of local irritant properties, fluvoxamine
cannot be administered parenterally (Physicians’ Desk Reference 2015).
Mechanism of Action
Like other SSRIs, fluvoxamine binds to the presynaptic serotonin transporter
(SERT) and prevents it from reabsorbing serotonin into the presynaptic
terminals. This increases the amount of serotonin in the synaptic cleft. How this
increase translates into efficacy remains unclear, but it has been hypothesized to
involve downstream effects, including serotonin1A (5-HT1A) autoreceptor
desensitization (Stahl 1998); increased sensitivity of dopamine2 (D2)-like
receptors in the nucleus accumbens (Gershon et al. 2007); enhanced
neurogenesis (Dranovsky and Hen 2006); changes in mitochondrial production
of cerebral adenosine triphosphate (ATP) (Ferreira et al. 2014); and individual
pharmacogenomics factors involving SERT and catechol-O-methyltransferase
(COMT) gene variants (Fukui et al. 2014; Mancama and Kerwin 2003).
Furthermore, sigma-1 receptors appear to modulate several neurotransmitter
pathways, and evidence suggests that fluvoxamine’s affinity for the sigma-1
receptor exceeds that of all other SSRIs (Ishikawa et al. 2007).
Pharmacological Profile
Fluvoxamine is a more potent inhibitor of serotonin reuptake than the tricyclic
antidepressants, including clomipramine, but is less potent than the other SSRIs.
It is highly selective for the serotonin transporter (Ki=2.3 nmol/L) and has
minimal affinity for the norepinephrine and dopamine transporters, or the
muscarinic, α1-adrenergic, histaminic, and 5-HT2C receptors. It possesses no
monoamine oxidase–inhibiting properties (Lapierre et al. 1983; Owens et al.
2001; Palmer and Benfield 1994; Ware 1997).
Depression
The first trial of fluvoxamine treatment of depression dates to 1976. Since then,
several randomized, single- or double-blind studies conducted have tested
fluvoxamine’s antidepressant efficacy against placebo, SSRIs, serotonin–
norepinephrine reuptake inhibitors, tricyclic antidepressants, tetracyclic
antidepressants, and a reversible inhibitor of monoamine oxidase. The trials vary
in design but, taken together, support the efficacy and safety of fluvoxamine in
treating depression—including psychotic depression—across all age groups
(Fukuchi and Kanemoto 2002; Haffmans et al. 1996; Kiev and Feiger 1997;
Otsubo et al. 2005; Rapaport et al. 1996; Rossini et al. 2005; Ware 1997; Zanardi
et al. 2000; Zohar et al. 2003). Study durations ranged from 4 to 7 weeks, and
dosages ranged from 50 to 300 mg/day. Further, benefits from fluvoxamine seem
to be sustained over at least 1 year (Terra and Montgomery 1998).
In a well-designed recent analysis of 54 randomized controlled trials
(N=5,122), no strong evidence was found to indicate that fluvoxamine was either
superior or inferior to other antidepressants regarding response and remission
(Omori et al. 2010). However, differing side-effect profiles were evident,
especially in regard to more frequent reports of nausea and vomiting for
fluvoxamine compared with some other antidepressants.
Finally, because of fluvoxamine’s potent sigma-1 agonist action and the
putative antipsychotic property such action might confer, some authors have
suggested that fluvoxamine monotherapy might be a useful alternative to
combined treatment with an antidepressant and an antipsychotic in cases of
psychotic depression (Furuse and Hashimoto 2009).
Panic Disorder
The largest randomized, double-blind, placebo-controlled study to test
fluvoxamine in the treatment of panic disorder involved 188 subjects who were
assigned to 8 weeks of fluvoxamine 100–300 mg/day or placebo. At study end,
significantly more subjects in the fluvoxamine group were free from panic
attacks (69% vs. 46%, P=0.002) (Figgitt and McClellan 2000).
Limited data suggest similar efficacy for fluvoxamine and the tricyclic
antidepressant imipramine, as well as a possible potentiating effect of
fluvoxamine when combined with cognitive or exposure therapy (Figgitt and
McClellan 2000).
Eating Disorders
In another study, 72 subjects with bulimia nervosa who had been treated
successfully with psychotherapy were randomly assigned to receive fluvoxamine
(100–300 mg/day) or placebo and were followed for 12 weeks. Fluvoxamine
was significantly superior in preventing relapse (P<0.05) (Fichter et al. 1996). A
small 12-week double-blind, placebo-controlled study in 12 subjects with acute
bulimia nervosa suggested that fluvoxamine 200 mg/day was superior to placebo
(Milano et al. 2005).
A 9-week double-blind, placebo-controlled study in 85 subjects with binge-
eating disorder found that fluvoxamine (50–300 mg/day) was significantly more
effective than placebo in reducing binge frequency (Hudson et al. 1998).
Delirium
Delirium, especially in hospitalized older patients, is associated with increased
morbidity and mortality, prolonged hospital stays, and cognitive deterioration.
Antipsychotic drugs have been widely used for treating delirium but are
associated with sedation, extrapyramidal side effects, and cardiac arrhythmias.
Furthermore, there is an elevated risk of mortality in older patients treated with
atypical antipsychotics. The endoplasmic reticulum protein sigma-1 receptors
are thought to play a key role in calcium signaling and cell survival and may
regulate a number of neurotransmitter systems implicated in the pathophysiology
of delirium. Several recent case reports have suggested that fluvoxamine,
because of its potent sigma-1 receptor agonism, may be effective in the treatment
of delirium (Furuse and Hashimoto 2010a, 2010b, 2010c).
Pain
Preliminary research has explored the potential anti-pain properties of
fluvoxamine. An animal study investigated fluvoxamine in the treatment of
neuropathic pain in diabetic rats. Experimental animals were given
intraperitoneal streptozotocin to induce neuropathic pain, followed by daily oral
fluvoxamine. Using the hind paw withdrawal threshold to assess hyperalgesia,
researchers concluded that fluvoxamine was associated with decreased pain
(Kato et al. 2013).
More recently, a randomized controlled trial in 120 subjects with cancer
accompanied by moderate to severe pain assigned participants to receive flexibly
dosed extended-release oxycodone either alone (n=60) or in combination with
fluvoxamine dosages of 150 mg/day or greater (n=60). Individuals in the
oxycodone-only group required maximum dosages of extended-release
oxycodone of 54 mg/day and 132 mg/day for moderate and severe pain,
respectively, compared with 44.7 mg/day and 110 mg/day in the combination
group. Subjects who received fluvoxamine augmentation required lower doses of
oxycodone, but the difference was statistically significant only for severe pain.
Additionally, treatment with fluvoxamine was associated with improved overall
quality of life (Xiao et al. 2014).
Side Effects and Toxicology
Data from 34,587 patients enrolled in postmarketing fluvoxamine studies were
combined in a database to assess safety. Dosages ranged from 50 to 300 mg/day
taken over 4–52 weeks (Wagner et al. 1994). Overall, 14% of participants
discontinued treatment because of side effects, most frequently nausea and
vomiting (4.6% and 1.7%, respectively). The adverse events reported at greater
than 5% incidence were nausea, somnolence, and asthenia (15.7%, 6.4%, and
5.1%, respectively). The rate of weight gain was only 1%. Sexual side effects
were not mentioned in the analysis (only side effects with >1% incidence were
listed), although a separate open-label study designed to assess SSRI-induced
sexual dysfunction in men and women showed statistically similar rates for
fluvoxamine, fluoxetine, sertraline, and paroxetine (range: 54.4%–64.7%)
(Montejo-González et al. 1997).
Another postmarketing surveillance review covering 17 years (Buchberger
and Wagner 2002) analyzed 6,658 individual reports, including 16,110 adverse
drug reactions. The frequency of death was calculated at 0.9 per 100,000
patients. Suicide, mostly by overdose, was the cause of death in nearly half, but
only 1.2% of overdoses involved fluvoxamine alone. The rate of suicidality
(ideation, attempts, and completed suicides) was estimated at 2.81 events per
100,000 patients. Drug interactions were reported at a rate of 0.85 cases per
100,000 patients, most commonly with clozapine. Cases of switch to mania and
discontinuation syndrome were also rare, occurring at rates of 0.47 and 0.38
events per 100,000 patients, respectively. Serotonin syndrome was even less
frequent.
A more recent study assessed the cardiac effects of fluvoxamine in beagle
dogs (n=4). Dogs were administered 0.1 mg/kg of fluvoxamine intravenously,
corresponding to the recommended daily oral dose, followed by a second and
third dose of 1 mg/kg and 10 mg/kg, respectively. Both supratherapeutic doses
were associated with QT interval prolongation (Yamazaki-Hashimoto et al.
2015).
Two studies found no consistent treatment-related changes in laboratory
values or vital signs in fluvoxamine-exposed subjects (Wagner et al. 1994).
Drug–Drug Interactions
Fluvoxamine is a potent inhibitor of cytochrome P450 (CYP) 1A2. Drugs
partially metabolized by CYP1A2 whose levels may rise as a result of
fluvoxamine’s inhibition of this isozyme include tizanidine, tertiary-amine
tricyclic antidepressants (imipramine, amitriptyline, clomipramine), clozapine,
tacrine, theophylline, propranolol, and caffeine. Doses of theophylline and
clozapine should be reduced if co-administered with fluvoxamine (DeVane and
Gill 1997).
Fluvoxamine also inhibits CYP2C19 and CYP3A4. CYP2C19 metabolizes
warfarin, and elevations in warfarin concentration have been reported in patients
taking fluvoxamine. As a result, closer monitoring of anticoagulation status is
indicated in these patients. Alprazolam and diazepam are metabolized in part
through CYP3A4, and fluvoxamine has been shown to prolong their elimination
(DeVane and Gill 1997). Carbamazepine is partially metabolized through
CYP3A4, and elevated carbamazepine levels have been documented in patients
concomitantly taking fluvoxamine (Palmer and Benfield 1994). Other drugs
whose metabolism through CYP3A4 may be affected by fluvoxamine include
pimozide, methadone, and thioridazine. Also, because of the serious QT interval
prolongation that can occur when terfenadine or astemizole is combined with the
potent CYP3A4 inhibitor ketoconazole, it is recommended that fluvoxamine be
avoided in patients who require these antihistamines (DeVane and Gill 1997).
Fluvoxamine is contraindicated for use with thioridazine, tizanidine, pimozide,
alosetron, ramelteon, and monoamine oxidase inhibitors (MAOIs) (Jazz
Pharmaceuticals 2011).
Conclusion
More than three decades of research and clinical experience with fluvoxamine
have established it as a generally well-tolerated SSRI with potential efficacy
across a broad range of disorders. While millions of patients have taken
fluvoxamine and benefited from it worldwide, two factors may have prevented
even more widespread use: drug–drug interactions, which make fluvoxamine a
less attractive choice in patients on complex drug regimens; and a perception,
especially in the United States, that it is primarily an anti-OCD drug.
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CHAPTER 14
Structure–Activity Relations
Citalopram has a single chiral center (Figure 14–1). A chiral center is an atom
surrounded by an asymmetrical arrangement of atoms such that the three-
dimensional configuration is not superimposable on its mirror image. At this
chiral center, there are two possible stereoisomers. Often, drugs are produced as
a mixture of both stereoisomers, referred to as the racemate. However, because
desired pharmacological activity or unwanted toxicity may reside in only one of
the stereoisomers, a stereoisomer-selective formulation may be superior
(Agranat et al. 2002). Citalopram was originally characterized and marketed as
the racemate, but subsequently the single stereoisomer of citalopram,
escitalopram (Figure 14–2), was developed for the treatment of depression and
other psychiatric disorders. Preclinical studies indicate that inhibition of 5-HT
transporter activity resides in the S-enantiomer (Hyttel et al. 1992), with
escitalopram being 30 times more potent than R-citalopram at inhibiting 5-HT
transport (Owens et al. 2001).
FIGURE 14–1. Chemical structure of citalopram hydrobromide.
*Indicates chiral center.
Pharmacological Profile
Citalopram
Of the selective serotonin reuptake inhibitors (SSRIs) approved to date,
citalopram is one of the most selective, with a 524-fold lower potency for
inhibiting the human norepinephrine (NE) transporter and a >10,000-fold lower
potency for inhibiting the human dopamine transporter (Owens et al. 2001). In
addition, citalopram has low affinity for a wide variety of neurotransmitter
receptors (for a review, see Hyttel et al. 1995). Citalopram has been reported to
have submicromolar affinity for the histamine type 1 (H1) receptor (Hyttel 1994;
Richelson and Nelson 1984), but this appears to be true only for the R-
enantiomer (Owens et al. 2001). Citalopram does not show significant inhibition
of monoamine oxidase (MAO) (Hyttel 1977). Behavioral studies in rats and
mice have shown citalopram to be a potent and selective inhibitor of 5-HT
reuptake (Christensen et al. 1977; Hyttel 1994). In contrast, citalopram is
ineffective in models that reflect in vivo inhibition of dopamine and NE reuptake
(Hyttel 1994). Citalopram is active in various behavioral models related to
antidepressant activity (Martin et al. 1990; Sánchez and Meier 1997) and
anxiolytic activity (Inoue 1993; Sánchez 1995).
Escitalopram
Escitalopram is also a highly potent inhibitor of 5-HT reuptake, with a Ki for
binding to the human 5-HT transporter of 1.1 nM compared with a Ki of 1.9 nM
for citalopram and 36 nM for R-citalopram (Owens et al. 2001). Escitalopram is
the most selective SSRI approved for clinical use, with a 2,600-fold lower
potency for inhibiting the human NE transporter and a >45,000-fold lower
potency for inhibiting the human dopamine transporter. Escitalopram has no
appreciable binding affinity for a large number of other neurotransmitter
receptors (Owens et al. 2001; Sánchez et al. 2003). Escitalopram shows potent
activity in various in vivo paradigms, including a model of 5-HT reuptake
inhibition and behavioral models of antidepressant, antiaggressive, and
anxiolytic activity (for a review, see Sánchez et al. 2003). In these in vivo
paradigms, escitalopram’s potency ranges from being similar to that of
citalopram to being approximately twofold greater than that of citalopram. In
contrast, in the majority of these paradigms, R-citalopram is severalfold less
potent than either escitalopram or citalopram.
Citalopram
Citalopram is well absorbed after oral administration, with an absolute
bioavailability of 80% for citalopram tablets (Joffe et al. 1998). The peak plasma
concentration is normally observed 2–4 hours following an oral dose (Kragh-
Sørensen et al. 1981). The bioavailability of citalopram is not affected by food
(Baumann 1992), and it is subject to very little first-pass metabolism (Kragh-
Sørensen et al. 1981). The apparent volume of distribution is 12–16 L/kg
(Fredricson Overø 1982; Kragh-Sørensen et al. 1981), which indicates that the
drug distributes widely. There is a linear relationship between steady-state
plasma concentration and dose (Bjerkenstedt et al. 1985), and plasma protein
binding is approximately 80% (Baumann 1992). Systemic clearance of
citalopram is 0.3–0.4 L/minute (Baumann 1992), and renal clearance of
citalopram is approximately 0.05–0.08 L/minute (Sindrup et al. 1993).
Racemic citalopram undergoes N-demethylation by the hepatic cytochrome
P450 (CYP) system to the major metabolite monodesmethylcitalopram (DCT).
CYP enzymes 2C19, 3A4, and 2D6 all contribute approximately equally to the
formation of DCT (Kobayashi et al. 1997; Rochat et al. 1997; von Moltke et al.
1999). DCT also undergoes N-demethylation to the minor metabolite
didesmethylcitalopram (DDCT) by the actions of CYP2D6 (Sindrup et al. 1993;
von Moltke et al. 2001). Clinical studies indicate that the half-lives for
citalopram, DCT, and DDCT are approximately 36 hours, 50 hours, and 100
hours, respectively (Dalgaard and Larsen 1999; Fredricson Overø 1982; Kragh-
Sørensen et al. 1981). Citalopram is metabolized by human cytochromes that
display genetic polymorphisms, and metabolism of citalopram and DCT is
impaired in subjects who show poor metabolism via the CYP2C19 and CYP2D6
pathways (Baumann et al. 1996; Sindrup et al. 1993; Yu et al. 2003).
Escitalopram
The clinical pharmacokinetics of escitalopram, reviewed by Rao (2007), are
similar to those described for citalopram. The pharmacokinetic characteristics of
escitalopram are essentially the same regardless of whether patients are given a
single oral dose of 20 mg of escitalopram or 40 mg of racemic citalopram (which
contains 20 mg of escitalopram); this indicates that there is no pharmacokinetic
interaction or interconversion between R-citalopram and escitalopram (Rao
2007).
Mechanism of Action
The majority of studies on mechanism of action have focused on citalopram,
with a relatively limited number of studies using escitalopram. Because the
antidepressant activity of citalopram results from escitalopram, the majority of
the conclusions from these studies pertain to both citalopram and escitalopram.
Citalopram is a potent and selective inhibitor of 5-HT reuptake and acts by
binding directly to the 5-HT transporter. Citalopram selectively inhibits
radioligand binding to the 5-HT transporter (Ki=0.75 nM) versus the NE
transporter (Ki=3,042 nM) in rat cortical membranes. A similar selectivity was
found for inhibiting the binding of the same radioligands to the cloned human 5-
HT and NE transporters expressed in transfected cells and for inhibiting [3H]5-
HT (Ki=8.9 nM) and [3H]NE (Ki=30,285 nM) reuptake into these transfected
cells (Owens et al. 1997).
Several studies have described how repeated dosing alters the effects of
citalopram on serotonergic neuronal function. As with other SSRIs, the ability of
citalopram to inhibit the firing of 5-HT neurons in the dorsal raphe nucleus is
greatly reduced after 14 days of repeated administration (Chaput et al. 1986).
This change is associated with an increase in the ability of citalopram to elevate
the extracellular levels of 5-HT in the cortex (Invernizzi et al. 1994). These two
effects appear to result from a desensitization of 5-HT1A autoreceptors (Chaput
et al. 1986; Cremers et al. 2000; Invernizzi et al. 1994). This adaptive change of
5-HT1A receptors following repeated administration of citalopram, or other
SSRIs, has been postulated to underlie the slow onset of antidepressant efficacy
that is observed clinically (Blier and de Montigny 1994).
Evidence suggests that a variety of antidepressants, including those that block
monoamine reuptake or metabolism, produce their therapeutic response in part
by overcoming depression-associated decreases in neurogenesis and
synaptogenesis, possibly through effects on brain-derived neurotrophic factor
(BDNF) expression. Citalopram, like several other antidepressants, has been
shown to increase the levels of BDNF messenger RNA (mRNA) in various
subregions of the rat ventral hippocampus (Russo-Neustadt et al. 2004) and to
induce signaling through the BDNF receptor tyrosine kinase receptor B (TrkB)
(Rantamäki et al. 2007). Interestingly, this effect of antidepressants on TrkB
appears to be independent of BDNF release and 5-HT transporter blockade and
does not involve a direct binding of the antidepressant to TrkB (Rantamäki et al.
2011). Escitalopram treatment has been demonstrated to affect circulating BDNF
levels. A study in depressed subjects (n=18) showed elevated plasma levels of
BDNF and decreased platelet levels of BDNF compared with healthy control
subjects (n=14), and these differences were normalized with 24 weeks of
escitalopram (10–40 mg/day) treatment (Serra-Millàs et al. 2011). Additionally,
there are preliminary clinical data suggesting that a polymorphism within the
coding region for BDNF (Val66Met) is associated with therapeutic response to
citalopram (Choi et al. 2006).
A number of studies have implicated the 5-HT2A receptor in a variety of
neuropsychiatric disorders (Norton and Owen 2005), and there is evidence
implicating the 5-HT2A receptor in the mechanism of action of antidepressants,
including citalopram (Chen and Lawrence 2003; Peremans et al. 2005). Also, a
large-scale clinical study involving 1,953 patients who participated in the
Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial
identified a significant association between a polymorphism contained in the
second intron of the gene for the 5-HT2A receptor (rs7997012) and treatment
response to citalopram (McMahon et al. 2006). While perhaps relevant to
clinical work, the functional significance of this intronic polymorphism on the 5-
HT2A receptor has yet to be determined.
Several cellular and in vivo animal model studies have shown that
antidepressants can increase glucocorticoid receptor (GR) translocation, induce
GR downregulation, and decrease GR agonist–mediated effects (Anacker et al.
2011; Carvalho and Pariante 2008), and there is evidence suggesting that similar
effects occur in vivo in humans. In a double-blind, placebo-controlled, crossover
study in healthy men, treatment for 4 days with citalopram 20 mg/day was
associated with a diminished ability of cortisol to increase electroencephalogram
alpha power and to impair working memory (Pariante et al. 2012). These results
suggest that GR activation by antidepressants does occur in the human brain.
Corticotropin-releasing factor (CRF) mediates many of the effects of
psychological stress and is postulated to play a role in the pathophysiology of
depression and anxiety disorders (Arborelius et al. 1999). In rats, lentiviral-
mediated chronic elevation of amygdala CRF reproduces many of the behavioral
and endocrine consequences of chronic stress that are consistent with a
depressive or anxious phenotype (Flandreau et al. 2012). Interestingly, chronic
escitalopram treatment of these CRF-overexpressing rats for 4 weeks reversed
some but not all of the CRF-induced anxiety-like and depressive-like behavioral
alterations (Flandreau et al. 2013).
Depression
Citalopram
The efficacy of citalopram (dosage range 20–80 mg/day) in the treatment of
depression has been shown in at least 11 placebo-controlled clinical trials (for a
review, see Keller 2000). In addition, meta-analyses of multiple placebo-
controlled studies reported similar findings (Bech and Cialdella 1992;
Montgomery et al. 1994). In the United States, three large multicenter clinical
trials have demonstrated citalopram’s efficacy in the treatment of major
depression (Feighner and Overø 1999; Mendels et al. 1999; Stahl 2000). More
recently, primary care patients in the United Kingdom were given citalopram 20
mg/day (n=274) or the NE reuptake inhibitor reboxetine 4 mg twice daily
(n=272), which were found to be equally effective in the treatment of severe
depression (defined as scores ≥15 on the Beck Depression Inventory) (Wiles et
al. 2012).
Citalopram
Only a limited number of clinical studies have examined the effectiveness of
citalopram in the treatment of depression in youth. In one double-blind trial
involving 174 children and adolescents (ages 7–17 years), citalopram (20
mg/day) showed a modest superiority over placebo in the treatment of
depression (Wagner et al. 2004). Conversely, citalopram (10–40 mg/day) was not
superior to placebo in a clinical trial involving 244 adolescents (ages 13–18
years) receiving treatment for 12 weeks (von Knorring et al. 2006). Clearly,
additional clinical trials are required to establish the efficacy and safety of
citalopram in the treatment of childhood depression.
Escitalopram
Three studies have addressed the effectiveness of escitalopram in the pediatric
population. Escitalopram was shown to be effective in the treatment of
depression in adolescents (ages 12–17 years) in a randomized, double-blind,
placebo-controlled multicenter clinical trial (Emslie et al. 2009). In this study,
the group given escitalopram 10–20 mg/day (n=155), compared with the group
given placebo (n=157), had greater improvement based on change from baseline
to week 8 in scores on the Children’s Depression Rating Scale—Revised
(CDRS-R). In another randomized, double-blind trial investigating treatment of
major depressive disorder in children and adolescents (ages 6–17 years), those
given escitalopram 10–20 mg/day (n=131) did not improve significantly more
than those given placebo (n=133). However, in a post hoc analysis of just the
adolescents (ages 12–17 years), those given escitalopram (n=80), compared with
those given placebo (n=77), had significantly improved CDRS-R scores from
baseline to week 8 (Wagner et al. 2006). Finally, the long-term benefits of
escitalopram treatment for depression in adolescents were demonstrated in an
extension trial that enrolled a subset of the sample participating in the
aforementioned Emslie et al. (2009) study. This double-blind 16- to 24-week
trial (Findling et al. 2013) showed that in comparison with subjects given
placebo (n=40), those given escitalopram 10–20 mg/day (n=37) had a modest
but statistically significantly greater improvement in CDRS-R score from
baseline of the lead-in study to treatment week 24 (8-week lead-in study plus 16-
week extension) (P=0.005).
Escitalopram
The efficacy of escitalopram in the treatment of GAD has been established in
several randomized controlled clinical trials (Baldwin and Nair 2005).
Escitalopram’s effectiveness in acute treatment of GAD was shown in three
double-blind, placebo-controlled clinical trials that were also subjected to pooled
analysis. These studies demonstrated that escitalopram (10–20 mg/day
administered for 8–12 weeks) was superior to placebo (Davidson et al. 2004;
Goodman et al. 2005; Stein et al. 2005). The efficacy of escitalopram (10–20
mg/day) in the long-term treatment of GAD was demonstrated in two 24-week
controlled clinical trials, one open label (Davidson et al. 2005) and the other
double blind (Bielski et al. 2005). Escitalopram also showed efficacy in the
prevention of GAD relapse for an additional 24–76 weeks (Allgulander et al.
2006).
Panic Disorder
Citalopram
Few well-controlled studies have evaluated the effectiveness of citalopram in the
treatment of panic disorder. In a 1-year placebo-controlled, double-blind study of
279 patients who agreed to continue treatment after an acute treatment period
during which they had been randomly assigned to receive citalopram (20 or 30
mg/day, or 40 or 60 mg/day), clomipramine (60 or 90 mg/day), or placebo, all
drug-treated groups showed significantly greater improvement compared with
placebo on a variety of anxiety rating instruments, including the Clinical Anxiety
Scale (CAS) panic attack item. The authors concluded that citalopram at a
dosage range of 20–60 mg/day was an effective long-term therapy for the
management of panic disorder (Lepola et al. 1998).
Escitalopram
Escitalopram 5–10 mg/day was shown to be effective in the treatment of panic
disorder in a 10-week randomized, double-blind, placebo-controlled, flexible-
dosage study in patients with a diagnosis of panic disorder with or without
agoraphobia (Stahl et al. 2003). The relative panic attack frequency was
significantly lower in the escitalopram group (n=125) than in the placebo group
(n=114), and at the end of the study, a greater proportion of patients had zero
panic attacks in the escitalopram group (50%) than in the placebo group (38%)
(P=0.051).
Escitalopram
Two large-scale, multinational, multicenter clinical trials have demonstrated the
effectiveness of escitalopram in the treatment of social anxiety disorder. In a 24-
week fixed-dosage trial in patients with a diagnosis of social anxiety disorder,
escitalopram at three dosages—5 mg/day (n=167), 10 mg/day (n=167), or 20
mg/day (n=170)—and paroxetine 20 mg/day (n=169) each showed a statistically
superior therapeutic effect compared with placebo (n=166) by week 12 (Lader et
al. 2004). Further improvement was seen by week 24 for all dosages of
escitalopram and for paroxetine, and escitalopram 20 mg/day was superior to
paroxetine 20 mg/day. In a 12-week study, escitalopram 10–20 mg/day (n=181)
produced a superior therapeutic response compared with placebo (n=177) based
on mean change from baseline in the Liebowitz Social Anxiety Scale score
(Kasper et al. 2005). In a long-term study, escitalopram treatment at dosages of
10 or 20 mg/day for up to 24 weeks was shown to be effective in preventing
relapse of social anxiety disorder following successful short-term therapy, with
relapse being 2.8 times more likely with placebo treatment (n=181) than with
escitalopram treatment (n=190) (Montgomery et al. 2005).
Escitalopram
The effectiveness of escitalopram in the treatment of anxiety symptoms
associated with major depressive disorder was evaluated in a pooled analysis of
five clinical trials (Bandelow et al. 2007). These placebo-controlled trials were
originally designed to examine the effectiveness of escitalopram in treating
major depression. In the pooled analysis, escitalopram 10–20 mg/day (n=850)
was consistently superior to placebo (n=737) in relieving the anxious symptoms
associated with depression, as evaluated with several different assessments of
anxiousness. The analyses presented in this pooled study indicate that
escitalopram is effective in relieving anxiety symptoms in depressed patients.
Obsessive-Compulsive Disorder
Citalopram
To date, a limited number of clinical studies have evaluated the effectiveness of
citalopram in the treatment of obsessive-compulsive disorder (OCD). In the only
published large-scale (N=401) double-blind, placebo-controlled study of
citalopram in the treatment of OCD, all three dosages of citalopram (20, 40, and
60 mg/day) given for 12 weeks were significantly more effective than placebo in
relieving the symptoms of OCD (Montgomery et al. 2001a). Citalopram appears
to be effective in treating both obsessions and compulsions.
Escitalopram
The effectiveness of escitalopram in the treatment of OCD was demonstrated in
a 24-week double-blind, placebo-controlled multicenter clinical trial (Stein et al.
2007). In this study, escitalopram 20 mg/day (n=116) and paroxetine 40 mg/day
(n=119) produced significant improvement compared with placebo, and by week
24, all treatments, including escitalopram at 10 mg/day (n=116), were superior to
placebo (n=115). Long-term treatment with escitalopram was shown in one
large-scale study to prevent relapse of OCD in patients who had responded to
initial treatment (Fineberg et al. 2007). Patients treated with escitalopram 10 or
20 mg/day (n=163) showed a significantly greater time to relapse compared with
those receiving placebo (n=157).
Investigational Uses
Alzheimer’s Disease
Citalopram
Brain accumulation of amyloid plaques formed by the aggregation of the
amyloid-β peptide (Aβ) is thought to be central to the pathophysiology of
Alzheimer’s disease (AD) (Holtzman et al. 2011). The aggregation of Aβ into
plaques is concentration dependent (Bero et al. 2011; Lomakin et al. 1997);
therefore, methods to decrease Aβ levels may be therapeutic. Previous studies
have shown that serotonin signaling suppresses the generation of Aβ in vitro and
in animal models of AD (Cirrito et al. 2011; Nitsch et al. 1996). In an aged
transgenic AD mouse model (APP/PS1 plaque-bearing mice), acute citalopram
treatment led to a dose-dependent decrease in brain interstitial fluid Aβ levels,
and chronic citalopram treatment arrested the growth of preexisting plaques and
reduced the appearance of new plaques by 78% (Sheline et al. 2014). In addition,
in a double-blind study, acute administration of citalopram (60 mg/day) in 23
healthy humans (ages 18–50 years, 11 females) resulted in lower cerebrospinal
fluid Aβ production (37%) and concentration (38%) compared with placebo
(Sheline et al. 2014). To the extent that AD involves the accumulation of Aβ,
these results suggest a potential role for SSRI treatment in the prevention of AD,
and future studies should be aimed at defining the mechanism by which
citalopram treatment lowers Aβ levels.
Citalopram
In a meta-analysis of 746 depressed patients involved in several short-term
clinical trials, the most common adverse events associated with citalopram were
nausea and vomiting (20%), increased sweating (18%), and dry mouth and
headache (17%) (Baldwin and Johnson 1995). Analysis of an integrated safety
database, which includes data from 3,107 patients enrolled in 24 clinical trials,
indicated that in placebo-controlled trials, nausea, dry mouth, somnolence,
increased sweating, tremor, diarrhea, and ejaculatory failure of mild to moderate
severity occurred with significantly greater frequency in patients given
citalopram than in those given placebo (Muldoon 1996). The incidences of these
adverse events with citalopram were less than 10% above those seen with
placebo and were comparable to those reported with other SSRIs. Citalopram
had a tolerability that was superior to that of the tricyclic antidepressants, with
the exception that nausea and ejaculatory failure occurred with a 5% greater
frequency in patients given citalopram (Keller 2000).
Escitalopram
In general, the side effects associated with escitalopram are similar to those
observed with citalopram. In three placebo-controlled clinical trials performed
with escitalopram, rates of discontinuation due to adverse events did not differ
for patients given a dosage of 10 mg/day versus patients in the placebo group
(Burke et al. 2002; Montgomery et al. 2001b; Wade et al. 2002). In the trial that
included an escitalopram dosage of 20 mg/day, the rate of discontinuation was
10.4% for the group given escitalopram versus 2.5% for the group given placebo
(Burke et al. 2002). In addition, the rate of adverse events overall in the group
receiving escitalopram 20 mg/day (85.6%) was significantly greater than the rate
in the placebo group (70.5%). Regardless of dosage, the adverse events that have
been reported to occur more frequently with escitalopram compared with
placebo are nausea, diarrhea, insomnia, dry mouth, and ejaculatory disorder,
with nausea being reported most frequently, at a rate of 15% (McRae 2002). No
published studies have reported clinically significant findings in laboratory test
values, vital signs, weight gain or loss, or ECG values.
Hyponatremia
Citalopram and escitalopram have been shown to produce hyponatremia in case
reports involving elderly patients, and this information has been reviewed
elsewhere (Jacob and Spinler 2006). In addition to advanced age, other factors
that may increase the likelihood of hyponatremia include female gender,
concurrent diuretic use, low body weight, and recent pneumonia. Treatment of
SSRI-induced hyponatremia usually involves fluid restriction and/or
administration of a loop diuretic such as furosemide and may include
discontinuation of the SSRI.
Discontinuation Syndrome
The abrupt cessation of antidepressant therapy can result in a discontinuation
syndrome characterized by dizziness, nausea and vomiting, lethargy, and flulike
symptoms. This syndrome is more common with short-half-life SSRIs such as
paroxetine and less common with long-half-life SSRIs such as fluoxetine. The
data obtained from clinical trials suggest that the adverse events associated with
discontinuation of citalopram or escitalopram tend to be mild and transient
(Baldwin et al. 2007; Markowitz et al. 2000; Montgomery et al. 1993). Dose
tapering is recommended for patients discontinuing treatment.
Drug–Drug Interactions
Even though the majority of a dose of citalopram is metabolized in the liver
(75%), because multiple P450 enzymes (CYP2C19, CYP3A4, and CYP2D6)
contribute equally to the metabolism of citalopram and escitalopram, inhibition
of any one of these enzymes by another drug is unlikely to significantly impact
the overall metabolism of citalopram or escitalopram. Consistent with this, there
are relatively few reports in the literature of drug–drug interactions involving
citalopram or escitalopram. Because of the possibility of a potentially fatal
pharmacodynamic interaction resulting in the serotonin syndrome, neither
citalopram nor escitalopram should be administered with an MAO inhibitor or
within 14 days of discontinuing an MAO inhibitor.
Conclusion
Citalopram and escitalopram are highly selective 5-HT reuptake inhibitors that
are well tolerated and effective for the treatment of depression, with
escitalopram also having proven efficacy in large-scale clinical trials in the
treatment of GAD. Although the use of citalopram and escitalopram in the
treatment of other psychiatric conditions has not been as thoroughly studied, the
few well-controlled trials that have been completed suggest that both drugs may
have a significant role in treating a wide range of psychiatric illnesses, including
panic disorder, social anxiety disorder, anxiety associated with depression, and
OCD. An advantage of citalopram and escitalopram compared with some other
common SSRIs is a relatively weak inhibition of liver CYP450 enzymes, which
reduces the potential for adverse pharmacokinetic drug–drug interactions. In
addition, because escitalopram does not share with citalopram a modest affinity
for the histamine H1 receptor, it may have a lower potential for antihistaminergic
side effects compared with citalopram, a difference that has yet to be
demonstrated in a clinical trial. In terms of effects on cardiac function,
escitalopram’s risk of producing QT interval prolongation appears to be lower
than that of citalopram, and careful monitoring must accompany use of
citalopram in patients at risk for QT prolongation. There are a number of clinical
trials comparing escitalopram with a variety of other antidepressants, including
citalopram and venlafaxine, that suggest that escitalopram may have a faster
onset of antidepressant efficacy and modest superiority in the treatment of
individuals who are severely depressed. However, a clinically significant
superiority of escitalopram over citalopram in the “real world” of psychiatric
practice remains to be definitely established.
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CHAPTER 15
Trazodone
Pharmacological Profile
Trazodone is a relatively weak SSRI; however, it is relatively specific for
serotonin (5-HT) uptake inhibition, with minimal effects on norepinephrine (NE)
or dopamine reuptake (Hyttel 1982) (Figure 15–1). Trazodone appears to
increase extracellular 5-HT concentrations through a combination of
mechanisms involving the 5-HT transporter (5-HTT) and the serotonin2A/2C (5-
HT2A/2C) receptors (Pazzagli et al. 1999). In addition, trazodone has some 5-HT
receptor antagonist activity (Haria et al. 1994). Its active metabolite, m-
chlorophenylpiperazine (mCPP), is a potent direct 5-HT receptor agonist. Thus,
trazodone can be viewed as a mixed serotonergic agonist–antagonist, with the
relative amount of mCPP accumulation affecting the relative degree of the
predominant agonist activity. Sustained administration is associated with
enhanced serotonergic neurotransmission in vivo in the rat brain (Ghanbari et al.
2010).
Mechanism of Action
The ultimate mechanism of action of trazodone remains unclear. Although the
drug is described as a 5-HT reuptake inhibitor, its effects on this neurotransmitter
system are complex. Trazodone has relative selectivity for 5-HT reuptake sites
(Hyttel 1982); however, in vivo, it blocks the head twitch response induced by
classic 5-HT agonists in animals. The potent 5-HT receptor agonist properties of
trazodone’s major metabolite, mCPP, may play a role in the mechanism of action
of the parent compound. Trazodone, unlike the vast majority of antidepressants,
does not produce downregulation of β-adrenergic receptors in rat cortex (Sulser
1983).
Drug–Drug Interactions
Trazodone can potentiate the effects of other central nervous system (CNS)
depressants. Patients should be warned about increased drowsiness and sedation
when trazodone is combined with other CNS depressants, including alcohol.
The combination of trazodone with an MAOI, as with other antidepressants,
should be handled with great caution, although there are case reports of the
successful combination of trazodone with an MAOI. Development of the
serotonin syndrome has been associated with the combination of trazodone with
other proserotonergic agents. Trazodone inhibits the antihypertensive effects of
clonidine. Trazodone can cause hypotension, especially orthostatic hypotension,
and concomitant administration of trazodone with antihypertensive therapy may
require a reduction in the dose of the antihypertensive agent.
Clinically significant cases of suspected trazodone–warfarin interactions have
been described.
Nefazodone
Pharmacological Profile
Nefazodone is a 5-HT2 receptor antagonist and a weak inhibitor of 5-HT and NE
reuptake (Figure 15–2). It has little affinity for α2-adrenergic, β-adrenergic, or
serotonin1A (5-HT1A) receptors, and its affinity for the α1-adrenergic receptor is
less than that of trazodone. Nefazodone is inactive at most other receptor-
binding sites (Taylor et al. 1986).
Nefazodone demonstrates several of the classic preclinical characteristics of
antidepressants. In humans, nefazodone does not suppress REM sleep, in
contrast to most other antidepressants (Sharpley et al. 1996).
Mechanism of Action
The mechanism of action of nefazodone is poorly understood. The manufacturer
has indicated that nefazodone antagonizes 5-HT2 receptors and also inhibits
neuronal uptake of both 5-HT and NE (Bristol-Myers Squibb 2003). Several
reviews refer to nefazodone as a “dual acting” antidepressant, suggesting that it
enhances both serotonergic and noradrenergic neurotransmission via uptake
blockade. Although nefazodone has similar effects on the 5-HT and NE
transporters, this observation is potentially misleading. Nefazodone’s inhibition
of NE reuptake is weaker than that of the SSRI fluoxetine and is approximately
three orders of magnitude weaker than what is seen with conventional NE
reuptake inhibitors. Furthermore, nefazodone’s inhibition of 5-HT reuptake is
nearly identical to that of desipramine and more than 100-fold less than that of
fluoxetine (Bolden-Watson and Richelson 1993). Thus, the “dual action” of
nefazodone refers to minimal, albeit equal, effects on 5-HT and NE reuptake
inhibition.
In humans, therapeutic doses of nefazodone do not cause sustained 5-HT
uptake inhibition at the platelet 5-HTT (Narayan et al. 1998). The active
metabolite m-CCP, which appears to predominate in the brain because of greater
penetration of the blood–brain barrier (Nacca et al. 1998), may play an important
role in the mechanism of action.
Drug–Drug Interactions
The manufacturer of triazolam warns that its concurrent use with nefazodone is
contraindicated. Increases in the plasma concentration of digoxin occur with
concurrent nefazodone administration. Nefazodone increases the plasma
concentrations of terfenadine and loratadine (with associated QTc prolongation),
carbamazepine, and cyclosporine.
Conclusion
Trazodone was one of the earliest second-generation antidepressants. Its lack of
anticholinergic effects provided an advantage over the TCAs for many patients;
its sedative properties are helpful for some patients but problematic for others;
and orthostatic hypotension is a concern for elderly patients. Nefazodone is
related to trazodone, and the two drugs share an active metabolite, mCPP, that
may play an important role in their mechanism of action. The risk of serious
liver damage led to Serzone’s removal from the market in several countries,
although generic nefazodone is currently available in the United States.
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CHAPTER 16
Vortioxetine
Pierre Blier, M.D., Ph.D.
Structure–Activity Relations
Vortioxetine is a piperazine derivative, and its chemical name is 1-[2-(2,4-
dimethylphenyl-sulfanyl)-phenyl]-piperazine (Figure 16–1).
Pharmacological Profile
Vortioxetine is described as a multimodal serotonin agent because it acts on two
types of neuronal elements: the 5-HT transporter and several 5-HT receptor
subtypes (Zohar et al. 2015). Among monoamine transporters, it binds
selectively to the 5-HT transporter, but only to the same extent as other SSRIs at
its maximum recommended dosage, as shown in positron emission tomography
studies in humans (Areberg et al. 2012; Meyer et al. 2004; Stenkrona et al.
2013). Vortioxetine is a 5-HT3 antagonist, a full 5-HT1A agonist, a 5-HT7
antagonist, a partial 5-HT1B agonist, and a 5-HT1D antagonist (Mørk et al. 2012).
On the basis of plasma levels and affinity values, all of these targets could be
engaged by vortioxetine to physiologically relevant levels within its usual
therapeutic dosage range. Although the clinical significance of these various
activities at 5-HT receptors in the presence of lower occupancy of 5-HT
transporters has not been determined, synergies between such neuronal elements
on neurotransmitter levels have been documented in the brains of laboratory
animals (Sanchez et al. 2015).
Pharmacokinetics and Disposition
Vortioxetine is well absorbed from the gastrointestinal tract, and its
bioavailability is similar under fasting and fed conditions. It reaches peak plasma
concentrations in 7–11 hours and is 98% bound to plasma proteins. Vortioxetine
is not a substrate for the permeability glycoproteins, indicating that brain levels
will not be affected by possible polymorphisms of these efflux carriers. The
terminal half-life of vortioxetine is about 66 hours, and steady-state
concentrations are achieved after 2 weeks; consequently, complete elimination
requires 2 weeks as well (Areberg et al. 2014; Bundgaard et al. 2016).
Vortioxetine is extensively metabolized through oxidation and subsequently
by glucuronic conjugation. The cytochrome P450 (CYP) 2D6 isoenzyme is the
main enzyme catalyzing its catabolism to its major carboxylic acid metabolite,
which is pharmacologically inactive. About two-thirds of the inactive
metabolites are excreted in the urine, and the last third are excreted in the feces.
A very small amount of unchanged vortioxetine is excreted in the urine. No
dosage adjustment is necessary in patients with renal impairment or mild to
moderate hepatic impairment; however, vortioxetine is not recommended in
patients with severe hepatic insufficiency. The plasma levels of vortioxetine are
about two times higher in poor metabolizers of CYP2D6 (Chen et al. 2013).
Drug–Drug Interactions
Vortioxetine must never be coadministered with a monoamine oxidase inhibitor
(MAOI). Before a patient is started on vortioxetine, there must be an elimination
period of 14 days for an irreversible MAOI or 2 days for the reversible MAOI
moclobemide. Similarly, a 14-day elimination period for vortioxetine is
necessary before initiating either an irreversible MAOI or moclobemide.
Vortioxetine is neither an inhibitor nor an inducer of any metabolic enzymes.
Consequently, it will not alter the levels of other medications through metabolic
interference. Complete inhibitors of CYP2D6, such as fluoxetine and paroxetine,
as well as moderate inhibitors, such as bupropion and duloxetine, will
approximately double the exposure (area under the curve) to vortioxetine. These
interactions are expected to occur mainly in switch situations, which are
discussed in the following section. In such concomitant regimens, the
vortioxetine dosage should be reduced by half (D’Empaire et al. 2011;
Hvenegaard et al. 2012).
Triptans used in the treatment of migraines may be less effective in the
presence of vortioxetine. This class of agents acts mainly by activating 5-HT1D
receptors, whereas vortioxetine is a 5-HT1D receptor antagonist. However,
because vortioxetine’s affinity for the 5-HT1D receptor is very low compared
with its affinities for other 5-HT receptor subtypes (Mørk et al. 2012), the
dampened activity of triptans may not occur with lower dosages of vortioxetine.
Conclusion
Vortioxetine is a multimodal serotonergic agent that inhibits the 5-HT
transporter, albeit to a lesser extent than other SSRIs, and has a variety of actions
at five 5-HT receptor subtypes. Its only approved indication is for the treatment
of major depressive disorder. Although it may produce as much mild to
moderate nausea as SSRIs on treatment initiation, this effect is generally
transient and seldom leads to treatment discontinuation. At dosages of 10
mg/day or less, vortioxetine is expected to produce less sexual dysfunction than
SSRIs and SNRIs. Vortioxetine does not impact the cardiovascular system, even
at twice its maximum recommended dosage. Vortioxetine will not alter the levels
of other medications because it is not a hepatic enzyme inducer or inhibitor. It is
still too early to determine vortioxetine’s role in treatment-resistant depression.
However, in some patients with major depressive disorder, vortioxetine may
exert a beneficial action on cognitive functioning.
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26527055
CHAPTER 17
Mirtazapine
Alan F. Schatzberg, M.D.
Structure–Activity Relations
Mirtazapine (Figure 17–1) is a member of the piperazinoazepines, a class of
chemical compounds that is unrelated to any other class used in the treatment of
psychiatric conditions (Maris et al. 1999). Mirtazapine is also known by its
chemical name, 1,2,3,4,10,14b-hexahydro-2-methylpyrazino[2,1-a]pyridol[2,3-
c]benzazepine (Dahl et al. 1997; Dodd et al. 2000).
FIGURE 17–1. Chemical structure of mirtazapine.
Pharmacological Profile
Mirtazapine is described as a noradrenergic and specific serotonergic
antidepressant (NaSSA) (Holm and Markham 1999; Kent 2000; Nutt 1998). It is
a potent serotonin2 (5-HT2), serotonin3 (5-HT3), and central α2-adrenergic
receptor antagonist (de Boer 1996; De Boer et al. 1995; Kooyman et al. 1994).
Antagonism of 5-HT2 and 5-HT3 receptors results in an increase in serotonin1A
(5-HT1A) receptor–mediated transmission and, thus, a more specific effect on
serotonergic transmission, relative to the selective serotonin reuptake inhibitor
(SSRI) class of antidepressants (Bengtsson et al. 2000; Berendsen and
Broekkamp 1997; Kent 2000). In addition, because α2-adrenergic receptors
normally act to inhibit transmission at serotonergic and noradrenergic axon
terminals, mirtazapine acts to increase the release of both serotonin (5-HT) and
norepinephrine via blockade of central α2 receptors (Numazawa et al. 1995).
Mirtazapine has no significant affinity for dopamine receptors, low affinity for
muscarinic cholinergic receptors (de Boer 1996), and high affinity for histamine1
(H1) receptors (de Boer 1996). Mirtazapine appears to have no effect on 5-HT
and dopamine reuptake and only a minimal effect on norepinephrine reuptake
(de Boer 1996; Kent 2000). The drug appears to significantly reduce cortisol
levels (Laakmann et al. 2004; Schmid et al. 2006).
Pharmacokinetics and Disposition
Absorption
Mirtazapine is well absorbed from the gastrointestinal tract, and bioavailability
does not appear to be affected by the presence of food in the stomach (Fawcett
and Barkin 1998b). An oral rapidly disintegrating tablet has been available since
2001 (Benkert et al. 2006).
Distribution
Mirtazapine appears to be 85% bound to plasma proteins (Fawcett and Barkin
1998b).
Metabolism
Mirtazapine is primarily metabolized by the liver via demethylation and
hydroxylation, followed by glucuronidation (Fawcett and Barkin 1998b; Merck
& Co., Inc. 2016). Its major metabolite, desmethylmirtazapine, is weakly active
but is present in lower serum concentrations than the parent compound (Fawcett
and Barkin 1998b; Kent 2000). Mirtazapine lacks both autoinduction and
autoinhibition of hepatic cytochrome P450 (CYP) enzymes (Fawcett and Barkin
1998b). Although in vitro studies do not demonstrate an inhibitory effect,
mirtazapine is a substrate for CYP1A2, 2D6, and 3A4 (Fawcett and Barkin
1998b; Merck & Co., Inc. 2016). Mirtazapine is a mild competitive inhibitor of
CYP2D6 (Barkin et al. 2000; Fawcett and Barkin 1998b). A pharmacogenetic
study of CYP2D6 in geriatric depressed patients failed to reveal that slow and
intermediate metabolizers demonstrate increased dropout rates due to side effects
of the drug (Murphy et al. 2003b).
These findings suggest that mirtazapine is well tolerated in individuals who
are slow metabolizers of CYP2D6.
Elimination
Mirtazapine and its metabolites are eliminated primarily in the urine (up to 75%)
and feces (up to 15%) (Fawcett and Barkin 1998b). The elimination half-life of
mirtazapine is 20–40 hours (Fawcett and Barkin 1998b; Merck & Co., Inc. 2016;
Stimmel et al. 1997). Of note, the clearance of mirtazapine may be affected by
hepatic or renal impairment (Fawcett and Barkin 1998b). The elimination half-
life may increase by 30%–40% in patients with hepatic impairment (Fawcett and
Barkin 1998b; Kent 2000). In patients with moderate to severe renal impairment,
the clearance of mirtazapine may be decreased by 30%–50% (Fawcett and
Barkin 1998b; Kent 2000; Merck & Co., Inc. 2016).
Dysthymia
In a 10-week open-label trial of the use of mirtazapine in 15 patients with DSM-
IV dysthymic disorder, 8 patients demonstrated at least a 40% reduction in Ham-
D scores, and 4 of these 8 patients showed symptom remission by study endpoint
(Dunner et al. 1999).
Obsessive-Compulsive Disorder
Koran et al. (2005) reported on a two-phase study (a 12-week open-label phase
followed by an 8-week double-blind discontinuation phase) of mirtazapine
(maximum dosage of 60 mg/day) in 30 patients with obsessive-compulsive
disorder (OCD). In the 8-week discontinuation phase, mirtazapine was
significantly more effective than placebo in preventing symptom recurrence.
Mirtazapine augmentation of citalopram was assessed in 49 nondepressed
OCD patients (Pallanti et al. 2004). Subjects were treated with citalopram plus
placebo or citalopram plus mirtazapine under single-blind conditions.
Mirtazapine appeared to speed the response to citalopram but not to improve
overall response.
Sleep Disorders
Because of its sedating properties in depression, mirtazapine has been studied in
patients with breathing-related sleep disorders. In a double-blind crossover study
in 7 patients with obstructive sleep apnea, mirtazapine at dosages of 4.5 mg/day
and 15 mg/day produced significantly greater reductions (on the order of 46%–
52%) in apnea-hypopnea index (AHI) scores in comparison with placebo (Carley
et al. 2007). However, because of concerns regarding weight gain and sedation,
the authors concluded that mirtazapine could not at present be recommended as a
primary therapy in this disorder.
Chronic or Recurrent Pain
A number of case reports indicate that mirtazapine could be beneficial in chronic
or recurrent pain (Brannon and Stone 1999; Brannon et al. 2000; Kuiken et al.
2005; Nutt and Law 1999).
In a large observational study conducted in Germany (Freynhagen et al. 2006)
and involving 600 patients with comorbid pain and depression treated with
mirtazapine, the drug appeared to reduce pain effectively, with a relatively low-
order risk of side effects (7%) at a mean dosage of 35 mg/day.
Mirtazapine at 15–30 mg/day was reported to be effective in a double-blind
crossover study in 24 nondepressed patients with chronic tension headaches
(Bendtsen and Jensen 2004). Area under the curve (intensity × duration) for
headache was significantly lower for mirtazapine than for placebo.
Nausea
A case series of 20 patients with breast or gynecological cancer who were treated
with mirtazapine demonstrated a significant reduction in symptoms of
depression, anxiety, nausea, anorexia, and insomnia in 19 of the patients, as well
as a lack of adverse drug interactions with oncology treatment regimens,
including chemotherapy (Thompson 2000).
A 7-week open-label crossover trial of mirtazapine in 20 patients with cancer
found significant improvements in mood, anxiety, insomnia, appetite, weight,
and pain symptoms by study endpoint (Theobald et al. 2002).
It has been suggested that mirtazapine could prove to be a safe and effective
adjunct to cancer chemotherapy because of its ability to treat nausea via a 5-HT3
receptor antagonism effect; insomnia, anorexia, and weight loss via H1 receptor
antagonism; symptoms of depression via enhanced 5-HT and noradrenergic
transmission by way of α2, 5-HT2, and 5-HT3 receptor blockade; and symptoms
of anxiety via 5-HT2 and 5-HT3 receptor antagonism (Kast 2001). A
randomized, double-blind trial reported that the incidence of nausea and
vomiting after spinal anesthesia with intrathecal morphine was significantly
lower in orthopedic surgery patients who received preoperative mirtazapine (30
mg) than in those who received placebo (Chang et al. 2010).
A review of seven cases of pregnant patients with treatment-refractory
hyperemesis gravidarum and symptoms of depression and anxiety concluded
that treatment with mirtazapine produced resolution of symptoms without
adverse effects on the newborns (Saks 2001).
Vasomotor Symptoms
Waldinger et al. (2000) described four cases in which women (ages between 39
and 60 years) experienced a near-complete resolution of symptoms of hot flushes
and perspiration within the first week of treatment with mirtazapine.
Akathisia
Poyurovsky et al. (2003, 2006) conducted two double-blind, placebo-controlled
studies of mirtazapine treatment of antipsychotic-induced akathisia in patients
with schizophrenia. In the first study (Poyurovsky et al. 2003), mirtazapine 15
mg/day was compared with placebo in 26 patients. The drug was significantly
superior to placebo. In the second study (Poyurovsky et al. 2006), mirtazapine
15 mg/day was compared with propranolol 80 mg/day or placebo in 90 patients.
Both drugs separated from placebo, but propranolol was associated with
clinically significant bradycardia and hypotension.
Overdose
Mirtazapine appears to be safe in overdose. In one report (Holzbach et al. 1998),
the cases of 2 patients who had overdosed with 30–50 times the average daily
dose of mirtazapine were presented. In each case, the patient recovered fully and
without any complications.
Symptoms reported in cases of mirtazapine overdose include disorientation,
drowsiness, impaired memory, and tachycardia (Fawcett and Barkin 1998b; Kent
2000; Montgomery 1995; Stimmel et al. 1997).
A review of 117 mirtazapine overdoses (average ingestion: 450 mg) in
Scotland revealed the adverse consequences to be relatively mild (Waring et al.
2007). Decreased consciousness was seen in 27% of subjects; 30% demonstrated
tachycardia.
A more recent study of overdoses seen at six general hospitals in the United
Kingdom between 2000 and 2006 indicated that mirtazapine was of intermediate
toxicity between tricyclic antidepressants and venlafaxine, on the one hand, and
SSRIs, on the other (Hawton et al. 2010). Another study of 239,000 patients in
the United Kingdom reported that mirtazapine was significantly more likely than
citalopram to be associated with suicide, attempted suicide, or self-harm;
however, the number of events was low (Coupland et al. 2015). Trazodone and
venlafaxine also were associated with more overdose events. That mirtazapine
and trazodone—two sedating antidepressants often prescribed for depressed
patients with comorbid sleep problems—were both noted to be associated with
suicidal behavior raises the possibility that baseline insomnia, rather than
specific drug effects, might explain at least some of the increased risk of suicide
attempts.
Drug–Drug Interactions
In vitro data suggest that mirtazapine is unlikely to have clinically significant
effects on the metabolism of drugs by CYP enzymes (Barkin et al. 2000; Fawcett
and Barkin 1998b; Kent 2000). Analyses of data from the clinical development
program for mirtazapine and postmarketing surveillance reveal no clinically
relevant drug–drug interactions from the concomitant use of medications such as
opiates, anticonvulsants, analgesics, antihypertensives, diuretics, or nonsteroidal
anti-inflammatory drugs (NSAIDs) (Barkin et al. 2000; Fawcett and Barkin
1998b). However, few formal drug interaction studies involving mirtazapine
have been conducted (Barkin et al. 2000; Fawcett and Barkin 1998b; Holm and
Markham 1999). Of note, a study of elderly patients with depression allowed for
patients to be on drugs that are CYP2D6 substrates (Schatzberg et al. 2002). In
this study, no increase in side effects was observed in these patients compared
with patients who were not taking CYP2D6 substrate agents (Schatzberg et al.
2002).
Conclusion
Mirtazapine is derived from the piperazinoazepine class of compounds and, as
such, is structurally unrelated to any other psychotropic medications.
Mirtazapine also is unique as an antidepressant because of its 5-HT2, 5-HT3, and
α2 receptor antagonist pharmacodynamic profile, which results in enhancement
of noradrenergic and serotonergic transmission. It is an antidepressant that has
been shown to be efficacious and well tolerated in the treatment of depression,
and there are indications that it may be effective in a number of other medical
and psychiatric conditions. Moreover, mirtazapine may offer a more rapid
amelioration of symptoms of depression and anxiety compared with other
antidepressants. The most common side effects reported with mirtazapine are
somnolence, increased appetite, weight gain, and dry mouth. It otherwise
appears to be free of many of the adverse effects typical of the SSRIs, especially
sexual dysfunction.
Furthermore, mirtazapine appears to be well tolerated and effective in the
treatment of geriatric depression and to have benefit as an add-on agent in
schizophrenia. In addition, mirtazapine is considered to be relatively safe in
overdose, with case reports documenting complete and uncomplicated recovery
following ingestion of up to 50 times the average daily dosage. Finally,
mirtazapine appears to be devoid of clinically significant drug–drug interactions,
although larger formal clinical trials are still needed to verify this.
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CHAPTER 18
Bupropion
David V. Hamilton, M.D., M.A.
Anita H. Clayton, M.D.
Structure–Activity Relations
Bupropion, 2-(tert-butylamino)-1-(3′-chlorophenyl)propan-1-one, is a
monocyclic antidepressant and a member of the aminoketone group (Figure 18–
1). It was designed as a simple chemical structure that in vivo would result in
relatively innocuous metabolites (Mehta 1983). Chemically, bupropion is an
organic base with a high degree of both water and lipid solubility, resulting in
good systemic absorption. Its relatively benign side-effect profile in comparison
with that of tricyclic and tetracyclic antidepressants is due to the absence of
heterocyclic rings as well as other common functional groups (Mehta 1983).
Pharmacological Profile
Bupropion inhibits the reuptake of dopamine and norepinephrine by acting as a
nonselective inhibitor of the dopamine transporter (DAT) and the norepinephrine
transporter (NET). Studies show that bupropion also acts as an antagonist to
nicotinic acetylcholine (nACh) receptors. Bupropion does not inhibit
monoamine oxidase A or B, nor are its effects mediated by serotonin (Ascher et
al. 1995).
Studies have demonstrated that bupropion raises dopamine concentrations by
causing a rapid and reversible increase in vesicular dopamine reuptake via
cellular redistribution of the vesicular monoamine transporter 2 (VMAT2)
protein. By increasing the presynaptic pool of dopamine available for release,
the concentration of dopamine in the extracellular space is further augmented,
adding to the therapeutic efficacy of this compound (Dwoskin et al. 2006; Rau et
al. 2005).
Although more is known about the dopaminergic effects of bupropion,
interaction with the noradrenergic system also plays an important role in the
drug’s antidepressant activity. Bupropion is a weak competitive inhibitor of
norepinephrine; in comparison with imipramine, it is 65 times less potent (Ferris
and Beaman 1983). Research using various cellular expression systems has
elucidated the ability of bupropion to interact with specific nACh receptors.
Bupropion has been shown to work by noncompetitive inhibition of nACh
receptors (Dwoskin et al. 2006). This action may partially contribute to
bupropion’s efficacy not only as an antidepressant but also as an agent to
facilitate tobacco cessation.
It has been noted that bupropion shares some structural and neurochemical
properties with sympathomimetics and has a phenylethylamine skeleton similar
to that of amphetamine. An early study by Griffith et al. (1983) comparing the
effects of bupropion and amphetamine in individuals with a history of
amphetamine abuse concluded that bupropion had little abuse potential in
humans. However, recent reports have described cases in which bupropion was
perceived as a psychostimulant by patients with a previous history of cocaine
abuse (Vento et al. 2013). An 11-year review by Lewis et al. (2014) of data from
the California Poison Control Center found that 3.6% of all calls to the center
regarding bupropion were due to intentional insufflation in order to achieve a
psychostimulant effect, with an average dose of 1,500 mg. Hilliard et al. (2013)
reported that bupropion is especially valued as a stimulant of abuse in the
incarcerated population. These preliminary data point to the need to continue to
monitor bupropion users for potential abuse, especially in patient populations
that are at increased risk of developing substance use disorders and in those
patients with a history of stimulant use disorders.
Mechanism of Action
Despite considerable effort spent in elucidating bupropion’s mechanism of
action, what we know is limited. Preclinical data indicate that bupropion does
not bind to postsynaptic histamine, α- or β-adrenergic, or serotonin receptors, nor
does it inhibit monoamine oxidase (Ascher et al. 1995; Baldessarini 2001; Fava
et al. 2005; Stahl et al. 2004). Thus, among the myriad of antidepressants now
available, bupropion is the only agent without substantial serotonergic activity
(Ascher et al. 1995; Richelson 1996; Stahl et al. 2004).
Bupropion’s three major metabolites—hydroxybupropion,
threohydrobupropion, and erythrohydrobupropion—play a crucial role in its
antidepressant activity (GlaxoSmithKline 2016a, 2016b). In vitro studies have
demonstrated that bupropion and its active metabolites inhibit both the NET and
the DAT (described in Fava et al. 2005).
Although other antidepressants that affect NET receptors are thought to
produce their effects by downregulation of postsynaptic noradrenergic receptors,
bupropion differs in that it decreases the firing rate of neurons in the locus
coeruleus in a dose-dependent manner (B.R. Cooper et al. 1994; T.B. Cooper et
al. 1984). Acute administration of bupropion not only decreases firing of brain-
stem norepinephrine and dopamine neurons but also increases extracellular
norepinephrine and dopamine concentrations in the nucleus accumbens (Fava et
al. 2005). Furthermore, the efficacy of bupropion and hydroxybupropion has
been shown to diminish in animal models when norepinephrine- or dopamine-
blocking drugs are administered (B.R. Cooper et al. 1980; Dwoskin et al. 2006).
Indications and Efficacy
Primary Indications
Major Depressive Disorder
Bupropion’s efficacy in the treatment of major depressive disorder (MDD) is
supported by many clinical trials. The drug’s three formulations are equally
useful for this therapeutic indication (Fabre et al. 1983; Lineberry et al. 1999).
Comparison trials have demonstrated that bupropion is as effective as other
classes of antidepressants, including TCAs and SSRIs (Branconnier et al. 1983;
Clayton et al. 2006; Coleman et al. 1999, 2001; Croft et al. 1999; Feighner et al.
1986; Kavoussi et al. 1997; Mendels et al. 1983; Thase et al. 2005; Weihs et al.
2000). In comparisons with specific drugs, bupropion’s efficacy in depression
was found to be equal to that of fluoxetine (Feighner et al. 1991) and of
trazodone (Weisler et al. 1994).
The development of bupropion SR launched several comparison studies with
SSRIs, including fluoxetine, sertraline, and paroxetine. In most studies, the
effective daily dosage of bupropion SR was between 300 mg and 400 mg. All
studies demonstrated that bupropion’s effectiveness in treating symptoms of
depression was equal to that of SSRIs (Coleman et al. 1999, 2001; Croft et al.
1999; Kavoussi et al. 1997; Weihs et al. 2000). In a meta-analysis of remission
data from all existing bupropion SR versus SSRI comparative trials, Thase et al.
(2005) found that remission rates were essentially the same for the two types of
antidepressants. Although both bupropion SR and SSRIs were generally well
tolerated, bupropion SR treatment was associated with lower rates of sexual
dysfunction (Thase et al. 2005). Bupropion SR has also been shown to prevent
relapse of depressive symptoms in continuation treatment extending up to 1 year
(Weihs et al. 2002).
The release of bupropion XL in 2003 also generated several comparison
studies. In two 8-week placebo-controlled comparative trials with bupropion XL
and escitalopram, pooled analysis confirmed equivalent efficacy of the two
agents based on mean change in Hamilton Rating Scale for Depression (Ham-D;
Hamilton 1960) score. Both antidepressants produced remission rates greater
than the rate with placebo alone (Clayton et al. 2006). Other studies comparing
bupropion XL with the serotonin–norepinephrine reuptake inhibitor (SNRI)
venlafaxine XR demonstrated clinical equivalence for the two drugs in the
treatment of depression. Notably, a study that used higher dosages of bupropion
XL (300–450 mg/day) found statistically significantly higher remission rates for
bupropion XL relative to venlafaxine XR (Thase et al. 2006). By contrast, two
studies by Hewitt and colleagues found low dosages of venlafaxine XR (75–150
mg/day) to be superior to low dosages of bupropion XL (150–300 mg/day). In
both studies, a flexible dosing schedule was employed; that is, patients were
given the option of doubling the dosage at week 5 if their response was
inadequate. Of note, in these studies bupropion XL was not superior to placebo
(Hewett et al. 2009, 2010).
Although bupropion has not been shown in a naturalistic setting to have better
effectiveness than other antidepressant agents, specific neurocognitive markers
may help steer the clinician toward the choice of bupropion for a specific patient.
In a small-sample study, Bruder et al. (2014) found that performance on brief
tests of word fluency and psychomotor speed predicted which patients would
preferentially respond to bupropion monotherapy relative to either SSRI
monotherapy or SSRI + bupropion combination therapy. However, other small
(but statistically significant) studies have suggested that SSRIs may be more
effective than bupropion in decreasing suicidal thoughts during the initial weeks
of pharmacotherapy in high-risk patients (Grunebaum et al. 2013).
Studies have shown bupropion to be efficacious in the treatment of MDD not
only as monotherapy but also as an augmenting agent with SSRIs or SNRIs
(Bodkin et al. 1997; DeBattista et al. 2003; Fava et al. 2003; Ferguson et al.
1994; Lam et al. 2004; Rush et al. 2006; Spier 1998; Stern et al. 1983; Trivedi et
al. 2006). Whereas the “triple monoamine approach” (i.e., using an SSRI with
bupropion in order to block reuptake of serotonin, dopamine, and
norepinephrine) is often a useful strategy, Stewart et al. (2014) demonstrated that
the addition of bupropion XL at a relatively high dosage (i.e., 450 mg/day) to a
similarly high dosage of escitalopram (i.e., 40 mg/day) increased neither the
speed of recovery nor the likelihood of recovery from a major depressive
episode. Nasr et al. (2014) compared the outcomes of patients who received
either aripiprazole or bupropion as an adjunct to SSRI treatment. Although no
overall differences were found between the two augmenting agents, bupropion
was significantly more helpful in treating poor energy and motivation, whereas
aripiprazole proved superior in reducing suicidal ideation. This finding suggests
that a careful symptom inventory is the best guide in selecting an augmenting
agent.
The Sequenced Treatment Alternatives to Relieve Depression (STAR*D)
study was the largest protocol-driven study of MDD ever undertaken, with an
initial study population of 4,041. A retrospective analysis of this study directly
addressed the question of which next-step strategy—medication augmentation or
medication switching—yields the best outcome for patients whose symptoms
have not improved after an adequate trial of antidepressant monotherapy
(Gaynes et al. 2012). Findings specific to bupropion suggested that patients who
completed an initial 12-week period of citalopram treatment without
experiencing complete symptom remission received more benefit from
augmenting citalopram with bupropion than from discontinuing citalopram and
switching to bupropion.
Smoking Cessation
In 1997, bupropion SR received FDA approval for use as a smoking-cessation
aid under the trade name Zyban (GlaxoSmithKline 2015). The beneficial effect
of bupropion on smoking cessation was first noted when researchers observed
unplanned suspension of smoking in depressed subjects who were being treated
with bupropion (reviewed in Hudziak and Rettew 2004). In a double-blind,
placebo-controlled trial of bupropion SR therapy for smoking cessation (Hurt et
al. 1997), 615 subjects received bupropion SR at dosages of 100, 150, or 300
mg/day for 7 weeks, with a target quit date of 1 week after beginning treatment.
Brief counseling was also provided. Rates of smoking cessation at the end of 7
weeks were 29% for the 100-mg/day group, 39% for the 150-mg/day group, and
44% for the 300-mg/day group, versus 10% for placebo. At 1 year, rates for the
three bupropion dosage groups were 20%, 23%, and 23%, respectively,
compared with 12% for the placebo group.
Studies examining the long-term efficacy of bupropion SR for smoking
relapse prevention have reported mixed findings. Hays et al. (2001) showed that
subjects who had successfully stopped smoking for 7 weeks with bupropion
treatment had a significant delay in smoking relapse with continued bupropion
SR therapy compared with placebo. By contrast, a trial looking specifically at
extended treatment with bupropion SR for smoking cessation reported that
bupropion SR did not surpass placebo in efficacy (Killen et al. 2006). However,
a meta-analysis of randomized controlled trials of pharmacotherapies for
smoking cessation subsequently confirmed the efficacy of bupropion in
promoting smoking abstinence (Eisenberg et al. 2008).
Although more work needs to be done in the areas of relapse prevention and
long-term abstinence, it appears evident that bupropion SR is helpful in smoking
cessation. Recommended dosing is 150 mg/day for 3 days, increasing to 150 mg
two times a day for 7–12 weeks, with patients setting a quit date of 1–2 weeks
after treatment has been initiated. In 2003, Ferry and Johnston published a 5-year
review of the accumulated efficacy and safety data for bupropion SR since its
1997 approval for smoking cessation. A benefit–risk analysis assuming a 30% 1-
year quit rate concluded that for every 10,000 smokers treated with bupropion
SR, 19 lives are saved and 86 cases of smoking-attributed morbidity are avoided,
whereas the risk of a serious adverse effect from treatment is 0.22% (Ferry and
Johnston 2003). Recent data have confirmed that bupropion evidences no
increased risk of self-harm, suicide, or depression compared with either
varenicline or nicotine replacement therapy (Thomas et al. 2013).
Obesity
Unlike other classes of antidepressants, bupropion is well known for its lack of
association with weight gain. Alternatively, mild, acute weight loss has been
noted in many clinical trials. To further investigate this observation, Gadde et al.
(2001) conducted a randomized, placebo-controlled trial investigating the
tolerability and efficacy of bupropion (100–400 mg/day) for weight loss in 50
obese women. All subjects kept a food journal and were placed on a 1,600
kcal/day diet. At 8 weeks, subjects receiving bupropion had achieved greater
weight loss compared with those on placebo. At 24 weeks, responders to
bupropion had lost an average of 13% of their baseline body weight (Gadde et
al. 2001). Following this initial study of bupropion for weight loss, two larger
studies confirmed these results (Anderson et al. 2002; Jain et al. 2002).
In 2013, the FDA approved Contrave (Orexigen Therapeutics 2014), a
bupropion/naltrexone combination, for the treatment of patients who are obese
(defined as body mass index [BMI] ≥30 kg/m2) or overweight (defined as BMI
≥27 kg/m2) and have at least one cardiovascular risk factor (Apovian et al.
2013). FDA approval followed studies showing that bupropion/naltrexone
combination therapy led to reductions in total and visceral adiposity (Smith et al.
2013). A drug safety evaluation of bupropion/naltrexone concluded that it led to
greater weight loss compared with two other medications FDA approved for the
treatment of obesity, orlistat and lorcaserin, but less weight loss compared with
topiramate/phentermine combination therapy (Verpeut and Bello 2014).
Furthermore, a study using functional magnetic resonance imaging demonstrated
decreased reactivity to food cues following a course of bupropion/naltrexone
therapy (Wang et al. 2014).
Other Uses
Attention-Deficit/Hyperactivity Disorder
Currently there is no FDA indication for bupropion’s use in ADHD, although
studies have demonstrated that it may be helpful in treating symptoms of ADHD
in both children and adults (Conners et al. 1996; Simeon et al. 1986). Clinical
trials in children with ADHD have shown bupropion to be a safe and effective
alternative for treatment of this disorder (Conners et al. 1996). A comparison
trial of bupropion and methylphenidate found that both drugs were effective in
the treatment of ADHD and had similar efficacy (Barrickman et al. 1995).
Bupropion has also been studied in adults with ADHD and has demonstrated
statistically significant symptom improvement in this population (Wilens et al.
2001). In a meta-analysis by Peterson et al. (2008), long-acting forms of
bupropion appeared to exhibit similar clinical effectiveness compared with long-
acting stimulants in adults. An open trial by Riggs et al. (1998) suggested that
bupropion may also be useful for the treatment of ADHD in adolescents with
comorbid conduct disorder and substance use disorders. A recent large review of
meta-analyses to date (Moriyama et al. 2013) concluded that bupropion therapy
is more effective than placebo but less effective than stimulant therapy in the
treatment of ADHD.
Sexual Dysfunction
Bupropion has been studied as an antidote to SSRI-induced sexual dysfunction.
A placebo-controlled comparative trial of bupropion SR treatment in 42 patients
with SSRI-induced sexual dysfunction concluded that bupropion SR improved
both the desire to engage in sexual activity and the frequency of engaging in
sexual activity relative to placebo (Clayton et al. 2004). Safarinejad et al. (2010)
demonstrated bupropion’s efficacy in reversing SSRI-induced sexual dysfunction
in men.
Segraves et al. (2001) found that bupropion may be helpful in the treatment of
DSM-IV-TR HSDD. Subsequently, a double-blind, placebo-controlled trial
supported this finding and also revealed increases in sexual arousal, orgasm
completion, and sexual satisfaction in women with DSM-IV-TR HSDD who
received bupropion (Segraves et al. 2004). Another study of bupropion SR
treatment of patients with SSRI-induced sexual dysfunction found that
bupropion improved the desire to engage in sexual activity and increased the
frequency of engaging in sexual activity (Clayton et al. 2004). Additional studies
have also demonstrated that bupropion may be helpful for treating sexual
disorders in both men and women (Modell et al. 2000). In a review of
nontestosterone treatment options available for HSDD, Lodise (2013, p. 411)
concluded that “bupropion is the primary pharmacologic agent that has shown
positive results.”
Drug–Drug Interactions
As discussed earlier, the main enzyme responsible for the metabolism of
bupropion is CYP2B6. Competitive inhibition of metabolism can occur with
other drugs processed by this enzyme, such as paroxetine, sertraline, diazepam,
clonazepam, clopidogrel, ritonavir, and efavirenz (Hesse et al. 2000; Jefferson et
al. 2005). A study examining the effects of concurrent use of lopinavir/ritonavir
on bupropion pharmacokinetics in 12 healthy subjects found that maximum
plasma concentrations of bupropion and hydroxybupropion decreased by 57%
and 31%, respectively (Hogeland et al. 2007).
Bupropion and its major metabolite hydroxybupropion are also inhibitors of
CYP2D6, an enzyme that plays a role in the metabolism of several classes of
medications, including antidepressants, antipsychotics, β-blockers, and
antiarrhythmic agents (Wilkinson 2005). Studies of the effects of bupropion on
CYP2D6 activity are limited, but results of those conducted suggest that
bupropion may increase blood levels of drugs metabolized by CYP2D6, such as
desipramine and venlafaxine (Jefferson et al. 2005; Kennedy et al. 2002). An 8-
week open-label study of bupropion SR coadministered with venlafaxine,
paroxetine, or fluoxetine found inhibition of venlafaxine metabolism and higher
concentrations of venlafaxine. No significant interaction effects from bupropion
were found for paroxetine or fluoxetine (Kennedy et al. 2002). Other agents
known to induce various metabolic pathways have also been shown to affect the
metabolism of bupropion. Carbamazepine, which induces CYP2B6, 3A4, and
1A2 activity, has been shown to decrease bupropion concentrations but increase
hydroxybupropion concentrations (Ketter et al. 1995).
Bupropion should be used with caution in combination with other
psychotropic agents that can lower the seizure threshold, such as tramadol,
certain antidepressants, and antipsychotics (Delanty et al. 1998; Gardner et al.
2000). It should also be used with caution in patients who abuse alcohol, because
this population may have a higher risk of seizures (Dunner et al. 1998). In
addition, because bupropion increases dopamine reuptake, additive effects with
other dopaminergic agents (e.g., levodopa) are a possibility (Goetz et al. 1984).
Conclusion
Bupropion is unique among the newer antidepressants in that it functions as a
dopamine and norepinephrine reuptake inhibitor and as an antagonist of nACh
receptors. Because bupropion has very little serotonergic activity, its side-effect
profile differs markedly from that of other first-line agents, providing a treatment
alternative for patients who cannot tolerate or who do not respond to SSRIs.
Although its current FDA-approved indications are limited to the treatment of
MDD, tobacco use disorder, and obesity and the prevention of seasonal major
depressive episodes, bupropion has also demonstrated utility in child and adult
ADHD and in sexual disorders. For targeted treatment of depression
characterized by decreased energy and interest, depression with concomitant
anxiety, and bipolar depression, bupropion may be particularly beneficial.
Bupropion may also be used to augment other antidepressants in the treatment of
MDD and to reverse SSRI-induced side effects. Greater tolerability, including
low risk of weight gain, minimal sedation, and few sexual side effects, adds to
bupropion’s value as an effective antidepressant.
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CHAPTER 19
Mechanism of Action
Venlafaxine and desvenlafaxine are potent inhibitors of 5-HT reuptake at
minimum therapeutic dosages; inhibition of norepinephrine reuptake is lower at
these dosages (Bolden-Watson and Richelson 1993; Deecher et al. 2006; Owens
et al. 2008; Vaishnavi et al. 2004). Studies using positron emission tomography
(PET) to estimate receptor occupancy demonstrate that the minimum effective
total daily dosage of venlafaxine (75 mg) yields about 80% occupancy of the 5-
HT transporter (Voineskos et al. 2007). It has long been thought that the
ascending dose–response relationship of venlafaxine is linked to a dose-
dependent increase in norepinephrine transporter (NET) occupancy (Kelsey
1996; Thase and Sloan 2006). Although some experimental (Harvey et al. 2000)
and clinical (Davidson et al. 2005; Entsuah and Gao 2002; Rudolph et al. 1998;
Thase 1998; Thase et al. 2006) data support this hypothesis, significant effects
on autonomic measures of noradrenergic function are evident in healthy
volunteers at “5-HT selective” dosages (i.e., 37.5 and 75 mg/day) of venlafaxine
(Bitsios et al. 1999; Siepmann et al. 2007). To date, PET studies of NET
occupancy in depressed patients receiving venlafaxine have not been conducted.
Results of one small PET study in primates suggested that in vivo NET
occupancy of SNRIs is greater than would be predicted from in vitro studies
(Takano et al. 2013). There is no consensus about the optimal degree of NET
inhibition during SNRI therapy.
Panic Disorder
The efficacy of venlafaxine XR in panic disorder was demonstrated in three
placebo-controlled studies of acute-phase therapy (Bradwejn et al. 2005; Pollack
et al. 2007a, 2007b). These studies, which used a 37.5-mg/day starting dosage to
minimize side effects, established an effective dosage range for venlafaxine of
75–225 mg/day. Two of the studies included paroxetine (40 mg/day) as an active
comparator (Pollack et al. 2007a, 2007b). In the first comparison study, two
fixed dosages of venlafaxine XR (75 mg/day or 150 mg/day) were comparable to
paroxetine in both efficacy and tolerability (Pollack et al. 2007a). In the second
comparison study, an RCT in which two fixed dosages (75 mg/day or 225
mg/day) were also used, the higher dosage of venlafaxine was significantly more
effective than paroxetine on several secondary outcome measures, including
proportion of patients experiencing complete relief from full-symptom panic
attacks (70% vs. 58%) (Pollack et al. 2007b). Finally, a fourth study using a
relapse prevention design demonstrated sustained efficacy for venlafaxine XR
across 6 months of therapy (Ferguson et al. 2007).
Drug–Drug Interactions
Venlafaxine undergoes extensive metabolism in the liver by the cytochrome
P450 (CYP) enzyme system, particularly by the CYP2D6 isoenzyme, which is
the pathway for conversion of venlafaxine into O-desmethylvenlafaxine. People
who are poor metabolizers of CYP2D6 thus have unusually low plasma levels of
the metabolite ODV (Preskorn et al. 2009) and may be less likely to benefit from
treatment with the parent drug than patients who are normal or extensive
metabolizers (Lobello et al. 2010; Shams et al. 2006). Such patients therefore
could potentially be better candidates for therapy with desvenlafaxine than for
therapy with the parent drug.
In vitro and in vivo studies have shown that venlafaxine and ODV are weak
inhibitors of CYP2D6 and cause little or no inhibition of other CYP isoenzymes,
including 1A2, 2C9, 2C19, and 3A4 (Ball et al. 1997; Oganesian et al. 2009;
Owen and Nemeroff 1998).
Use of venlafaxine or desvenlafaxine is contraindicated in patients taking
monoamine oxidase inhibitors (MAOIs) because of the risk of serotonin
syndrome. As with TCAs and SSRIs, venlafaxine or desvenlafaxine should not
be initiated until 2 weeks after discontinuation of an MAOI, and MAOI therapy
should not be initiated until at least 7 days after discontinuation of venlafaxine or
desvenlafaxine.
Conclusion
Venlafaxine, the first member of the SNRI class in the United States and much
of the world, is one of the more effective newer-generation antidepressants, with
an overall safety profile that is intermediate between that of the SSRIs and that
of the TCAs. There is evidence of an efficacy advantage for venlafaxine over
fluoxetine and perhaps over other SSRIs; however, such an advantage has not
been specifically demonstrated for all members of the SSRI class, most
particularly escitalopram. Venlafaxine’s treatment efficacy has also been
established in GAD, social anxiety disorder, and panic disorder. Desvenlafaxine,
which is approved only for the treatment of MDD, has several advantages
relative to venlafaxine, including simpler dosing and metabolism that is not
dependent on CYP2D6. Until generic formulations of desvenlafaxine are
available, however, it seems likely that it will be more cost-effective to use
generic formulations of venlafaxine XR, except for patients who cannot tolerate
venlafaxine or who are known to be poor CYP2D6 metabolizers.
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CHAPTER 20
In Vitro Assessments
The first data to consider in determining the biochemical profile of reuptake
inhibitors are their affinity values for membranal carriers. Finding these values
involves determining the concentration of a medication necessary to displace
50% of the specific binding of a standard ligand for a given transporter subtype
in a cell lysate preparation. This technique generally provides rough estimates of
the potential for drugs to inhibit reuptake. A somewhat more informative
approach involves determining the concentration of a drug necessary to inhibit
the uptake of a given transmitter in intact cells from either animal brains or
human cell lines. These physiological results are more reliable than mere binding
data because of the integrity of the tissue. Indeed, data indicate that for some
norepinephrine reuptake blockers, binding varies markedly depending on
whether they are tested in membrane preparations or in intact cells, whereas for
others, such as tricyclic antidepressants (TCAs), binding does not vary (Mason
et al. 2007). As can be seen in Table 20–1, both the absolute potencies and the
ratios vary between the two preparations.
In Vivo Assessments
Ideally, the potency of reuptake inhibitors in animal experiments should be
assessed in vivo with the medications administered peripherally. One common
technique involves the use of microdialysis studies in which extracellular levels
of neurotransmitters are estimated from the perfusion of artificial cerebrospinal
fluid. Data generated with duloxetine indicate that it first increases the levels of
serotonin in the rat brain, and with escalating dosage it then increases the levels
of norepinephrine (Koch et al. 2003). In the case of milnacipran, the levels of
serotonin and norepinephrine are generally increased to the same extent (in
guinea pigs; Moret and Briley 1997), although pronounced regional differences
have been observed (Bel and Artigas 1999). Levomilnacipran increases rat
cortical extracellular levels of norepinephrine and serotonin, with a
norepinephrine-to-serotonin potency ratio of 2:1 (Auclair et al. 2013).
Potency ratios also can be assessed in vivo with electrophysiological
approaches. Specifically, by determining the capacity of reuptake inhibitors to
suppress the firing of norepinephrine and serotonin neurons, reliable potency
estimates can be obtained. As reuptake transporters are dose-dependently
inhibited from their peripheral injection, there will be an accumulation of
serotonin and norepinephrine at the cell-body level of those neurons that will
activate their respective autoreceptors, thereby decreasing their firing activity.
Use of this technique reveals that duloxetine suppresses the firing rate of
serotonin neurons by 50% with an intravenous dose of 0.1 mg/kg and that of
norepinephrine neurons with 0.5 mg/kg (Kasamo et al. 1996). This in vivo ratio
of 1:5 is therefore quite different from the in vitro affinity ratio of 1:12
(Vaishnavi et al. 2004; see Table 20–1). In contrast, use of the same technique
reveals that the dose of milnacipran necessary to inhibit the firing rate of
serotonin neurons by 50% is 5.7 mg/kg (Mongeau et al. 1998). The latter results
therefore suggest that milnacipran is a much less potent inhibitor of serotonin
reuptake than is duloxetine.
Assessments of Serotonin and
Norepinephrine Reuptake in Humans
Reuptake of neurotransmitters cannot be assessed as directly in humans as it can
be in the brains of laboratory animals. However, several approaches can provide
useful estimates. For instance, serotonin reuptake inhibition can be estimated
with blood platelet uptake of radioactive serotonin, because platelets do not
synthesize serotonin and they contain a 5-HTT that is nearly identical to the one
present on serotonin neurons in the brain. And because more than 90% of the
serotonin present in the blood is in platelets, whole-blood serotonin depletion by
a reuptake inhibitor is an even simpler measure. With use of a peripheral
(platelet) assay, duloxetine produces a dose-dependent depletion of the serotonin
level that reaches about 60% with a dosage of 60 mg/day, an effect still
significantly inferior to that seen with 100 mg/day of the TCA clomipramine
(Turcotte et al. 2001). Milnacipran produces only a 64% inhibition of serotonin
uptake with the usual recommended dosage of 100 mg/day (Palmier et al. 1989).
By comparison, platelet assays reveal that SSRIs produce greater than 80%
inhibition of serotonin uptake at clinically effective dosages (Gilmor et al. 2002).
Occupancy of the 5-HTT in the human brain can be assessed directly through
positron emission tomography (PET) studies using carbon 11 (11C)–labeled
ligands of this transporter. All SSRIs and venlafaxine produce 80% occupancy of
the 5-HTT at their minimum effective dosages in depression (Meyer et al. 2004).
A duloxetine daily dosage of 60 mg, but not of 40 mg, produces a sustained 80%
occupancy (Takano et al. 2006). PET studies show that milnacipran daily
dosages of 100 mg and 200 mg produce 5-HTT occupancies of 40% and 60%,
respectively (Nogami et al. 2013). To our knowledge, levomilnacipran has not
been tested with this approach.
Researchers have attempted to assess occupancy of the NET in the human
brain with PET. However, issues remain regarding the specificity of the
reboxetine derivative used in several reports (i.e., the lack of a plasma
concentration–occupancy relation; Takano et al. 2014). A variety of peripheral
measures can, however, be used. In particular, the intravenous tyramine pressor
test has produced consistent results. Tyramine penetrates into peripheral
norepinephrine terminals through the NET and releases norepinephrine in a
calcium-independent manner, thereby transiently elevating the systolic blood
pressure. Any drug that effectively blocks the NET attenuates this pressor
response in a dose-dependent manner. Whereas the SSRIs paroxetine and
sertraline do not affect pressor response, the TCAs desipramine, nortriptyline,
and clomipramine attenuate the pressor response, as also do the selective
norepinephrine reuptake inhibitors maprotiline, reboxetine, and atomoxetine
(Blier et al. 2007; Gobbi et al. 2003; Harvey et al. 2000; Turcotte et al. 2001).
Venlafaxine significantly attenuates the tyramine response in depressed patients
only at dosages in the range of 225–375 mg/day (Blier et al. 2010; Debonnel et
al. 2007). Duloxetine exerts a clear effect starting at 120 mg/day (Vincent et al.
2004), whereas milnacipran and levomilnacipran have not yet been tested in this
model. A variety of other peripheral measures suggest that duloxetine may begin
to inhibit norepinephrine reuptake at 60 mg/day (Chalon et al. 2003; Vincent et
al. 2004).
Taken together, these results obtained in humans indicate that duloxetine is a
potent serotonin reuptake inhibitor at 60 mg/day. The exact degree of
norepinephrine reuptake inhibition occurring in humans at a duloxetine dosage
of 60 mg/day remains unclear, but duloxetine clearly achieves physiologically
relevant norepinephrine reuptake inhibition at a dosage of 120 mg/day. A
definitive answer regarding the degree of norepinephrine reuptake inhibition
produced by duloxetine in the human brain awaits the availability of a specific
PET ligand for the NET. Such experiments also will help determine the NET
reserve beyond which the overall function of the norepinephrine system is
altered, as was determined for the 5-HTT (i.e., 80%; Meyer et al. 2004).
Milnacipran appears to preferentially block norepinephrine reuptake, as has
easily been demonstrated in the brains of laboratory animals even at low doses
(Bel and Artigas 1999; Mongeau et al. 1998), whereas blockade of serotonin
reuptake can only be documented with high doses. In humans, robust serotonin
reuptake inhibition (>80% transporter blockade) appears to be achieved only
with supratherapeutic doses (i.e., 300–400 mg; Palmier et al. 1989). Similar
preclinical results have been obtained with levomilnacipran (Auclair et al. 2013).
Mechanism of Action
SNRIs produce rapid inhibition of reuptake transporters in the brain, but their
antidepressant effects are generally not seen for at least 2 weeks. Extensive
electrophysiological and microdialysis studies in laboratory animals have
consistently shown a similar delay before SNRIs produce a net enhancement of
serotonin and/or norepinephrine transmission (see Blier 2006 for a review). This
delay may occur because, as a result of 5 HTT inhibition, potent serotonin
reuptake inhibitors initially suppress the firing of serotonin neurons through
activation of serotonin type 1A (5-HT1A) autoreceptors on neuron cell bodies.
After 2–3 weeks of sustained administration, 5-HT1A autoreceptors desensitize,
and the serotonin neuronal firing rate returns to normal. At this point, there is a
net enhancement of 5-HT transmission in the forebrain (Blier and De Montigny
1983).
In the case of drugs that inhibit the NET, the firing rate of norepinephrine
neurons is promptly diminished through activation of the α2-adrenergic
autoreceptors on neuron cell bodies. After 2–3 weeks of sustained
administration, the firing rate remains attenuated because the cell body α2-
adrenergic autoreceptors do not become desensitized. In contrast, α2-adrenergic
autoreceptors on norepinephrine terminals generally become desensitized with
sustained administration, leading to a net enhancement of norepinephrine
transmission in the forebrain (Invernizzi and Garattini 2004; Rueter et al. 1998a,
1998b; Szabo and Blier 2001).
Milnacipran
A meta-analysis of three short-term (4- to 8-week) double-blind, acute efficacy
multicenter trials in inpatients and outpatients with moderate to severe
depression concluded that milnacipran provides a superior antidepressant effect
compared with placebo at dosages of 50 mg and 100 mg twice daily but not at a
dosage of 25 mg twice daily (Lecrubier et al. 1996; Macher et al. 1989).
Several studies have compared milnacipran with SSRIs or TCAs (Table 20–4).
Milnacipran was noted to have equal efficacy but superior tolerability relative to
the TCA imipramine (Puech et al. 1997). A meta-analysis concluded that
evidence was insufficient to suggest a difference in response rates between
milnacipran and any SSRI. Pooling response rates between agents yielded an
overall response rate of 62% for milnacipran and of 58% for the SSRIs
(Papakostas and Fava 2007). A 24-week randomized, double-blind study
demonstrated the safety, tolerability, and efficacy of flexible dosages of
milnacipran and venlafaxine (100–200 mg/day) in MDD (Olié et al. 2010).
There is no maximum recommended dosage for milnacipran, but it is important
to note that the highest daily dosage tested so far, 300 mg, was tested in only 41
patients and for only 2 weeks (Ansseau et al. 1991). The maximum
recommended dosage of milnacipran in fibromyalgia is 200 mg/day.
Levomilnacipran
Although it is recommended that levomilnacipran be started at 20 mg/day for the
first few days, the minimum effective dosage of 40 mg/day is generally well
tolerated as a starting dosage. The dosage can then be increased to 80 mg/day
and 120 mg/day, according to tolerability and response. Four of the five
controlled studies (involving a total of 3,020 patients) reported effectiveness for
the 40–120 mg/day dosage range in patients with MDD ages 18–80 years (Table
20–5). No active comparator study has yet been published.
Milnacipran
The capacity of milnacipran to relieve chronic pain has been reported in open
trials, but no RCTs have been published to date.
Fibromyalgia
Duloxetine
A 12-week RCT of duloxetine 120 mg/day versus placebo in patients with
fibromyalgia with or without depression found significant improvement in pain
scores and in tender points in duloxetine recipients compared with placebo
recipients (Arnold et al. 2005). Duloxetine 120 mg/day improved fibromyalgia
symptoms and pain severity regardless of the extent of the accompanying
depressive disorder. This direct effect of duloxetine on painful physical
symptoms was later confirmed (Robinson et al. 2013).
Milnacipran
An initial placebo-controlled study of milnacipran in fibromyalgia patients found
that 37% of those who received 100 mg of milnacipran twice daily experienced a
significant reduction (50% or more) in pain intensity compared with 14% of
those who received placebo (Vitton et al. 2004). Subsequent studies led to
milnacipran’s approval in the United States for fibromyalgia (Häuser et al.
2011).
Drug–Drug Interactions
Serotonin syndrome, a serious and potentially lethal pharmacodynamic
interaction, can result if milnacipran, levomilnacipran, or duloxetine is taken
concomitantly with a monoamine oxidase inhibitor (MAOI). To avoid this
catastrophic outcome, an MAOI must not be initiated until at least 5 days after
duloxetine, milnacipran, or levomilnacipran has been discontinued. A longer
elimination period than that expected from plasma half-life is recommended,
because brain elimination generally lags behind plasma elimination. At least a
14-day washout of MAOIs must be respected before starting any SNRI.
Duloxetine
Inhibitors of CYP1A2, such as ciprofloxacin, increase plasma levels of
duloxetine, and concomitant use may require that duloxetine dosages be reduced
or that duloxetine be discontinued. When duloxetine is coadministered with a
CYP2D6 inhibitor of moderate potency, such as bupropion or diphenhydramine,
duloxetine levels may increase. However, such alterations of duloxetine levels
are in general not clinically significant.
Duloxetine does not inhibit or induce the activity of the CYP1A2, 2C9, or
3A4 systems. It does, however, moderately inhibit the activity of the CYP2D6
isoenzyme. If duloxetine is coadministered with an agent metabolized by
CYP2D6, clinicians should prescribe dosages that are approximately half those
usually recommended for the concomitant medication. Duloxetine does not
potentiate the psychotropic effects of ethanol or benzodiazepines.
Conclusion
At their minimum effective dosages, duloxetine (60 mg/day) and milnacipran
(100 mg/day) potently block the reuptake of serotonin and norepinephrine,
respectively. In the case of duloxetine, it is difficult to imagine how an increase
from a subtherapeutic dosage of 40 mg/day, at which it does not perform as a
weak SSRI, to 60 mg/day could produce marked norepinephrine reuptake
inhibition when the in vivo serotonin-to-norepinephrine reuptake potency ratio is
1:5. In the case of milnacipran, a 100-mg daily dosage produces suboptimal
platelet serotonin reuptake inhibition. Duloxetine, at its maximum recommended
dosage (120 mg/day), and milnacipran, at its upper therapeutic range (200
mg/day), are dual reuptake inhibitors. Consequently, none of the four SNRIs
currently available can be considered equal reuptake inhibitors. They all show
efficacy in the treatment of depression and pain syndromes, with emerging
evidence also suggesting a potential role for duloxetine in the treatment of stress
urinary incontinence and generalized anxiety disorder.
These medications are generally well tolerated, with most adverse effects
occurring early in treatment, being mild to moderate in severity, and having a
tendency to decrease or disappear with continued treatment.
Either duloxetine or milnacipran may be used as a first-line treatment for
depression, because these medications are not toxic in overdose, and they can be
used at a therapeutic dosage from treatment initiation onward with minimal side
effects. Furthermore, data suggest that treatment with a dual reuptake inhibitor
may be superior to treatment with an antidepressant with only one mechanism of
action, such as an SSRI (Nemeroff et al. 2008; Poirier and Boyer 1999; Sagman
et al. 2011; Thase et al. 2007). Consequently, these drugs may be beneficial in
patients whose symptoms have been unresponsive to treatment with SSRIs and
norepinephrine reuptake inhibitors, provided that they are taken at dosages at the
upper end of the therapeutic range.
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CHAPTER 21
Ketamine
David S. Mathai, B.S.
Sanjay J. Mathew, M.D.
Structure–Activity Relations
Ketamine (2-[2-chlorophenyl]-2-[methylamino]cyclohexanone) is an
arylcycloalkylamine compound that is structurally similar to PCP and
cyclohexylamine (Figure 21–1). The free-base form of ketamine is highly lipid
soluble and is commercially available as an aqueous preparation of the
hydrochloride salt. Ketamine is a chiral compound that exists pharmaceutically
as a racemic mixture of (S)-ketamine (esketamine) and (R)-ketamine
(arketamine) enantiomers.
Pharmacological Profile
Ketamine has high lipid solubility and low plasma protein binding. It undergoes
biotransformation in the liver to norketamine, its primary active metabolite.
Approximately 90% of ketamine is excreted in the urine in metabolite form with
minimal clearance of unchanged drug, and another 5% undergoes fecal excretion
(Clements et al. 1982). Ketamine has a wide therapeutic index and has been
shown to have a low risk of lethal overdose (Green et al. 1999). Its main
pharmacological action is on glutamate as an open-channel, nonselective N-
methyl-D-aspartate (NMDA) receptor antagonist.
Anesthesia
Ketamine gained FDA approval in 1970 for the following indications: 1) as the
sole anesthetic agent for diagnostic and surgical procedures that do not require
skeletal muscle relaxation, 2) for induction of anesthesia prior to administration
of other general anesthetic agents, and 3) to supplement low-potency anesthetic
agents, such as nitrous oxide (Par Pharmaceutical Companies 2014). Ketamine
was an attractive drug for these indications because of its potent anesthetic
properties and its safety profile, characterized by a large therapeutic window and
low risk of respiratory depression. Recommended dosages for induction of
anesthesia are 6.5–13.0 mg/kg intramuscular and 1.0–4.5 mg/kg intravenous,
with alternative off-label recommendations for situations that involve
administration of adjuvant drugs (Miller et al. 2010). For maintenance of
anesthesia, the manufacturer recommends administering one-half to the full
induction dose or a continuous infusion of 0.1–0.5 mg/minute of ketamine;
however, clinical studies have suggested that higher dosages may be needed to
maintain an adequate concentration for anesthesia (White et al. 1982). Although
only the racemic mixture of ketamine is marketed in the United States, (S)-
ketamine was approved in Europe in 1998 and is available in a number of
European Union countries for induction and maintenance of general anesthesia,
supplementation of local anesthesia, and analgesia in emergency medicine.
Off-Label Applications
Sedation, Analgesia, and Reduction of Postsurgical Pain,
Nausea, and Vomiting
In regard to off-label applications, various laboratory and clinical studies support
the use of ketamine for sedation, analgesia, and improved postoperative
outcomes (Adam et al. 2005; Green et al. 2011; Hocking and Cousins 2003;
Menigaux et al. 2000; Remérand et al. 2009; Zakine et al. 2008). A systematic
review of low-dosage ketamine for chronic noncancer pain (e.g., neuropathic,
ischemic, fibromyalgia) administrated by multiple routes concluded that
although ketamine provided relief, its long-term use should be restricted to
controlled trials (Bell 2009). Another review of ketamine as an analgesic for
phantom limb pain reached a similar conclusion (Alviar et al. 2011).
Randomized controlled trial (RCT) evidence (Schwartzman et al. 2009;
Sigtermans et al. 2009) pointed to ketamine’s benefit in complex regional pain
syndrome type 1 at a variety of dosages and routes of administration; however, a
larger review (Azari et al. 2012) suggested that stronger evidence (drawn from
larger studies that include data on unsuccessful trials) is needed before ketamine
can be recommended for that indication. Subanesthetic doses of ketamine have
also been found to be effective in the management of acute postoperative pain,
reducing morphine requirements during the first 24 hours after surgery and
additionally improving nausea and vomiting (Bell et al. 2006).
Investigative Applications
Ketamine has been investigated in a number of other psychiatric conditions.
Glutamate-modulating agents have been considered as therapeutic candidates in
treatment-refractory OCD based on lines of evidence pointing to an underlying
role of glutamate dysregulation in this disorder; however, studies examining the
benefit of these agents in OCD have been inconclusive (Pittenger 2015). In a
randomized, placebo-controlled crossover trial of ketamine in unmedicated
patients with refractory OCD, participants who received ketamine first showed
significant and rapid antiobsessional effects during the 0.5 mg/kg infusion that
persisted until 1 week postinfusion, compared with participants who received
placebo (saline infusion) first (Rodriguez et al. 2013). A subsequent study of the
neurochemical effects of ketamine versus saline infusions using proton magnetic
resonance spectroscopy (1H MRS) suggested that the therapeutic effect of
ketamine in OCD may in fact occur independently of the glutamate–glutamine
activity (Rodriguez et al. 2015).
In patients with chronic PTSD, preliminary RCT evidence demonstrated that a
single intravenous ketamine infusion (0.5 mg/kg) was associated with a
significant and rapid reduction in PTSD symptom severity compared with
midazolam when assessed 24 hours after administration (Feder et al. 2014).
Ketamine was well tolerated, with no clinically significant or persistent
dissociative symptoms.
In regard to substance use disorders, there is evidence that infusions of
ketamine at subanesthetic doses improved motivation to quit and reduced cue-
induced craving in nondepressed cocaine-dependent volunteers (Dakwar et al.
2014). Efforts to enhance a patient’s motivation for change have been previously
recognized as an important aspect of addiction-oriented psychotherapy, but this
particular use of ketamine marks one of the first times that the psychological
parameter of motivation has been targeted as a focus of pharmacotherapy.
In the realm of experimental psychopharmacology, ketamine has been
explored as a safe research tool to transiently induce or provoke
multidimensional schizophrenia-like symptoms (Anticevic et al. 2012; Lahti et
al. 1995; Perry et al. 2007). Models of psychosis based on acute or chronic
administration of noncompetitive NMDA receptor antagonists in both humans
and rats show phenomenological validity with promise for testing new
substances with potential antipsychotic effects (Bubeníková-Valesová et al.
2008). It is important to note that these uses are investigational as of the time of
this writing (2015).
Drug–Drug Interactions
Drugs such as rifampin and St. John’s wort (which are potent inducers of
CYP3A4) increase the metabolism and clearance of ketamine—and, to a much
greater extent, of norketamine (Mion and Villevieille 2013). Enzyme-inhibiting
substances have the opposite effect and include clarithromycin and grapefruit
juice (CYP3A4 inhibitors) and ticlopidine (a potent CYP2C19 inhibitor and a
weak CYP2B6 inhibitor) (Domino et al. 1984). Several studies have also
reported ketamine’s synergistic effects when administered with other sedatives
(Akhavanakbari et al. 2014; Eker et al. 2011; Hui et al. 1995; Lo and Cumming
1975). The clinical relevance of these interactions remains unclear.
Conclusion
Whereas much is known about the pharmacological profile of ketamine from its
long history of use as an anesthetic and analgesic agent, far less is known about
the mechanisms associated with ketamine’s antidepressant efficacy at
subanesthetic doses. Early studies implicated a number of pathways that may be
involved in the therapeutic effects of ketamine, including pathways mediated by
BDNF, TrkB, mTOR, and AMPA. Further investigations of NMDA receptor
activity and the efficacy of other potential glutamate-modulating agents are
ongoing. Therefore, as the use of ketamine in clinical practice becomes
increasingly more common in U.S. hospital and clinic-based settings, it is
imperative that the field develop standard operating procedures to guide clinical
use. Despite the promise shown in initial trials of ketamine, it is important to
recognize that ketamine therapy is still an experimental approach. The transient
nature of ketamine’s antidepressant activity and its potential for abuse suggest
that routine adoption of this drug in psychiatric practice settings may be
premature at this time. Future research will need to work toward improving our
understanding of ketamine’s mechanism of action, developing administration
strategies that offer sustained therapeutic benefit, and providing continued
longitudinal assessment of safety and tolerability.
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CHAPTER 22
Benzodiazepines
David V. Sheehan, M.D., M.B.A.
Structure–Activity Relations
Currently marketed benzodiazepines are similar in that they have the 1,4-
benzodiazepine ring system. Modification of this ring system results in
benzodiazepines with somewhat different properties (Figure 22–1).
FIGURE 22–1. Chemical structures of commonly used
benzodiazepine anxiolytics (A) and hypnotics (B).
CYP
Group Medication Metabolism enzyme(s) hours
Desmethyldiazepam Diazepam Oxidation 2C19, 26–
3A4 50
Bromazepam Oxidation 3A4 1–5
Prazepam Oxidation >21
Chlordiazepoxide Oxidation 3A4 >21
Desalkylflurazepam Flurazepam Oxidation 40–
120
Clonazepam Oxidation 24–
56
Triazolobenzodiazepine Triazolam Oxidation 3A4 2–4
Alprazolam Oxidation 3A4 10–
15
Imidazobenzodiazepine Midazolam Oxidation 3A4 1–3
Thienodiazepine Brotizolam Oxidation 3A4 4–8
Nitrazepam Reduction 3A4, 2D6 20–
50
Flunitrazepam Reduction 10–
25
Oxazolobenzodiazepine Oxazepam Glucuronidation 5–
15
Lorazepam Glucuronidation 10–
20
Temazepam Glucuronidation 6–
16
Note. CYP=cytochrome P450; Ki=kinetic inhibition constant value (nM); NA=not available;
t½=half-life.
Rate of Absorption
Benzodiazepines that are rapidly absorbed from the gastrointestinal tract enter
and peak in the circulation quickly and have a quicker onset of action than those
that are absorbed more slowly. Diazepam and clorazepate are rapidly absorbed
and act quickly, chlordiazepoxide and lorazepam have intermediate rates of
absorption and onset of action, and prazepam is slowly absorbed and has a
slower onset of action.
Gastrointestinal absorption of benzodiazepines is dictated by intrinsic
physiochemical properties of the drug and characteristics of the formulation such
as particle size (Greenblatt et al. 1983a, 1983b). Benzodiazepine absorption
when given intramuscularly is dictated by other factors. For example,
chlordiazepoxide and lorazepam, when given orally, are absorbed at similar rates
in the gastrointestinal tract. When given intramuscularly, lorazepam is more
reliably, rapidly, and completely absorbed than chlordiazepoxide (Greenblatt et
al. 1979, 1982b, 1983a, 1983b).
Lipophilicity
The lipid solubility (lipophilicity) of a benzodiazepine at physiological pH
influences the rate at which it crosses the blood–brain barrier by passive
diffusion from the circulation, and this, in turn, determines the rapidity of onset
of action and intensity of effect (Greenblatt et al. 1983a, 1983b). Highly
lipophilic drugs cross the blood–brain barrier rapidly, and although all
benzodiazepines are highly lipophilic, they differ in their degree of lipophilicity.
Because diazepam is more lipophilic than lorazepam or chlordiazepoxide, it
provides more rapid anxiety reduction and onset of side effects.
Duration of Action
With benzodiazepines, the duration of therapeutic action is determined mainly
by the rate and extent of drug distribution rather than by the rate of elimination.
Benzodiazepine distribution is largely determined by its lipophilicity. Diazepam,
which has a longer half-life than lorazepam, has a shorter duration of clinical
action after a single dose. The reason for this is that diazepam, because of its
greater lipid solubility, is more extensively distributed to peripheral sites,
particularly to fat tissue. Consequently, it is more rapidly moved out of the blood
and brain into inactive storage sites, and its central nervous system (CNS) effects
end more rapidly. Conversely, less lipophilic benzodiazepines maintain their
effective brain concentrations longer because they are less extensively
distributed to the periphery (Greenblatt et al. 1983a, 1983b).
Rate of Elimination
The rate of elimination (elimination half-life) influences the speed and extent of
accumulation and the time to reach a steady state. It also influences the time for
drug washout after termination of multiple doses. Accumulation is slow and
extensive when the half-life is long. When the rate of metabolic removal equals
the rate of ingestion, the drug is said to have reached steady state. A useful rule
of thumb is that when treatment has been in progress for at least four to five
times as long as the elimination half-life, then the accumulation process is more
than 90% complete (Greenblatt et al. 1983a, 1983b). When drugs with long
elimination half-lives are stopped, they are washed out slowly, and the symptoms
recur gradually over a period of days, with less intense or sudden rebound
phenomena (Greenblatt et al. 1981, 1982a; Kales et al. 1982). Side effects from
long-term treatment with long-half-life benzodiazepines last longer than with
short-half-life benzodiazepines. Because of greater drug accumulation with long-
half-life benzodiazepines, frequent drowsiness and sedation are a theoretical
concern (Greenblatt et al. 1981). Tolerance to sedation occurs with long-term
use, even though the plasma drug level remains the same. However, as a matter
of caution, it is prudent to choose a benzodiazepine with a shorter or
intermediate half-life for the elderly (Greenblatt et al. 1982c), individuals
operating heavy machinery, and those engaging in high-level intellectual tasks.
Biotransformation Pathway
Benzodiazepines are metabolized in the liver by microsomal oxidation or by
glucuronide conjugation. Hepatic disease, age, several medical illnesses, and a
number of drugs that impair oxidizing capacity, such as cimetidine, estrogens,
and the hydrazine monoamine oxidase inhibitors (MAOIs), all influence the
oxidation pathway. These factors usually magnify the side effects of the
benzodiazepine. Consequently, in the elderly and in individuals with liver
disease, benzodiazepines that are conjugated (e.g., temazepam, oxazepam, and
lorazepam) are safer than benzodiazepines that are metabolized by oxidation
(e.g., diazepam and alprazolam).
Mechanism of Action
Benzodiazepines produce anxiolysis by their effect on the γ-aminobutyric acid
(GABA)–benzodiazepine receptor complex. GABA is synthesized from glutamic
acid, which is also the most abundant free amino acid in the CNS. Like
serotonin, norepinephrine, and dopamine neurons, the presynaptic GABA neuron
has a reuptake pump that transports GABA from the synapse for storage or
destruction by GABA transaminase. GABA has three target receptors: GABAA,
GABAB, and GABAC. The chloride ion channel is controlled by GABAA.
Four distinct pharmacological properties have been described for the
benzodiazepine receptor: anxiolytic, hypnotic, anticonvulsant, and muscle
relaxation effects. GABAA receptors with α2 (and/or α3) subunits mediate the
anxiolytic effects, whereas GABAA receptors with an α1 subunit mediate the
sedative-hypnotic actions. Most benzodiazepines interact with both these
receptor subtypes. Typically, when GABA occupies the GABAA receptor site,
opening and closing of the chloride channel occur more frequently, and this
effect is inhibitory. If at the same time a benzodiazepine binds to the nearby
benzodiazepine receptor, the GABAA receptor is allosterically modulated, and
GABA exerts a greater effect (greater frequency of opening and closing) on the
chloride channel and conductance. Although GABA works alone at the GABA
receptor, the action of GABA is stronger in the presence of a benzodiazepine.
The benzodiazepine in the absence of GABA cannot influence the chloride
channel by itself.
Therapeutic Uses
Because of their multiple pharmacological actions, benzodiazepines are useful in
many areas of medical practice, such as induction of anesthesia, use as a muscle
relaxant, and control of seizures. It is beyond the scope of this chapter to
elaborate on these nonpsychiatric uses. In psychiatry, benzodiazepines are used
to control anxiety, to treat insomnia, and to acutely manage agitation and
withdrawal syndromes.
In the treatment of anxiety disorders, benzodiazepines have a greater effect in
some disorders than in others. In panic disorder, they have a significant effect on
all dimensions of the illness, with the exception of depression. Alprazolam, for
example, has been shown to be effective in panic disorder at a mean dosage of
5.7 mg/day (range=1–10 mg/day) (Ballenger et al. 1988; Chouinard et al. 1982;
Cross National Collaborative Panic Study 1992; Sheehan et al. 1982, 1984,
1993). Rapid improvement was seen within the first week in the form of
decreased panic attacks, phobic fears and avoidance, anticipatory anxiety, and
disability. These benefits were shown to persist during a follow-up period of 8
months (Schweizer et al. 1993). Efficacy also has been established for lorazepam
(Rickels and Schweizer 1986) and clonazepam (Pollack et al. 1993; Tesar et al.
1991). In the latter studies, clonazepam 2.5 mg/day was as effective and well
tolerated as alprazolam 5.3 mg/day.
Despite the well-documented efficacy of benzodiazepines in panic disorder,
they have been displaced in clinical practice by the SSRIs and SNRIs. However,
some clinicians initiate treatment with both classes of drug simultaneously and
then withdraw the benzodiazepine after 6 weeks. The benefits and practicality of
this approach to treating panic disorder are reinforced by the findings from two
studies (Goddard et al. 2001, 2008). The American Psychiatric Association
(1998) guidelines for the treatment of panic disorder recommending SSRI
monotherapy as the treatment of first choice have failed to achieve traction,
because more than two-thirds of the SSRI prescriptions were accompanied by a
concomitant benzodiazepine (Keller and Craske 2008). The study by Goddard et
al. (2008) lends justification to the rationale for using the combination treatment
more frequently and blessing it as a reasonable alternative first-line treatment for
many patients with panic disorder.
Three double-blind studies have shown efficacy for benzodiazepines in the
treatment of social phobia (Davidson et al. 1993; Gelernter et al. 1991; Versiani
et al. 1997).
In a double-blind, placebo-controlled study, Rickels et al. (1993) found that
the tricyclic antidepressant imipramine was better than diazepam in the treatment
of generalized anxiety disorder (GAD) without depression over 8 weeks.
Imipramine showed a trend of being significantly better on the primary outcome
measure scale (the Hamilton Anxiety Scale [Ham-A]) and was statistically
superior to diazepam on the Psychic Anxiety factor of the Ham-A. Psychic
anxiety includes the items of worry, anxious mood, tension, fears, and
concentration problems. Diazepam and imipramine had identical endpoint Ham-
A Somatic Anxiety factor scores, suggesting that they are equally effective
against the somatic anxiety symptoms in GAD. This suggests that imipramine is
a better “anti-worry” medication than the benzodiazepine. Patients taking
diazepam had an earlier response than those taking imipramine.
Generally, benzodiazepines are thought to be ineffective in the treatment of
obsessive-compulsive disorder (OCD).
The strongest evidence for effective pharmacotherapy in posttraumatic stress
disorder (PTSD) is with SSRIs. A meta-analysis of medications in treating PTSD
found effect sizes of 0.49 and 1.38 for benzodiazepines and SSRIs, respectively
(Van Etten and Taylor 1998).
Intramuscular clonazepam has been compared with intramuscular haloperidol
in the management of acute psychotic agitation. Clonazepam use reduced
agitation, but haloperidol use had a more rapid onset (Chouinard et al. 1993).
Individuals with schizophrenia have high levels of anxiety and frequently
experience panic attacks. Overall, it appears that benzodiazepines have a role in
the acute management of agitation, and their use can reduce the need for or the
dose of antipsychotics used.
Clinical Issues
Despite decades of research, the optimal extent and duration of appropriate
benzodiazepine use in the treatment of anxiety and related disorders remain
unresolved. This is primarily because of concerns expressed by prescribers,
regulators, and the public about issues such as tolerance, dependence, and abuse
liability of this class of medications.
Tolerance
In a study of persistent users of alprazolam and lorazepam, Romach et al. (1995)
found that most were not abusing these benzodiazepines, nor were they addicted
to them; rather, they were using them appropriately for a chronic disorder and at
a constant or a decreasing dose. Soumerai et al. (2003) found no relation
between long-term use of benzodiazepines and escalation to high doses in 2,440
long-term (at least 2 years) users of benzodiazepines and noted that escalation to
a high dose was very rare.
The cross-tolerance between the benzodiazepines, although good, is not
perfect, and it is preferable to switch patients gradually from one benzodiazepine
to another and to use comparable doses of each during the switch. One milligram
of alprazolam is approximately equivalent to 0.7 mg of clonazepam, 10 mg of
diazepam, or 1 mg of lorazepam.
Withdrawal
A withdrawal syndrome is defined as a predictable constellation of signs and
symptoms involving altered CNS activity (e.g., tremor, convulsions, or delirium)
after the abrupt discontinuation of, or a rapid decrease in, dosing of the drug
(Rinaldi et al. 1988). Typically, a withdrawal syndrome from short-half-life
benzodiazepines will intensify by the second day, will usually have peaked by
day 5, and will begin to decrease and taper off by day 10. After 2 weeks,
withdrawal symptoms usually have become minimal or are absent. Drug factors
associated with withdrawal symptoms include length of use, dose, potency, and
rate of discontinuation. The most common are anxiety, restlessness, irritability,
insomnia, agitation, muscle tension, weakness, aches and pains, blurred vision,
and racing heart, in that order (O’Brien 2005). Nausea, sweating, runny nose,
hypersensitivity to stimuli, and tremor are less frequent. Severe withdrawal
symptoms, such as psychosis, seizures, hallucinations, paranoid delusions, and
persistent tinnitus, are relatively rare and are more likely to occur in abrupt
withdrawal from high doses of high-potency benzodiazepines and in the elderly
(American Psychiatric Association 1990; Lader 1990; Petursson and Lader
1981).
The minimum duration of use after which clinically significant withdrawal
symptoms can be expected has not been definitively determined. At the end of
any course of treatment with therapeutic doses and of duration greater than 3–6
weeks, withdrawal of the benzodiazepine should be done as a very slow taper.
This reduces the risk of unpleasant withdrawal symptoms and the danger of
withdrawal seizures and minimizes rebound reactivation of the underlying
anxiety disorder (Fontaine et al. 1984; Pecknold et al. 1988; Power et al. 1985).
In a 3-year follow-up of patients who tapered successfully in a benzodiazepine
taper program, 73% remained benzodiazepine free. Among those who were able
to reduce intake by 50%, only 39% were benzodiazepine free at the end of 3
years. In the group that could not tolerate taper at all, only 14% were
benzodiazepine free (Rickels et al. 1991).
Addiction Potential
In our zeal to heal an anxiety disorder, are we creating a population of addicted
individuals? Much misinformation and concern are generated because terms like
addiction are used without precise definition and pejoratively. Terms such as
addiction, physical dependency, and withdrawal syndrome are often used
interchangeably. Some presume that a medicine’s being associated with a
withdrawal syndrome is evidence that the medicine is addicting. Some clinicians
believe that benzodiazepines that require frequent dosing during the day are
more addicting than those that require less frequent dosing. In reality, frequency
of dosing is a function of the duration of therapeutic action of the drug rather
than of any innate addiction potential of the drug.
Most of the literature discussing benzodiazepine dependence liability uses
older terminology. Substance dependence is defined as a maladaptive pattern of
substance use, leading to clinically significant impairment or distress, as
manifested by the presence of three (or more) of seven criteria, occurring at any
time in the same 12-month period (American Psychiatric Association 2000).
Addiction, by contrast, is defined as a chronic disorder associated with
compulsive use of a drug, resulting in physical, psychological, or social harm to
the user and continued use despite that harm (Rinaldi et al. 1988). Addiction
involves both intense drug-seeking behavior and difficulty in stopping the drug
use. If these criteria are used, benzodiazepines are not addictive drugs. Physical
dependence is different from addiction and is defined as a physiological state of
adaptation to a drug, with the development of tolerance to the drug’s effects and
the emergence of a withdrawal syndrome during prolonged abstinence. During
withdrawal after chronic use, biochemical, physiological, or behavioral problems
may be triggered. When used on a regular schedule, benzodiazepines are
associated with physical dependence and have a withdrawal syndrome.
In DSM-5 (American Psychiatric Association 2013), the terms abuse and
dependence are no longer used in relation to substances. Instead, DSM-5 uses
the more neutral term substance use disorder to capture the wider range of
disorders previously subsumed under substance dependence and substance
abuse. DSM-5 also uses the terms substance intoxication and substance
withdrawal. Substance use disorder is defined as a problematic pattern of
substance use leading to clinically significant impairment or distress, as
manifested by the presence of 2 (or more) of either 10 or 11 criteria, occurring
within a 12-month period. At this time, no large epidemiological studies have
used these new criteria in relation to benzodiazepines.
Abuse
Studies of abuse use four criteria for benzodiazepine abuse. A benzodiazepine is
being abused if it is used 1) to get high, 2) to promote psychological regression,
3) at doses higher than prescribed, and 4) after the medical indication has passed
(Dietch 1983). On the basis of this definition, the data suggest that the incidence
of benzodiazepine abuse in clinical practice is low.
The incidence of benzodiazepine dependence in the therapeutic setting
(among those for whom the drug is medically correctly prescribed) was
estimated to be 1 case in 50 million patient-months (Marks 1978). Of these
cases, 92% were associated with alcohol or other drugs of abuse. This estimate is
probably on the low side because it is based on the number of published cases of
dependence from 1961 to 1977.
In Basel, Switzerland, with a catchment area of 300,000 people, physicians
were surveyed on the prevalence of benzodiazepine abuse in their patients. Only
31 patients were identified—a prevalence of 0.01%, or 1 in 10,000. An
additional 88 polysubstance abusers were identified (Ladewig and
Grossenbacher 1988). In a random sample of all psychiatric hospitalizations over
15 years (1967–1983) in Sweden (N=32,679), Allgulander (1989) found only 38
admissions for substance dependence on sedative-hypnotics. Twenty-one of the
38 had polysubstance abuse, and 17 had sedative-hypnotic abuse.
In another study of all medical and psychiatric hospitalizations (N=1.6
million) in Stockholm County, Sweden, Allgulander (1996) found that 0.04% of
“prescribed medication” users (including benzodiazepines) were ever admitted
for medical problems relating to their drug use. In a study of 5,426 U.S.
physicians randomly selected from the American Medical Association Physician
Masterfile database, Hughes et al. (1992) found that although 11.9% had used
benzodiazepines in the past year, only 0.6% met DSM-III-R (American
Psychiatric Association 1987) criteria for benzodiazepine abuse, and 0.5% met
criteria for benzodiazepine dependence. In 1990, the American Psychiatric
Association task force concluded that benzodiazepines were not normally drugs
of abuse but noted that people who abused alcohol, cocaine, and opiates were at
increased risk for benzodiazepine abuse (Salzman 1991).
A number of studies have noted no increase in dosage with chronic therapy of
duration from 1 to 2.5 years, even though many of the patients had residual
symptoms that would have benefited from a dose increase or more intensive or
additional treatment strategies (Pollack et al. 1986; Sheehan 1987). Nonanxious
subjects and those with low anxiety levels find benzodiazepines dysphoric (Reed
et al. 1965), prefer placebo to diazepam (Johanson and Uhlenhuth 1978, 1980),
or rate their mood as less happy and pleasant after they were given 10 mg of
diazepam (Svensson et al. 1980).
Although the data suggest that the prevalence of benzodiazepine abuse or
dependence is generally low, this is not true among those who abuse alcohol and
other drugs. In a study of chronic alcoholic individuals who were high
consumers of benzodiazepines, 17% got their benzodiazepines from nonmedical
sources (Busto et al. 1983). In a study of 1,000 admissions to an alcohol
treatment unit, 35% of the patients used benzodiazepines, but only 10% of the
total sample were considered abusers or misusers (Ashley et al. 1978). A study
of 427 patients seeking treatment in Toronto, Ontario, who met DSM-III
(American Psychiatric Association 1980) criteria for alcohol abuse or
dependence found that 40% were recent benzodiazepine users, and 20% had a
lifetime history of benzodiazepine abuse or dependence. By contrast, only 5% of
108 alcoholic patients treated for a year with benzodiazepines for anxiety and
tension showed evidence of abuse, and 94% believed that the medication helped
them function and remain out of the hospital (Rothstein et al. 1976).
Benzodiazepines were the primary drug of abuse in one-third of polydrug
abusers (Busto et al. 1986), in 29% of 113 drug abusers admitting to the street
purchase of diazepam in the previous month (Woody et al. 1975b), and in 40%
of patients at a methadone maintenance clinic (Woody et al. 1975a). The
principal reasons for benzodiazepine use among drug-addicted persons are self-
treatment of withdrawal symptoms, relief from rebound dysphoria, or
potentiation of alcohol or street drug effects (Perera et al. 1987). In one study at
an addiction treatment center, 100% of urine samples tested were positive for
benzodiazepines, and 44% were positive for multiple nonprescribed
benzodiazepines (Iguchi et al. 1993). A survey of patients at three different
methadone maintenance clinics found that 78%–94% admitted to a lifetime use
of benzodiazepines, and 44%–66% admitted to use in the prior 6 months.
Snorting of benzodiazepines by individuals addicted to cocaine has been
reported (Sheehan et al. 1991), primarily as a means of blunting the anxiogenic
effect of cocaine and allowing for a more pleasant and “less edgy” high from
that drug. Overall, the existing evidence suggests that the prevalence of
benzodiazepine abuse is uncommon, except among those individuals who abuse
alcohol and/or other drugs.
Despite extensive data and discussion on this topic, the issue remains and will
continue to be controversial, with strong opinions held by opposing camps.
Klerman characterized these camps as “pharmacological Calvinism” and
“psychotropic hedonism,” respectively (Klerman 1972; Rosenbaum 2005). The
middle ground suggests that we should not hesitate to prescribe benzodiazepines
when it is reasonable, but that we should exercise restraint in using them when
we see any evidence of abuse (Pomeranz 2007).
Medicolegal Issues
In addition to issues of dependence and withdrawal described in the previous
section, use of benzodiazepines is associated with several potential medicolegal
pitfalls. These include issues of teratogenicity, injury, and interaction with
substances.
Breast Feeding
Neonates have only limited capacity to metabolize diazepam (Morselli et al.
1973). Benzodiazepines are excreted in breast milk (Llewellyn and Stowe 1998).
Because of the neonate’s limited capacity to metabolize these drugs, they can
potentially accumulate and cause sedation, lethargy, and loss of weight in the
nursing infant. Although the extent to which benzodiazepines actually
accumulate in the serum of breast-feeding infants is a matter of debate
(Birnbaum et al. 1999), and three decades of studies support a low incidence of
toxicity and adverse effects (Birnbaum et al. 1999; Llewellyn and Stowe 1998),
caution taking benzodiazepines while breast feeding is advised.
Psychomotor Impairment
Another area of risk of benzodiazepine use relates to issues of psychomotor
impairment resulting in injury. An examination of the medical records of a group
of benzodiazepine users and nonusers found that the benzodiazepine users were
more likely to experience at least one episode of accident-related health care and
a greater number of accident-related inpatient days and also utilized significantly
more non-accident-related health care services than did nonusers. Accident-
related utilization of health care was more likely in the first month after the drug
was prescribed (Oster et al. 1987). In the elderly, the issue of benzodiazepine use
increasing the risk for falls and fractures is of great concern because hip
fractures are associated with increased morbidity and mortality. A number of
studies (Boston Collaborative Drug Surveillance Program 1973; Cummings et al.
1995; Greenblatt et al. 1977; Hemmelgarn et al. 1997; Ray et al. 1992; Roth et
al. 1980) have found a greater risk for falls with the use of long-half-life
benzodiazepines, and others (Cumming and Klineberg 1993; Herings et al. 1995;
Leipzig et al. 1999) have found the risk to be greater with short-half-life drugs. A
more recent study (Wang et al. 2001) found the risk for hip fracture in the elderly
to be the same with the use of short- or long-half-life benzodiazepines. The
researchers did find that the risk increased when benzodiazepine dosages were
greater than 3 mg/day in diazepam equivalents. They also found the greatest risk
to be shortly after initiation of therapy and after 1 month of continuous use. A 5-
year prospective cohort study followed a large group of elderly people newly
exposed to benzodiazepines (Tamblyn et al. 2005). Elderly persons using
benzodiazepines were at greater risk for a motor vehicle accident (Hemmelgarn
et al. 1997). On the other hand, a study of the effect of New York State requiring
triplicate forms for prescribing benzodiazepines showed that despite a 50%
decrease in the number of prescriptions written, no significant change was seen
in age-adjusted risk for hip fractures (Wagner et al. 2007).
Patients receiving benzodiazepines are nearly five times more likely than
nonusers to experience a serious motor vehicle accident (Skegg et al. 1979). In
the first 2 weeks after persons start using benzodiazepines, there is a several-fold
increased risk for hospitalization related to accidental injury compared with
persons using antidepressants or antipsychotics (Neutel 1995).
The best protection is a discussion of these issues with the patient before
prescribing a benzodiazepine. This discussion, including cautionary statements
about driving or operating dangerous machinery, should be documented in the
chart at the start of therapy. The patient should be educated about potentiation by
alcohol or other sedating drugs. He or she should be strongly advised never to
abruptly discontinue the medicine because of a risk of seizures (Noyes et al.
1986), and this should be documented. Prescribing benzodiazepines for patients
with a current or lifetime history of substance abuse or dependence should be
done infrequently and only after documenting a risk–benefit discussion in the
chart. It is good practice to routinely screen for substance abuse before
prescribing a benzodiazepine and to document that this was done.
Conclusion
Benzodiazepines, if given in adequate doses, are effective in the treatment of
anxiety. They have a lower mortality and morbidity per million prescriptions
than some of the alternatives (Girdwood 1974), including atypical
antipsychotics. Benzodiazepines are quicker in onset of action, easier for the
clinician to use, associated with better compliance, and less subjectively
disruptive for the patient than any of the other medication alternatives. Until
benzodiazepines are replaced by another class of medicine that is safer, better
tolerated, and as rapidly effective, it is likely that they will continue to be
prescribed to a significant proportion of patients.
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CHAPTER 23
Buspirone
Donald S. Robinson, M.D.
Karl Rickels, M.D.
Pharmacological Profile
Buspirone has low affinity in vitro for noradrenergic, cholinergic, and
histaminergic receptors and does not displace [3H]diazepam or [3H]nitrazepam
from the benzodiazepine receptor complex (Riblet et al. 1982). Although
buspirone displaces [3H]spiperone from rat striatal membranes at high
concentrations (Mennini et al. 1986, 1987), dopamine receptor binding appears
to play no role in either the therapeutic effects or the side effects of buspirone
(Eison et al. 1991). In the frontal cortex of freely moving rats, buspirone
produces dose-dependent decreases in dialysate levels of 5-HT and increases in
levels of dopamine and norepinephrine, findings indicative of multiple
mechanisms by which buspirone may modify monoaminergic neurotransmission
(Gobert et al. 1999).
The discovery that nanomolar quantities of buspirone displaced [3H]5-HT
from hippocampal membranes (Glaser and Traber 1983) led to elucidation of
buspirone’s actions on specific central 5-HT receptors. Buspirone inhibits [3H]5-
HT binding to cortical and hippocampal membranes (Skolnick et al. 1985) and
selectively displaces [3H]8-OH-DPAT from 5-HT1A receptor–binding sites in rat
hippocampal membranes with high affinity (24 nM) (Yocca 1990).
The antianxiety properties of buspirone reflect its actions at both pre- and
postsynaptic 5-HT1A receptors (Eison and Eison 1994; Yocca 1990). At
presynaptic 5-HT1A receptors in the dorsal raphe, buspirone acts as a full
agonist, inhibiting neuronal 5-HT synthesis and firing, whereas at postsynaptic
receptors in hippocampus and cortex, it functions as a partial agonist. It is
postulated that the anxiolytic effect of buspirone is mediated by serotonergic
actions in the presence of a pre-existing deficiency of this neurotransmitter.
Buspirone differs from benzodiazepines in that it does not inhibit motor
coordination or spontaneous motor activity but can produce serotonin syndrome
in rats (Barrett and Witkin 1991; Eison et al. 1991). Unlike benzodiazepines,
buspirone lacks abuse potential and does not impair psychomotor performance
alone or in combination with ethanol (Griffith et al. 1986; Smiley 1987; Sussman
and Chow 1988). The behavioral effects of buspirone and benzodiazepines differ
somewhat in animal models of anxiety (Barrett and Witkin 1991) in that
buspirone does not uniformly increase punished or conflict responding in rats
and monkeys. In pigeons, by contrast, buspirone enhances punished response
equivalently to benzodiazepines, a characteristic of 5-HT1A receptor agonists
such as 8-OH-DPAT, whereas TCAs, SSRIs, opioids, antipsychotics, and
psychomotor stimulants do not. Buspirone enhances exploratory and social
interaction behavior in rodents, similar to benzodiazepines.
5-HT1A agonists are active in animal models of depression. Similar to TCAs
and SSRIs, 5-HT1A agonists such as 8-OH-DPAT and the azapirones produce
antidepressant-like behavior in the forced-swim test in rats (Wieland and Lucki
1990). This effect occurs in the absence of changes in locomotor activity and is
not diminished by pretreatment with the 5-HT synthesis inhibitor pCPA,
suggesting that 5-HT1A agonists produce an antidepressant response through
postsynaptic effects on 5-HT1A receptors. Buspirone’s activity in preclinical
models of depression comports with findings in placebo-controlled trials of
buspirone indicative of its antidepressant properties (Rickels et al. 1991;
Robinson et al. 1989a). The buspirone metabolite 1-(2-pyrimidinyl)piperazine
(1-PP) is devoid of such activity.
Mixed Anxiety–Depression
In initial trials of patients with anxiety disorder and subsyndromal depression,
depressive symptoms improved significantly with buspirone treatment (Feighner
et al. 1982; Goldberg and Finnerty 1979). This finding fostered interest in the
potential antidepressant properties of buspirone because of the high comorbidity
of GAD and MDD (Brown and Barlow 1992) and led to the speculation that
GAD and MDD may represent differing clinical manifestations of a single
underlying diathesis. Genetic studies in patients with MDD and GAD suggest
that genetic vulnerability for the two disorders is largely shared (Kendler et al.
1992). The relationship of MDD and GAD and their clinical treatment have been
reviewed (Kendler et al. 1992; Roy-Byrne 2008).
Buspirone treatment of patients with MDD associated with significant anxiety
symptoms was assessed in placebo-controlled trials (Rickels et al. 1991;
Robinson et al. 1989a, 1990). Patients with MDD were eligible for inclusion in
these studies if their Hamilton Rating Scale for Depression (Ham-D; Hamilton
1960) and Ham-A scores were ≥18 and ≥15, respectively. The daily dosage
ranged up to a maximum of buspirone 90 mg/day (mean ∼50 mg/day).
Buspirone treatment was superior to placebo treatment, with a global response
rate (based on Clinical Global Impressions–Improvement [CGI-I] scale scores)
of 70% for buspirone and 35% for placebo (Rickels et al. 1991). In a subsequent
placebo-controlled study involving 177 geriatric depressed outpatients,
Schweizer et al. (1998) compared buspirone and imipramine treatment for 8
weeks. There was a statistically significant treatment effect for both buspirone
(mean daily dosage, ∼50 mg) and imipramine (mean daily dosage, ∼90 mg)
compared with placebo treatment.
Buspirone augmentation of SSRI treatment of partially responding depressed
patients leads to further improvement (Dimitriou and Dimitriou 1998; Gonul et
al. 1999; Jacobsen 1991; Landén et al. 1998). These findings were confirmed in
a report of the Sequenced Treatment Alternatives to Relieve Depression
(STAR*D) program. Patients who initially did not respond to an adequate
therapeutic trial with an SSRI responded when their medication was augmented
with either buspirone or bupropion (Trivedi et al. 2006). In an exploratory
double-blind, placebo-controlled study in patients with an MDD diagnosis, Fava
et al. (2012) reported significant antidepressant efficacy for combined buspirone
15 mg and melatonin slow release (SR) 3 mg. This preliminary finding is
mentioned only to indicate persisting interest in buspirone as a potential
augmenter of other antidepressants, not as a treatment recommendation.
We speculate that had buspirone’s sponsor pursued a depression rather than a
GAD indication, buspirone might well have become the first 5-HT1A partial
agonist developed as an antidepressant. At present, however, buspirone exists in
the shadow of numerous approved antidepressant drugs with high clinical
exposure and promotion. The fact that the product life cycle of buspirone
(BuSpar) was relatively short, whereas SSRIs with longer patent lives had
already received a clinical indication for GAD, served to restrain buspirone’s
sponsor from seeking an approved indication for MDD and limited the drug’s
approved indication to treatment of anxiety and anxiety with associated
depression.
Substance-Related Disorders
Several placebo-controlled trials have demonstrated the usefulness of buspirone
in facilitating smoking cessation (Hilleman et al. 1992; West et al. 1991),
although its main effect was in smokers who were also highly anxious
(Cinciripini et al. 1995).
Buspirone has been assessed in several double-blind, placebo-controlled trials
involving anxious outpatients with coexisting alcohol use disorder and found to
be efficacious (Rickels et al. 2003). Buspirone’s lack of abuse potential and
negligible additive effects on psychomotor and cognitive functions when
coadministered with alcohol (Mattila et al. 1982) make it a useful addition to
pharmacotherapies for alcohol-related disorders.
Buspirone was found to ameliorate symptoms of opioid withdrawal in a
placebo-controlled trial (Buydens-Branchey et al. 2005).
Although elevations in synaptic dopamine levels have been demonstrated to
play a pivotal role in the reinforcing effects of cocaine, neither D1 nor D2
receptor antagonists have proved clinically effective in cocaine addiction.
Speculating that dopamine D3 and D4 receptors might be possible targets for
pharmacotherapy, Bergman et al. (2013) undertook an investigation of
buspirone, which has been found to bind with high affinity to these receptors, to
evaluate its functional effects in animal models. On the basis of their finding that
buspirone produced a downward shift in the dose–effect function for cocaine-
maintained behavior, Bergman and colleagues proposed that buspirone be
evaluated for its utility in the management of cocaine addiction. However, in a
16-week double-blind multicenter pilot trial, Winhusen et al. (2014) found that
buspirone at dosages titrated up to 60 mg/day was not beneficial in preventing
relapse to cocaine use.
A small placebo-controlled pilot trial originally found buspirone to be
significantly superior to placebo on several measures in the treatment of DSM-
IV (American Psychiatric Association 1994) marijuana dependence (McRae-
Clark et al. 2009). However, a 12-week trial with a larger sample size found no
advantage for buspirone (titrated to 60 mg/day) over placebo in reducing
cannabis use (McRae-Clark et al. 2015).
Other Disorders
Buspirone’s utility has been explored in a variety of other disorders. Two small
double-blind clinical trials indicated modest efficacy for buspirone over placebo
in the symptomatic treatment of premenstrual syndrome (Brown et al. 1990;
Rickels et al. 1989). Lee et al. (2005), in a placebo-controlled study, showed
beneficial effects of buspirone in migraine patients with anxiety symptoms.
Buspirone was evaluated under double-blind conditions in Alzheimer’s patients
with aggressive behavior and agitation (Cantillon et al. 1996) and was found to
be superior to haloperidol. In a randomized double-blind study, buspirone was as
effective as methylphenidate in treating aggressive behavior in attention-
deficit/hyperactivity disorder (Davari-Ashtiani et al. 2010). Studies in animal
models and clinical trials indicate that buspirone may be useful in treating
tardive dyskinesia (Howland 2011) as well as L-dopa-induced and graft-induced
dyskinesias of Parkinson’s disease (Loane and Politis 2012).
Conclusion
Discovery of the 5-HT1A receptor was instrumental in linking modulation of 5-
HT neurotransmission with anxiety disorders. Buspirone, a selective partial
agonist of the 5-HT1A receptor, is the only drug in this class of antianxiety agents
approved for the treatment of GAD and anxiety with associated depressive
symptoms.
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Antipsychotics
CHAPTER 24
Classic Antipsychotic
Medications
Henry A. Nasrallah, M.D.
Rajiv Tandon, M.D.
Structure–Activity Relations
Phenothiazines
Members of the phenothiazine class of classic antipsychotics share the same
basic phenothiazine ring but differ in substitutions at both their R1 and R2
positions (Figure 24–1). Based on the side chain attached to the nitrogen atom in
the middle ring (R1), the phenothiazines are further subdivided into three
subtypes: aliphatic, piperidine, and piperazine phenothiazines.
FIGURE 24–1. Chemical structures of various classic
antipsychotics.
*No longer available in the United States.
Aliphatic Phenothiazines
The aliphatic phenothiazines share a dimethylamide substitution at their tenth
carbon. Chlorpromazine (Thorazine or Largactil) is the prototypical member of
this class and remains the aliphatic phenothiazine most widely used throughout
the world. With a chlorine atom attached to its second carbon, chlorpromazine is
heavily sedating because of its high level of anticholinergic, anti-α-adrenergic,
and antihistaminergic actions.
Piperidine Phenothiazines
Piperidine phenothiazines—for example, thioridazine (Mellaril) and its
metabolite, mesoridazine (Serentil)—are named for the presence of a piperidine
ring at their tenth carbon. Although members of this group have similar efficacy
and side effects compared with aliphatic phenothiazines, they are notable for
having a less potent effect on nigrostriatal dopamine2 (D2) receptors and a higher
level of anticholinergic activity; consequently they are associated with a lower
frequency of EPS. The use of these agents has been virtually extinguished by a
black box warning about significant QTc prolongation that was added to their
product label in 2000.
Piperazine Phenothiazines
With a substitution of a piperazine group at the tenth carbon of a phenothiazine,
the piperazines have greatly increased dopamine type 2 (D2) receptor blockade
and a lower affinity for muscarinic, α-adrenergic, and histaminergic receptors.
Some of the most potent conventional antipsychotics available in the United
States, including fluphenazine (Prolixin), perphenazine (Trilafon), and
trifluoperazine (Stelazine), belong to this class. The well-known antiemetic
prochlorperazine (Compazine) is also part of this class; although approved for
the treatment of psychosis, it is rarely utilized as an antipsychotic.
Thioxanthenes
Structurally and pharmacologically similar to the phenothiazines, the
thioxanthenes also differ widely in their pharmacological profiles based on
similar side-chain substitutions (see Figure 24–1). For instance, chlorprothixene
shares the same dimethylamide and chloride substitution as chlorpromazine,
with which it also shares its pharmacological profile. Thiothixene (Navane) has
both a piperazine side chain and a strongly electrophilic substitution
[SO2N(CH3)CH3], thus sharing the pharmacological profile of the piperazines.
Butyrophenones
The butyrophenone class has a piperidine ring with a three-carbon chain ending
in a carbonyl-substituted p-fluorobenzene ring. Haloperidol, arguably the best-
known classic antipsychotic, is the most widely used member of this class.
Haloperidol and other members of this class are strong dopamine receptor
antagonists and show little antimuscarinic, antihistaminergic, and antiadrenergic
activity.
Dibenzoxazepines
Loxapine, the only FDA-approved agent within the dibenzoxazepine class, is
composed of a tricyclic ring structure with a seven-member central ring. It has a
piperazine side chain and chlorine at position R2 (see Figure 24–1). It exhibits
an intermediate level of D2 blockade, as well as some serotonin2 (5-HT2)
antagonism. Its side-effect profile is characterized by intermediate sedation and
autonomic effects. Loxapine has the distinction of being the most “atypical” of
the classic antipsychotics because it is structurally similar to the
dibenzodiazepine clozapine. Another notable feature of loxapine is that one of its
metabolites, amoxapine, is marketed as an antidepressant.
Dihydroindoles
Molindone is the only member of the dihydroindoles available in the United
States. Sharing a similar structure with the indoleamines (see Figure 24–1), such
as serotonin, molindone has the distinction of being the only classic
antipsychotic not associated with any weight gain or a lowering of the seizure
threshold.
Diphenylbutylpiperidines
Pimozide, the only agent within the diphenyl-butyl-piperidine class available in
the United States, is approved only for the treatment of Tourette syndrome and
has the distinction of possessing the highest selectivity and potency for
dopamine D2 receptors among the conventional antipsychotics. It significantly
prolongs the QTc interval, and this has limited its utilization. Derived from
benperidol, pimozide shares many characteristics of the butyrophenones (see
Figure 24–1).
Pharmacological Profile
The classic conventional antipsychotic drugs have a multitude of effects on
various physiological variables through their actions on different
neurotransmitter systems. The antipsychotic effects of these agents are believed
to occur primarily through antagonism of D2-type dopaminergic receptors.
Therapeutic and adverse effects of D2 antagonism have been conceptualized in
the context of the major dopaminergic tracts present in the brain, which include
the mesocortical, mesolimbic (A10), tuberoinfundibular (A12), and nigrostriatal
(A8 and A9) tracts.
The effect of D2 receptor blockade on the mesolimbic dopaminergic systems
is believed to represent the putative mechanism of action of conventional
antipsychotics, but D2 blockade in other tracts is believed to result in a number
of adverse cognitive and behavioral side effects. Such side effects are frequently
observed in both animals and human subjects. D2 receptor antagonism in the
mesocortical dopaminergic pathway leads to a blunting of cognition
(bradyphrenia) and avolition-apathy (sometimes referred to as the neuroleptic-
induced deficit syndrome), which can be difficult to differentiate from the
primary negative symptoms of schizophrenic illness itself.
Blockade of the tuberoinfundibular tract projecting to the hypothalamus and
pituitary gland results in multiple neuroendocrine side effects processed through
the pituitary gland. Although dopamine is involved in enhancing the release of
most pituitary hormones, it is actually responsible for the tonic inhibition of
prolactin release. With significant dopaminergic blockade of the
tuberoinfundibular tract, prolactin release is no longer prevented, and the release
of other pituitary hormones is no longer enhanced. High levels of prolactin
combined with decreased levels of follicle-stimulating hormone and luteinizing
hormone often result in amenorrhea, galactorrhea, gynecomastia, decreased bone
density, impaired libido, and erectile dysfunction.
High levels (exceeding 78%) of D2 dopaminergic blockade within the
nigrostriatal system, which projects to the basal ganglia and caudate, produce
some of the most undesirable side effects of conventional antipsychotics.
Movement disorders or EPS such as akathisia, rigidity, and hypokinesia were
once believed to be necessary “evidence” of a therapeutic antipsychotic dosage.
However, the advent of the new-generation antipsychotics that are associated
with minimal EPS conclusively dispensed with this misconception. At higher
levels of D2 blockade, one may also observe dystonia, catalepsy, and a rigid,
immobile catatonic state.
Classic antipsychotic agents have varying degrees of activity at serotonergic,
cholinergic, noradrenergic, histaminergic, and other nondopaminergic receptors.
Although it is unclear whether any of these activities contribute to or interfere
with their effectiveness in the treatment of psychotic symptoms, they clearly
result in a variety of adverse effects. Because of differences in the
pharmacological activity of different classic antipsychotic agents at these
receptors, there are predictable differences in their side-effect profiles.
Pharmacokinetics
Generally, the pharmacokinetic profiles of the conventional antipsychotics
remain poorly understood. Even for some of the more extensively studied
agents, many hundreds of potential metabolites remain undiscovered, and the
physiological activity of several metabolites has yet to be adequately defined.
Nonetheless, certain general statements can be made concerning the classic
antipsychotics as a group.
Distribution
Most of the conventional antipsychotics are highly protein bound (85%–90%).
This feature is of importance when other highly protein-bound medications are
used concomitantly because of the risk of increasing levels of free or unbound
drugs into the toxic range. The antipsychotic drugs are highly lipophilic, which
allows unbound portions of the drug to readily cross the blood–brain barrier,
with concentrations twofold higher in the brain than in the peripheral circulation.
The drugs also readily cross the placenta to the fetus in pregnancy.
Metabolism
The conventional antipsychotics are metabolized in the liver by hydroxylation
and demethylation to forms that are more soluble and readily excreted by the
kidneys and in the feces. Many of these compounds undergo further
glucuronidation and remain active as dopamine receptor antagonists. Because of
the many active metabolites of the antipsychotic agents, it has not been possible
to obtain meaningful correlations between plasma levels and clinical response.
Variables such as age, genetic variability among individuals, and
coadministration of other drugs cause plasma levels to vary 10- to 20-fold across
individuals. The majority of conventional antipsychotics are metabolized by the
cytochrome P450 (CYP) enzyme subfamilies. Since CYP2D6 is important for
the metabolism of many of these antipsychotics, genetic variation in the rate of
2D6 metabolism should be considered. CYP1A2 and 3A4 subfamily enzymes
are also involved in the metabolism of some classic antipsychotics, and this may
be relevant to understanding drug–drug interactions of those agents.
Excretion
The major routes of excretion of the classic antipsychotics are through urine and
feces by way of bile. These drugs are also excreted in sweat, saliva, tears, and
breast milk. Elimination half-life varies from 18 to 40 hours for these drugs.
Lower doses of antipsychotics are generally needed in elderly patients because
of decreased renal clearance. Because of the long elimination half-lives of the
classic antipsychotics, once-a-day dosing is possible for each of these agents
following stabilization.
Mechanism of Action
Dopamine has been at the center of neurobiological theories of psychosis for the
past half-century, and even today, all agents approved as antipsychotics share the
single common attribute of dopamine D2 receptor antagonism. Amphetamine
intoxication served as a drug-induced model of the positive symptoms of
schizophrenia. Drugs that blocked dopaminergic receptors, specifically the D2
receptor, were noted to have greater efficacy and potency as antipsychotics.
Since dopaminergic agonists exacerbate psychosis and dopaminergic blockade
treats it, dopamine has held central importance in our conceptualization of the
neuropharmacology of schizophrenia.
Substance-Induced Psychosis
As noted previously, conventional agents can reverse the psychosis associated
with acute and chronic amphetamine intoxication as well as that associated with
cocaine use. However, the risk of acute dystonia must be considered in these
populations, as dopamine receptor downregulation is common, resulting in
greater sensitivity to rapid D2 blockade. Results in treatment of psychosis
secondary to drugs acting in non-dopaminergic mechanisms (such as
hallucinogens) are less satisfactory, although there may be some role for the
classic antipsychotics in treating phencyclidine (PCP) psychosis.
Personality Disorders
Although any personality disorder can be associated with transient psychotic
features emerging under stressful conditions, Cluster B disorders are most often
associated with this phenomenon. Treatment for transient psychotic episodes has
included short-term use of low doses of a high-potency antipsychotic. Although
some symptoms of personality disorders may be amenable to such
pharmacological treatment, long-term conventional antipsychotic treatment is
not recommended.
Mood Disorders
The utility of antipsychotic agents in the treatment of mood disorders with
psychotic features is well known. However, their utility in the treatment of
nonpsychotic depression and bipolar disorder is described as well. Several
conventional antipsychotics (such as thioridazine) are FDA approved for the
treatment of depression and anxiety without overt psychosis. However, they are
no longer used for this purpose because of the availability of other, more
effective and better-tolerated agents. The utility of conventional agents as
adjuncts to mood stabilizers in the treatment of patients with bipolar and related
disorders has been well described, both in the acute management of mania and in
the maintenance treatment of bipolar disorder with severe mood disturbance
and/or psychotic features. However, the newer atypical antipsychotics have
largely replaced conventional antipsychotics in the management of bipolar
disorder.
Tourette Syndrome
The tics present within Tourette syndrome are believed to be due to a hyper-
dopaminergic state that is amenable to treatment by dopamine receptor
antagonists. Pimozide is the only conventional antipsychotic with this indication,
which is its only FDA-approved indication.
Huntington’s Disease
Although there is no cure for Huntington’s disease, the psychosis and choreiform
movements associated with this disease may be ameliorated by dopamine
receptor antagonism. Several conventional antipsychotics carry FDA indications
for treatment of this disease.
Nausea, Emesis, and Hiccups
The lower-potency antipsychotics exert a potent antiemetic effect through
histamine1 (H1) receptor antagonism. This effect is closely related to their
original role in reducing perioperative stress and emesis. Many well-known
antiemetics, such as promethazine (Phenergan), are phenothiazines with a short-
chain substitution. In addition, chlorpromazine is approved for oral or
intramuscular therapy of intractable hiccups.
Acute-Onset EPS
Acute-onset EPS include medication-induced parkinsonism, acute dystonia, and
akathisia. Antipsychotic-induced parkinsonism occurs in 15% of patients after
several weeks of treatment. It is more common in patients older than 40 years,
although it can occur at any age. Symptoms are identical to those of Parkinson’s
disease and include muscle stiffness (“lead-pipe” rigidity), cogwheel rigidity,
shuffling gait, stooped posture, drooling, bradykinesia, resting tremor, masked
facies, and akinesia. Slowed, restricted movements of the body and face
(akinesia) may be mistakenly diagnosed as being due to depression or the
negative symptoms of schizophrenia.
It is estimated that up to 10% of patients may experience an acute dystonic
episode, which usually occurs within the first few hours or days of treatment. It
is more common in youth, in recent cocaine users, and with intramuscular doses
of high-potency antipsychotics. Dystonia is an acute, sustained, painful muscular
contraction. Potential areas of involvement include the tongue (protrusions,
twisting), jaw, neck (spasmodic retrocollis or torticollis), and back
(opisthotonos). If the dystonia involves the eyes, it results in a symmetrical or
unilateral upward lateral movement called an oculogyric crisis. Laryngeal
dystonia can result in sudden death secondary to a patient’s inability to breathe.
Dystonia can be extremely uncomfortable and frightening for patients and can
lead to noncompliance with medication for fear of recurrence. Treatment of
dystonia requires rapid diagnosis and intravenous administration of
antihistaminergic or anticholinergic agents. Anticholinergic agents are often
initiated with high-potency antipsychotics in an effort to avoid this side effect.
Akathisia is a subjective feeling of motor restlessness in which patients feel an
irresistible urge to move continuously. It is described as an unpleasant sensation
and may result in dysphoria. Akathisia can occur at any time during treatment
and is the most prevalent of the EPS. It frequently leads to noncompliance with
medications and is believed to increase suicide risk in some patients.
Late-Onset EPS
Tardive dyskinesia is characterized by a persistent syndrome of involuntary
choreoathetoid movements of the head, limbs, and trunk. It generally takes at
least 3–6 months of exposure to antipsychotics before the disorder develops.
Perioral movements involving buccolingual masticatory musculature are the
most common early manifestation of tardive dyskinesia. Tardive dyskinesia has
an estimated yearly incidence of 5% among adults and as high as 25% in the
elderly who receive continuous conventional antipsychotic therapy and has been
a major source of litigation in past psychiatric practice. The risk of developing
tardive dyskinesia is reported to increase with age and to be higher in certain
ethnic groups; female gender, presence of mood disorders, and early onset of
EPS have also been associated with increased risk of tardive dyskinesia.
Tardive dyskinesia may be masked by continuing dopamine blockade and has
a variable course following development. Over time, spontaneous resolution or
improvement has been described in some individuals. There is no single
effective treatment, although treatment with clozapine has been reported to
improve symptoms. Cases of tardive dyskinesia have been described with every
antipsychotic, although classic antipsychotics are associated with a much greater
risk of tardive dyskinesia than second-generation or atypical agents (Correll et
al. 2004). Other tardive syndromes include tardive dystonia, tardive akathisia,
and tardive pain.
Cardiac Effects
α-Adrenergic antagonism is associated with orthostatic hypotension with reflex
tachycardia, with tolerance possibly developing later in the treatment course.
Orthostasis is important because of an increase in falls and related injuries.
Recent studies involving several antipsychotics have drawn attention to the
risk of cardiac dysrhythmias, which is especially prominent with use of lower-
potency conventional antipsychotics. High dosage, rapid titration, intramuscular
administration, and especially intravenous administration may be associated with
a lengthening of the QTc interval, with resulting risk of serious dysrhythmias
such as torsades de pointes and ventricular fibrillation. Studies with thioridazine
have raised concerns about piperidine antipsychotics, leading to a decrease in the
use of this class. In reality, torsades de pointes is rarely encountered during
treatment with conventional antipsychotics, although some have speculated that
a syndrome of unexplained sudden death described with all conventional
antipsychotics may be related to sudden dysrhythmias.
Protein Binding
Because conventional antipsychotics are tightly protein bound, care must be
taken when these medications are administered with other highly protein-bound
medications. Mutual displacement of medications such as phenytoin, digoxin,
warfarin, and valproate could lead to a short-term increase in serum levels of
these drugs and of the conventional antipsychotic. However, protein binding has
not been of serious clinical significance.
Conclusion
The classic antipsychotics revolutionized the practice of psychiatry and the
treatment of the severely mentally ill throughout the world. Second-generation
“atypical” antipsychotics have commercially eclipsed these first-generation
agents to a large extent, in that more than 90% of patients with schizophrenia
and related psychoses in the United States are currently receiving one of the
atypical oral agents. In regard to long-acting (depot) agents, second-generation
injectable agents are gradually displacing classic antipsychotic injectables such
as haloperidol decanoate and fluphenazine decanoate. The landmark National
Institute of Mental Health–funded CATIE study, which compared four SGA oral
agents (olanzapine, quetiapine, risperidone, and ziprasidone) against one FGA
oral agent (perphenazine), showed that there was no difference between the two
generations in clinical effectiveness (defined as all-cause discontinuation)
(Lieberman et al. 2005). However, the CATIE study excluded subjects with
tardive dyskinesia from random assignment to perphenazine and instead
assigned them to one of the atypical agents. This methodological stipulation may
have confounded the findings, because the 231 subjects with tardive dyskinesia
were later found to have a higher severity of psychopathology and a much
greater likelihood of substance use (Nasrallah 2006). Additionally, the subjects’
low propensity to develop EPS led to a “ceiling effect” finding of no EPS
differences between perphenazine and the SGAs. Nonetheless, both classic
antipsychotics and atypical antipsychotics can cause serious side effects, with
neurological adverse events being much more likely with the FGAs and
metabolic complications being more common with the SGAs.
Conventional antipsychotics will always be remembered for their critical role
as the foundation of antipsychotic pharmacotherapy and as the main impetus for
the remarkable neuropharmacological progress in psychiatric neuroscience over
the second half of the twentieth century. They retain an important, if limited, role
in the antipsychotic armamentarium of the twenty-first century.
Suggested Readings
Glazer WM: Review of incidence studies of tardive dyskinesia associated with
typical antipsychotics. J Clin Psychiatry 61 (suppl 4):15–20, 2000 10739326
Janicak PA, Marder SR, Tandon R, Goldman M: Schizophrenia—Recent
Advances in Diagnosis and Treatment. Springer, Berlin, 2014
Meyer JM, Nasrallah HA (eds): Medical Illness and Schizophrenia, 2nd Edition.
Washington, DC, American Psychiatric Publishing, 2010
Nasrallah HA, Smeltzer D: Contemporary Diagnosis and Management of
Schizophrenia, 2nd Edition. Newtown, PA, Handbooks in Health Care, 2011
Sachdev PS: Neuroleptic-induced movement disorders: an overview. Psychiatr
Clin North Am 28(1):255–274, x, 2005 15733622
Smith D, Pantelis C, McGrath J, et al: Ocular abnormalities in chronic
schizophrenia: clinical implications. Aust N Z J Psychiatry 31(2):252–256,
1997 9140633
Tandon R, Belmaker RH, Gattaz WF, et al; Section of Pharmacopsychiatry,
World Psychiatric Association: World Psychiatric Association
Pharmacopsychiatry Section statement on comparative effectiveness of
antipsychotics in the treatment of schizophrenia. Schizophr Res 100(1–
3):20–38, 2008 18243663
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with second-generation antipsychotics: a systematic review of 1-year studies.
Am J Psychiatry 161(3):414–425, 2004 14992963
Dodd M, Samara MT, Tardy M, et al: Haloperidol versus first-generation
antipsychotics for the treatment of schizophrenia and other psychotic
disorders. Cochrane Database Syst Rev 1:CD009831, 2015 25592299
Himelhoch S, Taylor SF, Goldman RS, et al: Frontal lobe tasks, antipsychotic
medication, and schizophrenia syndromes. Biol Psychiatry 39(3):227–229,
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Lieberman JA, Stroup TS, McEvoy JP, et al; Clinical Antipsychotic Trials of
Intervention Effectiveness (CATIE) Investigators: Effectiveness of
antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med
353(12):1209–1223, 2005 16172203
Nasrallah HA: CATIE’s surprises: In antipsychotics’ square-off, were there
winners or losers? Curr Psychiatr 5(2):49–65, 2006
Tandon R, Halbreich U: The second-generation ‘atypical’ antipsychotics: similar
improved efficacy but different neuroendocrine side effects.
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Tandon R, Nasrallah HA, Keshavan MS: Schizophrenia, “just the facts” 5.
Treatment and prevention. Past, present, and future. Schizophr Res 122(1–
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CHAPTER 25
Clozapine
Stephen R. Marder, M.D.
Yvonne S. Yang, M.D., Ph.D.
Structure–Activity Relations
Clozapine, or 3-chloro-6-(4-methylpiperazin-1-yl)-5H-benzo[b]
[1,4]benzodiazepine (PubChem Compound Database 2016a), belongs to the
group of tricyclic antipsychotics known as the dibenzepines. This group is
characterized by a seven-member dibenzazepine central ring substituted with
oxygen, nitrogen, sulfur, or carbon (Iskra and Decker 2012). The antipsychotic
dibenzepines include a loxapine-like group of compounds (the
dibenzoxazepines) and a clozapine-like group (the dibenzodiazepines). The
structures of clozapine and its derivatives olanzapine and quetiapine can be seen
in Figure 25–1. Interestingly, the structure of the FGA antipsychotic loxapine
(PubChem Compound Database 2016b) is quite similar to that of clozapine, with
only two substitutions distinguishing them.
Dopamine Receptors
Clozapine is a D2 antagonist that binds to D2 receptors approximately 50–100
times less strongly than haloperidol and 10 times less strongly than
chlorpromazine (Ashby and Wang 1996). At therapeutic concentrations,
clozapine occupies only 40%–60% of D2 receptors, in contrast to most FGAs,
which occupy more than 80% of D2 receptors (Wenthur and Lindsley 2013).
Clozapine binds less strongly to D2 receptors than to dopamine itself and may be
displaced by endogenous dopamine (Seeman 2014). It also has equivalent
occupancy of dopamine D1 and D2 receptors at therapeutic dosages (Tauscher et
al. 2004). In order, clozapine binds most strongly to D4 > D1 > D5 > D2 > D3
receptors (Wenthur and Lindsley 2013).
Serotonin Receptors
Clozapine binds to 5-HT2A, 5-HT2B, and 5-HT2C receptors 15–30 times more
strongly than to D2 receptors (Stahl 2013; Wenthur and Lindsley 2013).
Clozapine also has high affinity for 5-HT5 receptors and acts as a partial agonist
at 5-HT1A receptors.
Muscarinic Receptors
Clozapine binds strongly to muscarinic M1 receptors, and to other muscarinic
receptors in the following order: M1 > M3 > M4 > M2. Clozapine’s high affinity
for muscarinic receptors likely causes many of clozapine’s well-known side
effects of sedation, constipation, and the dangerous complication of ileus.
Adrenergic Receptors
Clozapine binds strongly to α1-adrenergic receptors in the central nervous
system, based on positron emission tomography studies of 3H-prazosin binding
displacement in animal studies (Ashby and Wang 1996). Clozapine’s antagonism
of α1-adrenergic receptors likely contributes to its sedative properties as well as
some of its cardiac side effects including orthostatic hypotension and
tachycardia.
Histamine Receptors
Clozapine binds very strongly to histamine type 1 (H1) receptors, which likely
contributes to clozapine’s associated sedation, increase in appetite, weight gain,
and therefore possibly diabetes and metabolic syndrome. Preliminary research
has been done on histamine agonists to counteract the metabolic effects of
SGAs; however, no well-powered placebo-controlled, randomized trials have
been performed (Poyurovsky et al. 2005).
Glutamate Receptors
Although clozapine does not bind directly to glutamate receptors, it has been
shown to inhibit the reuptake of glycine at the synapse in rats, resulting in
increased glycine at the synapse, and thus increasing N-methyl-D-aspartate
(NMDA) receptor signaling (Javitt et al. 2005). Moreover, clozapine’s main
metabolite, N-desmethylclozapine (NDMC), or norclozapine, is an M1 agonist
known to increase NMDA receptor activity (Wenthur and Lindsley 2013).
GABA Receptors
Clozapine has a low affinity for γ-aminobutyric acid (GABA) receptors.
Animal Studies
Animal behavioral models have been of limited use in schizophrenia, due to a
lack of well-accepted animal models of psychopathology in schizophrenia. The
reasons for this are numerous. First of all, no single model has been identified
that can represent the genetic complexity and breadth and variability of symptom
domains of schizophrenia. Second, the subjective quality of many psychotic
experiences, such as paranoia, hallucinations, and delusions, makes these
symptoms and experiences difficult to measure in animals. Third, unlike the
heart or the pancreas, the human brain is many times more complex than even
that of a monkey, not to mention a rodent brain, for instance as evidenced by the
large number of folds in the human brain and the complete absence of folds in
the rodent brain. Last, schizophrenia and psychosis continue to function as
“umbrella terms” for what are likely numerous diseases presenting with
overlapping symptoms and syndromes, making differentiation of one illness
from another difficult in humans, not to mention animal models.
Despite these limitations, a number of constructs, including prepulse
inhibition and the conditioned avoidance response, are being studied from a
more reductionist standpoint. These models are being looked to less as complete
representations of the disease than as models of specific neurophysiological
aspects of psychosis that can inform us about particular characteristics of the
illness (Wong and Josselyn 2016). The use of animal models in this manner has
suggested unique properties of clozapine. For instance, as reviewed by Geyer et
al. (2001), among four techniques to induce prepulse inhibition, a sensory gating
phenomenon that is thought to relate to the relative difficulty patients with
schizophrenia have separating salient from nonsalient environmental
information, deficits in prepulse inhibition induced by NMDA receptor
antagonists were most likely to respond to clozapine-like SGAs, and not to
FGAs.
The conditioned avoidance response is another well-established construct used
to predict efficacy of a potential antipsychotic agent. Conditioned avoidance
response refers to learned behavior to avoid a conditioned stimulus once it has
been associated with a negative unconditioned stimulus. Early on in the
development of antipsychotic drugs, it was found that effective agents
specifically disrupted this response, and thus exhibited dopaminergic blockade
(Wadenberg 2010). Although clozapine did not meet the commonly accepted
criteria of capability to cause catalepsy at higher dosages and to antagonize
amphetamine-induced stereotypies in animals, it does block the conditioned
avoidance response, suggesting that it has antipsychotic efficacy.
Pharmacogenetic Profile
In recent years, a number of studies have been done linking genetic
polymorphisms to either response to clozapine or likelihood of side effects such
as weight gain and agranulocytosis in patients. Specific genetic polymorphisms
include the D3 receptor gene rs6280, where substitution of glycine for serine in a
coding region of the genes is associated with higher response rates to clozapine
and risperidone (Moore et al. 2014). Polymorphisms of the HLADQB1 gene, an
allele at the major histocompatibility complex, are associated with greater
likelihood of developing agranulocytosis, especially during rechallenge with
clozapine after a prior episode of agranulocytosis. CYP genetic variants have
been associated with decreased response to clozapine, and polymorphisms in the
gene for brain-derived neurotrophic factor (BDNF) have been found to be
associated with improved response (Sriretnakumar et al. 2015). The Pro12Ala
polymorphism of the PPAR-γ2 gene appears to predispose patients on clozapine
to metabolic syndrome: patients with the Pro-Ala substitution had a 53.8%
likelihood of having metabolic syndrome, whereas Pro-Pro polymorphism
patients had only a 16.3% likelihood (Fernández et al. 2012). Although not yet
integrated into clinical practice, the pharmacogenetics of clozapine may soon
help to inform clinicians about the likelihood of a patient to either respond to
clozapine treatment or to develop a concerning side effect.
Mechanism of Action
The effectiveness of antipsychotics was previously thought to be associated with
dopamine D2 receptor blockade, and induction of EPS was thought to be
necessary for antipsychotic action. Clozapine’s low rates of EPS but superior
efficacy as an antipsychotic undermined and eventually overturned these ideas.
Currently, the exact mechanism of clozapine’s antipsychotic effect remains
unknown, but several theories have been proposed. In this section, we will
discuss the possible mechanisms of both clozapine’s low rate of EPS as well as
its highly effective antipsychotic effect.
D4 Receptor Binding
Clozapine also has a very high affinity for the dopamine 4 (D4) receptor. The D4
receptor is widely distributed in the cortex and less so in striatal areas. Because
of clozapine’s specific high binding to D4 receptors, it was thought this D4
binding could be the unique characteristic giving clozapine its superior efficacy
against psychosis. However, other agents with high D4 receptor activity have
failed to demonstrate antipsychotic activity.
Metabolites
It has been thought that clozapine’s primary metabolite, NDMC, or
norclozapine, may have a role in its antipsychotic effect, because it represents
10%–90% of circulating active drug in patient serum (Wenthur and Lindsley
2013). However, trials of norclozapine have not demonstrated antipsychotic
efficacy.
Treatment-Refractory Schizophrenia
Early studies suggested that clozapine was particularly effective in patients with
more severe treatment-refractory forms of schizophrenia. This was important
when it was discovered that clozapine was associated with a risk of
agranulocytosis. Given that clozapine was viewed as an agent that might be
helpful for patients who had not responded to other antipsychotics, a study was
designed to test whether there was a role for clozapine in this population. The
result was the design of a multicenter study comparing clozapine with
chlorpromazine in severely ill patients with treatment-refractory schizophrenia
(Kane et al. 1988). Treatment-refractory illness was characterized on the basis of
a history of drug nonresponsiveness and a lack of improvement during a 6-week
trial of up to 60 mg of haloperidol. Treatment with clozapine resulted in greater
improvement in nearly every dimension of psychopathology. Thirty percent of
the clozapine-treated patients met stringent improvement criteria, compared with
only 4% of those treated with chlorpromazine.
Other studies suggest that the proportion of patients improving with clozapine
treatment will be higher if clozapine is continued for a longer time. For example,
a 16-week trial by Pickar et al. (1992) found a 38% improvement rate. A more
recent report (Kane et al. 2001) found that 60% of patients with treatment-
refractory illness improved after a 29-week trial of clozapine.
Two large trials compared clozapine with SGAs in patients with treatment-
resistant illness. In the United States, the National Institute of Mental Health
Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) compared
clozapine with risperidone, olanzapine, or quetiapine in patients with
schizophrenia who had not shown a positive response in an earlier phase of the
study because of a lack of efficacy (Stroup et al. 2006). Clozapine was
administered open-label, whereas the other antipsychotics were administered
double-blind. Patients assigned to clozapine had the lowest discontinuation rates,
with 56% of patients taking clozapine discontinuing treatment, compared with
71% of those taking olanzapine, 86% of those taking risperidone, and 93% of
those taking quetiapine. Clozapine-treated patients also showed greater symptom
improvement than those receiving the other agents. Another trial in the United
Kingdom, the Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia
Study—band 2 (CUtLASS-2) (Lewis et al. 2006), randomly assigned 136
patients who had responded poorly to two prior antipsychotics to either
clozapine or an SGA selected prior to the randomization. Patients who received
clozapine demonstrated greater improvement than those taking the comparison
drugs.
A large body of evidence indicates that clozapine has an important role in the
treatment of patients who have not responded to either FGAs or other SGAs.
Clozapine’s advantages are clearest in patients who have not responded to FGAs,
but they are still apparent in those who have had an inadequate response to other
SGAs. Because clozapine is associated with a risk of agranulocytosis and other
side effects (summarized in this chapter in the section “Side Effects and
Toxicology”), patients should probably receive a trial of one or two other SGAs
before receiving a trial of clozapine. Clinical guidelines (Lehman et al. 2004a,
2004b; Marder et al. 2002; Miller et al. 2004) differ to a minor degree on the
number of trials that should precede a trial with clozapine, but most recommend
at least two agents, one of which is an SGA. There is a consensus that patients
should not be considered to have treatment-refractory illness until they have
received an adequate treatment trial with clozapine.
Other Indications
Clozapine may also help patients with polydipsia-hyponatremia syndrome
(Canuso and Goldman 1999). Patients with this syndrome tend to intoxicate
themselves through excessive water drinking, and the resultant hyponatremia
may result in seizures.
Clozapine has historically been used to treat tardive dyskinesia (TD), although
it has not been formally studied extensively for this purpose. In a 1991 review,
Lieberman et al. reviewed eight small studies and conducted their own study of
30 patients with TD and found that in 50% of patients with TD, clozapine
reduced their TD symptoms by approximately 43% (Lieberman et al. 1991).
Other studies found equivocal results; however, in no study did clozapine cause
TD to worsen. Kimiagar et al. (2012) found TD symptoms were reversed with a
combination of clozapine, clonazepam, and tetrabenazine. Clozapine’s
mechanism of action in reducing TD remains unknown.
Hematological Effects
The side effects of clozapine make it one of the most challenging medications
for psychiatrists to prescribe. The main factor that limits its use is the potential
serious side effect of agranulocytosis. Agranulocytosis is defined as a drop in
absolute neutrophil count (ANC) to levels below 500/mm3. In 1975, there were
17 cases of agranulocytosis in Finland, and widespread use of the medication for
the treatment of schizophrenia was temporarily halted (Amsler et al. 1977; de la
Chapelle et al. 1977).
Agranulocytosis is a potentially lethal side effect that occurs in less than 1%
of patients treated in the United States (Alvir et al. 1993). In the United States,
all patients who are taking clozapine are entered into a national registry known
as the Clozapine Risk Evaluation and Mitigation Strategy (REMS) Program
(www.clozapinerems.com). Through this national registry, patients are
prescribed the medication only if their ANC count shows no signs of clinically
meaningful suppression (Honigfeld 1996). In a review of the morbidity and
mortality of clozapine-treated patients (Honigfeld et al. 1998) over a 5-year
period, 99,502 patients were registered through the previous Clozaril National
Registry. Of these, 2,931 (2.95%) patients developed leukopenia (WBC
count=3,500/mm3), and 382 (0.38%) patients developed agranulocytosis (ANC
<500/mm3). Twelve of the cases of agranulocytosis (0.012%) were fatal.
When clozapine treatment is discontinued upon identification of marked
leukopenia, patients usually recover within 14–24 days and without any long-
term consequences. However, rechallenging patients who have experienced
agranulocytosis almost always leads to recurrence of the problem. The onset of
the second episode is more aggressive than that of the first. In nine patients who
were known to be rechallenged, the average time to onset of the second episode
was 10 weeks shorter (14 weeks) than for the first episode (24 weeks)
(Safferman et al. 1992). Agranulocytosis has been successfully treated by
discontinuing the medication, providing supportive measures, and administering
granulocyte colony–stimulating factor, a medication that is commonly prescribed
to patients with medical illnesses that precipitate WBC count suppression
(Raison et al. 1994; Weide et al. 1992; Wickramanayake et al. 1995).
In January 2006, Novartis and the FDA issued a notification to clinicians
regarding modifications to the recommended monitoring schedule for patients
receiving clozapine. In October 2015, these guidelines were updated under a
unifying national registry, the Clozapine REMS Program. In order to prescribe
clozapine, the prescribing physician, the dispensing pharmacy, and the patient
must be registered with the REMS Program. Under the new monitoring
guidelines, a patient beginning clozapine treatment must have a baseline ANC
count of no less than 1,500/mm3, or 1,000/mm3 if the patient has benign ethnic
neutropenia. If during clozapine treatment a patient’s ANC drops below
1,000/mm3, clozapine must be stopped; for patients with benign ethnic
neutropenia, treatment must be stopped if the ANC drops below 500/mm3.
Weekly ANC levels must be obtained for 6 months, at which time the frequency
can be reduced to every 2 weeks, provided that treatment and monitoring have
not been interrupted and WBC counts and ANCs have remained within
acceptable ranges. After 1 year, monitoring can be reduced to monthly blood
tests.
Cardiac Effects
Well-known side effects of clozapine on the cardiovascular system include
tachycardia, bradycardia, syncope, and orthostatic hypotension. Tachycardia is
thought to be attributable to the anticholinergic activity of the medication at the
M2 receptor, leading to vagal nerve inhibition, hypotension is due to α-
adrenergic blockade, and bradycardia is thought to be neurally mediated reflex
bradycardia, also known as the vasovagal response. The forms of cardiovascular
toxicity that are of greatest concern, however, are clozapine-associated
myocarditis and cardiomyopathy. In January 2002, Novartis reported that there
had been 213 cases of myocarditis, 85% of which occurred at recommended
dosages of clozapine within the first 2 months of therapy (Novartis 2002). The
presence of eosinophilia in many of the reported cases indicates that an
immunoglobulin E (IgE)–mediated hypersensitivity reaction may be involved
(Kilian et al. 1999). Novartis (2002) also reported 178 cases of clozapine-
associated cardiomyopathy, 80% of which were in patients younger than 50
years. Almost 20% of the incidents resulted in death, an alarming figure that
may reflect delay in diagnosis and treatment. A later review spanning the years
1970 through 2004, however, indicated that overall the rate of potentially fatal
cardiomyopathy or myocarditis was between 0.015% and 0.188%, low enough
to justify continued treatment with clozapine (Merrill et al. 2005).
The detection of cardiac toxicity is challenging, because its manifestations
(tachycardia, fatigue, and orthostatic hypotension) are frequently observed in
clozapine-treated patients, particularly when alterations in dosage are made
(Lieberman and Safferman 1992). Alawami et al. (2014) found in a 2014 review
that cardiac toxicity in the form of cardiomyopathy occurred, on average, 14.4
months after initiation of treatment, indicating this potentially life-threatening
condition could occur long after the greatest threat of other side effects such as
agranulocytosis has passed. The poor specificity of signs for cardiac toxicity
demands that patients with any personal or family history of heart disease be
identified, and the threshold for medical evaluation of patients developing
respiratory and cardiovascular symptoms must be low (Wooltorton 2002).
Therefore, we recommend monitoring of erythrocyte sedimentation rate and/or
C-reactive protein, eosinophil count, and troponins on a weekly basis for the first
4 weeks of therapy (Freudenreich and McEvoy 2016). The etiology of the
myocarditis and cardiomyopathy remains unclear at this time.
For hypotension caused by clozapine, we also recommend a slow upward
titration of the medication and monitoring of orthostatic vital signs during the
first weeks of therapy. Patients should be educated about the risk of orthostatic
hypotension and should be taught to rise slowly from supine positions.
Concomitant treatment with β-blocking agents may be necessary for persistent
tachycardia. However, the use of β-blockers may exacerbate the hypotensive
effects of clozapine and should be used cautiously.
Metabolic Effects
Weight Gain
Weight gain has been observed in both premarketing and postmarketing trials of
clozapine (Henderson 2001; Simpson and Varga 1974; Wirshing et al. 1998,
1999). Allison et al. (1999) performed a meta-analysis of the weight-gain data in
short-term trials of medications. The average weight gain observed with
clozapine was 4.45 kg, which exceeded the weight gain observed with all of the
other medications in the study, including the conventional agent thioridazine
(3.19 kg), a medication known for its weight-gain liability. The weight gain
observed with clozapine seems to occur for a prolonged period of time—up to
40 weeks. In one naturalistic study, Henderson (2001) observed patients in a
clozapine clinic for 5 years and noted weight gain occurring for up to 46 months
in some patients.
Phase II of CATIE provided an opportunity to compare weight gain among
patients assigned to clozapine, olanzapine, risperidone, and quetiapine (McEvoy
et al. 2006). The numbers of patients assessed in the analyses were small, with
only 45 patients in the clozapine group, 17 in the olanzapine group, 14 in the
quetiapine group, and 14 in the risperidone group. Although the differences in
weight gain among these agents were not statistically significant, they were
interesting, with patients taking clozapine gaining a mean of 0.5 lb per month,
compared with 1.0 lb with olanzapine, 0.4 lb with quetiapine, and 0.5 lb with
risperidone.
Diabetes
The weight gain observed with clozapine can place patients at risk for significant
health problems. Diabetes is naturally the most concerning potential sequela of
this weight gain. Numerous case reports have linked clozapine with new-onset
diabetes (Wirshing et al. 1998). In Henderson’s (2001) naturalistic study of 81
patients observed over a 5-year period, 36.6% of the patients developed diabetes.
Patients treated with clozapine should be routinely screened for diabetes and
other metabolic abnormalities, including raised lipid levels. Patients with risk
factors for diabetes should be monitored more closely. Reports and clinical
experience suggest that in a case of antipsychotic-associated diabetes or diabetic
ketoacidosis, discontinuation of the antipsychotic agent may result in reversal of
the hyperglycemia and diabetes. During clozapine therapy, we recommend
monitoring fasting glucose, cholesterol, and lipids at baseline and every 6
months thereafter.
Prevention of weight gain with clozapine, through nutrition and diet
counseling, is recommended. Caloric restriction and exercise for 30 minutes per
day should be recommended. Screening questions by physicians that we find
useful include the following: “Have you noticed if your belt or pants size has
changed?” “Have you noticed an increase in thirst or urinary frequency?”
Dyslipidemias
Clozapine treatment is associated with dyslipidemias, including elevations in
triglycerides and cholesterol, particularly low-density lipoprotein cholesterol
(McEvoy et al. 2006; Wirshing et al. 2002a).
In 2004, in response to growing concern that the majority of antipsychotic
medications may be associated with weight gain and other metabolic changes,
the American Diabetes Association and other groups published a set of
guidelines for monitoring weight, glucose, and lipids (American Diabetes
Association et al. 2004). Also in 2004, a very comprehensive literature review
was conducted by Marder et al. (2004) to provide guidance to clinicians
regarding monitoring of weight, glucose, lipids, and other parameters of physical
health in patients with schizophrenia. Labeling changes were made for all
antipsychotic medications, including clozapine, regarding these metabolic risk
factors.
Seizures
A well-known side effect of clozapine treatment is the risk for seizures, which
are thought to occur in 5%–10% of patients treated with this medication (Welch
et al. 1994). The cause of seizures is unclear, but it is generally thought that rapid
escalations in dosage and possibly high plasma levels of clozapine may account
for the development of seizures (Klimke and Klieser 1995). Clozapine-
associated seizures occur most often at dosages greater than 600 mg/day. The
relationship between clozapine plasma levels and seizures is somewhat
inconsistent in the literature (Simpson and Cooper 1978; Vailleau et al. 1996).
The anticonvulsant agents sodium valproate, gabapentin, and topiramate have
been used successfully to treat clozapine-induced seizures (Navarro et al. 2001;
Toth and Frankenburg 1994; Usiskin et al. 2000). Topiramate has an advantage
over sodium valproate in that it is associated with very little weight gain. In
cases in our clinic where patients have developed seizures while taking
clozapine, we institute rapid loading with anticonvulsant medication and
temporarily discontinue the clozapine treatment. We then slowly reintroduce and
retitrate the clozapine once the patient is taking an adequate dose of
anticonvulsant medication.
Anticholinergic Effects
Anticholinergic side effects resulting from clozapine’s muscarinic receptor
antagonism include sedation, weight gain, dry mouth, constipation, and, in some
cases, ileus and/or bowel obstruction. Constipation can be a difficult but
important side effect to manage in severely mentally ill individuals, who may not
complain about the problem until a medical emergency, such as acute bowel
obstruction, occurs. In institutional settings and in prisons, where patients may
have little access to exercise and where monitoring of patients’ fluid intake is not
performed, constipation from clozapine can be serious or even fatal (Drew and
Herdson 1997; Hayes and Gibler 1995; Levin et al. 2002). Typically,
constipation can be avoided by proactive modifications in patients’ diets and
education about adequate fluid intake and exercise. The medical treatment that
we favor is prophylactic therapy with sorbitol. We are less inclined to
recommend treatments involving bulking agents, particularly in the setting of
poor fluid intake. High-fiber diets can also be beneficial.
Drug–Drug Interactions
As mentioned in the section “Pharmacokinetics and Disposition,” clozapine is
predominately metabolized by CYP1A2, although CYP2D6 and CYP3A3/4 also
contribute to its metabolism (Buur-Rasmussen and Brøsen 1999). Smoking,
which induces CYP1A2, lowers clozapine plasma levels, and up to two times
normal doses of clozapine may be required to maintain a therapeutic serum
level. Fluvoxamine and ciprofloxacin, potent inhibitors of CYP1A2,
dramatically increase plasma levels of clozapine (Heeringa et al. 1999; see also
the FDA table “Drug Development and Drug Interactions: Table of Substrates,
Inhibitors and Inducers” at
www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsL
and on occasion, adverse effects are seen (Koponen et al. 1996). Other reports
suggest that inhibitors of CYP2D6, including paroxetine and fluoxetine, can
elevate clozapine levels (Joos et al. 1997; Spina et al. 1998). In general, if the
patient initiates a strong CYP1A2 inhibitor, use one-third of their normal dose.
For moderate or weak CYP1A2 inhibitors, or CYP2D6 or CYP3A3/4 inhibitors,
consider decreasing their dose. If they initiate strong CYP3A3/4 inducers, or
moderate or weak CYP1A2 inducers, monitor for decreased effectiveness and
consider increasing their clozapine dose if necessary. Cytochrome-related
problems can be avoided by monitoring clozapine plasma levels while gradually
increasing clozapine from a low starting dose.
Conclusion
Clozapine maintains an important place in the treatment of severe psychosis.
Side effects, including agranulocytosis, cardiomyopathy, seizures, sedation, and
weight gain, make it the most difficult antipsychotic to prescribe. For this reason,
clozapine should be reserved for patients who have not responded to one or more
other antipsychotics. On the whole, however, this very effective treatment is
underutilized in most communities. This is unfortunate, because patients’
conditions should never be labeled treatment refractory or patients deemed
partial responders until they have received an adequate trial of clozapine.
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CHAPTER 26
Olanzapine
Amy L. Silberschmidt, M.D.
Jacob S. Ballon, M.D., M.P.H.
S. Charles Schulz, M.D.
Looking for ways to achieve the same treatment benefit with fewer side
effects, investigators at Eli Lilly began to screen numerous compounds for
potentially useful psychotropic properties. In 1990, the company applied for and
received a patent for the compound olanzapine. It is interesting to note that the
new compound had many structural similarities to clozapine, which in 1989 had
been approved for use in treating refractory schizophrenia. Hailed as a novel
second-generation antipsychotic drug, clozapine was thought to have potential
for schizophrenia, mania, and anxiety. Clozapine was noted for its efficacy as
well as its freedom from neurological side effects.
Olanzapine was first given to patients with schizophrenia in 1995 (Baldwin
and Montgomery 1995). The patients in the study experienced a substantial
decrease in their symptoms while receiving 5–30 mg/day of the compound. The
study researchers noted a low degree of extrapyramidal side effects (EPS),
although concern was raised regarding elevation of liver enzymes, as one patient
had to discontinue the study for that reason.
The initial testing of olanzapine had useful results and led to a program of
three pivotal trials of the drug. These first three controlled studies compared
olanzapine (at two fixed dosages: 1 mg/day and 10 mg/day) against placebo
(Beasley et al. 1996a); olanzapine at three fixed dosages (low, medium, or high)
against olanzapine at 1.0 mg/day or haloperidol at 15 mg/day or placebo
(Beasley et al. 1996b); and olanzapine against haloperidol in a large international
study (Tollefson et al. 1997). The positive results for olanzapine led to U.S. Food
and Drug Administration (FDA) approval in 1997 and subsequent widespread
use in the United States and around the world.
Structure–Activity Relations
Olanzapine is a thiobenzodiazepine derivative that bears a close structural
resemblance to clozapine. The formal chemical name of olanzapine is 2-methyl-
4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b] [1,5]benzodiazepine. Structurally,
olanzapine differs from clozapine by two additional methyl groups and the lack
of a chloride moiety (Figure 26–1). The in vitro receptor binding profiles of
olanzapine and clozapine are relatively similar. According to the package insert,
olanzapine is known to have a high affinity for dopaminergic (D1–4),
serotonergic (5-HT2A/2C, 5-HT6), histaminergic (H1), and α-adrenergic (α1)
receptors, with moderate affinity for muscarinic (M1–5) receptors and weak
activity at benzodiazepine, γ-amino-butyric acid type A (GABAA), and β-
adrenergic receptors (Eli Lilly 2015).
FIGURE 26–1. Chemical structure of olanzapine.
Pharmacological Profile
In vitro and preclinical behavioral studies of olanzapine predicted significant
antipsychotic activity with a low propensity to induce EPS. Because clozapine is
the prototype for second-generation antipsychotic action, it serves as the
yardstick for “atypicality” of comparator compounds. Despite widespread
general use of the term atypical to refer to any antipsychotic developed after
clozapine, the term was originally coined to connote medications with an EPS
risk no greater than that of placebo. While it is true that olanzapine carries a
lower risk of tardive dyskinesia than do many other antipsychotics, its risk is still
appreciably greater than that of placebo, and therefore the term atypical does not
apply (Farah 2013).
One property that may lower a compound’s risk of EPS is nonselective
binding of dopamine receptors. Classical antipsychotics selectively block
dopamine D2-like (D2, D3, and D4) receptors over D1-like (D1 and D5) receptors
—for example, haloperidol has a D2-to-D1 binding ratio of 25:1. Clozapine
nonselectively binds all five dopamine receptor subtypes, with a D2-to-D1 ratio
of 0.7:1, whereas olanzapine is only partially selective for the D2-like group,
with a D2-to-D1 ratio of approximately 3:1, intermediate between those of
haloperidol and clozapine.
In animal models predictive of antipsychotic efficacy, olanzapine produces
effects indicating dopamine antagonism, with a low propensity to produce EPS.
For example, in rats, olanzapine reduces climbing behavior induced by
apomorphine and antagonizes stimulant-induced hyperactivity, both
characteristic of antipsychotic effects. The ratio of the dose needed to produce
catalepsy to the dose needed to inhibit conditioned avoidance, another model for
atypical efficacy, is higher for olanzapine than for conventional agents (Moore
1999).
Another potential mechanism whereby dopamine antagonists may exert
antipsychotic effects with minimal EPS is through selective activity in the A10
dopaminergic tracts from the ventral tegmentum to mesolimbic areas compared
with effects antagonizing the A9 nigrostriatal projections that mediate EPS.
Olanzapine in chronic administration, like clozapine, selectively inhibits firing
of A10 neurons without significant inhibition of A9 tracts (Stockton and
Rasmussen 1996a). Olanzapine shows increased c-fos activity in the nucleus
accumbens relative to the dorsolateral striatum, thus demonstrating selective
blockade of the mesolimbic dopamine tract compared with the nigrostriatal tract
(Robertson and Fibiger 1996).
A leading theory regarding atypicality relates to the fleeting effects of atypical
antipsychotics at the D2 receptor, coupled with regional selectivity of these
compounds (Seeman 2002). Olanzapine’s D2 receptor occupancy saturation—
which has been shown to be intermediate between that of clozapine and that of
haloperidol—may be responsible for its decreased risk of EPS (Tauscher et al.
1999). However, because the current second-generation antipsychotic
medications have substantially differing effects at many of the targets thought to
play a role in atypicality, there is not yet consensus regarding the true rationale
for atypicality in these agents compared with the first-generation antipsychotics
(Farah 2005).
Amphetamine administration in rats is often used as a model for psychosis.
The sympathomimetic activity and dopamine release provide a target for testing
antipsychotic medications. Olanzapine disrupts the activity of amphetamines in
rats (Gosselin et al. 1996). Olanzapine was shown in a rat model to decrease
dopamine release in the A10 dopaminergic neurons of the ventral tegmentum
greater than the A9 dopaminergic neurons of the striatum after chronic
administration and after an amphetamine challenge (Stockton and Rasmussen
1996a, 1996b). Olanzapine does not induce catalepsy in rats at doses needed for
antipsychotic efficacy.
Another model of psychosis in rats is produced by administration of the
glutamatergic N-methyl-D-aspartate (NMDA) receptor antagonist phencyclidine
(PCP). Chronic PCP use in humans is associated with symptoms similar to those
in schizophrenia, including negative symptoms, thus making it a putative model
for schizophrenia (Krystal et al. 1994). Olanzapine has been shown to decrease
the hyperactivity of NMDA receptors under chronic PCP administration, which
may have a bearing on its effect on negative symptoms (Ninan et al. 2003). With
chronic administration, glutamatergic activity continues to be affected by
olanzapine (Jardemark et al. 2000). Despite these findings, olanzapine has no
direct affinity for the NMDA receptor (Stephenson and Pilowsky 1999).
Receptor-binding studies show that olanzapine has a broad range of
neurotransmitter effects (Bymaster et al. 1996). Although olanzapine has potent
muscarinic M1–5 receptor affinity in vitro (another contributor to putative anti-
EPS effects), in practice few olanzapine-treated patients have anticholinergic
side effects that are clinically significant. α1-Adrenergic and H1 histaminergic
antagonism contribute to olanzapine’s adverse-effect profile of orthostatic
hypotension (α1), sedation (H1), and possibly weight gain (H1). Olanzapine, like
other second-generation antipsychotics, has a higher affinity for 5-HT2 receptors
than for D2 receptors (Kapur et al. 1999). There is also indirect evidence that
olanzapine blocks 5-HT2C receptors (Sharpley et al. 2000). Olanzapine has little
or no effect on α2- and β-adrenergic, H2, nicotinic, GABA, opioid, sigma, or
benzodiazepine receptors.
Mechanism of Action
In discussing olanzapine’s mechanism of action in the treatment of
schizophrenia, it should be noted that there is no established molecular
mechanism that can unify the symptoms of schizophrenia. No precise animal or
in vitro model for the illness exists, nor is there a consensus on its precise
etiology or pathophysiology. Numerous neurochemical hypotheses have been
proposed, including theories implicating abnormalities in dopaminergic,
glutamatergic, serotonergic, and other systems, such as neurotensin (Boules et al.
2007) or neuregulin (Benzel et al. 2007). However, the discovery that multiple
receptor types exist for each neurotransmitter has added many layers of
complexity to the search for explanations regarding the root causes of
schizophrenia. Thus, it is no longer possible to use broad terms such as
“increased dopamine” when discussing ideas about the etiology of the disorder.
Despite the caveats mentioned above regarding our rudimentary knowledge of
the nature of schizophrenia, it is important to note that all approved
antipsychotic medications have a significant effect on the dopaminergic system,
largely through the blockade of D2 receptors (Kapur and Remington 2001). Even
though there are substantial differences in D2 receptor affinity among the
traditional antipsychotics and the second-generation antipsychotics, they all are
either full antagonists or partial agonists at the dopamine D2 receptor. Of interest
is evolving research indicating the importance of multiple-receptor blockade to
the effectiveness of the second-generation antipsychotic class. As the various
neurotransmitter systems have been investigated in the
neuropsychopharmacology of schizophrenia, evidence is emerging that the
second-generation antipsychotics, and olanzapine in particular, may improve
different schizophrenia symptom domains by means of effects on 5-HT
receptors, on multiple-receptor binding, on region-specific and more fleeting
binding to dopamine receptors, on glutamate neurotransmission, and perhaps on
neuropeptide neurotransmitters. In the following paragraphs, we discuss each of
these specific ideas about olanzapine’s mechanism of action in turn.
In clinical investigations with positron emission tomography (PET) imaging,
Kapur et al. (1998) showed that olanzapine at a wide range of dosages blocks a
high percentage (95% or greater) of 5-HT2A receptors and also blocks dopamine
receptors in a dose-dependent fashion—crossing the putative antipsychotic
blockade line at dosages commonly used to diminish psychotic symptoms of
schizophrenia. This study indicated that olanzapine’s primary mechanism was
related to the blockade of dopamine receptors and additionally noted that
olanzapine showed stronger affinity for 5-HT2A receptors than for dopamine
receptors at all dosage ranges.
A more compelling hypothesis regarding the mechanism of olanzapine’s
effects emerged from in vivo PET scanning work performed in a series of
experiments at the University of Toronto and in Sweden. Results of the initial
PET scanning studies of patients receiving clozapine indicated that atypical
dopamine D2 receptor binding was occurring (Farde and Nordström 1992; Farde
et al. 1992; Kapur et al. 2000). The group subsequently found similar unusual D2
receptor binding with quetiapine and, to some degree, olanzapine (Kapur et al.
1998). The authors proposed that the so-called atypical antipsychotic effect—
successful treatment of psychotic symptoms without induction of movement
disorder side effects—may be the result of a “fast off” property of some second-
generation agents, wherein the drug blocks the dopamine D2 receptor but leaves
it quickly, a receptor occupancy pattern that effectively decreases psychosis yet
causes minimal interference to the body’s own dopamine receptor activity. Thus,
for olanzapine, this mechanism might help explain how the drug can exert strong
therapeutic effects on schizophrenia symptoms yet cause few EPS at standard
dosages. From a clinical viewpoint, it is important to note that at higher
olanzapine dosages (30 mg/day), greater dopamine receptor blockade is seen,
and movement disorder side effects, such as akathisia, are more likely to occur.
Over the past 30 years, there has been substantial interest in the role of
glutamate, an excitatory neurotransmitter, in the pathophysiology of
schizophrenia (see, e.g., Coyle 2006; Kim et al. 1980; Krystal et al. 1994;
Moghaddam and Javitt 2012). Glutamate’s inclusion in theories about the
development of schizophrenia is supported by the psychotomimetic properties of
glutamate antagonists such as PCP and ketamine. These NMDA receptor
antagonists induce a group of behaviors that often show closer parallels to
schizophrenia than do those induced by dopamine sympathomimetic agents, in
both mice and humans. Clinical trial evidence points to the potential usefulness
of glutamatergic agonists (e.g., D-cycloserine) in treating schizophrenia
(Kantrowitz et al. 2010). One way of examining the potential effectiveness of
medication is to look at changes in deficits in prepulse inhibition (i.e.,
attenuation of the startle response), a measure of sensory motor gating that is
diminished in patients with schizophrenia and can be similarly diminished
pharmacologically through administration of PCP (Dulawa and Geyer 1996). In
a study of rats with isolation-induced disruption of prepulse inhibition, both
quetiapine and olanzapine successfully reversed the prepulse inhibition deficit
(Bakshi et al. 1998).
Neurotensin receptors are collocated with and modulate mesolimbic
dopaminergic neurons (Boules et al. 2014). Cerebrospinal fluid (CSF)
concentrations of neurotensin are abnormal in some untreated patients with
schizophrenia and have been found to normalize with antipsychotic
administration. The degree of clinical improvement, particularly in negative
symptoms, was found to correlate with the degree of increase in CSF
neurotensin (Sharma et al. 1997). In rats, olanzapine administration was shown
to increase extracellular neurotensin in the ventral striatum and medial prefrontal
cortex acutely. Over time, chronic olanzapine administration decreased the
concentration of neurotensin in the medial prefrontal cortex but increased the
concentration in the ventral striatum. Furthermore, chronic olanzapine
administration abolished the stimulatory effects of amphetamine administration
in these regions (Gruber et al. 2011). Olanzapine does not bind to the
neurotensin 1 (NT1) receptor in humans (Theisen et al. 2007) but may influence
neurotensin through its action on other subtypes of neurotensin receptor or its
downstream effects.
Neuregulins are a family of growth factors that stimulate the ERbB receptor
tyrosine kinases and have been shown to play a role in the assembly of neural
circuitry, myelination, neurotransmission, and synaptic plasticity. The
neuregulin-1 gene (NRG1) has been associated with schizophrenia in several
large genomewide association studies and meta-analyses (Mei and Nave 2014).
In rats, (NRG1) expression increases in the hippocampus after 1 week of
olanzapine administration; however, after 12 weeks, its expression decreases in
the prefrontal cortex and cingulate cortex (Deng et al. 2015). In a study using
immortalized lymphocytes from schizophrenia patients and control subjects from
unrelated families, expression of the NRG1 glial growth factor isoform was
found to be lower in schizophrenia patients than in control subjects, both before
and after stimulation with olanzapine (Chagnon et al. 2008).
In summary, olanzapine works at least at the dopamine, 5-HT, and glutamate
receptors. There is intriguing circumstantial evidence that olanzapine may
modulate neurotensin and neuregulin. Current theories suggest that dopamine
receptor–blocking capabilities are a necessary but not sufficient requirement for
antipsychotic effectiveness. The other studied mechanisms, when taken in total,
may be the factors leading to olanzapine’s broad efficacy and side-effect profile.
Approved Indications
Schizophrenia
As noted earlier, olanzapine was originally developed as a medication with
potential for treating schizophrenia, mania, and anxiety. To gain FDA approval
for the treatment of schizophrenia, olanzapine was tested in four pivotal studies
to assess the compound for efficacy, safety, and dosage range. The earliest
testing of olanzapine was an assessment of olanzapine dosages of 5–30 mg/day
following an initial starting dosage of 10 mg/day. Brief Psychiatric Rating Scale
(BPRS) scores were reduced substantially, and EPS incidence was low (Baldwin
and Montgomery 1995). These encouraging results led to further studies and
pointed to a dosage range to be tested.
Off-Label Uses
Dementia-Related Agitation and Psychosis
Olanzapine does not have an FDA-approved indication for the treatment of
dementia. Because elderly people are generally more sensitive to the EPS and
tardive dyskinesia associated with first-generation antipsychotic medications, the
second-generation medications are often preferred when antipsychotics are
needed.
A large placebo-controlled trial of olanzapine in Alzheimer’s patients showed
that the lower dosages of olanzapine (5–10 mg/day) were significantly better
than placebo in treating target symptoms of agitation, hallucinations, and
delusions (Street et al. 2000, 2001). The FDA placed a black box warning on the
prescribing information of antipsychotic medications calling attention to the
increased risk of death, primarily from cardiovascular and infectious
complications. According to the warning, second-generation antipsychotic use
over a 10-week period carries a 1.6- to 1.7-fold increased risk of mortality based
on data from 17 placebo-controlled trials of second-generation antipsychotics in
dementia-related psychosis. Ultimately, clinical judgment and thorough
documentation are important, as in certain situations the hazards of untreated
psychotic agitation may outweigh the potential risks of treatment.
Several studies have examined olanzapine in the treatment of dementia
without agitation (Brooks and Hoblyn 2007). A placebo-controlled multicenter
trial conducted by researchers at Eli Lilly evaluated olanzapine at low fixed
dosages (1.0, 2.5, 5.0, and 7.5 mg/day) in the treatment of dementia-related
psychosis (De Deyn et al. 2004). Although olanzapine did not separate from
placebo on the primary outcome measure, Hallucinations and Delusions items of
the Neuropsychiatric Inventory—Nursing Home edition (NPI/NH),
improvements were seen in each of the dosage groups studied. All patients who
received dosages of 2.5 mg/day or greater were initially started on 2.5 mg/day,
with the dosage titrated upward by 2.5 mg/week (as indicated based on their
assigned study group), and there was an overall difference from placebo in the
acute phase of the study, suggesting that a 2.5-mg dose was an effective starting
dose in the more acute setting. On some secondary outcome measures, the
greatest improvement was seen with the highest olanzapine dosage (7.5 mg/day),
suggesting that for some patients, an increase to 7.5 mg/day is beneficial.
Because no higher dosages were used in the study, it is unclear whether
continuing to increase the dosage would lead to greater efficacy (De Deyn et al.
2004).
Acetylcholine has been the focus of treatments aimed at slowing the rate of
cognitive deterioration among individuals with dementia. Cholinesterase
inhibitors have been used on that basis. Olanzapine may have beneficial effects
on prefrontal cortex cholinergic and serotonergic neurons that may facilitate
acetylcholine release to that region. However, in a double-blind study conducted
by researchers at Eli Lilly, olanzapine was shown to worsen cognitive
functioning, as assessed on the Alzheimer’s Disease Assessment Scale for
Cognition (ADAS-Cog), and there was no statistical difference between the
olanzapine and placebo groups in scores on the Clinician’s Interview-Based
Impression of Change (CIBIC) scale (Kennedy et al. 2005). Patients in the
olanzapine group also showed cognitive worsening on the Mini-Mental State
Examination (MMSE). Previous studies found little or no benefit on cognition
from olanzapine treatment in nonagitated patients with dementia (De Deyn et al.
2004; Street et al. 2000).
The CATIE study also had an Alzheimer’s disease component in which
olanzapine, risperidone, and quetiapine were compared with placebo in the
treatment of psychosis and agitation in outpatients (Schneider et al. 2006b).
Patients were included if they had psychotic symptoms and resided either in an
assisted living facility or at home, but they were excluded if they had skilled
nursing needs or primary psychotic disorders. Patients who were to receive
cholinesterase inhibitors or antidepressants were also excluded from the study.
As in the schizophrenia portion of CATIE, the primary outcome variable was
time to discontinuation. No difference was found among the groups in time to
discontinuation, and no benefit was seen on the Alzheimer’s Disease
Cooperative Study—Clinical Global Impression of Change (ADCS-CGIC). The
average time to discontinuation ranged from 5 to 8 weeks among the treatments.
Discontinuation due to lack of efficacy occurred sooner for patients receiving
placebo or quetiapine than for those receiving risperidone or olanzapine. Side
effects such as parkinsonism, sedation, and increased body mass index occurred
more frequently with the study medications than with placebo (Schneider et al.
2006b).
Overall, there are limited data to support the effectiveness of second-
generation antipsychotics in the treatment of dementia, and the available
evidence does not support olanzapine as the first choice in this medication class.
Risks for worsened cognitive function and metabolic concerns must be
considered when use of antipsychotic medications is contemplated. Nonetheless,
there are times when behavioral consequences and patient safety require more
aggressive treatment, and antipsychotic medication may be warranted.
Olanzapine is considered an intermediate-risk antipsychotic in this population
(Kales et al. 2014). Ultimately, a painstaking evaluation of the risk–benefit ratio
of antipsychotic medication use must precede any decision to prescribe these
agents, in both the acute and the long-term time frames. Further study is needed,
however, regarding the use of second-generation antipsychotic medications in
this population (Schneider et al. 2006a).
Anorexia Nervosa
Anorexia nervosa is a common and severe psychiatric illness that may well have
the highest mortality rate of any mental disorder. Severe restriction of food
intake, leading to low weight, is a primary feature of the illness; however,
patients also have psychotic-like disturbances in self-perceived body size or
shape, as well as unusual ideas about food and metabolism. Some investigators
have begun to explore the possibility that olanzapine may help with this patient
group. Initial reports were largely from pilot studies, including case series, but
data are now emerging from small controlled trials.
In an open-label trial, 17 patients hospitalized for anorexia nervosa were given
olanzapine in conjunction with concurrent cognitive-behavioral therapy (CBT)
and DBT group treatment (Barbarich et al. 2004). Olanzapine was initiated at a
dosage of 1.25–5.00 mg/day, with upward titration as needed, balancing sedation
and side effects against efficacy. Although patients showed improvement in
weight as well as in Beck Depression Inventory (BDI) and Spielberger State-
Trait Anxiety Inventory (STAI) scores, the lack of a control group limited the
validity of these results (Barbarich et al. 2004). A trial of 15 women with
anorexia nervosa randomly assigned to either olanzapine or chlorpromazine in a
balanced block design found that olanzapine reduced anorexic ruminations (as
measured by the impaired control over mental activities subscale of the Padua
Inventory). There was no difference in weight gain between the two groups.
However, this study was somewhat limited by its lack of blinding (Mondraty et
al. 2005). A case series evaluating low-dosage olanzapine treatment in 13
adolescent girls with restricting-type anorexia nervosa (Leggero et al. 2010)
found improvements in weight and reductions in hyperactivity in the 7 girls who
were olanzapine responders (defined as improvement of at least 50% in Eating
Attitudes Test–26 scores).
Results of randomized double-blind, placebo-controlled trials have been
mixed. In a 10-week trial of 34 women with anorexia nervosa, Bissada et al.
(2008) found significant increases in weight and reductions in obsessive
symptoms among those treated with olanzapine. Similarly, in an 8-week study of
23 outpatient women with anorexia nervosa, end-of-treatment body mass index
was greater in women receiving olanzapine as compared with placebo.
Psychological symptoms improved equally in both groups (Attia et al. 2011).
However, a trial of olanzapine versus placebo in 20 adolescent girls with
anorexia found no difference in median body weight from baseline at either
week 5 or week 10. The two groups showed similar improvements in eating
attitudes, psychological functioning, and resting energy expenditure (Kafantaris
et al. 2011). A planned fourth clinical trial of adolescent girls was discontinued
owing to inability to adequately recruit subjects, primarily because potential
subjects did not meet study criteria (71% of those screened) and eligible subjects
declined participation due to concerns about medication use (74% of those
eligible) (Norris et al. 2010).
Given that weight gain is a prominent side effect of olanzapine, studies have
begun to examine the mechanisms underlying this effect and the possibility that
olanzapine might be useful as a weight-gain agent. In a double-blind, placebo-
controlled trial investigating whether olanzapine might induce weight gain
through modulation of ghrelin and leptin (hormones associated with satiety),
patients with anorexia received olanzapine concurrently with CBT, with levels of
ghrelin and leptin assessed over 3 months. Although both the olanzapine patients
and the placebo patients gained weight, there was no statistical difference
between the groups in amount of weight gained or in leptin or ghrelin levels,
which remained unchanged over the course of the study (Brambilla et al. 2007).
The role of olanzapine as an augmentation to psychotherapy in anorexia
nervosa is limited as best. The majority of studies using the most rigorous
methods did not find psychological improvement for patients after olanzapine
augmentation. However, in patients for whom timely weight gain is medically
imperative, there may be a limited role for olanzapine. Trials have been small,
with mixed results; further research is required to clarify the potential benefits
and risks for patients.
Safety in Overdose
Reviews of case series and reports of olanzapine toxicity in adults describe
predominantly circulatory and central nervous system effects, including coma,
psychomotor agitation, hypertension and hypotension, tachycardia and
bradycardia, hyperthermia and hypothermia, miosis and mydriasis, and QTC
prolongation (QTC prolongation only with >1,040-mg ingestion and in mixed
overdoses) (Ciszowski et al. 2011; Tan et al. 2009). Olanzapine overdose was
rarely fatal in the aforementioned case reports, and a systematic study of second-
generation antipsychotic overdose found that of 422 olanzapine overdoses, there
were no fatalities and 14% required ventilation (Berling et al. 2016). There are
very few data describing olanzapine overdose in children. Available case report
data are consistent with adult presentations of EPS and elevated prolactin levels
(Tanoshima et al. 2013) and circulatory and neurological symptoms (McAllister
et al. 2012; Singh et al. 2012; Theisen et al. 2005).
Use in Pregnancy
Exposure to second-generation antipsychotics was associated with gestational
diabetes in a Swedish birth cohort study (Bodén et al. 2012). The risk was
similar for medications known to have severe anabolic effects (olanzapine and
clozapine) and other antipsychotic medications. Fetuses exposed to antipsychotic
medication in utero were more likely than those not exposed to be born small for
gestational age, but this association was not robust to adjustment for maternal
factors. Because of the difficulty in studying medication use during pregnancy,
data on antipsychotic use during pregnancy are extremely sparse. No specific
fetal abnormalities have been reported with olanzapine, although there is some
evidence suggesting an association between antipsychotic use in pregnancy and
neonatal respiratory distress and withdrawal symptoms (Kulkarni et al. 2015).
Further research is needed to aid clinicians in maximizing infant and maternal
well-being.
Drug–Drug Interactions
Olanzapine is metabolized primarily via glucuronidation and via oxidation by
CYP1A2 (see section “Pharmacokinetics and Disposition” earlier in this
chapter). Other drugs that affect the activity of these metabolic pathways would
therefore be expected to affect olanzapine pharmacokinetics. Indeed, drugs that
inhibit CYP1A2 activity have been shown to decrease olanzapine clearance,
thereby increasing olanzapine plasma concentrations.
Fluvoxamine, a known inhibitor of CYP1A2, has been shown to inhibit
olanzapine metabolism in several studies. In an 11-day study of 10 healthy male
smokers, coadministration of fluvoxamine (50–100 mg/day) with olanzapine
(2.5–7.5 mg/day for 8 days [beginning on day 4]) resulted in an 84% increase in
olanzapine peak serum concentrations (Cmax) and a 119% increase in AUC0–24
compared with placebo coadministered with olanzapine. No change in half-life
was observed in either olanzapine or 4′-N-desmethylolanzapine, suggesting that
fluvoxamine inhibited olanzapine’s first-pass metabolism (Maenpaa et al. 1997).
Fluoxetine and imipramine, although not known to be significant inhibitors of
CYP1A2, when coadministered with olanzapine have been associated with small
but statistically significant changes in olanzapine pharmacokinetics.
Coadministration of fluoxetine with olanzapine resulted in a 15% decrease in
olanzapine clearance and an 18% increase in Cmax, with no significant difference
in olanzapine half-life (Callaghan et al. 1999). Coadministration of imipramine
with olanzapine resulted in an approximately 14% increase in olanzapine Cmax
and a non–statistically significant increase in olanzapine AUC of 19%
(Callaghan et al. 1997).
Inducers of the CYP1A2 enzyme increase olanzapine clearance, thereby
decreasing olanzapine systemic exposure. Carbamazepine, an inducer of several
CYP enzymes (including 1A2), affects olanzapine disposition. A study in healthy
volunteers reported that a single 10-mg dose of olanzapine taken after 2 weeks
of pretreatment with carbamazepine (200 mg twice daily) had significantly
higher clearance and apparent volume of distribution—but significantly lower
Cmax, AUC, and half-life—compared with a single 10-mg dose taken before
carbamazepine pretreatment (Lucas et al. 1998).
Smoking, also known to induce CYP1A2, can affect olanzapine disposition. A
study comparing 19 male smokers with 30 male nonsmokers found that
olanzapine clearance in smokers was 23% higher than that in nonsmokers
(Callaghan et al. 1999). A population pharmacokinetic analysis of 910 patients
receiving olanzapine found that clearance among nonsmokers was 37% lower in
men and 48% lower in women than it was in the corresponding group of
smokers (Patel et al. 1996). A smaller analysis of healthy volunteers also found
higher drug clearances among smokers (Patel et al. 1995). The polycyclic
aromatic hydrocarbons in cigarette smoke are responsible for inducing the aryl
hydrocarbon hydroxylases, thereby leading to enzymatic induction (Desai et al.
2001). For this reason, dosage adjustments may be needed when a patient who
smokes is placed in a smoke-free inpatient unit, even if adequate nicotine
replacement is provided. Conversely, when there is a sudden increase in cigarette
consumption (often associated with stress or impending relapse), a dosage
increase may be needed to prevent an abrupt worsening of symptoms.
In vitro studies suggest that olanzapine does not significantly inhibit the
activity of CYP 1A2, 3A, 2D6, 2C9, or 2C19 (Ring et al. 1996a). In vivo studies
suggest that olanzapine does not affect the disposition of aminophylline (Macias
et al. 1998), diazepam, alcohol, imipramine (Callaghan et al. 1997), warfarin,
biperiden, or lithium (Callaghan et al. 1999; Demolle et al. 1995).
Conclusion
From review of the research focused on olanzapine, it is clear that this
compound, which has been approved for use in the United States since 1997, has
wide utility and some distinct advantages compared with traditional
antipsychotics. In addition to its positive effects on a broad group of symptoms
in schizophrenia, olanzapine is approved for the treatment of mania, both acute
and long term, in bipolar disorder. Recent research has shown that olanzapine
may be beneficial for disorders beyond psychosis (e.g., borderline personality
disorder, anorexia nervosa, PTSD, OCD). The extension of olanzapine’s uses is
in many ways made possible by its low rate of movement disorders.
Olanzapine’s low risk of dystonia, parkinsonism, and tardive dyskinesia has led
to its greater acceptability in chronic schizophrenia and has encouraged
clinicians to prescribe it for other conditions, although concerns about metabolic
side effects limit the drug’s overall utility.
As noted in the earlier section “Side Effects and Toxicology,” olanzapine is
not free of adverse effects. Weight gain and metabolic disturbances are of
significant concern and are the focus of intense research in both pathophysiology
and prevention/treatment. Because of these concerns, the FDA does not
recommend olanzapine as a first-line agent in young people.
In addition to providing better treatment for schizophrenia and other disorders,
olanzapine promotes actions in the brain that have revealed new directions for
research on the pathophysiological mechanisms underlying psychiatric disease.
As noted previously, investigation of olanzapine’s effects on glutamate,
neurotensin, neuregulin, and other neurotransmitters may improve our
understanding of the pathophysiology of these diseases and open new avenues of
treatment.
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CHAPTER 27
Quetiapine
Peter F. Buckley, M.D.
Adriana E. Foster, M.D.
Matthew Byerly, M.D.
Structure–Activity Relations
Quetiapine is an SGA of the dibenzothiazepine class (Figure 27–1). Its complex
neuropharmacology includes a relatively low binding profile for dopamine type
2 (D2) receptors (Kapur et al. 2000). Indeed, considering the idea that an
antipsychotic needs to occupy 60% or more of D2 receptors in order to be
clinically efficacious (Kapur et al. 2000), quetiapine’s low D2 binding—
typically, approximately 30%—is noteworthy.
Mood Disorders
There is evidence that quetiapine is an effective and well-tolerated antipsychotic
for treating patients with bipolar mania and bipolar depression. Bowden et al.
(2005) demonstrated that quetiapine was superior to placebo in the treatment of
mania. In this multicenter study, significantly more patients treated with
quetiapine than with placebo met criteria for response (greater than 50%
decrease from baseline score on the Young Mania Rating Scale) at 7, 21, and 84
days. Building on initial evidence for mood effects that was derived from
observations on mood assessment items in the pivotal schizophrenia trials, the
Quetiapine Experience with Safety and Tolerability (QUEST) study compared
quetiapine with risperidone in a 4-month open-label, flexible-dose trial (Mullen
et al. 2001). This study included patients with schizophrenia, schizoaffective
disorder, bipolar disorder, and depression. At week 16, the mean dosage of
quetiapine was 317 mg/day, and the mean dosage of risperidone was 4.5 mg/day.
Mean improvement on the Hamilton Rating Scale for Depression was
significantly greater in quetiapine recipients than in risperidone recipients.
Calabrese et al. (2005) and Thase et al. (2006) have studied quetiapine use in
patients with bipolar depression. In an 8-week trial, Calabrese et al. (2005)
compared two dosages of quetiapine (300 mg/day and 600 mg/day) with
placebo. Both dosages were efficacious, with improvements observed across the
full range of depressive and anxiety symptoms. Fifty-eight percent of patients
met a priori criteria for treatment response. Additionally, this antidepressant
effect was observed with a once-daily dosage regimen. In a subsequent similar
study (Thase et al. 2006) of the same two dosages (300 mg/day and 600
mg/day), quetiapine was again compared with placebo in an 8-week trial in
patients with bipolar depression. Again, both dosages of quetiapine showed
efficacy across a broad range of depressive symptoms. These two studies led to
FDA approval of quetiapine for treating bipolar depression.
Two large 8-week international multicenter studies—Efficacy of Monotherapy
Seroquel in BipOLar DEpressioN (EMBOLDEN) I (Young et al. 2010) and II
(McElroy et al. 2010)—compared quetiapine 300 mg/day and 600 mg/day with
lithium 600–1,800 mg/day and placebo (EMBOLDEN I) and with paroxetine 20
mg/day and placebo (EMBOLDEN II) in bipolar patients with a major
depressive episode. In the first study (Young et al. 2010), quetiapine at both
dosages, but not lithium, led to significant improvement in symptoms of
depression and anxiety. Compared with patients receiving placebo, patients
treated with quetiapine 300 mg/day and 600 mg/day showed significant
improvement on the Sheehan Disability Scale. In the second study (McElroy et
al. 2010), quetiapine 300 mg/day and 600 mg/day, but not paroxetine 20 mg/day,
led to significant improvement in depressive and anxiety symptoms. Neither
lithium nor paroxetine led to significant functional improvement over placebo in
these studies. In both studies, a small subgroup of patients with rapid-cycling
bipolar disorder did not improve significantly from baseline with any of the
drugs administered (quetiapine, lithium, or paroxetine).
In a long-term naturalistic study (Ketter et al. 2010) of quetiapine
administered to 96 patients with bipolar disorder in a clinical setting, 38.5% of
patients continued taking quetiapine for 328 days without the addition of other
psychotropics, whereas 22.9% of patients continued taking quetiapine for 613
days with the addition of another psychotropic, most often for depression. In a
small double-blind, placebo-controlled pilot study (DelBello et al. 2009) of
quetiapine 300–600 mg/day in depressed adolescents with bipolar disorder,
quetiapine neither differentiated from placebo nor induced significant change in
symptoms from baseline to endpoint on measures of depressive, anxiety, or
manic symptoms or clinical global impressions of bipolar severity. Bourin et al.
(2014) reported superior efficacy when lithium was added to quetiapine XR, and
this combination was well tolerated.
Dorée et al. (2007) reported that in a pilot study (n=20), quetiapine was an
efficacious augmenting agent for antidepressant treatment in major depression.
Anderson et al. (2009) also reported on quetiapine’s efficacy as an adjunctive
treatment for patients with refractory depression. Quetiapine XR monotherapy at
a mean daily dosage of 162.2 mg was shown to decrease symptoms of major
depression at 8 weeks versus placebo (Bortnick et al. 2011). Cutler et al. (2009)
reported that quetiapine XR 300 mg/day led to significantly higher rates of
response and remission versus placebo in major depression, whereas quetiapine
XR 150 mg/day had a significant effect only on response versus placebo.
Quetiapine at dosages of 150–300 mg/day is now approved by the FDA as an
adjunct to antidepressant treatment for a major depressive episode. In one of the
studies leading to FDA approval of quetiapine XR for this indication, El-Khalili
et al. (2010) demonstrated that quetiapine XR at 300 mg/day led to significant
improvement in symptoms of depression from the first week of treatment when
compared with placebo. In a review of registration studies for the major
depression indication, McIntyre et al. (2009) concluded that quetiapine XR
provides rapid and sustained relief of major depressive symptoms. Weisler et al.
(2012) also reported substantial improvement in depressive symptoms in two 6-
week clinical trials of quetiapine XR. Remission at 6 weeks was achieved by
23.5% of patients taking 150 mg/day and by 28.8% of patients taking 300
mg/day of quetiapine. Lin et al. (2014) used a national insurance database from
Taiwan to compare in a mirror image design the effect of augmentation of
antidepressant therapy over 1 year in patients with major depressive disorder.
Quetiapine, olanzapine, and aripiprazole augmentations were each effective in
reducing health care utilization. Masi et al. (2015) reported improvement from
and tolerability of quetiapine in a small open-label study comparing quetiapine
and risperidone in adolescents with bipolar disorder and comorbid conduct
disorder.
Anxiety Disorders
The sedative/calming effect of quetiapine was well described in a variety of
product registration trials (Chengappa et al. 2003a; Weiden et al. 2006), and
studies in bipolar I disorder and bipolar depression (Calabrese et al. 2005;
Hirschfeld et al. 2006; Thase et al. 2006) demonstrated improvements in anxiety
symptoms with quetiapine.
In a small 8-week study (Vaishnavi et al. 2007) of social phobia treatment,
there was no significant difference in Brief Social Phobia Scale scores between
the quetiapine and placebo groups, although people who took quetiapine did
show a robust response as measured by Clinical Global Impression—
Improvement Scale (CGI-I) scores.
Two small studies of quetiapine augmentation in patients with generalized
anxiety disorder (GAD) who had not responded to antidepressant therapy
(Katzman et al. 2008; Simon et al. 2008) yielded contradictory results. A large
double-blind, randomized, placebo-controlled study of monotherapy for GAD
(Bandelow et al. 2010) compared quetiapine XR 50 mg/day or 150 mg/day,
paroxetine 20 mg/day, and placebo. Significant separation from placebo on the
primary outcome variable (mean reduction in Hamilton Anxiety Scale (Ham-A)
total score) was seen for quetiapine XR 50 mg/day and 150 mg/day as early as 4
days into treatment, but not for paroxetine. After 8 weeks of treatment, both
quetiapine 150 mg/day and paroxetine 20 mg/day had higher anxiety remission
rates (Ham-A score ≤7) compared with placebo. Weight gain greater than or
equal to 7% of body weight was noted in a higher percentage of patients treated
with quetiapine than of those taking placebo. In a parallel-group, double-blind,
placebo-controlled study by Katzman et al. (2011), 432 patients with GAD were
randomly assigned to continue treatment long term with quetiapine XR (50
mg/day, 150 mg/day, or 300 mg/day) or to switch to placebo after an open-label
run-in and stabilization period. During the randomized treatment period (from
the point of random assignment to the end of the study), quetiapine XR
significantly increased the time to occurrence of an anxiety event and decreased
anxiety symptoms compared with placebo.
An analysis of the tolerability of quetiapine in patients with various disorders
showed that patients with GAD, bipolar depression, or refractory major
depression had significantly higher rates of discontinuation due to adverse
effects versus placebo than did patients with schizophrenia or mania when
treated with quetiapine XR dosages of ≥300 mg/day (Wang et al. 2011). In a
systematic review and meta-analysis of all available trials of SGA medications,
quetiapine was observed to have the most robust effect on anxiety symptoms
(LaLonde and Van Lieshout 2011). The antianxiety effects of quetiapine were
observed at lower dosages (typically 150 mg/day) than those used in
schizophrenia studies, and the effects included overall improvement as well as
remission. However, quetiapine was also associated with weight gain and high
rates of medication discontinuation in these studies of anxiety disorder (LaLonde
and Van Lieshout 2011). In three 8-week studies of quetiapine XR, Stein et al.
(2011) reported rates of study discontinuation due to side effects of 13%, 16%,
and 24% for quetiapine dosages of 50 mg/day, 150 mg/day, and 300 mg/day,
respectively. In an 8-week placebo-controlled comparative trial of quetiapine XR
and escitalopram, comparable improvements in anxiety symptoms, occurring
early in the study, were observed with quetiapine and escitalopram (Merideth et
al. 2012). In a more “real-world” population of patients with bipolar depression
with substantial comorbidities (especially GAD), quetiapine XR showed no
advantages over placebo in an 8-week trial (Gao et al. 2014).
At present, the FDA has not approved quetiapine for use in any anxiety
disorders.
Other Disorders
Several small studies of quetiapine augmentation (at dosages up to 400 mg/day)
of SSRI pharmacotherapy in refractory OCD yielded contradictory results
(Atmaca et al. 2002; Carey et al. 2005; Fineberg et al. 2005); although
improvement in Yale-Brown Obsessive Compulsive Scale (Y-BOCS) scores was
noted in patients treated with quetiapine, the response to quetiapine did not
differentiate from placebo. Quetiapine’s efficacy as an augmenting agent with
antidepressants in treatment-resistant OCD was recently reviewed in a meta-
analysis of five double-blind randomized controlled trials (RCTs) (Komossa et
al. 2010). Adjunctive quetiapine was not superior to placebo in reducing Y-
BOCS scores by 25% (the criterion for response in these studies), but it did
reduce the Y-BOCS score significantly by the endpoint compared with placebo.
A small case series also showed that adjunctive quetiapine response may be
enduring (Dell’Osso et al. 2006). Veale et al. (2014) conducted a meta-analysis
of SGAs in OCD. In contrast to benefits seen with risperidone or aripiprazole,
there was no effect seen with augmentation with either quetiapine or olanzapine.
Quetiapine has been studied in the treatment of posttraumatic stress disorder
(Ahearn et al. 2006; Byers et al. 2010; Hamner et al. 2003; Kozaric-Kovacic and
Pivac 2007; Sokolski et al. 2003; Stathis et al. 2005). All but one of the studies
(Stathis et al. 2005) involved quetiapine being administered to veterans as an
adjunctive agent added to selective serotonin reuptake inhibitors (SSRIs), other
antidepressants, sedative–anxiolytics, or anticonvulsants. All were open-label
studies, and with the exception of a retrospective chart review comparing
quetiapine with the α1 receptor antagonist prazosin (Byers et al. 2010), none had
a comparison group. The average quetiapine dosage used in these studies was
100–335 mg/day administered for 6–8 weeks. Quetiapine decreased symptoms
of avoidance, hyperarousal, and recollection in the populations studied.
Metabolic Effects
There is major concern about antipsychotic-induced weight gain and metabolic
disturbances (Allison et al. 1999; Newcomer 2005; Newcomer et al. 2002).
Quetiapine is clearly associated with weight gain, although the weight gain
effect is not as great as that seen with clozapine or olanzapine. On the other
hand, the weight-effects profile of quetiapine is not as favorable as that of
ziprasidone or aripiprazole (Newcomer 2005) or that of the newer agents
asenapine and lurasidone (Allergan 2015; Sunovion 2013)
In the 8-week comparative study by Zhong et al. (2006), weight gain that was
clinically significant (a 7% increase above baseline weight) was observed in
10.4% of patients taking quetiapine and in 10.5% of patients taking risperidone.
In the Phase I CATIE study, quetiapine had a moderate effect on weight (and
other aspects of the metabolic profile) compared with other agents (Lieberman et
al. 2005). Those data are shown in Table 27–2. In the first-episode CAFE study,
quetiapine had a less favorable weight-effects profile compared with olanzapine
or risperidone. Eighty percent of patients taking quetiapine gained weight,
compared with 50% of those taking olanzapine and 2% of those taking
risperidone. Interestingly, females taking quetiapine were less likely than males
to gain weight in this 1-year study of patients treated for their first episode of
psychosis (Patel et al. 2009). It is also important to consider quetiapine’s
propensity to induce weight gain among bipolar patients (especially because
these patients may also be taking lithium or valproic acid). In the 8-week
EMBOLDEN I (Young et al. 2010) and EMBOLDEN II (McElroy et al. 2010)
trials, weight gain of more than 7% body weight was present in 4.6% and 9%,
respectively, of patients taking quetiapine 300 mg/day versus 8.3% and 11.3%,
respectively, of those taking quetiapine 600 mg/day. In EMBOLDEN I and
EMBOLDEN II, the average weight gains in quetiapine-treated patients were 0.6
kg and 1.1 kg, respectively, for the 300-mg/day groups and 0.8 kg and 1.7 kg,
respectively, for the 600-mg/day groups.
TABLE 27–2. Comparative metabolic profiles of antipsychotics in the Phase I C
schizophrenia trial: change from baseline
OlanzapineQuetiapinePerphenazineRisperidone Ziprasidone
Weight gain 92/307 49/305 29/243 (12) 42/300 (14) 12/161 (7)
>7%, n/total (30) (16)
N (%)
Weight change 9.4±0.9 1.1±0.9 −2.0±1.10 0.8±0.9 −1.6±1.10
(lb), mean
±SE
Blood glucose 13.7±2.50 7.5±2.5 5.4±2.8 6.6±2.5 2.9±3.4
change
(mg/dL),
exposure-
adjusted
mean±SE
Glycosylated 0.40±0.07 0.04±0.08 0.09±0.09 0.07±0.08 0.11±0.09
Hb (%),
exposure-
adjusted
mean±SE
Cholesterol 9.4±2.4 6.6±2.4 1.5±2.7 −1.3±2.40 −8.2±3.20
(mg/dL),
exposure-
adjusted
mean±SE
Triglycerides 40.5±8.90 21.2±9.20 9.2±10.1 −2.4±9.10 −16.5±12.20
(mg/dL),
exposure-
adjusted
mean±SE
Note. Hb=hemoglobin; SE=standard error. P values for laboratory values and for the cha
weight are based on ranked analysis of covariance with adjustment for whether patient
exacerbation in the preceding 3 months and the duration of exposure to the study drug in P
Mean values for metabolic factors (other than weight change) were also adjusted for dura
exposure to study drug.
Source. Adapted from Lieberman et al. 2005.
In the bipolar depression study by Calabrese et al. (2005), the mean changes
in glucose levels were 6 mg/dL and 3 mg/dL with quetiapine dosages of 600
mg/day and 300 mg/day, respectively. In the comparative study of quetiapine and
risperidone in the treatment of schizophrenia (Zhong et al. 2006), the mean
changes from baseline in fasting glucose levels were 1.8 mg/dL with quetiapine
and 5.6 mg/dL with risperidone. The metabolic profile of quetiapine appeared
moderate in the Phase I CATIE schizophrenia study (see Table 27–2). Newcomer
et al. (2009) conducted a euglycemic clamp study of quetiapine and found little
evidence of insulin insensitivity. A recent meta-analysis by the Cochrane group
involving head-to-head comparisons of SGAs (Komossa et al. 2010) found that
quetiapine was associated with significantly greater cholesterol elevations than
risperidone (mean difference 8.61 mg/dL) and ziprasidone (mean difference
16.01 mg/dL). In the CATIE Phase I trial (Lieberman et al. 2005), which
included patients with chronic schizophrenia, quetiapine led to a mean change
from baseline fasting triglyceride levels of +19.2 mg/dL, whereas a mean change
of +42.9 mg/dL was observed for olanzapine, +8.3 mg/dL for perphenazine, −2.6
mg/dL for risperidone, and −18.1 mg/dL for ziprasidone. In a population of
young patients with early psychosis treated with quetiapine, olanzapine, or
risperidone, the CAFE study (Patel et al. 2009) found that elevations in fasting
triglyceride levels at 52 weeks were significantly greater in quetiapine-treated
patients than in risperidone-treated patients (44.3 vs. 8.2 ng/mL, respectively).
Correll et al. (2014) reported baseline results from the pragmatic study Recovery
After an Initial Schizophrenia Episode (RAISE). All patients were in their first
episode of psychosis, with less than 6 months of exposure to antipsychotics. Use
of quetiapine was associated with a high ratio of triglycerides to high-density
lipoprotein (HDL) cholesterol. The extent to which patients traverse during
treatment from a normative metabolic state to dysregulation is also informative.
In the first-episode CAFE study, treatment-emergent metabolic syndrome was
observed among 51 patients (13.4% of the population in a study where 4.3% met
metabolic syndrome criteria at study onset), with a distribution of 22 patients
taking olanzapine, 18 taking quetiapine, and 11 taking risperidone (Patel et al.
2009). Another recent study of antipsychotic use in adolescents found an
elevated risk of type 2 diabetes mellitus, with longer duration of antipsychotic
exposure and olanzapine use conferring greater risk (Correll et al. 2014). In
another first-episode comparative study, Pérez-Iglesias et al. (2014) found that
first-episode patients treated with quetiapine, aripiprazole, or ziprasidone gained
weight over 12 weeks of treatment, with >7% weight increase noted for 32% of
patients receiving quetiapine, 45% of those receiving aripiprazole, and 23% of
those receiving ziprasidone. Quetiapine and aripiprazole were also associated
with greater increases in total cholesterol and low-density lipoprotein (LDL)
cholesterol. Overall, quetiapine appears to carry a risk of causing weight gain
and other metabolic disturbances. The potential that quetiapine may
preferentially raise triglycerides is noteworthy, given that this effect could be a
harbinger for later insulin resistance. This observation merits further
consideration and vigilance over time.
Quetiapine is associated with a low risk of raising prolactin levels (Hamner et
al. 1996; Lieberman et al. 2005; Small et al. 1997; Zhong et al. 2006).
Cardiovascular Effects
Quetiapine’s prescribing information (AstraZeneca 2013a, 2013b) carries a
warning similar to that required in the prescribing information of many other
antipsychotics concerning cardiovascular risks. The CATIE trial found no
evidence of a heightened QTc risk with quetiapine relative to other SGAs and
perphenazine (Lieberman et al. 2005). A curious and unsubstantiated claim is
that quetiapine might have abuse potential (Pierre et al. 2005; Pinta and Taylor
2007). This observation merits further consideration and vigilance.
Other Effects
The potential of quetiapine to induce cataracts was studied in a pragmatic
follow-up trial of patients (N=37; mean age 23 years) with first-episode
psychosis that included regular slit-lamp ophthalmological examinations
(Whitehorn et al. 2004). After exposure to quetiapine 500–600 mg/day for a
mean of 22.4 months, none of the patients developed any ocular changes. Most
clinicians do not obtain specialist eye examinations when prescribing quetiapine.
Abnormalities in thyroid hormone levels were observed in the large
premarketing trials of quetiapine (Arvanitis and Miller 1997). A small RCT did
find lower total thyroid hormone levels with quetiapine use, but no significant
changes in free thyroxine (T4) or thyroid-stimulating hormone (TSH) levels
(Kelly and Conley 2005).
Conclusion
Quetiapine is now a well-established and widely prescribed antipsychotic. As
detailed earlier, there is strong evidence for its efficacy in all of the current FDA-
approved indications. Quetiapine is also used extensively under circumstances
not approved by the FDA (i.e., off-label use), and evidence for its efficacy in
some of these uses has been reviewed in this chapter. Additional clinical trials of
quetiapine are ongoing (https.clinicaltrials.gov).
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CHAPTER 28
Pharmacological Profile
Risperidone, or 3-[2-(4-[6-fluoro-1,2-benzisoxazol-3-yl]-1-
piperidinyl)ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-
one, is a benzisoxazole derivative characterized by very high affinity for 5-HT2A
receptors and moderately high affinity for D2, histamine 1 (H1), and α1- and α2-
adrenergic receptors (Figure 28–1). In vitro, the affinity of risperidone for 5-
HT2A receptors is roughly 10- to 20-fold greater than that for D2 receptors
(Leysen et al. 1994; Schotte et al. 1996); in vivo binding to rat striatal D2
receptors occurs at a dosage 10 times higher than does binding to 5-HT2A
receptors (Leysen et al. 1994). The affinity for 5-HT2A receptors is more than
100-fold greater than for other serotonin receptor subtypes. Risperidone’s active
metabolite 9-hydroxyrisperidone (paliperidone) (Figure 28–2) has a similar
receptor affinity profile, although paliperidone has lower affinity for α1- and α2-
adrenergic receptors. Both risperidone and paliperidone display a high affinity
for 5-HT2A receptors in rat brain tissue and for cloned human receptors
expressed in COS-7 cells (Leysen et al. 1994). Risperidone binds to 5-HT2A
receptors with approximately 20-fold greater affinity compared with clozapine
and 170-fold greater affinity compared with haloperidol (Leysen et al. 1994).
Mechanism of Action
As previously discussed, risperidone was developed specifically to exploit the
apparent pharmacological advantages of combining 5-HT2 receptor antagonism
with D2 receptor blockade. Selective 5-HT2A receptor antagonists administered
alone have demonstrated activity in several animal models suggestive of
antipsychotic effect, including blockade of both amphetamine- and
phencyclidine (PCP)-induced locomotor activity (Schmidt et al. 1995).
Dizocilpine-induced disruption of prepulse inhibition is also blocked by 5-HT2A
receptor antagonists, suggesting that sensory gating deficits characteristic of
schizophrenia and perhaps resulting from glutamatergic dysregulation might also
benefit from the 5-HT2 receptor antagonism of risperidone (Varty et al. 1999).
The disruption of prepulse inhibition by dizocilpine (MK-801, a noncompetitive
N-methyl-D-aspartate [NMDA] receptor antagonist) is attenuated by SGAs, but
not by first-generation D2 receptor blockers (Geyer et al. 1990). From a study in
which the selective 5-HT2A receptor antagonist M100907 was added to low-dose
raclopride (a selective D2 receptor blocker), Wadenberg et al. (1998) concluded
that 5-HT2A antagonism facilitates D2 receptor antagonist blockade of
conditioned avoidance, another behavioral model associated with antipsychotic
efficacy, but does not block conditioned avoidance when administered alone.
One mechanism by which risperidone, paliperidone, and similar atypical
agents might produce enhanced efficacy for negative symptoms and cognitive
deficits and reduced risk for EPS is via 5-HT2A receptor modulation of
dopamine neuronal firing and cortical dopamine release. Prefrontal
dopaminergic hypoactivity has been postulated to underlie negative symptoms
and cognitive deficits in schizophrenia (Goff and Evins 1998); both clozapine
and ritanserin have been shown to increase dopamine release in prefrontal
cortex, whereas haloperidol does not (Busatto and Kerwin 1997). Following 21
days of administration, risperidone, but not haloperidol, continued to increase
dopamine turnover in the dorsal striatum and prefrontal cortex (Stathis et al.
1996). Ritanserin has been shown to enhance midbrain dopamine cell firing by
blocking a tonic inhibitory serotonin input (Ugedo et al. 1989). Ritanserin also
normalized ventral tegmental dopamine neuron firing patterns in rats after
hypofrontality was induced by experimental cooling of the frontal cortex
(Svensson et al. 1989).
Svensson et al. (1995) performed a series of elegant studies examining the
impact of atypical antipsychotics on ventral tegmental dopamine firing patterns
disrupted by glutamatergic NMDA receptor antagonists. In healthy human
subjects, administration of the NMDA antagonist ketamine is widely regarded as
a promising model for several clinical aspects of schizophrenia, including
psychosis, negative symptoms, and cognitive deficits (Goff and Coyle 2001;
Krystal et al. 1994). In rats, administration of the NMDA channel blockers
dizocilpine or PCP increased burst firing of ventral tegmental dopamine neurons
predominantly projecting to limbic structures but reduced firing of mesocortical
tract dopamine neurons and disrupted firing patterns. Administration of
ritanserin or clozapine preferentially enhanced firing of dopamine neurons with
cortical projections, and when added to a D2 blocker, ritanserin increased
dopamine release in prefrontal cortex. In addition to modulating ventral
tegmental dopamine neuron firing, risperidone also blocks 5-HT2 receptors on
inhibitory γ-aminobutyric acid (GABA)-ergic interneurons, which could also
influence activity of cortical pyramidal neurons that are regulated by these local
inhibitory circuits (Gellman and Aghajanian 1994).
In placebo-controlled clinical trials, 5-HT2 receptor antagonists have shown
efficacy in reducing antipsychotic-induced parkinsonism and akathisia
(Duinkerke et al. 1993; Poyurovsky et al. 1999). This effect may reflect 5-HT2A
antagonist effects on nigrostriatal dopamine release. When combined with
haloperidol, selective 5-HT2 receptor antagonists increase dopamine metabolism
in the striatum and prevent an increase in D2 receptor density, thereby possibly
reducing the effects of D2 receptor blockade and dopamine supersensitivity
(Saller et al. 1990). These agents do not affect dopamine metabolism in the
absence of D2 blockade.
The relative importance of 5-HT2 receptor antagonist activity in producing
atypical characteristics is the subject of debate. As argued by Kapur and Seeman
(2001) and Seeman (2002), most SGAs have dissociation constants for the D2
receptor that are larger than the dissociation constant of dopamine. This “loose
binding” to the D2 receptor may allow displacement by endogenous dopamine
and may contribute to a reduced liability for EPS and hyperprolactinemia.
Unique among atypical agents, risperidone is “tightly bound” to the D2 receptor,
with a dissociation constant smaller than that of dopamine (Seeman 2002). A
model for atypical antipsychotic mechanisms that emphasizes D2 dissociation
constants would predict that the apparent atypicality of risperidone, compared
with that of haloperidol, reflects the reduced D2 receptor occupancy achieved by
more favorable dosing rather than the intrinsic pharmacological characteristics
of risperidone. According to some binding data, a comparable clinical dosage of
haloperidol would be approximately 4 mg/day, rather than 20 mg/day as used in
the North American multicenter registration trial (Kapur et al. 1999). Consistent
with this view, benefits of risperidone for negative symptoms and EPS were less
apparent when compared with lower doses of haloperidol or with lower-potency
FGAs (see “Indications and Efficacy” section later in this chapter) than when
compared with high-dose haloperidol (20 mg/day).
An additional mechanism possibly contributing to the enhanced efficacy of
risperidone and paliperidone is their considerable α-adrenergic receptor
antagonism. In a placebo-controlled augmentation trial, Litman et al. (1996)
demonstrated significant improvement in psychosis and negative symptoms with
the α2-adrenergic receptor antagonist idazoxan when it was added to FGAs.
Idazoxan has been shown to increase dopamine levels in the rat medial
prefrontal cortex (Hertel et al. 1999). In aged rats (Haapalinna et al. 2000) and in
patients with frontal dementias (Coull et al. 1996), α2-adrenergic receptor
blockers have also been reported to improve cognitive functioning. Svensson et
al. (1995) found that prazosin, an α1 receptor antagonist, inhibited both the
behavioral activation and the increase in mesolimbic dopamine release produced
by PCP or MK-801.
In summary, risperidone and paliperidone possess at least two mechanisms
that may confer atypical characteristics. 5-HT2A receptor antagonism partially
protects against D2 antagonist–induced neurological side effects and may
improve negative symptoms and cognitive functioning via modulation of
mesocortical dopamine activity. In addition, blockade of adrenoceptors may
further increase prefrontal cortical activity and could enhance antipsychotic
efficacy by modulation of mesolimbic dopamine activity. Unlike other SGA
agents, risperidone and paliperidone do not differ from FGAs in their
dissociation constant for the D2 receptor; this feature perhaps accounts for the
risk of EPS at high doses, as well as their greater propensity to cause
hyperprolactinemia.
Schizophrenia
Clinical Trial Results for Risperidone
TABLE 28–2. Effect sizes on Positive and Negative Syndrome Scale (PANSS) sy
dimensions: North American trials (N=513)
Adjusted mean change scores
When risperidone (1, 4, 8, 12, and 16 mg/day) was compared with haloperidol
(10 mg/day) in a large 8-week European trial involving 1,362 subjects with
schizophrenia (Peuskens 1995), PANSS subscale change scores among
risperidone-treated subjects indicated a preferential response to daily doses of 4
mg and 8 mg. However, neither the risperidone group taken as a whole nor
individual risperidone doses achieved significantly better outcomes than
haloperidol (10 mg/day) on any measure except for EPS, suggesting that the
clinical superiority of risperidone over haloperidol in previous studies may have
resulted from excessively high dosing of the comparator.
Mood Disorders
Six controlled trials of 3–4 weeks’ duration that included a total of 1,343 patients
have examined the efficacy of risperidone as monotherapy or in combination
with a mood stabilizer for the acute treatment of bipolar mania (Rendell et al.
2006). As monotherapy and in combination, risperidone was more effective than
placebo and similar in efficacy to haloperidol but produced more weight gain
and fewer EPS (Rendell et al. 2006). In a placebo-controlled trial of open-label
risperidone LAI microspheres in the maintenance treatment of bipolar I disorder,
patients (n=303) with manic or mixed episodes who maintained response during
a preceding 26-week period of risperidone following an initial 3-week period of
oral risperidone were randomly allocated to placebo injections or continued
treatment with LAI risperidone for up to 24 months. A switch to placebo
injections significantly shortened the time to recurrence of manic episodes, but
not depressive episodes (Quiroz et al. 2010).
Risperidone 1–2 mg/day was evaluated as an adjunct to antidepressant therapy
in a 4-week placebo-controlled trial in 174 antidepressant-resistant patients with
major depressive disorder recruited from 19 primary care and psychiatric centers
(Mahmoud et al. 2007). Risperidone significantly lowered ratings of depressive
symptoms compared with placebo. Remission rates were 25% with risperidone
versus 11% with placebo (P=0.004). Risperidone was well tolerated, with an
81% completion rate (vs. 88% with placebo).
Other Disorders
Generalized Anxiety Disorder
In a 4-week placebo-controlled add-on trial of low-dose risperidone in 417
patients with persistence of generalized anxiety disorder symptoms despite 8
weeks of anxiolytic therapy, no benefit from risperidone was found in the
primary analysis; however, risperidone was associated with greater improvement
in patients with moderate or severe anxiety at baseline (Pandina et al. 2007).
Risperidone was highly effective for obsessive-compulsive disorder symptoms
in a 6-week placebo-controlled trial in 36 adults prospectively confirmed to be
nonresponsive to treatment with a selective serotonin reuptake inhibitor
(McDougle et al. 2000). Symptoms of anxiety and depression also responded to
risperidone compared with placebo. Fifty percent of risperidone-treated patients
responded (mean dosage 2.2 mg/day), compared with none in the placebo group.
Alzheimer’s Disease
In the CATIE–Alzheimer’s Disease (CATIE-AD) study, risperidone had the
longest time to discontinuation due to lack of effectiveness (27 weeks) among
the agents studied; comparison results were 22 weeks for olanzapine, 9 weeks
for quetiapine, and 9 weeks for placebo (Schneider et al. 2006). However,
because of poor tolerability, none of the three antipsychotics differed from
placebo on time to all-cause discontinuation.
Metabolic Effects
Weight gain with risperidone is intermediate—that is, the degree of weight gain
is between that associated with agents like molindone, amisulpride, and
ziprasidone, which appear to be relatively weight neutral, and that associated
with agents like clozapine, olanzapine, and low-potency phenothiazines
(Rummel-Kluge et al. 2010; Sikich et al. 2008). In a meta-analysis of controlled
trials, Allison et al. (1999), using a random effects model, estimated the mean
weight gain at 10 weeks with risperidone to be 2.0 kg, compared with 0.5 kg
with haloperidol, 3.5 kg with olanzapine, and 4.0 kg with clozapine. In the
CATIE, in which risperidone had the lowest rate of discontinuation due to side
effects, risperidone treatment was associated with a mean monthly weight gain
of 0.4 lb, olanzapine with 2.0 lbs, and quetiapine with 0.5 lb; by contrast,
perphenazine and ziprasidone were associated with a mean monthly weight loss
of 0.2 lb and 0.3 lb, respectively (Lieberman et al. 2005). Although determining
the risk for hyperglycemia is complex, and results of studies have not been
completely consistent, it appears that risperidone does not produce insulin
resistance to the degree associated with olanzapine and clozapine (American
Diabetes Association et al. 2004; Henderson et al. 2006; Lieberman et al. 2005).
A meta-analysis of head-to-head comparisons of SGAs found that risperidone
produced more cholesterol elevation than aripiprazole and ziprasidone and less
elevation than olanzapine and quetiapine (Rummel-Kluge et al. 2010). Metabolic
side effects in children tend to be more severe than those in adults; for example,
in one study of pediatric patients younger than 20 years, risperidone produced a
mean weight gain of 5.3 kg (11.7 lb) over the 12-week treatment period (Correll
et al. 2009). Metabolic side effects with paliperidone appear to be similar to
those with risperidone.
Hyperprolactinemia
Unlike other SGA agents, risperidone and paliperidone substantially increase
serum prolactin levels—in some studies, to a greater degree than does
haloperidol (Kearns et al. 2000; Markianos et al. 1999)—although prolactin
levels may decrease over time (Eberhard et al. 2007; Findling et al. 2003). The
relationship between serum prolactin concentrations and clinical side effects
remains somewhat unclear, however. Kleinberg et al. (1999) analyzed combined
results from the North American and European multicenter registration trials,
which included plasma prolactin concentrations from 841 patients and clinical
ratings of symptoms associated with hyperprolactinemia from 1,884 patients.
Mean prolactin levels significantly correlated with risperidone dosage;
risperidone 6 mg/day produced elevations roughly comparable to those seen with
haloperidol 20 mg/day and significantly higher than those seen with haloperidol
10 mg/day. The combined incidence of amenorrhea and galactorrhea in women,
which varied between 8% and 12%, was similar for all dosages of risperidone
and haloperidol (10 mg/day). Because symptom frequencies were available only
for 14 women treated with placebo, comparisons with placebo were not
informative. Sexual dysfunction or gynecomastia occurred in 15% of men
treated with risperidone (4–6 mg/day), compared with 14% of men treated with
haloperidol (10 mg/day) and 8% of men in the placebo group. Compared with
placebo, ejaculatory dysfunction was significantly more frequent only in the
group treated with risperidone (12–16 mg/day). Mean plasma prolactin levels
were not significantly related to clinical side effects for either men or women.
Decreased libido also did not differ between treatment groups and did not
correlate with plasma prolactin levels. In the CATIE, prolactin levels increased
by a mean of 15.4 ng/mL with risperidone, compared with a 0.4-ng/mL mean
elevation with perphenazine and decreases of 4.5–9.3 ng/mL with the other
SGAs (Lieberman et al. 2005). Despite having significantly higher serum
prolactin concentrations, patients treated with risperidone did not report
significantly higher rates of sexual dysfunction, gynecomastia, galactorrhea, or
irregular menses.
Two reports of clinical trials with extended-release paliperidone have
indicated low levels of prolactin-related side effects (1% and 4%) (Kane et al.
2007; Kramer et al. 2007). However, in the one publication that reported
prolactin levels, substantial increases in mean plasma prolactin concentrations
were observed (males: 17.4 ng/mL at baseline to 45.3 ng/mL at week 6; females:
38.0 ng/mL to 124.5 ng/mL) (Kane et al. 2007). A 13-week comparison of
paliperidone palmitate with risperidone microspheres reported that paliperidone
palmitate was associated with moderately higher elevations from baseline in
prolactin levels compared with risperidone (women: 21.8 vs. 15.6 ng/mL; men:
9.4 vs. 6.0 ng/mL) (Pandina et al. 2011); however, another study found that the
proportion of patients with abnormally elevated prolactin levels was higher in
the group receiving LAI risperidone than in that receiving paliperidone palmitate
(Fleischhacker et al. 2012). Two preliminary studies with risperidone found that
plasma prolactin concentrations correlated with 9-hydroxyrisperidone
(paliperidone) concentrations and not with risperidone concentrations
(Melkersson 2006; Troost et al. 2007). The ratio of 9-hydroxyrisperidone levels
to risperidone levels also correlated with prolactin concentration (Troost et al.
2007); in agreement with this finding, rapid metabolizers of CYP2D6 were
found to have higher prolactin concentrations than poor metabolizers (Troost et
al. 2007).
Cardiovascular Effects
Because of relatively high affinities for adrenoreceptors, risperidone would be
expected to produce orthostatic hypotension. However, by following a 3- to 7-
day dosage escalation schedule, initial postural hypotension and tachycardia
have been avoided in clinical trials, with only rare cases of hypotension and
syncope reported (Chouinard et al. 1993; Marder and Meibach 1994).
Risperidone has very modest effects on cardiac conduction. No significant
prolongation of the QTc interval was detected at dosages of up to 25 mg/day in
early safety trials, and no relationship between QTc interval and risperidone dose
was apparent (Mesotten et al. 1989). In the CATIE, risperidone was associated
with the least QTc prolongation (mean 0.2 msec) and quetiapine with the most
(mean 5.9 msec), although differences were not statistically significant
(Lieberman et al. 2005). A mean QTc prolongation of 10 msec, measured after
peak absorption of risperidone (16 mg/day), was found in a study comparing
SGAs and FGAs, according to data filed with the FDA by Pfizer Inc. (Harrigan
et al. 2004). In a retrospective cohort study of Medicaid enrollees in Tennessee,
risperidone was associated with a 2.9-fold increase in rate of sudden cardiac
death, compared with a 1.61-fold increase with haloperidol and a 3.67-fold
increase with clozapine (Ray et al. 2009).
Drug–Drug Interactions
Because CYP2D6 status affects the half-life of risperidone and the relative ratio
of risperidone to 9-hydroxyrisperidone in plasma, the total serum concentration
of the “active moiety,” or the sum of the concentrations of risperidone and 9-
hydroxyrisperidone, may be significantly increased with addition of a CYP2D6
inhibitor (e.g., fluoxetine) in rapid metabolizers but not in poor metabolizers
(Bondolfi et al. 2002; Spina et al. 2002). In one study of 9 patients treated with
risperidone, addition of fluoxetine resulted in a 75% increase in blood levels of
the active moiety (risperidone+9-hydroxyrisperidone); two patients developed
parkinsonian side effects (Spina et al. 2002). Paliperidone plasma concentrations
are not influenced by CYP2D6 status, nor are paliperidone plasma
concentrations likely to be affected by drug–drug interactions. It has been
hypothesized that the addition of a CYP2D6 inhibitor (e.g., fluoxetine) could
decrease risperidone-induced prolactin elevation by increasing the ratio of
risperidone to 9-hydroxyrisperidone (Troost et al. 2007), although this has not
been rigorously tested.
Conclusion
Risperidone was the first antipsychotic agent developed specifically to exploit
the clinical advantages of combined D2 and 5-HTA2 receptor antagonism. α-
Adrenergic antagonism additionally may contribute to the antipsychotic and
cognition-enhancing effects of risperidone. Risperidone’s active metabolite,
paliperidone, is pharmacologically quite similar to the parent drug and comprises
roughly 80%–90% of the serum concentration of the active moiety (risperidone
+ paliperidone) in most patients treated with risperidone. Risperidone and
paliperidone are generally quite well tolerated, producing moderate weight gain
and mild sedation. Initial dosage titration is necessary to prevent orthostatic
blood pressure changes and dizziness, although this may be less necessary with
extended-release paliperidone. EPS are dose related and are typically less
common with risperidone than with haloperidol but more common with
risperidone compared with other SGAs. Risperidone and paliperidone markedly
elevate prolactin levels, although the relationship between plasma prolactin
concentrations and clinical symptoms is complex. The efficacy of risperidone
was initially established in comparison with high-dose haloperidol, against
which it was significantly more effective for all five symptom clusters derived
from the PANSS. However, the magnitude of difference in effect size was not
large for individual symptom clusters. In the CATIE, risperidone (at a mean
daily dosage of 3.9 mg) did not differ from perphenazine in rates of
discontinuation due to lack of effectiveness but was less effective than
olanzapine (Lieberman et al. 2005). The risperidone microspheres product was
the first FDA-approved SGA long-acting IM formulation, and paliperidone
palmitate was the first SGA depot formulation that could be administered at an
interval of every 4 weeks. PP3M is the first depot antipsychotic that can be
administered on a quarterly schedule. Overall, risperidone and paliperidone are
well-tolerated SGA agents with efficacy comparable to that of most other agents
in their class.
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CHAPTER 29
The serotonin hypothesis may explain why the atypical agents, which have
antagonist activity at 5-HT2A receptors, are associated with fewer EPS and do
not exacerbate (and, in fact, partially alleviate) negative symptoms and cognitive
impairment (Leysen et al. 1993; Millan 2000; Rao and Möller 1994; Richelson
1999).
On the basis of aripiprazole’s pharmacodynamic profile—partial agonist
activity (rather than full antagonist activity) at both dopaminergic (D2; Burris et
al. 2002) and serotonergic (5-HT1A; Jordan et al. 2002) receptors, and full
antagonist activity at 5-HT2A receptors (McQuade et al. 2002)—it was
anticipated that aripiprazole treatment would be associated with a reduced
burden of unwanted D2 antagonist activity in the mesocortical, nigrostriatal, and
tuberoinfundibular pathways—the activity associated with some of the side
effects of typical and atypical antipsychotic agents (Figure 29–2).
FIGURE 29–2. Dopamine (DA) partial agonist activity: effect on
positive symptoms, extrapyramidal side effects (EPS), and
prolactin levels.
Aripiprazole
Aripiprazole—7-{4-(4-[2,3-dichlorophenyl]-1-piperazinyl)butoxy}-3,4-
dihydrocarbostyril, a dihydroquinolinone (Figure 29–3)—exhibits potent partial
agonist activity at D2 (Burris et al. 2002) and 5-HT1A (Jordan et al. 2002)
receptors, together with potent antagonist activity at 5-HT2A receptors. It also
has high affinity for D3 receptors; moderate affinity for dopamine4 (D4),
serotonin2C (5-HT2C), serotonin7 (5-HT7), α1-adrenergic, and histamine1 (H1)
receptors and the serotonin transporter (SERT); and negligible affinity for
cholinergic muscarinic receptors (Table 29–1). The active metabolite of
aripiprazole, dehydroaripiprazole, exhibits a similar affinity at D2 receptors and
has not been shown to have a pharmacological profile that is clinically
significantly different from that of the parent compound.
FIGURE 29–3. Chemical structure of aripiprazole.
Dopaminergic
D1 265
D2a 0.34
D3 0.8
D4 44
D5 95
Serotonergic
5-HT1Ab 1.7
5-HT2A 3.4
5-HT2C 15
5-HT6 214
5-HT7 39
SERT 98
Histaminic
H1 61
Adrenergic
α1c 57
Muscarinic IC50 (nM)
M 1c >1,000
Note. SERT=serotonin transporter.
Source. Adapted from McQuade RD, Burris KD, Jordan S, et al.: “Aripiprazole:
A Dopamine-Serotonin System Stabilizer.” International Journal of
Neuropsychopharmacology 5 (Suppl 1):S176, 2002, with the following
exceptions:
a
Burris KD, Molski TF, Xu C, et al.: “Aripiprazole, A Novel Antipsychotic, Is a
High Affinity Partial Agonist at Human Dopamine D2 Receptors.” Journal of
Pharmacology and Experimental Therapeutics 302:381–389, 2002.
b
Jordan S, Koprivica V, Chen R, et al.: “The Antipsychotic Aripiprazole Is a
Potent, Partial Agonist at the Human 5-HT1A Receptor.” European Journal of
Pharmacology 441:137–140, 2002.
c
Abilify (Aripiprazole) Tablets: U.S. Full Prescribing Information. Tokyo, Japan,
Otsuka Pharmaceutical Co., February 2012.
Brexpiprazole
Brexpiprazole—7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}quinolin-
2(1H)-one (Figure 29–4)—exhibits potent partial agonist properties at 5-HT1A,
D2, and D3 receptors. This is combined with potent antagonist activity at 5-HT2A
receptors and α1B/α2C adrenoceptors. It also displays antagonistic properties at
serotonin2B (5-HT2B) and serotonin7A (5-HT7A) receptors and moderate-potency
antagonism at H1 receptors. Brexpiprazole has negligible affinity for cholinergic
muscarinic receptors (Table 29–2) (Maeda et al. 2014a; Otsuka Pharmaceutical
2015).
Dopaminergic
D2 0.30
D3 1.1
Serotonergic
5-HT1A 0.12
5-HT2A 0.47
5-HT2B 1.9
5-HT7a 3.7
Histaminic
H1 19
Adrenergic
α1Aa 3.8
α1B 0.17
α1Da 2.6
α2C 0.59
Muscarinic
M1 67% at 10
μM
Source. Adapted from Maeda K, Sugino H, Akazawa H, et al.: “Brexpiprazole I:
In Vitro and In Vivo Characterization of a Novel Serotonin-Dopamine Activity
Modulator.” J Pharmacol Exp Ther 350:589–604, 2014, with the following
exception:
a
Rexulti (Brexpiprazole) Tablets: U.S. Full Prescribing Information. Tokyo,
Japan, Otsuka Pharmaceutical Co., August 2015.
Aripiprazole
Aripiprazole is available for oral administration as tablets in strengths of 2, 5, 10,
15, 20, and 30 mg. The effective dosage range is 10–30 mg/day for
schizophrenia patients and 15–30 mg/day for bipolar I disorder patients. For
adjunctive treatment of major depressive disorder (MDD) and irritability
associated with autism spectrum disorder, the recommended dosage range is 2–
15 mg/day. For Tourette’s disorder, body weight–based dosing of 2–10 mg/day
for patients weighing less than 50 kg and 2–20 mg/day for patients weighing 50
kg or more is indicated. Aripiprazole is taken once daily with or without food
and is well absorbed after oral administration, with peak plasma concentrations
occurring within 3–5 hours. Absolute oral bioavailability is 87%. In plasma,
aripiprazole and its major metabolite, dehydroaripiprazole, are both more than
99% bound to proteins, primarily albumin. Aripiprazole is extensively
distributed outside the vascular system, and human studies demonstrating dose-
dependent occupancy of D2 receptors have confirmed that aripiprazole
penetrates the brain. Elimination half-lives for aripiprazole and
dehydroaripiprazole are 75 hours and 94 hours, respectively (Otsuka
Pharmaceutical 2016a).
Of note, several aripiprazole formulations were withdrawn from the market by
the manufacturer in 2015 for reasons unrelated to efficacy, safety, or tolerability.
Discontinued formulations include the aripiprazole oral disintegrating tablet at
10-mg and 15-mg strengths, the oral solution, and the short-acting intramuscular
injection.
In February 2013, the U.S. Food and Drug Administration (FDA) approved a
long-acting injectable formulation of aripiprazole for the treatment of
schizophrenia. The effective dosage range is 300–400 mg once monthly. It is
recommended that oral aripiprazole supplementation (at 10–20 mg/day) or an
alternative antipsychotic be continued for 2 weeks after the first administered
injection of long-acting aripiprazole. The aripiprazole depot formulation consists
of a lyophilized powder of unmodified aripiprazole. The depot formulation is
reconstituted in water and injected into the gluteal muscle. The median peak
plasma concentration is reached after 5–7 days. The mean terminal half-lives of
the 300-mg and 400-mg doses are 29.9 and 46.5 days, respectively. Steady-state
plasma concentration is attained after the fourth dose (Otsuka Pharmaceutical
2016b). The aripiprazole once-monthly dose of 400 mg with supplemental oral
aripiprazole 10 mg/day for the first 2 weeks produces a pharmacokinetic profile
consistent with multiple daily dosing of aripiprazole 10–30 mg, with a maximum
plasma concentration comparable to the 30 mg/day dosage and a minimum
plasma concentration comparable to the 10 mg/day dosage (Mallikaarjun et al.
2013).
In October 2015, the FDA approved aripiprazole lauroxil, a second long-
acting injectable formulation of aripiprazole, for the treatment of schizophrenia.
The effective dosages (441 mg, 662 mg, and 882 mg once monthly) correlate
with oral aripiprazole dosages of 10 mg, 20 mg, and 30 mg/day, respectively.
Aripiprazole lauroxil 882 mg may be administered at a dosing interval up to 6
weeks. The recommended period of oral aripiprazole supplementation is 3 weeks
after the first administered injection.
Aripiprazole lauroxil, a prodrug of aripiprazole, initially undergoes enzyme-
mediated hydrolysis to N-hydroxymethyl aripiprazole and then undergoes water-
mediated hydrolysis to aripiprazole, the active form. After a single intramuscular
injection, aripiprazole appears in systemic circulation within 5–6 days.
Aripiprazole reaches steady state after four consecutive monthly injections.
Mean terminal half-life ranges from 29.2 to 34.9 days (Alkermes 2015).
Aripiprazole is metabolized primarily in the liver. Two hepatic cytochrome
P450 (CYP) enzymes, 2D6 and 3A4, catalyze its dehydrogenation to
dehydroaripiprazole. Therefore, coadministration of aripiprazole with inducers
or inhibitors of these CYP enzymes may require dosage adjustment. The active
metabolite accounts for 40% of drug exposure, but the predominant circulating
moiety is the parent drug. Aripiprazole does not undergo direct glucuronidation
and is not a substrate for the following CYP enzymes: 1A1, 1A2, 2A6, 2B6,
2C8, 2C9, 2C19, and 2E1. Interactions with inhibitors or inducers of these
enzymes, or with chemicals related to cigarette smoke, are therefore unlikely to
occur.
Brexpiprazole
Brexpiprazole is available for oral administration as tablets in strengths of 0.25,
0.5, 1, 2, and 3 mg. The effective dosage range is 2–4 mg/day for treatment of
schizophrenia and 1–3 mg/day for adjunctive treatment of MDD. Brexpiprazole
is taken once daily with or without food and is well absorbed after oral
administration, with peak plasma concentrations occurring within 4 hours.
Absolute oral bioavailability is 95%. Brexpiprazole is highly bound to serum
albumin and α1-acid glycoprotein (>99%). Elimination half-lives for
brexpiprazole and DM-3411, its major metabolite, are 91 hours and 86 hours,
respectively (Otsuka Pharmaceutical 2015).
Brexpiprazole is metabolized primarily through the liver by CYP enzymes
2D6 and 3A4. Therefore, coadministration of brexpiprazole with inducers or
inhibitors of these CYP enzymes may require dosage adjustment. At steady state
(which is reached in 10–12 days), the inactive metabolite DM-3411 represents
23%–48% of brexpiprazole AUC (area under the time–concentration curve) in
plasma (Otsuka Pharmaceutical 2015).
Mechanism of Action
Aripiprazole and brexpiprazole both have partial agonist activity at D2 receptors.
The activity of aripiprazole and brexpiprazole at D2 receptors has been studied in
animal models of schizophrenia (Kikuchi et al. 1995; Maeda et al. 2014b). In the
intact rat with repetitive stereotyped behavior (stereotypy) induced by
apomorphine, aripiprazole and brexpiprazole inhibit stereotypy and locomotion
(Kikuchi et al. 1995; Maeda et al. 2014a). These agents may therefore be
expected to inhibit hyperdopaminergic activity in the mesolimbic pathway of
patients with schizophrenia, thereby (like other available agents) exerting
antipsychotic action against the positive symptoms of schizophrenia. On the
other hand, in animal models of hypodopaminergic activity, such as the
reserpinized rat, aripiprazole and brexpiprazole have D2 receptor agonist activity
(Maeda et al. 2014b). Because aripiprazole and brexpiprazole may exert either
D2 antagonist activity under hyperdopaminergic conditions or D2 agonist activity
under hypodopaminergic conditions, they may be less likely than other
antipsychotics to cause excessive D2 receptor antagonism. In preclinical studies,
brexpiprazole showed lower intrinsic activity at D2 receptors, which suggests a
reduced propensity to cause D2 agonist–associated side effects such as nausea,
insomnia, and akathisia (Maeda et al. 2014a, 2014b). It is possible that this lower
activity may diminish the effects of excess D2 receptor antagonism, including
EPS. No comparative clinical trials of aripiprazole and brexpiprazole have yet
been conducted.
Both aripiprazole and brexpiprazole may offer further therapeutic benefits
through modulation of central serotonergic pathways. Preclinical studies showed
that aripiprazole and brexpiprazole have antagonist activity at 5-HT2A receptors
(Maeda et al. 2014b; McQuade et al. 2002), a characteristic that has been
associated with reductions in EPS (Meltzer 1999) and in negative symptoms. In
vitro studies also have shown that both aripiprazole and brexpiprazole have
partial agonist activity at 5-HT1A receptors (Jordan et al. 2002; Maeda et al.
2014b), a feature that has been associated with improvement in negative,
cognitive, depressive, and anxiety symptoms (Millan 2000).
The side effects of nausea/vomiting may be explained by the dopamine
agonist effects of aripiprazole and brexpiprazole, whereas orthostatic
hypotension and mild sedation/weight gain are likely related to these agents’
antagonist activity at α1-adrenergic and H1 receptors, respectively.
Aripiprazole lauroxil is a prodrug of aripiprazole. It initially undergoes
enzyme-mediated hydrolysis to N-hydroxymethyl aripiprazole and then
undergoes water-mediated hydrolysis to aripiprazole, the active form (Alkermes
2015).
Aripiprazole
In the United States, aripiprazole is approved by the FDA for the following
indications: treatment of schizophrenia in adults and in adolescents ages 13–17
years; acute treatment of manic or mixed episodes associated with bipolar I
disorder as monotherapy and as an adjunct to lithium or valproate in adults and
pediatric patients ages 10–17 years; maintenance treatment of manic or mixed
episodes associated with bipolar I disorder as monotherapy and as an adjunct to
lithium or valproate in adults; use as an adjunct to antidepressant treatment in
adults with MDD who have had an inadequate response to antidepressant
therapy; treatment of irritability associated with autism spectrum disorder in
pediatric patients ages 6–17 years; and treatment of Tourette’s disorder in
pediatric patients ages 6–18 years. Additionally, intramuscular aripiprazole
injection is approved for the acute treatment of agitation associated with
schizophrenia or bipolar disorder (manic or mixed) in adults, and currently is
available in two formulations for long-acting injectable depot maintenance and
relapse management of schizophrenia in adults. The previously available
formulations Abilify Discmelt orally disintegrating tablet (10 mg and 15 mg),
Abilify oral solution (1 mg/mL), and Abilify short-acting intramuscular injection
(9.75 mg/1.3 mL) were voluntarily withdrawn from the U.S. market in 2015.
Schizophrenia
The efficacy of aripiprazole in the treatment of an acute symptom relapse in
schizophrenia was demonstrated in four short-term (4-week) double-blind,
placebo-controlled studies. Among these was a pivotal Phase III parallel-group
multicenter study with four treatment arms comparing aripiprazole (15 or 30
mg/day) with placebo (Kane et al. 2002). Aripiprazole at either dosage produced
statistically significant improvements from baseline on standard psychometric
scales by week 2. This trial suggested that at daily dosages of 15 mg and 30 mg,
aripiprazole provides effective symptom control in patients experiencing an
acute exacerbation of schizophrenia symptoms.
In another short-term multicenter Phase III study involving acute symptom
relapse in schizophrenia or schizoaffective disorder (Potkin et al. 2003), patients
were randomly assigned to receive aripiprazole 20 mg/day, aripiprazole 30
mg/day, risperidone 6 mg/day, or placebo for 4 weeks. Compared with placebo,
aripiprazole (at both dosages) and risperidone produced statistically significant
improvements in scores on standard scales designed to measure antipsychotic
efficacy.
The antipsychotic efficacy of aripiprazole in acute symptom relapse in
schizophrenia was also demonstrated in two Phase II dose-ranging studies.
Patients were randomly assigned to receive aripiprazole 2 mg, 10 mg, or 30
mg/day or haloperidol 10 mg/day (Daniel et al. 2000). All three dosages of
aripiprazole produced improvements from baseline on efficacy measures, and
the 30-mg/day dosage produced statistically significant improvement compared
with placebo on all illness scores. Similarly, in a Phase II dosage titration study,
aripiprazole 5–30 mg/day was superior to placebo in improving Brief Psychiatric
Rating Scale (BPRS) Total, BPRS Core, Clinical Global Impression–Severity
(CGI-S), and Positive and Negative Syndrome Scale (PANSS)–Total scores
(Petrie et al. 1997).
Results from the three 4-week fixed-dosage studies discussed above were
pooled for analysis with those from an additional 6-week placebo-controlled,
fixed-dosage study of aripiprazole at 10 mg, 15 mg, or 20 mg/day (Lieberman et
al. 2002). The pooled analysis, involving 898 patients randomly assigned to
receive aripiprazole, showed that at all investigated dosages greater than 2
mg/day, aripiprazole exhibited antipsychotic efficacy superior to that of placebo.
Onset of effect was rapid, with improvement on psychometric scores detectable
within 1 week of starting treatment. These pooled efficacy results demonstrate
that dosages of 10–30 mg/day represent an effective therapeutic range for
aripiprazole treatment.
Two long-term double-blind, randomized controlled multicenter trials yielded
further confirmation of aripiprazole’s efficacy. A 26-week placebo-controlled
study in patients with chronic stable schizophrenia investigated the efficacy of
aripiprazole 15 mg/day in relapse prevention (Pigott et al. 2003). Aripiprazole
treatment significantly increased the time to relapse and resulted in significantly
fewer relapses at endpoint compared with placebo (34% vs. 57%). From week 6
of therapy, PANSS–Total and PANSS–Positive subscale scores were
significantly more improved with aripiprazole than with placebo.
In a 52-week study (Kasper et al. 2003), patients with schizophrenia who were
experiencing an acute symptom relapse were randomly assigned to receive
aripiprazole 30 mg/day or haloperidol 10 mg/day. Significantly more
aripiprazole-treated patients than haloperidol-treated patients were still taking
the medication and responding to treatment at weeks 8, 26, and 52. Both
treatments produced sustained improvements from baseline on PANSS–Total
and PANSS–Positive subscale scores. However, aripiprazole produced
significantly greater improvements in negative and depressive symptoms at
weeks 26 and 52 and was associated with significantly lower scores on all EPS
assessments compared with haloperidol.
The efficacy of aripiprazole monotherapy in antipsychotic-resistant
schizophrenia was evaluated in a 6-week double-blind, randomized trial in
patients whose symptoms had not improved during a prospective 4- to 6-week
open trial with either olanzapine or risperidone (Kane et al. 2007). Subjects were
randomly assigned to receive aripiprazole (15–30 mg/day) or perphenazine (8–
64 mg/day). After 6 weeks, there was no statistical difference between the two
groups on efficacy measures. However, compared with aripiprazole,
perphenazine was associated with higher rates of EPS and serum prolactin
elevations.
The efficacy of aripiprazole in the treatment of schizophrenia in pediatric
patients (ages 13–17 years) was evaluated in a 6-week placebo-controlled
outpatient trial comparing two fixed daily dosages of aripiprazole (10 mg or 30
mg) with placebo (Findling et al. 2008). Both aripiprazole dosages demonstrated
statistically significant differences from placebo in reductions in PANSS–Total
score; the 30-mg/day dosage was not shown to be more efficacious than the 10-
mg/day dosage. Adverse events occurring in more than 5% of either aripiprazole
group and with a combined incidence at least twice the rate for placebo were
EPS, somnolence, and tremor. Mean body weight changes were −0.8, 0.0, and
+0.2 kg for placebo, aripiprazole 10 mg/day, and aripiprazole 30 mg/day,
respectively.
Two studies have investigated the efficacy of aripiprazole long-acting depot
injection in the prevention of relapse in schizophrenia. In the first investigation,
a 52-week randomized, placebo-controlled, long-term multicenter maintenance
study, subjects requiring chronic treatment with an antipsychotic entered an oral
aripiprazole stabilization phase followed by an intramuscular depot conversion
and stabilization phase. Those patients meeting stabilization criteria for 12
consecutive weeks were then randomly assigned to receive aripiprazole 400-mg
long-acting depot or placebo depot for the 52-week double-blind maintenance
phase of the study. The primary outcome measure was time to relapse, defined as
meeting any or all of the following criteria at any time during the maintenance
phase: 1) clinical worsening (defined as Clinical Global Impression–
Improvement [CGI-I] score ≥5 plus increase in any core PANSS items), 2)
hospitalization, 3) risk of suicide, or 4) violent behavior. The aripiprazole group
showed a significantly lower rate of relapse compared with the placebo group
(9.6% vs. 36.8%, respectively) (Kane et al. 2012). The second investigation was
a 38-week double-blind noninferiority study that compared relapse rates for
aripiprazole once-monthly 400-mg depot injection, oral aripiprazole (10–30
mg/day), and aripiprazole once-monthly 50-mg depot injection, using criteria
similar to those used in the Kane et al. study discussed above. There was no
significant difference in rate of relapse with the once-monthly 400-mg depot
formulation (7.12%) versus the oral formulation (10–30 mg/day), and both were
significantly superior to the 50-mg depot formulation (21.8%; P<0.0001)
(Fleischhacker et al. 2014).
One 12-week randomized, double-blind, placebo-controlled Phase III
multicenter trial evaluated the efficacy of aripiprazole once-monthly injection for
the management of acute exacerbations in chronic schizophrenia. Patients were
randomly assigned to either the aripiprazole once-monthly 400-mg group with
concomitant oral aripiprazole (mean daily dosage=12.8 mg) for 2 weeks (n=168)
or the placebo group (n=172). The aripiprazole group showed sustained
improvements in PANSS–Total scores, PANSS–Positive and –Negative subscale
scores, and CGI-I scores, with improvements apparent within the first week of
administration (Kane et al. 2014).
An open-label mirror-image multicenter study in a naturalistic community
setting (Kane et al. 2013) compared total psychiatric hospitalization rates in 183
patients (18–65 years) who had previously been treated with oral antipsychotics
(retrospective phase) and who were then switched to the aripiprazole once-
monthly depot formulation for 6 months (prospective phase). The rate of
hospitalization for the 6-month prospective phase (14.2%) was found to be lower
than the rate for the 6-month retrospective oral antipsychotic period (41.5%;
P<0.0001). Additionally, the all-cause discontinuation rate for the prospective
phase was high (44.8%), with 26 patients discontinuing because of adverse
events including “psychiatric disorders” (e.g., worsening of psychoses, increased
paranoia, agitation, anxiety, decreased self-care; 20 patients) and “nervous-
system disorders” (akathisia; 2 patients). For all patients receiving at least one
dose of aripiprazole once monthly (n=181), the most common treatment-
emergent adverse events (occurring in ≥5% of patients) were psychotic disorder
(7.7%), akathisia (7.2%), and insomnia (7.2%) (Kane et al. 2013).
Meltzer et al. (2015) conducted a 12-week double-blind, placebo-controlled
multicenter study comparing once-monthly administration of aripiprazole
lauroxil 441 mg or 882 mg versus placebo for 12 weeks. Statistically significant
improvement was observed on the PANSS–Total score from baseline to day 85
in both medication groups, with placebo-adjusted differences of −10.9 (P<
0.001) and −11.9 (P<0.001) for aripiprazole lauroxil 441 mg and 882 mg,
respectively.
Bipolar Disorder
The efficacy of aripiprazole in the treatment of acute manic episodes was
established in two 3-week placebo-controlled trials in hospitalized patients
whose symptoms met DSM-IV (American Psychiatric Association 1994) criteria
for bipolar I disorder with manic or mixed episodes (Keck et al. 2003; Sachs et
al. 2006). Aripiprazole was superior to placebo in reducing the Young Mania
Rating Scale (YMRS) Total score and the Clinical Global Impression–Bipolar
(CGI-BP) Severity of Illness score. In a third large randomized, double-blind
trial (Vieta et al. 2005), aripiprazole was compared with haloperidol in the
treatment of acute bipolar mania over a 12-week period. Significantly more
patients remained in treatment and were classified as responders (>50%
reduction in YMRS score from baseline) at week 12 in the aripiprazole group
(49.7%) than in the haloperidol group (28.4%). EPS adverse events were more
frequent with haloperidol than with aripiprazole (62.7% vs. 24.0%).
The efficacy of adjunctive aripiprazole with concomitant lithium or valproate
in the treatment of manic or mixed episodes was established in a 6-week
placebo-controlled study with a 2-week lead-in mood stabilizer monotherapy
phase in adult patients who met DSM-IV criteria for bipolar I disorder (Vieta et
al. 2008). Adjunctive aripiprazole starting at 15 mg/day with concomitant
lithium or valproate (in a therapeutic range of 0.6–1.0 mEq/L or 50–125 μg/mL,
respectively) was found to be superior to lithium or valproate with adjunctive
placebo on the basis of reductions in YMRS Total scores and CGI-BP Severity
of Illness scores.
Aripiprazole monotherapy was evaluated in the treatment of nonpsychotic
depressive episodes associated with bipolar I disorder. The results of two
identically designed 8-week randomized, double-blind, placebo-controlled
multicenter studies were reported by Thase et al. (2008). The primary outcome
measure was mean change from baseline to week 8 (last observation carried
forward [LOCF]) in the Montgomery-Åsberg Depression Rating Scale
(MADRS) Total score. Although statistically significant differences were
observed during weeks 1–6, there were no statistically significant differences in
change in MADRS Total score between aripiprazole and placebo at week 8 in
either study.
To evaluate the long-term effectiveness of aripiprazole in delaying relapse in
bipolar I disorder, a trial was conducted in patients whose symptoms met DSM-
IV criteria for bipolar I disorder with a recent manic or mixed episode (Keck et
al. 2006). Patients whose condition had been stabilized while taking open-label
aripiprazole and who had maintained a clinical response for at least 6 weeks
were randomly assigned to receive aripiprazole or placebo for the 26-week,
double-blind phase. Aripiprazole-treated patients had significantly fewer
relapses than placebo-treated patients (25% vs. 43%). Aripiprazole was superior
to placebo in delaying the time to manic relapse but did not differ from placebo
in delaying time to depressive relapse. Significant weight gain (≥7% increase
from baseline) was seen in 13% of the aripiprazole patients and none of the
placebo patients.
The efficacy of aripiprazole in the treatment of bipolar I disorder in pediatric
patients (ages 10–17 years) was evaluated in two studies. The first study was a
4-week double-blind, placebo-controlled trial of outpatients whose symptoms
met DSM-IV criteria for bipolar I disorder manic or mixed episodes with or
without psychotic features. The trial compared two fixed daily dosages of
aripiprazole (10 mg or 30 mg). Both dosages of aripiprazole were superior to
placebo as measured by change from baseline to week 4 on the YMRS Total
score (Otsuka Pharmaceutical 2016a). The second study was a 30-week
randomized, placebo-controlled study comparing fixed daily dosages of
aripiprazole (10 mg and 30 mg) with placebo in the treatment of adolescent
bipolar disorder (Findling et al. 2013). Two hundred ten youths (ages 10–17
years) with bipolar I disorder (manic or mixed) with or without psychotic
features were randomly assigned to receive oral aripiprazole 10 mg/day, oral
aripiprazole 30 mg/day, or placebo. Both dosages of aripiprazole were superior
to placebo; at week 30, aripiprazole-treated patients demonstrated significantly
greater improvement on YMRS Total scores compared with placebo-treated
patients.
Acute Agitation
The efficacy of the injectable formulation of aripiprazole in controlling acute
agitation was evaluated in three short-term (24-hour) randomized, double-blind,
placebo-controlled studies in patients with schizophrenia (Andrezina et al. 2006;
Tran-Johnson et al. 2007) and patients with bipolar disorder (manic or mixed)
(Zimbroff et al. 2007). Aripiprazole injection was statistically superior to
placebo (P<0.05) in all three studies, as measured by PANSS–Excited
Component (PANSS-EC) scores. In the two studies in agitated patients with
schizophrenia, injectable aripiprazole and intramuscular haloperidol were both
superior to placebo. In the study in agitated patients with bipolar I disorder,
aripiprazole injection and lorazepam injection were both superior to placebo.
Off-Label Use
De Deyn et al. (2005) compared the efficacy, safety, and tolerability of
aripiprazole versus placebo in patients with psychosis associated with
Alzheimer’s disease in a 10-week double-blind multicenter study. The initial
aripiprazole dosage of 2 mg/day was titrated upward (to 5, 10, or 15 mg/day)
according to efficacy and tolerability, and evaluations included the
Neuropsychiatric Inventory (NPI) Psychosis subscale and the BPRS.
Aripiprazole-treated patients showed significantly greater improvements from
baseline in BPRS–Psychosis subscale and BPRS–Core subscale scores at
endpoint compared with patients receiving placebo.
In another double-blind multicenter study (Mintzer et al. 2007), patients with
psychosis associated with Alzheimer’s disease were randomly assigned to
receive either placebo or aripiprazole 2, 5, or 10 mg/day. The primary efficacy
measure was mean change from baseline to week 10 on the Neuropsychiatric
Inventory–Nursing Home (NPI-NH) Psychosis subscale score. Aripiprazole 10
mg/day showed significantly greater improvements than placebo on all efficacy
measures (NPI-NH Psychosis subscale, CGI-S, BPRS Total and Core, and
Cohen-Mansfield Agitation Inventory [CMAI] scores). Aripiprazole 5 mg/day
showed significant improvements versus placebo on BPRS and CMAI scores.
Aripiprazole 2 mg/day was not efficacious. No antipsychotic is currently
approved in the United States for treating the behavioral and psychotic
symptoms that frequently accompany dementia, and all carry a bolded warning
based on increased mortality observed in patients with dementia-related
psychosis treated with these agents.
Nickel et al. (2006) conducted a double-blind, placebo-controlled study in
individuals whose clinical presentation met DSM-III-R (American Psychiatric
Association 1987) criteria for borderline personality disorder. Subjects were
randomly assigned in a 1:1 ratio to receive either aripiprazole (15 mg/day) or
placebo for 8 weeks. At endpoint, significant changes in scores on most scales of
the Symptom Checklist–90—Revised (SCL-90-R), on the Hamilton Rating
Scale for Depression (Ham-D), on the Hamilton Anxiety Scale (Ham-A), and on
all subscales of the State-Trait Anger Expression Inventory were observed in
subjects who received aripiprazole. The improvements observed at 8 weeks were
maintained at 18-month follow-up (Nickel et al. 2007).
Tiihonen et al. (2007) conducted a study in which individuals whose
symptoms met DSM-IV criteria for intravenous amphetamine dependence were
randomly assigned to receive aripiprazole (15 mg/day), slow-release
methylphenidate (54 mg/day), or placebo for 20 weeks. The study was
terminated prematurely because of unexpected results in the interim analysis.
Contrary to the hypothesized result, patients who received aripiprazole treatment
had significantly more amphetamine-positive urine samples than did patients in
the placebo group, and patients who received methylphenidate had significantly
fewer amphetamine-positive urine samples than patients who received placebo.
Studies in subjects with cocaine use disorder are ongoing.
In a 12-week double-blind, placebo-controlled multicenter trial (Anton et al.
2008) evaluating the efficacy of aripiprazole in patients with DSM-IV alcohol
dependence, aripiprazole did not differ from placebo on the study’s primary
efficacy measure, mean percentage of days abstinent.
Brexpiprazole
Brexpiprazole is currently approved in the United States for schizophrenia and
for use as an adjunct to antidepressant treatment in adults with MDD who have
had an inadequate response to antidepressant therapy (Otsuka Pharmaceutical
2015).
Schizophrenia
The efficacy of brexpiprazole in the treatment of acute symptom exacerbations
in schizophrenia has been evaluated in two 6-week double-blind, placebo-
controlled multicenter studies. In the first study, a Phase III multicenter trial
(BEACON study), patients with acute schizophrenia were randomly assigned to
receive aripiprazole (1 mg, 2 mg, or 4 mg/day) or placebo. Brexpiprazole 4
mg/day produced statistically significant reductions (treatment difference −6.47;
P=0.0022) versus placebo on the PANSS–Total score. Brexpiprazole dosages of
1 mg/day and 2 mg/day also produced numerical improvements versus placebo,
although the degree of improvement was not statistically significant (P>0.05)
(Kane et al. 2015).
In another 6-week multicenter double-blind, placebo-controlled Phase III trial
(VECTOR study), patients experiencing an acute schizophrenia relapse were
randomly assigned to receive aripiprazole (0.25 mg, 2 mg, or 4 mg/day) or
placebo. At 6 weeks, both the 2-mg/day and the 4-mg/day dosages of
brexpiprazole had produced statistically significantly greater reductions on
PANSS–Total scores compared with placebo (treatment difference −8.72
[P<0.0001] and −7.64 [P=0.0006] for 2 mg/day and 4 mg/day, respectively)
(Correll et al. 2015).
Aripiprazole
A pooled analysis of safety and tolerability data from the five short-term studies
(Marder et al. 2003; Stock et al. 2002) showed that aripiprazole treatment was
well tolerated. The most commonly reported adverse events with aripiprazole
were headache, insomnia, agitation, and anxiety. The incidence of adverse events
was similar in the aripiprazole and placebo groups. The adverse-event profile of
aripiprazole did not vary according to patient characteristics of age, sex, and
race/ethnicity, and no deaths were reported during the short-term studies. Data
from the four fixed-dosage studies showed that somnolence was the only adverse
event seen with aripiprazole that was possibly dose related. Objective rating
scale assessments were used to measure changes in parkinsonian symptoms
(Simpson-Angus Scale [SAS]), dyskinesias (Abnormal Involuntary Movement
Scale [AIMS]), and akathisia (Barnes Akathisia Rating Scale [BARS]). SAS
scores with aripiprazole did not differ significantly from those with placebo,
whereas AIMS scores improved significantly from baseline with aripiprazole
compared with placebo. Aripiprazole did not produce consistent dose-dependent
changes in BARS scores. The rate of discontinuation due to adverse events was
7.3% (Otsuka Pharmaceutical 2016a). According to the product labeling for
aripiprazole in the United States, treatment-emergent adverse events most
commonly reported with aripiprazole (occurring in ≥10% of patients with an
incidence greater than that with placebo) in short-term trials of patients with
schizophrenia (up to 6 weeks) or bipolar disorder (up to 3 weeks), respectively,
included headache (aripiprazole 30% vs. placebo 25%), anxiety (20% vs. 17%),
insomnia (19% vs. 14%), nausea (16% vs. 12%), vomiting (12% vs. 6%),
dizziness (11% vs. 8%), constipation (11% vs. 7%), dyspepsia (10% vs. 8%),
and akathisia (10% vs. 4%). A 26-week trial in schizophrenia reported a similar
adverse-event profile except for a higher incidence of tremor (aripiprazole 8%
vs. placebo 2%).
The most frequently reported adverse events with aripiprazole injection were
headache (aripiprazole 12% vs. placebo 7%), nausea (9% vs. 3%), dizziness (8%
vs. 5%), and somnolence (7% vs. 4%). In the three aripiprazole injection trials,
the drug’s safety profile was comparable to that of placebo regarding the
incidence of EPS, akathisia, or dystonia. The incidence of akathisia-related
adverse events with aripiprazole injection was 2% (vs. 0% for placebo), while
the incidence of dystonia with aripiprazole injection was less than 1% (vs. 0%
for placebo). In addition, the incidence of QTc prolongation was also comparable
between aripiprazole injection and placebo.
The most common adverse events reported for the aripiprazole long-acting
injectable formulation in the Kane et al. (2012) 52-week trial were insomnia
(aripiprazole 10% vs. placebo 9%), tremor (5.9% vs. 1.5%), headache (5.9% vs.
5.2%), and akathisia (5.6% vs. 6%). In the Kane et al. (2014) 12-week acute
management of schizophrenia study, the most common adverse events were
increased weight (aripiprazole 16.8% vs. placebo 7%), headache (14.4% vs.
16.3%), and akathisia (11.4% vs. 3.5%). There was no significant difference in
rates of EPS other than akathisia between the 400-mg aripiprazole group and the
placebo group. In a 24-week open-label parallel-arm study conducted by
Mallikaarjun et al. (2013), the tolerability and safety of aripiprazole once
monthly in schizophrenia were comparatively evaluated for dosages of 200 mg,
300 mg, and 400 mg. The most common adverse events were injection-site pain
(aripiprazole 400 mg, 28.6%), tremor (aripiprazole 400 mg, 21.4%; aripiprazole
300 mg, 6.7%), and vomiting (aripiprazole 300 mg, 13.3%; aripiprazole 400 mg,
14.3%).
The most common adverse events in a 12-week Phase III trial of aripiprazole
lauroxil in the treatment of acute exacerbations of schizophrenia were akathisia,
headache, insomnia, and injection-site pain (occurring in >5% of patients).
Akathisia occurred at twice the rate of placebo for aripiprazole lauroxil 882 mg
and 441 mg (4.3%, 11.6%, and 11.5%, respectively) (Meltzer et al. 2015). The
majority (>75%) of akathisia episodes occurred within 3 weeks of receiving the
first injection.
Minimal changes in mean body weight were observed with aripiprazole
treatment in short-term studies (pooled data +0.71 kg) (Marder et al. 2003) and
in long-term studies (26-week: −1.26 kg; 52-week: +1.05 kg) (Kasper et al.
2003; Pigott et al. 2003).
Olanzapine and aripiprazole were compared on their propensity to cause
weight gain and other metabolic disturbances in a 26-week randomized, double-
blind multicenter trial (McQuade et al. 2004). Statistically significant differences
in mean weight change were observed between treatments beginning at week 1
and were sustained throughout the study. At week 26, there was a mean weight
loss of 1.37 kg (3.04 lb) with aripiprazole compared with a mean weight gain of
4.23 kg (9.40 lb) with olanzapine among patients who continued with therapy
(P<0.001). Changes in fasting plasma levels of total cholesterol, high-density
lipoprotein cholesterol, and triglycerides were significantly different in the two
treatment groups, with worsening of the lipid profile among patients treated with
olanzapine.
Aripiprazole treatment was not associated with increases in prolactin levels
during either short- or long-term studies. (In fact, prolactin levels were shown to
be slightly decreased by aripiprazole.)
Overall, aripiprazole treatment is associated with a low incidence of EPS
(other than akathisia) and EPS-related symptoms and with minimal or no effects
on weight gain, QTc interval, or circulating levels of cholesterol, glucose, and
prolactin. Treatment with aripiprazole may reduce the burden of antipsychotic-
associated side effects, thereby leading to improved patient adherence and
decreased risks of acute relapse.
Brexpiprazole
Overall, brexpiprazole has been well tolerated in the four short-term clinical
trials conducted thus far, with lower rates of discontinuation due to adverse
events compared with placebo. In pooled analyses for two trials of brexpiprazole
in the adjunctive treatment of MDD, the rate of discontinuation due to adverse
reactions for all dosages of brexpiprazole was 3%, compared with 1% for
placebo (Otsuka Pharmaceutical 2015). In the two Phase III trials for
brexpiprazole in acute schizophrenia, the overall rates of discontinuation due to
adverse event were lower than those for placebo (Correll et al. 2015; Kane et al.
2015).
The most common side effects varied per available studies. In one Phase III
trial in acute schizophrenia, the most common adverse events for brexpiprazole
were headache, agitation, and insomnia, with rates of akathisia lower than those
with placebo but with a dose-dependent increase for brexpiprazole (Correll et al.
2015). Comparatively, the most common adverse event in another Phase III trial
was akathisia for brexpiprazole 2 mg (4.4%) and 4 mg (7.2%) versus placebo
(2.2%), with akathisia most commonly occurring within the first 3 weeks of
treatment. In two short-term trials for adjunctive use in MDD, pooled analysis
showed that the most common adverse event was akathisia (8.6%) (Citrome
2015).
Pooled data from two short-term Phase III schizophrenia trials showed that
10% of brexpiprazole-treated patients had weight gains of 7% or greater from
baseline during a 6-week trial, compared with 4.1% of patients receiving
placebo. Similarly, the pooled data from both short-term MDD trials showed
weight gain in the brexpiprazole group to be higher than that in the placebo
group (6.7% vs. 1.9%), with the greatest increase being 1.6 kg for brexpiprazole
3 mg/day at 6 weeks (Citrome 2015; Otsuka Pharmaceutical 2015).
Change in prolactin level was studied in all treatment trials. In one Phase III
trial of brexpiprazole in schizophrenia, there was no statistically significant
change in prolactin level (Correll et al. 2015). In a second Phase III short-term
trial of brexpiprazole in schizophrenia, the incidence of potentially clinically
relevant prolactin values (one to two times the upper limit of normal) was
highest in the brexpiprazole 4-mg/day group (19.1%) versus the placebo group
(13.9%) (Kane et al. 2015). In a short-term Phase III trial of brexpiprazole in the
adjunctive treatment of MDD, 0.4% of patients receiving brexpiprazole 3
mg/day, compared with 1.4% of patients receiving placebo, had a prolactin level
greater than three times the upper limit of normal (Thase et al. 2015b).
The incidence of EPS was evaluated in all four short-term treatment trials by
means of the BARS and the SAS. The percentage of patients treated with
brexpiprazole plus an antidepressant who showed a shift from normal to
abnormal was greater versus placebo for both the BARS (4% vs. 0.6%) and the
SAS (4% vs. 3%). Similarly, the brexpiprazole group showed a greater shift from
normal to abnormal versus placebo in both the BARS (2% vs. 1%) and the SAS
(7% vs. 5%) in pooled data from both schizophrenia trials (Otsuka
Pharmaceutical 2015).
With an overall minimal incidence of EPS beyond akathisia and minimal
observed changes in QTc, lipid panel, and glucose panel values compared with
placebo, brexpiprazole is another antipsychotic with a tolerable side-effect
profile that may improve adherence long term (Correll et al. 2015; Kane et al.
2015; Thase et al. 2015a, 2015b).
Drug–Drug Interactions
Aripiprazole
Because aripiprazole is metabolized primarily by the hepatic CYP enzymes 2D6
and 3A4, it has the potential to interact with other substrates for these enzymes.
Inducers of these enzymes may increase clearance and thereby reduce blood
levels of aripiprazole, whereas inhibitors of CYP3A4 or CYP2D6 may inhibit
elimination and thereby increase blood levels of aripiprazole. In vivo studies
showed decreased levels of aripiprazole and dehydroaripiprazole in the plasma
when aripiprazole was coadministered with carbamazepine, a CYP3A4 inducer.
The aripiprazole dose should therefore be increased when the drug is
administered concomitantly with carbamazepine. In vivo studies coadministering
aripiprazole and ketoconazole (a CYP3A4 inhibitor) or quinidine (a CYP2D6
inhibitor) suggest that the aripiprazole dose should be reduced when aripiprazole
is administered with strong 3A4 or 2D6 inhibitors. Aripiprazole exhibits α1-
adrenergic receptor antagonist activity and therefore may enhance the effects of
certain antihypertensive agents.
Brexpiprazole
Brexpiprazole is metabolized primarily by hepatic CYP enzymes 2D6 and 3A4;
therefore, coadministration with inducers or inhibitors of these CYP enzymes
requires dosage adjustments for brexpiprazole. In vivo studies showed increased
levels of brexpiprazole when it was coadministered with ketoconazole (a
CYP3A4 inhibitor) or quinidine (a CYP2D6 inhibitor), and it is therefore
recommended that brexpiprazole dosages be reduced when brexpiprazole is
coadministered with known CYP2D6 and CYP3A4 inhibitors. Plasma levels of
brexpiprazole were decreased when the drug was coadministered with rifampin
(a CYP3A4 inducer) during in vivo studies, and it is therefore recommended that
brexpiprazole dosages be reduced when brexpiprazole is coadministered with
known CYP3A4 inducers. Brexpiprazole has limited induction or inhibition of
other CYP enzymes per multiple in vivo studies (Otsuka Pharmaceutical 2015).
Conclusion
Aripiprazole was the first agent that was not a full D2 receptor antagonist to
show rapid and sustained antipsychotic activity, and it may be considered the
first partial dopamine agonist combined with 5-HT-stabilizing properties. Short-
term and long-term clinical trials in adult and pediatric patients with
schizophrenia and bipolar I disorder have demonstrated that aripiprazole
combines sustained antipsychotic and mood-stabilizing efficacy with an
excellent safety and tolerability profile. Additional augmentation trials have
confirmed the utility of aripiprazole in alleviating depressive symptomatology in
patients with MDD who have not achieved adequate symptom relief with
antidepressants alone. The efficacy and safety of aripiprazole have also been
established in child and adolescent populations for the management of irritability
in autism spectrum disorders and Tourette’s disorder. Aripiprazole is now also
available in two different long-term depot injectable formulations for the
management of schizophrenia in adults.
Brexpiprazole shares multiple similarities with aripiprazole, including partial
dopamine agonism and 5-HT-stabilizing properties. However, brexpiprazole has
lower intrinsic dopaminergic activity than does aripiprazole, which may indicate
an even more favorable side-effect profile relative to the well-tolerated older
drug. Several short-term clinical trials in adult patients with acute schizophrenia
or with a lack of response to previous therapy for MDD have confirmed the
efficacy and tolerability of this newly established atypical antipsychotic. A
variety of clinical trials with brexpiprazole targeting different treatment
populations, including head-to-head trials with other antipsychotics to further
establish clinical efficacy, have been initiated or are ongoing.
In general, both aripiprazole and brexpiprazole are associated with low
liability for EPS, QTc interval prolongation, prolactin elevation, weight gain, and
disturbance of glucose or lipid metabolism. The combination of efficacy, safety,
and tolerability suggests that both aripiprazole and brexpiprazole represent
important options for the acute treatment of schizophrenia as well as for the
adjunctive treatment of MDD. Aripiprazole additionally represents an important
treatment option for bipolar I disorder, irritability in autism spectrum disorder,
and Tourette’s disorder, and for long-term management of schizophrenia.
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_____________
This chapter is an update and revision of Sharif ZA, Cole YI, Lieberman JA:
“Aripiprazole,” in Essentials of Clinical Psychopharmacology, Third Edition.
Edited by Schatzberg AF, Nemeroff CB. Arlington, VA, American Psychiatric
Publishing, 2013, pp 291–303.
CHAPTER 30
Ziprasidone
John W. Newcomer, M.D.
Elise Fallucco, M.D.
Martin T. Strassnig, M.D.
Pharmacological Profile
Dosing Recommendations
In addition to the PET data just described, evidence from clinical trials suggests
that ziprasidone target dosages should be higher than those originally
recommended. In the United States, it was initially recommended that
ziprasidone treatment in patients with schizophrenia be initiated at a dosage of
20 mg twice daily, with the dosage then titrated at intervals of no less than 2 days
to a maximum of 80 mg twice daily (Pfizer Inc. 2008). In contrast, subsequent
FDA approval of ziprasidone for the treatment of bipolar mania included a
recommendation that treatment be initiated at 40 mg twice daily with a more
rapid titration; on the second day of treatment, the dosage might be increased to
60 or 80 mg twice daily, with subsequent adjustment based on tolerability and
efficacy within a 40- to 80-mg twice-daily range.
Ziprasidone dosages of 120–160 mg/day are observed to be more effective
than lower dosages in the treatment of acute schizophrenia (Kane 2003b) and
bipolar disorders (Citrome et al. 2009b) in adults and also are associated with
lower rates of medication discontinuation (Citrome et al. 2009c). A 6-month
prospective, observational, naturalistic, uncontrolled study in Spain observed
that dosages greater than 120 mg/day were associated with a lower risk of
discontinuation for any cause (Arango et al. 2007). In an analysis of commercial
and Medicare prescription databases, Citrome et al. (2009a) observed
significantly lower discontinuation rates among schizophrenia and bipolar
disorder patients receiving ziprasidone at dosages of 120–160 mg/day compared
with those receiving ziprasidone at lower dosages. Similarly, a European
observational multicenter trial found that initial and overall underdosing of
ziprasidone were associated with high discontinuation rates (Kudla et al. 2007),
and a pooled analysis of both flexible-dose and fixed-dose studies (N=2,174)
observed greater efficacy in patients who received an initial dosage of 80 mg/day
compared with patients who received an initial dosage of 40 mg/day (Murray et
al. 2004). Finally, two large observational database analyses suggested that
higher dosages of ziprasidone are associated with better treatment outcomes than
lower dosages (Joyce et al. 2006; Mullins et al. 2006). Both studies used
prescription refills as an indicator of prescription adherence. Joyce et al. (2006)
examined records from more than 1,000 commercially insured patients with
schizophrenia or schizoaffective disorder and concluded that an initial daily
dosage of 120–160 mg was associated with a significantly lower risk of
medication discontinuation at 6 months than an initial daily dosage of 60–80 mg.
Mullins et al. (2006) evaluated more than 1,000 Medicaid recipients with
schizophrenia and similarly concluded that patients receiving an initial dosage of
120–160 mg/day had lower rates of medication discontinuation than patients
receiving 20–60 mg/day. Reported clinical experience with ziprasidone has also
suggested the need for dosages greater than 160 mg/day in selected patients
(Citrome et al. 2009a; Harvey and Bowie 2005; Nemeroff et al. 2005). A dosage
of 320 mg/day, twice the maximum recommended dosage of 160 mg/day, did not
lead to any additional symptom improvement in a small 8-week placebo-
controlled trial as compared with a dosage of 160 mg/day, and plasma drug
levels were similar between the two dosages at the end of the study period.
There was a trend toward increasing diastolic blood pressure, more prominent
negative symptoms, and greater QTc prolongation (Goff et al. 2013) with the
320 mg/day dosage.
Taken together, results from receptor occupancy studies, clinical trials, and
pharmacoepidemiological analyses support the conclusion that initiation and
treatment with ziprasidone at dosages greater than 120 mg/day, with rapid
titration, are more likely to be effective than lower dosages in the treatment of
schizophrenia, schizoaffective disorder, and bipolar disorder, while excessive
dosages may incur additional side effects rather than additional efficacy.
Maintenance Therapy
The maintenance efficacy of ziprasidone in treating schizophrenia and
schizoaffective disorder has been studied in a series of double-blind and open-
label extension trials (Arato et al. 2002; Hirsch et al. 2002; Kane 2003a;
Schooler 2003; Simpson et al. 2002, 2004b). These studies indicate that long-
term therapy with ziprasidone maintains clinical response and is effective in
preventing relapse.
Treatment-Resistant Schizophrenia
Several studies have evaluated ziprasidone use in refractory schizophrenia, albeit
using different criteria for “refractory.” A 12-week double-blind comparison of
ziprasidone and chlorpromazine (N=306 patients) defined treatment-resistant
status as inability to achieve criterion-level response after 6 weeks of prospective
treatment with haloperidol (Kane et al. 2006). The mean daily dose of
ziprasidone at study endpoint was approximately 154 mg, compared with a mean
daily chlorpromazine dose of approximately 744 mg. Treatment with ziprasidone
produced significantly greater improvement at endpoint in PANSS–Negative
subscale scores compared with chlorpromazine. In addition, ziprasidone
treatment was associated with a 1.3-fold higher likelihood of achieving a 50%
reduction in BPRS total score compared with chlorpromazine treatment. The
Monitoring Oral Ziprasidone As Rescue Therapy (MOZART) study in
antipsychotic-resistant/intolerant patients (Sacchetti et al. 2009), an 18-week
randomized, flexible-dose, double-blind trial, evaluated ziprasidone as an
alternative to clozapine in treatment-refractory schizophrenia. Patients had a
history of nonresponse and/or intolerance to at least three acute cycles of
different antipsychotic medications given at therapeutic doses, with persistent
PANSS–Total scores of at least 80. Patients were randomly assigned to receive
ziprasidone 80–160 mg/day or clozapine 250–600 mg/day. A progressive and
significant reduction from baseline in PANSS–Total score was observed from
day 11 in both study arms, without between-drug differences and with similar
rates of early discontinuation due to adverse events. Ziprasidone had a more
tolerable metabolic profile in the short-term treatment.
A small amount of literature suggests that the addition of a second
antipsychotic medication to clozapine in patients who do not respond to or
cannot tolerate standard dosages of clozapine may provide additional benefits. In
the context of safety concerns and increasing health care costs, there is currently
limited empirical evidence for the efficacy and safety of such antipsychotic
combinations (Kreyenbuhl et al. 2007). However, adjunctive treatment with
ziprasidone or risperidone, for example, was found helpful in patients with
refractory schizophrenia that was incompletely responsive to clozapine (Zink et
al. 2009). Both adjunctive antipsychotics produced additional reductions on
PANSS–Positive and –Negative symptom subscale scores after 6 weeks of
treatment, and the intervention was well tolerated. Further investigations are
needed before definitive recommendations can be made, and treatment resistance
should be operationalized uniformly so as to facilitate comparative research.
Bipolar Disorder
Acute Mania
Ziprasidone has received regulatory approval (e.g., by the FDA) for the acute
treatment of bipolar mania, with efficacy for acute mania demonstrated in two
double-blind, placebo-controlled trials, each 3 weeks in duration, in patients with
bipolar I disorder (Keck et al. 2003b; Potkin et al. 2005). In both studies, onset
of action was rapid (within 48 hours) and sustained through 3 weeks of treatment
in patients with bipolar mania or bipolar mixed states, with or without psychotic
symptoms. (The results of the study by Keck et al. [2003b] are shown in Figure
30–3.) At endpoint, approximately half of the treated patients from both studies
met response criteria for mania (≥50% reduction in Mania Rating Scale [MRS]
scores).
FIGURE 30–3. Effect of ziprasidone on mania: rating scale
scores in patients with bipolar disorder receiving 21-day
randomized treatment with ziprasidone or placebo.
*P<0.003 (F test), placebo-treated patients versus ziprasidone-treated patients.
**P<0.001 (F test), placebo-treated patients and ziprasidone-treated patients.
Source. Adapted from Keck et al. 2003b.
Bipolar Depression
Preliminary results indicate that ziprasidone may be a viable treatment option in
bipolar depression. For example, an 8-week open-label study investigating
ziprasidone monotherapy for depressive symptoms in bipolar II patients (n=30
completers) demonstrated effective attenuation of depression with a relatively
low mean dosage of 58 mg/day (Liebowitz et al. 2009). The authors concluded
that larger and controlled trials are required to confirm their findings.
Dysphoric Mania
Dysphoric mania is a common and often difficult-to-treat subset of bipolar mania
that is associated with significant depressive symptoms. Data from a post hoc
analysis of two similarly designed 3-week placebo-controlled trials (Stahl et al.
2010a) in acute bipolar mania that were pooled and analyzed indicated that
ziprasidone significantly improved both depressive and manic mood symptoms
in patients with dysphoric mania. A meta-analysis by Muralidharan et al. (2013)
suggested that SGAs, including ziprasidone, are effective for the treatment of
mixed states of bipolar disorder with predominant manic symptoms. A number
of trials could not be included because data for mixed episodes were not
presented separately. Similar to the preliminary results obtained in bipolar
depression, definitive conclusions await further prospective controlled trials.
Maintenance Treatment
Two 52-week open-label extension studies support the safety, tolerability, and
sustained efficacy of ziprasidone as maintenance treatment for bipolar disorder
(P.E. Keck et al. 2004, 2009; Weisler et al. 2004). P.E. Keck et al. (2004)
reported that treatment with ziprasidone (n=127; mean dosage, 123 mg/day) was
associated with significantly lower MRS and CGI-S scores compared with
baseline, beginning as early as the first week. Overall, improvements in manic
symptoms achieved during acute treatment continued to consolidate during
maintenance treatment with ziprasidone. During 52 weeks of treatment, only 6%
of patients discontinued ziprasidone use because of relapse of mania. Similarly,
only 4% of patients discontinued because of a clinical switch into depression. An
important caveat regarding these results is the high rate of attrition observed by
the end of 1 year, which is consistent with long-term studies involving other
SGAs but still limits the full interpretation of results. Comparable results were
observed in a separate extension study of adjunctive ziprasidone therapy (mean
dosage, 92.6 mg/day) by Weisler et al. (2004); this study reported a mean
improvement from baseline in MRS scores at all points throughout the study
(Patel and Keck 2006). Finally, subjects with DSM-IV bipolar I disorder
achieving 8 or more consecutive weeks of stability with open-label ziprasidone
(80–160 mg/day) and lithium or valproate were randomly assigned in a 6-month
double-blind maintenance period to receive ziprasidone plus mood stabilizer or
placebo plus mood stabilizer. The time to intervention for a mood episode and
the time to discontinuation for any reason were significantly longer for
ziprasidone compared with placebo (Bowden et al. 2010), indicating that
ziprasidone may be useful in combination with a classic mood stabilizer for
maintenance of euthymia in bipolar disorder.
Treatment-Resistant Depression
A randomized, double-blind, placebo-controlled study, as well as a series of
uncontrolled studies, has sparked interest in the efficacy of ziprasidone for
depression, especially treatment-resistant depression (Barbee et al. 2004; Jarema
2007; Papakostas et al. 2004, 2015).
Papakostas et al. (2004) reported the results of a small study of 20 patients
with major depression resistant to treatment with selective serotonin reuptake
inhibitors (SSRIs). Open-label treatment with ziprasidone for 6 weeks,
adjunctive to ongoing SSRI treatment, was evaluated with an intent-to-treat
analysis that identified 10 treatment responders (defined as having a ≥50%
decrease in depressive symptoms as measured by the 17-item version of the
Hamilton Rating Scale for Depression (Ham-D-17). In order to further evaluate
these effects, a randomized, double-blind, placebo-controlled trial was conducted
to compare adjunctive ziprasidone with adjunctive placebo among 139 adult
outpatients with major depressive disorder (MDD) that had not responded to an
8-week open-label trial of escitalopram alone (Papakostas et al. 2015).
Compared with the patients randomly assigned to receive adjunctive placebo,
those assigned to receive adjunctive ziprasidone (mean dosage, 98 mg/day;
SD=40) with escitalopram demonstrated significantly greater rates of clinical
response as well as significantly greater improvement on the Ham-D-17 Total
score and the Hamilton Rating Scale for Anxiety score. Ziprasidone has also
been tested in non-treatment-resistant depression. A 12-week randomized,
double-blind, placebo-controlled sequential parallel comparison trial of
ziprasidone as monotherapy for MDD in 120 outpatients with depression
conducted by Papakostas et al. (2012) showed no significant efficacy for
ziprasidone compared with placebo. The authors suggested that a larger trial may
be required to detect significant differences.
Agitation
The efficacy of intramuscular ziprasidone for the treatment of agitated psychosis
has been demonstrated in two randomized double-blind trials (2 mg
intramuscular vs. 10 mg or 20 mg intramuscular, respectively, with up to three
more doses allowed as needed at 4-hour or 2-hour intervals, respectively),
leading to regulatory approval by the FDA (Daniel et al. 2001; Lesem et al.
2001). Treatment with single 10- or 20-mg doses leads to rapid reductions in
symptom severity, with most patients having remission of agitation within 1 hour
of dosing. Treatment with intramuscular ziprasidone is associated with a
relatively low rate of concomitant benzodiazepine use (<20%) and may be better
tolerated than haloperidol (Zhang et al. 2013). Sequential use of intramuscular
ziprasidone followed by oral ziprasidone for the treatment of acute psychotic
agitation has demonstrated superior efficacy, compared with sequential use of
intramuscular and oral haloperidol, in two 7-day randomized open-label trials
(Brook et al. 2000; Swift et al. 1998) as well as in a 6-week randomized, single-
blind, flexible-dose study (Brook et al. 2005). Clinical improvement occurred
more rapidly than with haloperidol in one study and as quickly as 30 minutes
after the first intramuscular administration of ziprasidone (Swift et al. 1998).
Cumulative data from these studies indicate that intramuscular ziprasidone can
rapidly control agitation and psychotic symptoms and provide greater mean
improvements in acute agitation than seen with intramuscular haloperidol (e.g.,
greater mean improvements in BPRS total score, agitation, and CGI-S score)
(Brook 2003).
Pediatric Use
Ziprasidone is not approved in the United States by the FDA for use in pediatric
patients. Its use has been evaluated in children and adolescents (ages 10–17
years) experiencing manic or mixed episodes associated with bipolar disorder
(Kuehn 2009). In the European Union it has been approved for the treatment of
bipolar disorder (mania) in pediatric patients. Results from RCTs of ziprasidone
in children and adolescents (ages 10–17 years) with bipolar disorder (Versavel et
al. 2005) and with bipolar disorder, schizophrenia, or schizoaffective disorder
(DelBello et al. 2008) have been reported. In the former study, treatment with
ziprasidone was associated with improvement in mania and overall
psychopathology (Versavel et al. 2005). The latter study focused on safety and
did not report any unexpected tolerability findings in this age population, using a
starting dosage of 20 mg/day titrated to between 80 and 160 mg/day over 1–2
weeks for clinically determined optimal dosing (DelBello et al. 2008). Finally, a
4-week acute randomized, placebo-controlled multicenter trial, followed by a
26-week open-label extension study, in pediatric patients with bipolar disorder
(ages 10–17 years) showed benefits of ziprasidone and a benign short-term side-
effect profile (Findling et al. 2013a). In pediatric schizophrenia, in a study using
a 6-week randomized (2:1), double-blind, placebo-controlled design, ziprasidone
did not separate from placebo (Findling et al. 2013b).
Side Effects and Toxicology
Safety in Pregnancy
Ziprasidone is considered a Category C drug in pregnancy. Although some
specific developmental effects have been noted in animal studies at dosages
ranging from 0.5 to 8.0 times the maximal recommended human dosage (Pfizer
Inc. 2008), there are as yet no similar reports of such effects in humans. The
reader is advised to consult the current USPI for a detailed listing of potential
adverse drug effects identified in the regulatory approval process and
postmarketing surveillance.
Activation Effects
Clinical experience with ziprasidone in the years following initial U.S. approval
has suggested that a small subgroup of patients may experience insomnia, or
what has been characterized as activation or akathisia, soon after initiation of
treatment (Nemeroff et al. 2005). These presentations have been described as
transient manifestations of anxiety, restlessness, insomnia, increased energy, or
hypomania-like symptoms, occurring most commonly at what is now considered
the lower end of the dosage range. Anecdotal reports suggest that starting
dosages of 120 mg/day or greater and more rapid dose titration can substantially
reduce the incidence of these clinical presentations (Weiden et al. 2002). These
anecdotal clinical observations are consistent with controlled experimental
evidence indicating that a significantly lower rate of discontinuation occurs in
patients who begin ziprasidone therapy at higher dosages (120–160 mg/day) than
in patients who receive initial dosages of 80 mg/day or less (Joyce et al. 2006).
Several mechanisms may explain these observations. First, ziprasidone is less
intrinsically sedating than many other antipsychotics in current use (e.g., due to
less H1 receptor antagonism), so that patients initiating ziprasidone treatment
after months or years of receiving a more sedating therapy may experience initial
difficulties adjusting to the new level of drug-related sedation. Second, as
discussed earlier in this chapter (see “Pharmacological Profile” and “Indications
and Efficacy” sections), many patients have been treated with ziprasidone at
dosages that were insufficient to achieve optimal D2 receptor blocking, leading
to undertreatment of the underlying illness compared with what might have been
achieved with an appropriately dosed prior therapy.
Furthermore, ziprasidone underdosing with respect to D2 receptor binding can
produce a well-understood but unwanted pharmacodynamic situation with
respect to the differential balance of 5-HT2C receptor antagonism relative to D2
receptor antagonism. As was illustrated in Figure 30–2, use of ziprasidone
dosages at the lower end of the clinical dosage range can allow 5-HT2 receptors
to reach 50% or greater maximal receptor occupancy well before clinically
significant levels of D2 receptor occupancy are achieved (Mamo et al. 2004). 5-
HT2C receptor antagonist activity at this level disinhibits cortical monoaminergic
neurotransmission (e.g., dopamine release), which, in the absence of sufficient
D2 receptor blockade, may lead to clinically relevant excess monoaminergic
neurotransmission (Bonaccorso et al. 2002; Pozzi et al. 2002). Clinicians
commonly address these potential issues through appropriate dosing and through
the transient targeted use of concomitant medication strategies (e.g., adjunctive
benzodiazepine treatment) for relevant patients starting new treatment in the
acute inpatient setting or for stable outpatients needing a smooth transition to
new therapy.
DRESS Syndrome
In 2014, the FDA issued a warning that ziprasidone is one of more than 50
medications associated with a rare condition called Drug Reaction with
Eosinophilia and Systemic Symptoms (DRESS) syndrome. This potentially life-
threatening hypersensitivity reaction presents as a skin rash with fever,
eosinophilia, lymphadenopathy, and multiorgan inflammation. Patients who
develop this constellation of symptoms during treatment with ziprasidone should
be evaluated for possible DRESS syndrome, and if that syndrome is suspected,
their medication should be discontinued (Cacoub et al. 2011).
Ziprasidone’s effects on plasma glucose and lipid levels are best understood as
being a function of treatment-related changes in adiposity. Whereas some
antipsychotics, such as clozapine and olanzapine, have been reported to produce
adiposity-independent effects on insulin sensitivity and related changes in
glucose and lipid metabolism, ziprasidone has demonstrated no similar
adiposity-independent effects in this same experimental paradigm (Houseknecht
et al. 2007). In general, increases in adiposity are associated with decreases in
insulin sensitivity in individuals taking or not taking antipsychotic medications,
with reduced insulin sensitivity leading to increased risk for hyperglycemia,
dyslipidemia, and other adverse changes in cardiometabolic risk indicators
(Haupt et al. 2007; Newcomer and Haupt 2006; Strassnig et al. 2015).
Both short- and long-term studies have shown minimal adverse effects of
ziprasidone on glucose levels, plasma insulin levels, insulin resistance, or fasting
and nonfasting lipid levels (Daniel et al. 1999; Glick et al. 2001; Rettenbacher et
al. 2006; Simpson et al. 2004a, 2005), in contrast to the degree of adverse effects
detected with some active comparators. For example, olanzapine treatment can
produce statistically significant increases in fasting glucose and insulin levels
(Glick et al. 2001; Hardy et al. 2003; Simpson et al. 2002, 2005). In the CATIE
phase 1 study, ziprasidone treatment was associated with minimal drug
exposure–adjusted mean increases in blood glucose (+2.9±3.4 mg/dL) and
hemoglobin A1c (HbA1c) (+0.11 ±0.09%) and decreases in plasma triglycerides
(−16.5±12.2 mg/dL) and total cholesterol (−8.2±3.2 mg/dL) (Lieberman 2007).
In the CATIE phase 2 study, ziprasidone-treated patients showed minimal drug
exposure–adjusted mean increases in blood glucose (+0.8±5.6 mg/dL) and
HbA1c (+0.46±0.3%) and decreases in triglycerides (−3.5±20.9 mg/dL) and total
cholesterol (−10.7±5.1 mg/dL) (Stroup et al. 2006).
Similar to the effect of prior treatment conditions on changes in weight during
treatment with ziprasidone, improvements in plasma lipid levels observed during
ziprasidone treatment in the CATIE study can best be understood as the effect of
switching from a previous treatment that is associated with larger adverse effects
on lipid metabolism to a treatment with minimal adverse effects. Weiden et al.
(2003a) noted that ziprasidone treatment was associated with significant
decreases from baseline in both median nonfasting triglyceride levels and
median nonfasting total cholesterol levels at the end of the 6-week treatment
period in patients whose prior medication was olanzapine or risperidone, with
minimal change following prior treatment with high-potency FGAs like
haloperidol. Notably, the reductions in lipids observed during this study occurred
within the first 6 weeks of initiating treatment with ziprasidone, with substantial
reductions in total cholesterol (>20 mg/dL) and plasma triglycerides (78 mg/dL)
in the patients previously treated with olanzapine. In the 12-month extension of
this study, the reductions achieved in the initial weeks following the switch from
prior treatment were sustained during continued treatment with ziprasidone
(Weiden et al. 2008).
Conclusion
Ziprasidone was the fourth atypical antipsychotic following clozapine to become
available in the United States. This agent has a unique pharmacological profile,
with the highest 5-HT2A/D2 affinity ratio among currently available agents,
potent serotonin and norepinephrine reuptake inhibition activity, agonist activity
at 5-HT1A receptors, and clinically relevant antagonist activity at various 5-HT2
receptor subtypes. Ziprasidone has demonstrated rapid-onset and sustained
efficacy for the treatment of schizophrenia, schizoaffective disorder, and bipolar
mania, with promising evidence of favorable mood, cognitive, and prosocial
effects. It is also available in an intramuscular formulation for the treatment of
acute agitated psychoses, and it was approved for the use of bipolar mania in
children and adolescents 10–17 years of age.
Ziprasidone has highly favorable safety and tolerability profiles with limited
potential for drug–drug and drug–disease interactions—critical issues for a
patient population that generally has a high burden of medical comorbidity and
is commonly exposed to complex polypharmacy. The adverse-effect profile of
ziprasidone is particularly noteworthy in areas that are key to safety and
tolerability in patients with major mental disorders such as schizophrenia and
bipolar disorder, including low drug-related risk for acute EPS and minimal
effects on cardiometabolic risk factors such as obesity and dyslipidemia.
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CHAPTER 31
Asenapine
Leslie L. Citrome, M.D., M.P.H.
Pharmacological Profile
Asenapine is a second-generation (atypical) antipsychotic that belongs to the
chemical class of dibenzo-oxepino pyrroles (Figure 31–1). Its receptor-binding
profile is notable for high affinity (Ki [values in nM]) for several 5-
hydroxytryptamine (5-HT; serotonin) receptor subtypes, including 5-HT2C
(0.03), 5-HT2A (0.06), 5-HT7 (0.13), 5-HT2B (0.16), and 5-HT6 (0.25), and for
several dopamine receptor subtypes, including D3 (0.42), D2 (1.3), D1 (1.4), and
D4 (1.1) (Actavis 2015; Shahid et al. 2009). Asenapine also has high binding
affinities to histamine H1 (1.0) and to norepinephrine α1 (1.2) and α2 (1.2)
receptors. Asenapine binds with somewhat lower affinity to serotonin 5-HT5
(1.6), 5-HT1A (2.5), and 5-HT1B (4.0) receptors and histamine H2 (6.2) receptors.
Asenapine very weakly binds to muscarinic M1 (8,128) receptors. Asenapine
acts as an antagonist at all of the above receptors.
Approved Indications
Asenapine’s efficacy in acute schizophrenia in adults was tested in four pivotal
short-term randomized, double-blind, placebo- and active comparator–controlled
multicenter studies (Citrome 2011b, 2014b). Two studies were accepted by the
FDA as supportive of asenapine’s efficacy in the acute treatment of
schizophrenia in adults (Kane et al. 2010; Potkin et al. 2007). Asenapine’s
efficacy in the treatment of manic or mixed episodes of bipolar I disorder in
adults was supported in both of two completed Phase III randomized, placebo-
and active comparator–controlled 3-week trials (McIntyre et al. 2009a, 2010a).
Approximately 1 year after the initial approval of asenapine for these
indications, the FDA approved asenapine for the maintenance treatment of
schizophrenia (based on a double-blind, placebo-controlled multicenter clinical
trial [Kane et al. 2011]) and for use as adjunctive therapy with either lithium or
valproate in the acute treatment of manic or mixed episodes associated with
bipolar I disorder (again based on a placebo-controlled trial [Szegedi et al.
2012]). Approval of asenapine for the treatment of bipolar mania in pediatric
patients (ages 10–17 years) was obtained in 2015 based on a placebo-controlled
trial (Findling et al. 2015b).
In adults, the recommended dosage of asenapine for acute schizophrenia is 5
mg bid; that for bipolar manic or mixed episodes is 10 mg bid (5 mg bid if
administered with lithium or valproate), based on the clinical trials used to
obtain regulatory approval. Titration to these target dosages is not necessary. In a
modeling and simulation study (Friberg et al. 2009), asenapine dosages of 5 and
10 mg bid had similar efficacy in the acute treatment of schizophrenia. In the
maintenance study in schizophrenia on which asenapine’s approval for that
indication was based, the most commonly used dosage was 10 mg bid (Kane et
al. 2011).
In pediatric patients (ages 10–17 years) with bipolar mania, the recommended
starting dosage of asenapine as monotherapy is 2.5 mg bid, with increases up to
10 mg bid possible.
Schizophrenia
Short-Term Efficacy
In one of the two positive trials, 458 patients with acute schizophrenia were
randomly assigned to fixed-dosage treatment with asenapine at 5 mg bid,
asenapine at 10 mg bid, placebo, or an active control for assay sensitivity
(haloperidol at 4 mg bid) for 6 weeks (Kane et al. 2010). The primary efficacy
endpoint was change from baseline in the Positive and Negative Syndrome Scale
(PANSS; Kay et al. 1987) total score. On analyses of change in PANSS total
score, asenapine at 5 mg bid and haloperidol were both superior to placebo, with
statistically significant differences seen from day 21 onward. However,
asenapine at 10 mg bid did not demonstrate an advantage over placebo, a finding
that the authors suggested may have been due in part to the high placebo
response rate in this trial. Rates of response—defined as a minimum reduction of
30% in the PANSS total score or a Clinical Global Impression–Improvement
(CGI-I) score of 1 (very much improved) or 2 (much improved)—were 55% for
asenapine 5 mg bid, 49% for asenapine 10 mg bid, 43% for haloperidol, and
33% for placebo, yielding numbers needed to treat (NNTs) (Citrome 2008)
versus placebo of 5 for asenapine 5 mg bid, 7 for asenapine 10 mg bid, and 10
for haloperidol (Citrome 2011b).
In the second short-term acute schizophrenia trial that was considered positive
and supportive of asenapine’s efficacy, 182 patients were randomly assigned to
asenapine 5 mg bid, placebo, or an active control for assay sensitivity
(risperidone 3 mg bid) for 6 weeks (Potkin et al. 2007). The primary efficacy
endpoint was change from baseline in the PANSS total score. Compared with
placebo, asenapine produced significantly greater decreases in PANSS total
scores from week 2 onward. Risperidone did not statistically significantly
separate from placebo. Using the criterion of reduction in the PANSS total score
of at least 30%, 38% of the patients in the asenapine group were categorized as
responders, compared with 39% of those in the risperidone group and 25% of
those in the placebo group, yielding NNTs versus placebo of 8 for asenapine and
7 for risperidone (Citrome 2011b).
Two other 6-week acute schizophrenia trials were conducted (Citrome 2011b;
U.S. Food and Drug Administration 2009). One trial was considered negative
because asenapine at 5 or 10 mg bid failed to separate from placebo, whereas the
active control (olanzapine at 15 mg/day) did separate from placebo. The other
trial was considered a failed trial because neither asenapine at 5 or 10 mg bid nor
the active control (olanzapine 10–20 mg/day) separated from placebo. An
additional double-blind trial was conducted in Asian patients where 532 adult
participants from Japan, Korea, and Taiwan were randomly assigned to receive
asenapine 5 mg bid, 10 mg bid, or placebo for 6 weeks (Kinoshita et al. 2016).
The primary efficacy endpoint was change from baseline on the PANSS total
score. Improvements from baseline on PANSS total scores were significantly
greater in the patients receiving asenapine 5 mg bid or 10 mg bid, compared with
those receiving placebo, from days 14 and 7, respectively. Using the criterion of
reduction in PANSS total score of at least 30%, 39% of the patients in the
asenapine 5 mg bid group and 44% of those in the 10 mg bid group were
categorized as responders, compared with 21% of those in the placebo group,
yielding NNTs versus placebo of 6 for asenapine 5 mg bid and 5 for asenapine
10 mg bid.
An 8-week, placebo-controlled, double-blind trial in 306 adolescent (ages 12–
17 years) patients with schizophrenia failed to demonstrate asenapine’s efficacy
at dosages of 2.5 and 5 mg twice daily (Findling et al. 2015a).
Longer-Term Efficacy
Asenapine’s longer-term efficacy in schizophrenia was examined in a published
1-year double-blind study in 1,225 patients with schizophrenia or schizoaffective
disorder. Patients were randomly assigned to receive asenapine (5 mg bid for the
first week and then flexible dosing of 5 or 10 mg bid) or olanzapine (10 mg/day
for the first week and then flexible dosing of 10 or 20 mg/day) (Schoemaker et
al. 2010). There was no placebo arm. Rates of discontinuation because of
insufficient therapeutic effect were 25.1% for asenapine and 14.5% for
olanzapine (NNT=10 for olanzapine versus asenapine to avoid discontinuation
because of insufficient therapeutic effect). Changes from baseline in PANSS
total score were similar for asenapine and olanzapine at week 6 but showed a
statistically significant difference in favor of olanzapine at endpoint (last
observation carried forward). Among the patients who completed the entire year-
long trial, changes in PANSS total score were similar for asenapine and
olanzapine at week 6 and also at week 52. Completers were eligible to
participate in an extension study in which clinical stability was further
demonstrated (Schoemaker et al. 2012).
Asenapine’s efficacy in the maintenance phase of schizophrenia was
demonstrated in a published 26-week double-blind, placebo-controlled
multicenter clinical trial (Kane et al. 2011). Patients were randomly assigned
either to continue receiving asenapine or to receive placebo after establishing
stability on asenapine during the 26 weeks of open-label treatment immediately
prior. Of the 700 enrolled patients who were treated with open-label asenapine,
386 met stability criteria and entered the double-blind phase. Times to
relapse/impending relapse and to discontinuation for any reason were
significantly longer with asenapine than with placebo. The incidence of relapse
or impending relapse was 12.1% for asenapine and 47.4% for placebo (NNT=3).
Completion rates were 69.6% for asenapine and 37.5% for placebo (NNT=4).
The most commonly used dosage of asenapine was 10 mg bid in both the open-
label and the double-blind phases.
In two randomized, double-blind 26-week studies and their respective 26-
week extensions, Buchanan et al. (2012) tested the hypothesis that asenapine is
superior to olanzapine for persistent negative symptoms of schizophrenia and
assessed the comparative long-term efficacy and safety of the two agents.
Approximately 1,000 subjects participated. In the two core studies, 26-week
completion rates with asenapine were 64.7% and 49.6%, versus 80.4% and
63.8%, respectively, with olanzapine. In the two extension studies, completion
rates were 84.3% and 66.3% with asenapine versus 89.0% and 80.9%,
respectively, with olanzapine. Asenapine was not superior to olanzapine in
change in the 16-item Negative Symptom Assessment Scale total score in either
core study, but asenapine was superior to olanzapine at week 52 in one of the
extension studies. Weight gain was consistently lower with asenapine.
Extrapyramidal side effect (EPS)–related adverse-event incidence was higher
with asenapine, but Extrapyramidal Symptom Rating Scale–Abbreviated total
score changes did not differ significantly between treatments.
Bipolar Disorder
In two identically designed 3-week acute studies of asenapine in the treatment of
bipolar manic or mixed episodes (McIntyre et al. 2009a, 2010a), 977 subjects
were randomly assigned to receive flexibly dosed asenapine 5–10 mg bid
(starting dosage 10 mg bid), olanzapine 5–20 mg/day (starting dosage 15
mg/day), or placebo. The primary outcome measure for each of these studies was
change from baseline in the Young Mania Rating Scale (YMRS; Young et al.
1978) total score. In the first study (McIntyre et al. 2009a), YMRS total scores
were statistically significantly improved from baseline to day 21 for asenapine
and olanzapine compared with placebo. Sustained statistically significant
improvement in the YMRS score compared with placebo was noted for
asenapine and olanzapine from day 2 onward. Percentages of subjects meeting
criteria for response (50% decrease from baseline YMRS total score) and
remission (YMRS total score ≤12) were higher with asenapine (42.3% and
40.2%, respectively) than with placebo (25.2% and 22.3%, respectively),
yielding NNTs for response and for remission versus placebo of 6. The NNT for
response for olanzapine versus placebo was 5, and that for remission was 6.
In the second study (McIntyre et al. 2010a), YMRS total scores also were
statistically significantly improved from baseline to day 21 for asenapine and
olanzapine compared with placebo, with sustained statistically significant
improvement in the YMRS total score versus placebo noted for asenapine and
olanzapine from day 2 onward. In post hoc analyses, changes in YMRS total
scores from baseline to day 21 were significantly greater for olanzapine than for
asenapine with last observation carried forward analysis, but not with mixed
model for repeated measures analysis. Rates of response (42.6%) and remission
(35.5%) with asenapine did not differ significantly from those with placebo
(34% and 30.9%, respectively), yielding NNTs of 12 and 22, respectively.
Olanzapine was superior to placebo in rates of response (54.7%) and remission
(46.3%), with NNTs for olanzapine versus placebo of 5 and 7, respectively, and
for olanzapine versus asenapine of 9 and 10, respectively. Based on the above
studies, the recommended starting dose of asenapine monotherapy for acute
bipolar mania or mixed episodes in adults is 10 mg bid. However, additional
information is available from a 3-week, double-blind, placebo-controlled, fixed-
dose study of asenapine 5 mg bid and 10 mg bid in adults with an acute bipolar I
disorder manic or mixed episode (Landbloom et al. 2016). Both asenapine doses
were statistically superior to placebo in mean change from baseline to day 21 in
YMRS total score, suggesting that 5 mg bid can be an adequate dose for adults
with acute bipolar mania or mixed episodes. However, in this trial, neither
asenapine dose had significantly more YMRS responders or remitters at day 21
than placebo.
Asenapine’s longer-term efficacy in patients with manic or mixed episodes of
bipolar disorder was assessed in a 9-week extension (McIntyre et al. 2009b) to
the original two pivotal studies (McIntyre et al. 2009a, 2010a), followed by an
additional 40-week extension (McIntyre et al. 2010b). A total of 504 subjects
received at least one dose of double-blind trial medication during the 9-week
extension trial and included 181 subjects who were treated with asenapine and
229 who were treated with olanzapine from the feeder trials (and who continued
on the same treatment in the extension). In addition, 94 subjects who were
treated with placebo in the feeder trials were blindly allocated to receive
asenapine 5–10 mg bid in the extension trial. The primary efficacy analysis
demonstrated that asenapine was statistically noninferior to olanzapine as
measured by the YMRS total score from baseline to day 84 for the observed case
subjects who had 3 weeks of previous exposure to study medication. The
proportions of participants who were YMRS responders and remitters were
similar in the asenapine and olanzapine groups: the rates of response at last
observation carried forward endpoint were 77% and 82% with asenapine and
olanzapine, respectively, and the rates of remission were 75% and 79%,
respectively. For the 218 patients who were subsequently enrolled for another 40
weeks of double-blinded treatment, maintenance of efficacy was observed for
both asenapine and olanzapine, with no differences in response or remission
rates between the two agents.
Another study tested the efficacy of asenapine 5 mg bid in the treatment of an
acute manic or mixed episode when combined with lithium or divalproex over
12 weeks (Szegedi et al. 2012), and its findings supported this indication as
approved by the FDA (Actavis 2015). Adjunctive asenapine significantly
improved mania versus placebo at week 3 (primary endpoint) and weeks 2–12.
The YMRS response rates were similar at week 3 but significantly better with
asenapine at week 12. The YMRS remission rates and changes from baseline on
the Clinical Global Impression–Bipolar (CGI-BP) for mania and overall illness
were significantly better with asenapine at weeks 3 and 12. Patients completing
the core study were eligible for a 40-week double-blind extension assessing
safety and tolerability (Szegedi et al. 2012).
Asenapine’s efficacy in the treatment of acute mania in pediatric patients (ages
10–17 years) was established in a single 3-week placebo-controlled, double-
blind trial of 403 patients, of whom 302 received asenapine at fixed dosages of
2.5 mg, 5 mg, and 10 mg bid (Findling et al. 2015b). All patients were started on
2.5 mg bid, and dosages were titrated upward every 3 days in a stepwise fashion
for patients randomly assigned to receive the higher dosages. Asenapine was
statistically superior to placebo in improving YMRS total scores and CGI-BP
severity of illness scores. YMRS responder rates were 42%, 54%, and 52% for
asenapine 2.5 mg, 5 mg, and 10 mg bid, respectively, versus 28% for placebo,
yielding corresponding NNT values for asenapine versus placebo of 8, 4, and 5.
Agitation
Although asenapine is not approved for this indication, it was tested for the
management of agitation in a randomized controlled trial (Pratts et al. 2014).
Adults ages 18–65 years (N=120, any diagnosis) manifesting agitation in an
emergency department and found to have a score of ≥14 on the PANSS–Excited
Component (PANSS-EC) were randomly assigned to receive either a single
sublingual 10-mg tablet of asenapine or matching placebo. Changes in PANSS-
EC score at 2 hours were statistically significantly greater for the asenapine-
treated subjects compared with the placebo-treated subjects, with an effect noted
at 15 minutes, the earliest time point at which outcome was measured. The NNT
value for response versus placebo was 3, an effect size comparable to that
observed in prior studies of intramuscular antipsychotics. This study awaits
replication.
Conclusion
Asenapine’s efficacy is evidenced both in short-term acute clinical trials and in
longer-term studies. In the mind of the clinician, asenapine will likely be
measured against other “metabolically friendly” second-generation
antipsychotics such as ziprasidone, aripiprazole, iloperidone, lurasidone,
brexpiprazole, and cariprazine, as well as newer agents in the antipsychotic
development pipeline (Citrome 2011a, 2013, 2015). Differences among these
choices include dosing factors (daily versus twice-daily dosing, the need for
dosage titration, special requirements for administration with or without food) as
well as specific side-effect profiles.
Asenapine is unique in being the only antipsychotic that is absorbed primarily
in the oral mucosa. Nonadherence by “cheeking” becomes moot. The possibility
of oral hypoesthesia and dysgeusia (distorted or bad taste), a medication effect
likely not experienced previously by the patient, necessitates advance warning.
In summary, asenapine’s place in the treatment of schizophrenia and bipolar
manic or mixed episodes is likely to be in patients for whom metabolic concerns
are of import and in patients who would prefer a sublingual preparation.
Substantial heterogeneity exists among the different antipsychotics and among
individual patients (Volavka and Citrome 2009), so that asenapine has a
legitimate place on a formulary.
Specific obstacles to the first-line use of asenapine are the recommendations
for twice-daily versus once-daily administration and the recommendation to
avoid food or liquids for 10 minutes after dosing. Cost may be a further
impediment, given the availability of inexpensive generic versions of
risperidone, quetiapine, ziprasidone, and olanzapine in the United States, as well
as other generic second-generation antipsychotics in other countries.
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CHAPTER 32
Iloperidone
Peter F. Buckley, M.D.
Adriana E. Foster, M.D.
Oliver Freudenreich, M.D.
Scott Van Sant, M.D.
Schizophrenia
Pivotal Clinical Trials
Iloperidone’s FDA approval for the treatment of schizophrenia was
predominantly based on four short-term placebo-controlled trials, highlighted in
Table 32–1. In addition, two long-term trials have been published (Cutler et al.
2013; Kane et al. 2008). These studies are described in the following paragraphs.
A more complete review of drug development and initial trials in humans is
provided elsewhere (Citrome 2010; Rado and Janicak 2014).
Symptom
Iloperidone and Efficacy change from
comparator drug outcome baseline to
Study N and diagnosis dosages (mg/day) measure endpoint
Potkin et al. 1,943 patients Study 1: ILO 4, 8, Primary: Study 1
2008 Three with 12; HAL 15; PLA PANSS-T
6-week schizophrenia Study 2: ILO 4–8, or PANSS-
randomized, or 10–16; RIS 4–8; derived
double-blind schizoaffective PLA BPRS
studies disorder Study 3: ILO 12–16, change
comparing 20–24; RIS 6–8; from
ILO against PLA baseline to
PLA endpoint
Secondary:
PANSS-P,
PANSS-N,
PANSS-GP;
BPRS
change
from
baseline to
each
postbaseline Studies 2 and
assessment;
CGI-S in
Studies 2
and 3
Potkin et al. 1,553 patients All ILO
2008 who remained
Combined in the studies
analysis of at least 2
three studies weeks
Cutler et al. 593 patients with ILO 24; ZIP 160; Primary: ILO reduced
2008 4- schizophrenia PLA change
week study from
1-week baseline in
titration 3- PANSS-T
week for ILO vs. ILO and ZIP
double-blind PLA
treatment Secondary:
for acute change
exacerbation from
baseline in
BPRS, ILO reduced
PANSS-P,
PANSS-N,
PANSS-GP,
CGI-S,
CGI-C,
CDSS Neither ILO
Kane et al. 473 patients with ILO 4–16; HAL 5– Primary: Difference in
2008 Long- schizophrenia 20 time to
term (46- or Mean dosage at end relapse*
week) schizoaffective of Secondary:
double-blind disorder who maintenance=12.5 change
maintenance had responded
phase after to ILO for both drugs from
6-week (n=371) or baseline to
stabilization HAL (n=118) endpoint on
during PANSS,
stabilization BPRS, and Relapse rate
phase (36.6% CGI-C
responded to
ILO and
37.8% to HAL
in the acute Both groups
phase)
Potkin et al. (2008) reviewed the 6-week double-blind period of the pivotal
trials that evaluated iloperidone’s efficacy in the treatment of schizophrenia. All
of these trials included screening, an acute double-blind phase, and a long-term
maintenance phase.
Study 1 enrolled patients ages 18–65 years with acute or subacute
exacerbations of schizophrenia or schizoaffective disorder and with Positive and
Negative Syndrome Scale (PANSS) scores of 60 or greater. One hundred twenty-
one patients were randomly assigned to receive iloperidone 4 mg/day, 125 to
iloperidone 8 mg/day, 124 to iloperidone 24 mg/day, 124 to haloperidol 15
mg/day, and 127 to placebo. After a screening and a 3-day placebo run-in period
as well as a 7-day fixed-titration period, patients were placed on study
medication for 5 weeks. The primary objective was to determine the efficacy of
iloperidone versus placebo. The primary efficacy variable was change in PANSS
total score (PANSS-T) from baseline to endpoint (day 42 or last visit before
discontinuation). Although PANSS-T scores improved significantly from
baseline for the iloperidone 12 mg/day (P=0.047) and the haloperidol (P<0.001)
groups, improvement for the combined iloperidone 8 mg/day and 12 mg/day
group was not significantly different from that for the placebo group. The all-
cause discontinuation rates were 57%, 64%, and 58% for iloperidone 4 mg/day,
8 mg/day, and 12 mg/day, respectively; 65% for haloperidol; and 69% for
placebo (Potkin et al. 2008).
In Study 2, patients selected according to the same inclusion criteria used in
Study 1 were randomly assigned to receive iloperidone 4–8 mg/day (n=53; 52%
discontinued the study before endpoint) or 10–16 mg/day (n=154; 44%
discontinued), risperidone 4–8 mg/day (n=153; 42% discontinued), or placebo
(n=156; 60% discontinued). The primary objective was again to determine the
efficacy of iloperidone versus placebo. Both dosage ranges of iloperidone
resulted in significant symptom improvement (as measured by Brief Psychiatric
Rating Scale [BPRS] scores) from baseline compared with placebo (Potkin et al.
2008).
In Study 3, patients selected according to the previously described criteria
were randomly assigned to receive iloperidone 12–16 mg/day (n=244; 46%
discontinued) or 20–24 mg/day (n=145; 41% discontinued), risperidone 6–8
mg/day (n=157; 29% discontinued), or placebo (n=160; 46% discontinued). In
this study, the iloperidone 12–16 mg/day dosage failed to separate from placebo
(Potkin et al. 2008).
A combined analysis of all three studies was performed to eliminate the
impact of early discontinuations (i.e., those occurring in the initial 2 weeks of the
studies, during which the drug reaches steady state). When the analysis was
restricted to patients who had remained in double-blind treatment for at least 2
weeks (n=1,553), it showed that each of the iloperidone dosage ranges (4–8, 10–
16, and 20–24 mg/day) separated significantly from placebo (Potkin et al. 2008).
A 4-week double-blind study (Cutler et al. 2008) evaluated the efficacy of
iloperidone 24 mg/day against that of placebo and of ziprasidone 160 mg/day in
patients with an acute exacerbation of schizophrenia by measuring change from
baseline in the PANSS-T score and the PANSS positive, negative, and general
psychopathology scale scores; the Calgary Depression Scale for Schizophrenia
(CDSS) score; and the Clinical Global Impression–Severity (CGI-S) score.
Iloperidone significantly reduced PANSS-T scores at 4 weeks compared with
placebo. Although both iloperidone and ziprasidone significantly improved
negative and positive PANSS and CGI-S scores compared with placebo, none of
the drugs improved PANSS general psychopathology scores significantly, nor
did any drug affect CDSS scores.
Kane et al. (2008) conducted a long-term efficacy analysis using data from
patients who had completed the 6-week double-blind phase of the three pivotal
studies described above. Patients who had at least a 20% reduction in PANSS-T
scores and a CGI score of less than 4 and who had received at least one dose of
long-term-phase medication were randomly assigned to iloperidone or
haloperidol for 48 weeks of double-blind maintenance treatment (mean dosage at
endpoint=12.5 mg/day for both drugs). The primary efficacy variable was
relapse (defined as an increase of 25% or greater on the PANSS score).
Differences between the iloperidone group and the haloperidol group in time to
relapse were not significant—63.6% of patients in both groups completed the
long-term phase of the trial.
Cutler et al. (2013) reported on a 25-week open-label extension study. More
than 58% of patients discontinued iloperidone. Overall improvement was seen in
80% of patients.
Weiden et al. (2014) reported on a 12-week trial in which schizophrenia
patients who were taking risperidone, olanzapine, or aripiprazole but were
experiencing problems with tolerability or efficacy were switched to iloperidone
(up to 12 mg twice daily) via random assignment to either an immediate-
cessation or a gradual-downtitration strategy. The results were similar across all
groups, and the two switching strategies yielded comparable efficacy and
tolerability.
Pharmacogenetic Studies
Clinical trials of iloperidone sought to establish the drug’s pharmacogenetic
characteristics (Volpi et al. 2009a, 2009b) by exploring the relationship between
iloperidone’s efficacy and various candidate genes related to dopamine
receptors, dopamine β-hydroxylase, the serotonin 1B (5-HT1B) receptor, and the
ciliary neurotrophic factor (CNTF). CNTF is a cytokine in the interleukin-6
cytokine family that suppresses noradrenergic and serotonergic function (Galter
and Unsicker 1999). A null mutation in the CNTF gene leads to a non-G/G
rs1800169 genotype that cannot produce a functional protein and has been
linked to an increased risk of psychosis (Thome et al. 1996). However, a meta-
analysis involving more than 1,000 patients and a similar number of control
subjects (Lin and Tsai 2004) found no association between CNTF and
schizophrenia risk.
In a 4-week randomized, placebo-controlled study in 417 patients genotyped
for CNTF, 279 received iloperidone and 138 received placebo (Lavedan et al.
2008). Iloperidone improved symptom scores significantly versus placebo in
patients with an active CNTF gene, whereas patients with the CNTF null allele
showed no greater response to iloperidone than to placebo.
In a whole-genome study of 407 patients from the same sample, of which 218
patients received iloperidone, six single-nucleotide polymorphisms (SNPs)
associated with iloperidone efficacy were identified (Volpi et al. 2009b). The
identified loci included SNPs of the neuronal PAS domain protein 3 gene
(NPAS3); of the XK Kell blood group complex subunit–related family member 4
gene (XKR4); of the tenascin-R gene (TNR); of the glutamate receptor ionotropic
AMPA 4 gene (GRIA4); of the glial cell line–derived neurotrophic factor
receptor alpha 2 gene (GFRA2); and of the NUDT9P1 pseudogene located in the
chromosomal region of the serotonin receptor 7 gene (HTR7). More than 75% of
the iloperidone-treated patients in the group with the optimal genotype
combinations showed a ≥20% symptom improvement, whereas only 37% of
patients with other genotypes showed a ≥20% improvement.
Another whole-genome association study (Volpi et al. 2009a) was conducted
in 183 patients with schizophrenia who received an electrocardiogram (ECG) on
day 14 of treatment with iloperidone, after the drug had reached steady state.
DNA polymorphisms associated with QT prolongation were found in six loci,
including CERKL, thought to be part of the ceramide pathway; SLCO3A1, which
encodes the organic anion-transporting polypeptide; various genes involved in
myocardial infarction (PALLD), cardiac structure and function (BRUNOL4), and
cardiac development (NRG3); and an SNP on NUBPL with unknown function.
Each SNP defined two genotype groups associated with a low mean QT interval
change or a higher mean QT interval prolongation.
Although these findings have attracted considerable interest from the field,
pharmacogenomic approaches to drug optimization need to be tested further in
larger studies before these findings can be of clinical use. Nevertheless, the
incorporation of pharmacogenetic testing into the regulatory registration trials of
this drug represents an important new aspect of psychopharmacological drug
development.
Other Indications
Little information is available on the use of iloperidone in patients with first-
episode psychosis. Similarly, there are no studies to inform the use of
iloperidone in patients with treatment-refractory schizophrenia. There is no
information on the efficacy or tolerability of iloperidone in patients with
comorbid substance use disorders. Information on the use of iloperidone in other
comorbid conditions and/or in other primary psychiatric and neuropsychiatric
disorders is scant. Given the paucity of data to guide treatment, off-label use of
this drug cannot be recommended.
Orthostatic Hypotension
In view of its antagonism at α1-noradrenergic receptors, iloperidone possesses
the potential for autonomic side effects. In its clinical trials program, iloperidone
was associated with decreases in supine and standing systolic and diastolic blood
pressures in all dosage groups. Decreases in blood pressure were mostly
observed within the first week of treatment and were generally not sustained.
Orthostatic hypotension was observed more frequently in all active-treatment
groups (iloperidone, risperidone, and haloperidol) than in the placebo group.
Sustained orthostatic hypotension was observed in 0.4% (n=2), 3.8% (n=17),
and 4.8% (n=6) of patients receiving iloperidone 4–8 mg/day, 10–16 mg/day,
and 20–24 mg/day, respectively. According to the manufacturer’s full
prescribing information (Vanda Pharmaceuticals 2016), iloperidone must be
initiated slowly and gradually so as to avoid orthostatic hypotension, with a
starting dosage of 1 mg twice daily, increasing to 2 mg, 4 mg, 6 mg, 8 mg, 10
mg, and 12 mg twice daily on days 2, 3, 4, 5, 6, and 7, respectively, to a target
dosage range of 12–24 mg/day. Clinicians should therefore pay particular
attention to dizziness early in treatment with iloperidone. It is also important to
go even slower with initial titration in patients who may be at risk for postural
hypotension (Weiden 2012).
QT Interval Prolongation
With respect to potentially life-threatening side effects, there was evidence of
significant QT/QTc interval prolongation across all iloperidone groups in the
drug’s pivotal study program, and this potential drug effect was a focus of
review by the FDA. Specifically, the least square mean changes in QTc intervals
from baseline to endpoint in these studies were 2.9 msec, 3.9 msec, and 9.1 msec
for iloperidone 4–8 mg/day, 10–16 mg/day, and 20–24 mg/day, respectively. It is
noteworthy that no deaths or serious arrhythmias attributable to QT prolongation
occurred in these studies (Weiden 2012; Weiden et al. 2008). Potkin et al. (2013)
examined the incidence of QTc prolongation in patients randomly assigned to
receive iloperidone, quetiapine, or ziprasidone. To further test for metabolic
inhibition, there was a period of coadministration of paroxetine and paroxetine
plus ketoconazole. These conditions revealed QTc intervals of 60 mg or greater
in approximately 10% of patients receiving iloperidone. However, no patients
had clinical symptoms, and none had a QTc interval that reached or exceeded
500 mg.
Contraindications
According to the manufacturer’s prescribing information (Vanda
Pharmaceuticals 2016), iloperidone should be avoided in combination with other
drugs that are known to prolong the QTc interval, a group that includes Class Ia
(e.g., quinidine, procainamide) and Class III (e.g., amiodarone, sotalol)
antiarrhythmic medications, antipsychotic medications, and antibiotics. This
prohibition makes sense, given iloperidone’s metabolism through these
cytochrome pathways. In addition, it is recommended that iloperidone be
avoided in persons with congenital long-QT syndrome or cardiac arrhythmias.
In common with all other SGAs, iloperidone carries a black box warning
regarding the increased mortality risk associated with use of antipsychotic drugs
in elderly patients with dementia-related psychosis. That said, iloperidone is not
approved for the treatment of patients with dementia-related psychosis, and use
in the elderly should be avoided pending future clinical trials.
Conclusion
Iloperidone is an FDA-approved antipsychotic with proven efficacy in the
treatment of schizophrenia. There remains much to be studied regarding its use
in specific subgroups of psychotic patients. Iloperidone’s utility in nonapproved
mood disorder indications is currently unknown. There is a need for additional
dose-finding studies to guide the optimal use of this drug.
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24529610
CHAPTER 33
Lurasidone
Philip D. Harvey, Ph.D.
Pharmacological Properties
Receptor-Binding Profile
Lurasidone belongs to the chemical class of benzisothiazole derivatives (Figure
33–1). The compound is a full antagonist at dopamine D2 and serotonin 5-HT2A
receptors, a profile it shares with other atypical antipsychotics. Lurasidone also
has high affinity for 5-HT7 receptors, with in vitro affinity for 5-HT7 being
relatively higher than that shown by the drug for D2 and 5-HT2A receptors.
Lurasidone is a partial agonist at 5-HT1A receptors (Ishibashi et al. 2010), and it
has moderate affinity for noradrenergic receptors. Lurasidone’s minimal affinity
for α1-adrenergic receptors would be expected to convey a reduced risk for
orthostatic hypotension in comparison with compounds that have higher affinity
for this receptor. Lurasidone appears to have weak affinity for 5-HT2C receptors
and no affinity for histamine H1 receptors, a profile that should carry relatively
low risk for weight gain. Lurasidone lacks affinity for muscarinic acetylcholine
M1 receptors, which suggests reduced risk for cholinergic cognitive deficits and
other side effects.
Bipolar Depression
Two randomized placebo-controlled trials of lurasidone were conducted in
patients with bipolar depression. In the first study (Loebel et al. 2014a;
monotherapy), lurasidone at two different dosage ranges (20–60 mg/day and 80–
120 mg/day) was compared with placebo. Both dosage ranges separated from
placebo, with similar effect sizes. In the second study (Loebel et al. 2014b;
adjunctive therapy), lurasidone at 20–120 mg/day was added to stable treatment
with either valproate or lithium. Statistically significant separation from placebo
was found. Lurasidone treatment was administered at a mean modal dose of 75
mg/day, which translates to an available dose of 80 mg/day. The results of these
two studies led to lurasidone’s approval by the FDA for both augmentation of
lithium or valproate therapy and monotherapy of bipolar depression in June
2013.
In an additional post hoc analysis of the results of the monotherapy study,
McIntyre et al. (2015) reported that lurasidone was effective in the treatment of
bipolar depression with mixed features, an entity newly defined in DSM-5. The
presence of mixed features was defined as having a Young Mania Rating Scale
(YMRS; Young et al. 1978) score of 4 or greater. Fifty-six percent of the patients
in the study were found to have mixed features (272 out of 485 patients). Of the
patients with mixed features, 182 received treatment with active lurasidone and
90 received placebo treatment. Efficacy for the treatment of depression in
patients with and without mixed features was essentially equivalent: 15.7-point
decreases in Montgomery-Åsberg Depression Rating Scale (MADRS;
Montgomery and Åsberg 1979) scores were seen for patients without mixed
features, and 15.2-point decreases were found for those with mixed features.
Eighty-two percent of the patients without mixed features completed the trial
when treated with active lurasidone, and 73% of the patients with mixed features
completed the study with active treatment. These data indicate that the presence
of mixed features in bipolar depression should not be viewed as a
contraindication to treatment with lurasidone.
In a very recent study (Suppes et al. 2016), lurasidone was tested for efficacy
in major depression with mixed features. This newly defined condition is
characterized by the coexistence within a major depressive episode of a limited
set of manic symptoms (American Psychiatric Association 2013). Patients
selected for the presence of DSM-IV-TR (American Psychiatric Association
2000)–defined major depressive disorder and two or three manic symptoms were
randomly assigned to lurasidone (n=109) or placebo (n=100) for a 6-week trial.
Lurasidone was superior to placebo, leading to a 20.5-point change on the
MADRS for active treatment compared with a 13-point change for placebo
(P<0.001; effect size d=.80). Completion rates were similar for active treatment
and placebo (94% and 85%, respectively), and the remission rate was 49% for
active treatment. Switch into mania did not occur with lurasidone treatment, and
patients who received lurasidone manifested a 7-point decrease in their YMRS
scores. These data suggest efficacy for lurasidone in the treatment of depression
with mixed features as well as bipolar depression.
Class Warnings
The typical class warnings are present on the lurasidone label (Sunovion
Pharmaceuticals 2013), including the black box warning about increased stroke
risk in elderly individuals and a variety of other class warnings regarding
neuroleptic malignant syndrome, tardive dyskinesia, diabetes, hyperlipidemia,
weight gain, glucose abnormalities, hyperprolactinemia, agranulocytosis,
suicide, and seizures. Lurasidone has no warning for QTc alteration; a dedicated
cardiac safety study (referenced in the package insert) found no evidence of QTc
prolongation with lurasidone treatment.
Adverse-Event Reports
Safety information is available from the manufacturer’s safety database (see also
www.sunovionprofile.com/sp/latuda-bp.html). Dose-related adverse effects that
separated from placebo included somnolence, akathisia, and EPS (as measured
by total scores on clinical rating scales for EPS). Of note, weight and metabolic
parameters were only minimally affected in patients with schizophrenia or
bipolar depression in clinical trials. Although short-term changes in cholesterol,
triglycerides, and glucose are likely to be attributable to transition from
medications with more substantial adverse profiles in these domains, the weight-
gain data for lurasidone are very noticeable and consistent.
Promising Features
Studies in Schizophrenia
Three published studies in patients with schizophrenia have addressed the issue
of lurasidone’s cognitive benefit compared with that of other antipsychotics
(Harvey et al. 2011, 2013, 2015).
The first study, which was conducted during the early development phases of
lurasidone, was a 3-week double-blind, randomized head-to-head comparison of
lurasidone versus ziprasidone in generally clinically stable outpatients with
schizophrenia (Harvey et al. 2011). At the time this study was conducted, no
U.S. patients had ever been exposed to lurasidone. Patients were selected for
being naive to treatment with ziprasidone as well. The study examined changes
in performance on a neuropsychological assessment consisting of most of the
tests in the widely used Measurement and Treatment Research to Improve
Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB;
Nuechterlein et al. 2008) and an interview-based assessment of cognitive
functioning, the Schizophrenia Cognition Rating Scale (SCoRS; Keefe et al.
2006). The study found that lurasidone was associated with improvements on
neuropsychological tests that were generally consistent with practice effects
(Harvey et al. 2011). There was one exception, processing speed, which
manifested relatively greater improvement with lurasidone than with
ziprasidone. However, improvements seen with lurasidone on the SCoRS were
double the size of improvements seen on the neuropsychological assessments
and nearly significantly larger than the improvements associated with
ziprasidone. These results cannot be attributed to practice effects, given that the
SCoRS is an interview, not a performance-based measure. Furthermore, the fact
that the differential effects of lurasidone and ziprasidone were nearly significant
(P<0.06) argues against a generalized bias effect, because the lurasidone effects
were clearly larger.
The second study (Harvey et al. 2013) compared two dosages of lurasidone
(80 and 160 mg/day) with 600 mg/day of quetiapine XR and placebo. This
double-blind, placebo-controlled trial was conducted in patients experiencing an
acute exacerbation of psychosis. Lurasidone 160 mg/day was compared with
placebo, quetiapine XR, or lurasidone 80 mg/day over a 6-week period, followed
by a 6-month double-blind extension. Follow-ups were conducted at 3 and 6
months, and placebo patients were switched to lurasidone at flexible dosages;
quetiapine XR patients remained on the same treatment. The CogState
Computerized Cognitive Battery (Pietrzak et al. 2009) and the University of
California San Diego (UCSD) Performance-based Skills Assessment—Brief
version (UPSA-B; Mausbach et al. 2007; Patterson et al. 2001) were
administered at baseline and at each assessment point. When patients who
provided invalid baseline CogState data were censored from the analysis,
lurasidone at 160 mg/day separated from placebo on composite cognitive
improvement at the 6-week endpoint, whereas lurasidone at 80 mg/day and
quetiapine XR did not.
Harvey et al. (2015) presented an analysis of the dose–response relationships
of lurasidone compared with quetiapine during the full 6-month duration of the
trial. The full sample, regardless of the validity of baseline performance, was
examined at two follow-up assessments (at 3 and 6 months). Both dosages of
lurasidone were found to be superior to quetiapine XR at both assessments
(Harvey et al. 2015). Scores on the UPSA-B improved with all active treatments
at each of the assessment time points, with no between-group differences in
improvements.
Although these results clearly require replication, they suggest that lurasidone
may have beneficial cognitive effects. In all three studies, performance- and
interview-based assessments of functionally relevant cognitive processes showed
treatment-related improvements. In the Harvey et al. (2013) study, the
performance-based cognitive assessments also showed improvements that were
superior to those seen with placebo or the active comparator. This superiority to
the comparator was confirmed across all dosages of lurasidone in the Harvey et
al. (2015) study. The sleepiness-inducing effects of quetiapine XR may have
contributed to the difference between this compound and lurasidone (Loebel et
al. 2014c); however, that circumstance would not have explained the separation
of lurasidone from placebo.
Conclusion
Lurasidone is a new antipsychotic with some benefits compared with other
available medications, including low weight-gain propensity and reduced risk for
metabolic side effects. Little of the published data have been supported by
sources other than the sponsor of the medication. We will watch this medication
carefully to continue to determine its benefit over time. Since the previous
edition of this textbook, the indication for bipolar depression has been added and
additional cognitive and long-term safety data have become available. No new
safety concerns have emerged, and no new data raising efficacy questions have
appeared.
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728692
CHAPTER 34
Cariprazine
Sultan Albrahim, M.D.
Joseph H. Henry, M.D.
Charles B. Nemeroff, M.D., Ph.D.
Structure
Cariprazine, also known as RGH-188 and MP-214, is 3-[4-{2-[4-(2,3-
dichlorophenyl)piperazin-1-yl]ethyl}cyclohexyl]-1,1-dimethylurea (Figure 34–
2). The active ingredient is cariprazine hydrochloride, a compound synthesized
and selected for development on the basis of its high selectivity for dopamine D3
receptors over D2 receptors (Veselinovic et al. 2013). Cariprazine has two
clinically relevant active metabolites: desmethyl-cariprazine (DCAR) and
didesmethyl-cariprazine (DDCAR) (Citrome 2013b).
Receptor-Binding Profile
Cariprazine is a potent dopamine D3 and D2 receptor partial agonist with
preferential binding to D3 receptors, which is a unique pharmacological profile
among known antipsychotic medications (Kiss et al. 2010).
Whereas D2 receptor antagonism is required for antipsychotic efficacy, D3
receptor antagonism may impart beneficial effects on cognition while attenuating
the risk of extrapyramidal side effects (EPS) (Veselinovic et al. 2013).
Cariprazine acts as a partial agonist at dopamine D3 and D2 receptors with
very high binding affinity and at serotonin 5-HT1A receptors with high binding
affinity (see Table 34–1). Cariprazine acts as an antagonist at serotonin 5-HT2B
and 5-HT2A receptors with very high and moderate binding affinity, respectively,
and at histamine H1 receptors with moderate binding affinity. Cariprazine shows
weak binding affinity for serotonin 5-HT2C and 5-HT7 receptors, very low
affinity for α1A-adrenergic receptors, and no appreciable affinity for cholinergic
muscarinic receptors (Actavis Inc. 2015).
Dopamine Receptors
Serotonin Receptors
5-HT1A. Cariprazine has a high affinity for human serotonin 5-HT1A receptors
and acts as a partial agonist at these receptors. The effect of cariprazine depends
on the serotonin concentration at the site.
In vivo, at lower dosages, cariprazine’s partial agonism at 5-HT1A receptors
may contribute minimally to its antipsychotic-like activity and side-effect
profile; at higher dosages, the 5-HT1A receptor partial agonism may contribute to
cariprazine’s favorable side-effect profile (i.e., lack of EPS) (Kiss et al. 2010).
Cariprazine’s 5-HT1A receptor partial agonism may also contribute to its
antidepressant efficacy (Blier and Ward 2003) and to its beneficial effects on
negative symptoms and cognitive dysfunction (Bantick et al. 2001), as suggested
by preclinical studies.
5-HT2B. Cariprazine has very high binding affinity for human serotonin 5-
HT2B receptors (Ki=0.58 nM). Activity at these receptors may modulate
dopamine release in the nucleus accumbens (Citrome 2013a).
Cariprazine’s antagonist activity at 5-HT2B receptors may contribute to its
postulated effects on mood and cognition, as observed in preclinical studies.
Histamine H1 Receptors
Cariprazine’s moderate affinity for H1 receptors is roughly equivalent to the
affinity of aripiprazole and brexpiprazole for these receptors. Sedation and
orthostatic hypotension with high dosages of cariprazine might be related to this
property.
Pharmacokinetics
In a Phase II double-blind, placebo-controlled tolerance study, the
pharmacokinetic properties of cariprazine were similar in healthy volunteers and
schizophrenia patients, and there were no significant clinical changes in
pharmacokinetic properties by age, sex, or race/ethnicity (Kapás et al. 2008).
In premarketing studies investigating cariprazine’s tolerability in specific
populations, patients with either mild or moderate hepatic impairment (Child-
Pugh score between 5 and 9), in comparison with healthy subjects, had
approximately 25% higher exposure (peak serum concentration [Cmax] and AUC
[area under the concentration curve]) to the parent drug, and approximately 45%
lower exposure to the major active metabolites (DCAR and DDCAR), following
a single daily dose of 1 mg cariprazine or 0.5 mg cariprazine for 14 days).
Pharmacokinetic analyses in patients with renal impairment showed no
significant relationship between plasma clearance and creatinine clearance
(Actavis Inc. 2015).
Effective half- life (calculated from time to steady state) of total active
moieties was ±1 week. Terminal half-lives of cariprazine, DCAR, and DDCAR
range from 31.6 to 68.4, 29.7 to 37.5, and 314 to 446 hours, respectively
(Nakamura et al. 2016).
The mean half-life of cariprazine is 2–5 days over a dosage range of 1.5–12.5
mg/day, which is considerably longer (days) than the mean half-life in laboratory
animal studies (hours in rats and dogs) (Mészáros et al. 2008).
On the first day of dosing, systemic exposure to the metabolites (DCAR and
DDCAR) was relatively low compared with exposure to the parent drug.
However, on day 37, with the 12.5-mg/day dosage, systemic exposure to
DDCAR was threefold greater than that to cariprazine for the AUC over 24
hours and sixfold greater for the AUC over 7 days, indicating a slower
elimination and a substantially longer half-life for this metabolite than for the
parent compound (Veselinovic et al. 2013).
After initiating cariprazine therapy or changing the dosage, response and side
effects should be monitored for several weeks because of the long half-life of
cariprazine’s active metabolite DDCAR.
Drug–Drug Interactions
Cariprazine and its major active metabolites are weak competitive inhibitors of
the human CYP2D6 and CYP3A4 isozymes. They have no induction effect on
the CYP enzyme system in human hepatocytes. Cariprazine is a weak inhibitor
of a number of CYP450 isoenzymes in vitro: 1A2, 2C9, 2D6, 3A4, 2C19, 2A6,
and 2E1.
Because cariprazine is highly metabolized by CYP3A4 and to some degree by
CYP2D6, changes in steady-state plasma concentrations would be expected if
the drug were coadministered with potent CYP3A4 inhibitors or inducers.
However, CYP2D6 inducers or inhibitors are not expected to have this effect on
cariprazine metabolism, because CYP2D6 is known to be a poor metabolizer of
cariprazine and its metabolites.
Taking a strong CYP3A4 inhibitor (e.g., ketoconazole, fluoxetine, grapefruit
juice) with cariprazine will increase concentrations of the parent drug by about
3.5-fold, decrease DCAR by about one-third, and increase DDCAR by about
1.5-fold. The concomitant use of CYP3A4 inducers with cariprazine has not yet
been evaluated. When cariprazine is to be added to an existing regimen of a
strong CYP3A4 inhibitor, the recommended starting dosage is 1.5 mg every
other day, with a maximum dosage of 3 mg/day (Actavis Inc. 2015).
The absence of any significant effect on the CYP system permits cariprazine
to be used in combination with other psychotropics if needed clinically without
significant drug–drug interactions. No such combination studies have been
published to date.
FDA-Approved Indications
Schizophrenia
In the treatment of patients with schizophrenia, the recommended dosage of
cariprazine is 1.5–6 mg/day. The recommended starting dosage is 1.5 mg/day,
which can be increased to 3 mg/day on day 2, with further upward dosage
increments of 1.5 or 3 mg/day as necessary, depending on clinical response and
tolerability.
FDA approval for the schizophrenia was based on data from three positive 6-
week double-blind, randomized controlled studies of cariprazine that were
conducted in adult patients with schizophrenia between 2008 and 2011. Two of
the studies used fixed dosages and included active drug comparators (risperidone
and aripiprazole) and placebo. All three trials consisted of a washout period of
up to 1 week, 6 weeks of double-blind treatment, and a 2-week safety follow-up.
The primary efficacy measure in each study was change from baseline in
Positive and Negative Syndrome Scale (PANSS) Total score; assessments were
conducted at screening, at baseline, and at the end of each double-blind
treatment week (weeks 1–6) (Table 34–2).
Randomization
a
Trial (N) Efficacyb Side effects
NCT00694707 Total N: 732 At week 6, The most frequent
RGH-MD-16 64% completed statistically cariprazine
Phase II the study significant adverse events
Placebo (151) (P<0.001 (≥5% and twice
(Durgam et al.
[LOCF]) LSMD the rate of
2014) Cariprazine
in favor of placebo) were
fixed
cariprazine akathisia,
dosages: 1.5
versus placebo extrapyramidal
mg/day
were observed disorder,
(145) 3
for insomnia,
mg/day
PANSS–Total sedation, nausea,
(147) 4.5
(1.5 mg/day: dizziness, and
mg/day
−7.6; 3 mg/day: constipation.
(148)
−8.8; 4.5 Mean changes in
Active control: mg/day: −10.4) metabolic
Risperidone CGI–S (1.5 parameters were
4 mg/day mg/day: −0.4; 3 small and similar
(141)c mg/day: −0.5; between groups.
4.5 mg/day:
−0.6)
Risperidone was
superior to
placebo on both
measures
(LSMD:
PANSS=−15.1,
P<0.001
[LOCF; CGI-S=
−0.8, P<0.05
[LOCF]).
NCT01104766 Total N: 617 At week 6, Akathisia was
RGH-MD-04 Placebo (153) statistically reported (≥5%;
Phase III Cariprazine significant twice the rate of
fixed LSMD in favor placebo).
(Laszlovszky
dosages: 3 of cariprazine Changes in
et al. 2014)
mg/day versus placebo metabolic
(155) 6 were observed parameters were
mg/day for small and similar
(157) PANSS–Total (3 to those with
mg/day: −6.0, placebo.
Active control:
P=0.0044; 6
Aripiprazole
mg/day: −8.8,
10 mg/day
P<0.0001)
(152)c
CGI–S (3
mg/day: −0.4,
P=0.0044; 6
mg/day: −0.5,
P<0.0001)
Aripiprazole was
superior to
placebo on both
measures
(LSMD:
PANSS–Total=
−7.0, P=0.0008;
CGI-S=−0.4,
P=0.0001).
NCT01104779 Total N: 446 At week 6, The most frequent
RGH-MD-05 60.5% statistically cariprazine
Phase III completed significant adverse events
the study LSMD in favor (≥5%; twice the
(Kane et al.
Placebo (147) of cariprazine rate of placebo)
2015)
versus placebo in both
Cariprazine
were observed cariprazine
flexible for groups were
dosing: 3–6 PANSS–Total akathisia,
mg/day (3–6 mg/day: extrapyramidal
(151) 6–9 −6.8, P=0.003; disorder, and
mg/day 6–9 mg/day: tremor; most
(148) −9.9, P<0.001) were mild to
No active CGI-S (3–6 moderate in
control mg/day: −0.3, severity.
group P=0.012; 6–9 Mean changes in
mg/day: −0.5, metabolic
P<0.001) parameters were
generally small
and similar
between groups.
Prolactin levels
decreased in all
groups.
FDA approval for the bipolar disorder indication was based on data from three
3-week placebo-controlled trials in adults with manic or mixed episodes of
bipolar I disorder with or without psychotic features. All three studies
demonstrated cariprazine’s superiority over placebo (Table 34–3).
Randomization
a
Trial (N) Efficacyb Side effects
NCT01058668 Total N: 497 At week 3, The most common
Phase III 74% completed statistically (≥5%; twice the
(Calabrese et the study significant rate of placebo)
al. 2015) Cariprazine LSMD in favor treatment-related
flexible of cariprazine adverse events
dosing: 3–6 versus placebo for cariprazine
mg/day were observed were akathisia
(169) 6–9 for (both groups) and
mg/day YMRS–Total nausea,
(167) (3–6 mg/day, constipation, and
−6.1; 6–12 tremor (6–12
Placebo (161)
mg/day, −5.9; mg/day only).
P<0.001 [both])
CGI-S (3–6
mg/day, −0.6;
6–12 mg/day,
−0.6; P<0.001
[both])
NCT00488618 Total N: (235) At week 3, The most common
Phase II 61.9% of statistically adverse events
(Durgam et al. placebo significant (>10% for
2015) group and LSMD in favor cariprazine) were
63.6% of of cariprazine akathisia
cariprazine versus placebo (cariprazine:
group were observed 22%; placebo:
completed for 6%),
the study YMRS–Total extrapyramidal
Cariprazine (3–12 mg/day, symptoms
flexible −6.1; P<0.001) (parkinsonism)
dosing: 3–12 CGI-S (3–12 (cariprazine:
mg/day mg/day, −0.6; 16%; placebo:
(118) P<0.001) 1%), headache,
Placebo (117) constipation,
nausea, and
dyspepsia.
Changes in
metabolic
parameters were
similar between
groups, with the
exception of
fasting glucose
change.
NCT01058096 Total N: 310 At week 3, The most common
Phase III 68.4% statistically cariprazine-
(Sachs et al. completed significant related (>10%;
2015) the study LSMD in favor twice the rate of
Cariprazine of cariprazine placebo)
flexible versus placebo treatment-
dosing: 3–12 were observed emergent adverse
mg/day for events were
(158) YMRS–Total akathisia,
(3–12 mg/day, extrapyramidal
Placebo (152)
−4.3; P=0.0004) disorder, tremor,
CGI-S (3–12 dyspepsia, and
mg/day, −0.4; vomiting.
P=0.0027) Mean changes from
baseline in
metabolic
parameters were
generally small
and similar
between groups.
Note. CGI-S=Clinical Global Impression–Severity; LSMD=least squares mean
differences; YMRS–Total=Young Mania Rating Scale total score.
a
Trial registration: ClinicalTrials.gov identifiers NCT01058668, NCT00488618,
and NCT01058096.
b
In all trials, patients were adults (ages 18–65 years; mean age=39 years) whose
symptoms met DSM-IV-TR criteria for bipolar I disorder with manic or mixed
episodes and with or without psychotic features (YMRS score≥20). YMRS and
CGI-S were used as the primary and secondary efficacy measures, respectively;
the primary endpoint was decrease from baseline in YMRS–Total score at the
end of week 3. The change from baseline for cariprazine was superior to placebo
in all three trials. All three trials lacked an active comparator arm and had a
short duration.
TEAE n (%)
Akathisia 105 (15.5)
Insomnia 89 (13.1)
Headache 86 (13.1)
Weight increase 71 (10.5)
Anxiety 58 (8.5)
Tremor 47 (6.9)
Extrapyramidal disorder 45 (6.6)
Schizophrenia 38 (5.6)
Nausea 38 (5.6)
Restlessness 38 (5.6)
Dyspepsia 37 (5.4)
Nasopharyngitis 34 (5.0)
a
Reported by ≥5% of patients.
Source. Reprinted from Nasrallah HA, Cutler AJ, Wang Y, et al.: “P.3.d.025 Safety and Tolerability of
Cariprazine in Long-Term Treatment of Schizophrenia: Integrated Summary of Safety Data” (poster &
abstract). European Neuropsychopharmacology 24 (Suppl 2):S536, 2014, Table 2. Copyright © 2014,
Elsevier. Used with permission.
The boxed warnings are based on the pharmacological actions of this class.
No such effects were observed in the cariprazine studies, possibly because of the
short lengths of the trials.
Akathisia
Across clinical trials for both FDA-approved disorders, akathisia and
parkinsonism were among the more common side effects of cariprazine. Both
were usually mild, resulting in relatively few premature discontinuations.
Parkinsonism appeared to be somewhat dosage-related, whereas akathisia had no
clear relationship to dosage (Mattingly and Anderson 2016).
Conclusion
Cariprazine combines functional selectivity at dopamine D3 and D2 receptors,
partial agonist activity at serotonin 5-HT1A receptors, and antagonism at
serotonin 5-HT2B and 5-HT2A receptors. Cariprazine’s receptor-binding profile is
unique, with the highest affinity and selectivity for D3 receptors of any second-
generation antipsychotic. It has antipsychotic and mood-stabilizing effects, as
well as possible antidepressant, procognitive, anti-abuse, and antihostility
effects. Cariprazine has the potential to improve the cognitive and negative
symptoms of schizophrenia, as shown in preclinical trials.
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CHAPTER 35
History
The discovery of the therapeutic properties of chlorpromazine (Delay and
Deniker 1952; Laborit et al. 1952) was soon followed by the description of its
tendency to produce extrapyramidal side effects (EPS) that were
indistinguishable from the symptoms of classic Parkinson’s disease. A debate
soon arose regarding the relationship between EPS and therapeutic efficacy, with
some investigators suggesting that EPS were necessary for efficacy (Flügel
1953; Haase 1954).
Brooks (1956), on the other hand, suggested that “signs of parkinsonism
heralded the particular effect being sought” (p. 1122) but that “the therapeutic
effects were not dependent on extrapyramidal dysfunction. On the contrary,
alleviation of such dysfunction, as soon as it occurred, sped the progress of
recovery” (p. 1122).
Types
Four types of EPS have been delineated, and the treatment of each type should
be individualized. Acute dystonic reactions (ADRs) are generally the first EPS to
appear and are often the most dramatic (Angus and Simpson 1970b). Dystonias
are involuntary sustained or spasmodic muscle contractions that cause abnormal
twisting or rhythmical movements and/or postures. ADRs tend to occur suddenly
and generally involve muscles of the head and neck (as in torticollis, facial
grimacing, or oculogyric crisis). Nearly 90% of all ADRs occur within 4 days of
antipsychotic initiation or dosage increase, and virtually 100% of all ADRs
occur by day 10 (Singh et al. 1990; Sramek et al. 1986). Although tardive
dystonia can occur after this period, movements occurring beyond this time
frame are much less likely to be ADRs. Instead, other conditions, including
seizures, need to be considered.
Akathisia is the second type of EPS to appear. Akathisia, meaning “inability to
sit,” consists of both an objective restless movement and a subjective feeling of
restlessness that the patient experiences as the need to move. It may be difficult
for a patient to explain the sensation of akathisia, and the diagnosis can be
missed. At times, patients may display the classic movements of akathisia but
without the subjective distress, a condition that has been termed
pseudoakathisia, which may be a type of tardive syndrome (Barnes 1990).
The third type of EPS, pseudoparkinsonism, is virtually indistinguishable
from classic Parkinson’s disease. Symptoms of pseudoparkinsonism include a
generalized slowing of movement (akinesia), masked facies, rigidity (including
cogwheeling rigidity), resting tremor, and hypersalivation. Parkinson-like
symptoms generally appear after a few weeks or more of antipsychotic
treatment. Akinesia needs to be differentiated from both primary depression and
the blunted affect of schizophrenia (Rifkin et al. 1975).
Tardive syndromes make up the fourth group of EPS. Tardive dyskinesia (TD),
although clearly associated with the use of antipsychotic medications, was
actually described prior to the advent of antipsychotics (Simpson 2000). TD
consists of irregular stereotypical movements of the mouth, face, and tongue and
choreoathetoid movements of the fingers, arms, legs, and trunk. It tends to
appear after months to years of use of antipsychotic medications. Patients
frequently have no awareness of the abnormal movements. The lack of
awareness may be related to frontal lobe dysfunction (Sandyk et al. 1993).
Tardive dystonia, a variant of TD, also generally emerges months to years
after treatment with antipsychotics (Burke et al. 1982). Unlike in ADRs, the
movements associated with tardive dystonia tend to be persistent and more
resistant to medical treatment (Kang et al. 1988).
Anticholinergic Medications
Trihexyphenidyl.
Benztropine.
Antihistaminic Medications
Diphenhydramine.
History and discovery. Antihistaminic agents have been used for the
treatment of Parkinson’s disease. Diphenhydramine, one of the first
antihistamines developed and used clinically (Bovet 1950), has been the primary
antihistamine studied in the treatment of EPS. Although some antihistamines
may be effective, other antihistamines have not been systematically studied for
the treatment of EPS.
Dopaminergic Medications
Amantadine.
Side effects and toxicology. The side effects of β-blockers result from
β-receptor blockade. β2 blockade of bronchial smooth muscle produces
bronchospasm. Individuals with normal lung function are unlikely to be affected,
but smokers and others with lung disease can develop serious breathing
difficulties. β-Blockers can contribute to heart failure in susceptible individuals,
such as those with compensated heart failure, acute myocardial infarction, or
cardiomegaly. Abrupt cessation of β-blockers can also exacerbate coronary heart
disease in susceptible patients, producing angina or, potentially, myocardial
infarction (see Hoffman and Lefkowitz 1996 for details).
In individuals with normal heart function, bradycardia produced by β-blockers
is insignificant; however, in patients with conduction defects or when combined
with other drugs that impair cardiac conduction, β-blockers can contribute to
serious conduction problems.
β-Blockers can block the tachycardia associated with hypoglycemia,
eliminating this warning sign in patients with diabetes. β2 blockade also can
inhibit glycogenolysis and glucose mobilization, interfering with recovery from
hypoglycemia (Hoffman and Lefkowitz 1996).
β-Blockers can impair exercise performance and produce fatigue, insomnia,
and major depressive disorder. However, the development of major depressive
disorder probably only occurs in individuals with a predisposition to developing
depression.
Mechanism of Action
All benzodiazepines promote the binding of γ-aminobutyric acid (GABA) to
GABAA receptors, magnifying the effects of GABA. The mechanism of action
regarding improvement of EPS is unknown, but it may be related to
augmentation of the inhibitory GABAergic effect (Hobbs et al. 1996). For a
complete discussion of the properties of benzodiazepines, see Chapter 22 in this
volume, “Benzodiazepines,” by Sheehan.
Indications
Benzodiazepines have FDA approval for use in treatment of anxiety disorders,
agoraphobia, insomnia, and seizure disorders; management of alcohol
withdrawal; anesthetic premedication; and skeletal muscle relaxation; however,
they are not approved for use in treating any type of EPS. As noted earlier, a few
initial reports have indicated that benzodiazepines are beneficial for the
treatment of akathisia. Other studies also have reported similar benefit (Bartels et
al. 1987; Braude et al. 1983; Gagrat et al. 1978; Horiguchi and Nishimatsu 1992;
Kutcher et al. 1989; Pujalte et al. 1994).
Clonazepam has been reported to be effective in the treatment of TD (Bobruff
et al. 1981; Thaker et al. 1990). Dosages of 1–10 mg/day were used in the first
study, although the optimal dosage was found to be 4 mg/day, with many
patients unable to tolerate higher dosages. In the second study, dosages of 2–4.5
mg/day were used, and tolerance developed after 5–8 months.
Although some of the studies were limited by short duration and by the small
number of subjects also receiving other antiparkinsonian agents, the overall
conclusion was that benzodiazepines probably have some efficacy in the
treatment of akathisia and TD. However, the potential problems associated with
the chronic use of benzodiazepines (i.e., tolerance and abuse) need to be kept in
mind.
Lorazepam (intermediate-acting) and clonazepam (long-acting) are the two
primary benzodiazepines that have been studied in the treatment of EPS.
Because of its long duration of action, clonazepam often can be given once a
day. Lorazepam has the advantage of having no active metabolites, which
eliminates potential side effects and toxicity.
Structure–Activity Relations
There are seven immunologically distinct botulinum toxins (Simpson 1981).
Type A is the primary type used clinically (Hambleton 1992). Type F and
possibly type B also have clinical utility, but they have much shorter durations of
action (≤3 weeks, compared with ≥3 months for type A) (Borodic et al. 1996).
The toxin is quantified by bioassay and is expressed as mouse units, which refers
to the dose that is lethal to 50% of animals following intraperitoneal injection
(Quinn and Hallet 1989).
Pharmacological Profile
Botulinum toxin binds to cholinergic motor nerve terminals, preventing release
of acetylcholine and producing a functionally denervated muscle. The prevention
of acetylcholine release occurs within a few hours, but the clinical effect does
not occur for 1–3 days. The innervation gradually becomes restored, although
the number or size of active muscle fibers is reduced (Odergren et al. 1994).
Mechanism of Action
Botulinum toxin acts presynaptically to prevent the release of acetylcholine at
the neuromuscular junction. This produces a functional chemical denervation
and paralysis of the muscle. When botulinum toxin is used clinically, the aim is
to reduce the excessive muscle activity without producing significant weakness
(Hughes 1994).
Indications
The FDA has approved the use of botulinum toxin for strabismus,
blepharospasm, and other facial nerve disorders (see Jankovic and Brin 1991).
Botulinum toxin has been used to treat focal neuroleptic-induced dystonias that
may occur as part of TD, including laryngeal dystonia (Blitzer and Brin 1991)
and refractory torticollis (Kaufman 1994). For laryngeal dystonia, the toxin is
injected percutaneously through the cricothyroid membrane into the
thyroarytenoid muscle bilaterally. The response rate is 80%–90%, and the effect
lasts 3–4 months and sometimes longer. Botulinum treatment of tardive cervical
dystonia has been found to be effective; the observed improvement is similar to
the improvement seen in the treatment of idiopathic cervical dystonia, although
patients with tardive cervical dystonia required higher doses (Brashear et al.
1998).
Drug–Drug Interactions
Botulinum toxin has no known interactions with other drugs.
Indications
The only known indication for vitamin E is treatment of vitamin E deficiency,
which almost always results from malabsorption syndromes or abnormal
transport, such as with abetalipoproteinemia (Bieri and Farrell 1976).
Early studies of vitamin E treatment of TD reported a range of results from
general benefit (Adler et al. 1993; Dabiri et al. 1994; Lohr et al. 1988) to benefit
only in subjects with TD of less than 5 years’ duration (Egan et al. 1992; Lohr
and Caligiuri 1996) to no benefit (Schmidt et al. 1991; Shriqui et al. 1992).
Subsequently, a major double-blind study comparing vitamin E with placebo
found that vitamin E was no more beneficial than placebo (Adler et al. 1999).
There were no significant effects of vitamin E on total scores or subscale scores
for the Abnormal Involuntary Movement Scale (AIMS; Guy 1976), on
electromechanical measures of dyskinesia, or on scores for four other scales
measuring dyskinesia. The authors concluded that there was no evidence for
efficacy of vitamin E in the treatment of TD (Adler et al. 1999).
The use of vitamin E supplementation is not without risk. A meta-analysis of
high-dosage vitamin E supplementation trials showed a statistically significant
association between vitamin E dosage and all-cause mortality, with increased
risk for dosages greater than 150 IU/day (E.R. Miller et al. 2005). Given the lack
of data showing consistent effectiveness for TD, we do not recommend that
vitamin E be used for this purpose.
Antipsychotic Dopamine-Receptor
Blockade and EPS
No drug with antipsychotic activity has been identified that does not have
significant affinity for D2 dopamine receptors. D2 receptor blockade is the
pharmacodynamic property of all antipsychotics, and without this property, a
drug will not show any antipsychotic effects. This is true for both typical (first-
generation) and atypical (second-generation) antipsychotics. The antipsychotic
effects of typical antipsychotics are directly related to the degree of D2 receptor
blockade. The antipsychotic effects of atypical antipsychotics, however, are
more complicated (Meltzer 2002).
All of the atypical antipsychotics are potent serotonin type 2A (5-HT2A)
receptor antagonists and relatively weak D2 receptor antagonists compared with
the typical antipsychotics (except for cariprazine, which has relatively weak
blockade of 5-HT2A receptors compared with the other atypical antipsychotics
[Gyertyán et al. 2011]). The high ratio of 5-HT2A receptor blockade to striatal D2
receptor blockade that characterizes clozapine is thought to contribute to its lack
of EPS (Meltzer et al. 1989).
Blockade of 5-HT2A and dopamine receptors was first labeled in 1989 as a
pharmacodynamic mechanism that differentiated conventional from second-
generation antipsychotics (Meltzer 1989). Meltzer (2002) defined atypical
antipsychotics as drugs showing a higher affinity for 5-HT2A receptors than for
D2 receptors and a lower affinity for D2 receptors than that seen with
conventional antipsychotics. For the nigrostriatal dopaminergic pathway, one
proposed model suggested that blockade of 5-HT2A receptors would lead to
increased output of dopaminergic neurons into the striatum, causing an
antipsychotic drug to be displaced from its binding to D2 receptors. It was
theorized that this displacement could decrease the risk of EPS development
(Horacek et al. 2006).
Step Action
1 Reduce dosage of antipsychotic, if clinically possible.
2 Substitute a lower-potency antipsychotic, or carry out step 8.
3 Add an anticholinergic agent.
4 Titrate anticholinergic to maximum dosage tolerated.
5 Add amantadine in combination with anticholinergic or as a
single agent.
6 Add a benzodiazepine or a β-blocker.
7 In severe cases of extrapyramidal side effects, stop antipsychotic
temporarily and repeat process, beginning with step 3.
8 Substitute antipsychotic with atypical antipsychotic or clozapine.
Conclusion
The unique properties of chlorpromazine and other similarly active agents in
ameliorating psychotic symptoms and producing parkinsonian side effects were
described in the early 1950s by French psychiatrists. Theories soon arose
regarding the relationship between these two properties. Recognition of the
benefits of reducing parkinsonian side effects led to investigations of methods to
reduce EPS and to the development of instruments to measure EPS.
The debate regarding the routine and prophylactic use of antiparkinsonian
agents has continued since that time. It appears that prophylactic
antiparkinsonian agents need to be used in some situations, but probably with
less frequency and for briefer periods of time than has generally been the
practice. The trend toward the use of lower dosages of antipsychotics should also
lead to a decreased need for the use of antiparkinsonian agents.
Finally, the advent of atypical antipsychotic agents has opened a new chapter
in both the treatment and the prevention of EPS and suggests that in the future,
EPS will be less of a problem than they have been in the past.
A summary of an American Psychiatric Association Task Force report on TD
suggested that a “deliberate and sustained effort must be made to maintain
patients on the lowest effective amount of drug and to keep the treatment
regimen as simple as possible” (Baldessarini et al. 1980, p. 1168), and that
anticholinergic drugs should be discontinued as soon as possible. Apart from a
greater emphasis on avoiding the initial use of antiparkinsonian agents, this
statement remains valid.
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PLATE 1. (Figure 1–7) Cas9-based systems for altering gene
sequence or expression.
(A) Cas9 nuclease creates double-strand breaks at DNA target sites with complementarity to
the 5′ end of a gRNA. (B) Cas9 nickase created by mutation of the RuvC nuclease domain
with a D10A mutation. This nickase cleaves only the DNA strand that is complementary to
and recognized by the gRNA. (C) Cas9 nickase created by mutation of the HNH nuclease
domain with an H840A mutation. This nickase cleaves only the DNA strand that does not
interact with the small RNA. (D) Paired nickase strategy for improving Cas9 specificity. D10A
Cas9 nickase directed by a pair of appropriately oriented gRNAs leads to induction of two
nicks that, if introduced simultaneously, would be expected to generate a 5′ overhang. (E)
Catalytically inactive or “dead” Cas9 (dCas9) that can be recruited by a gRNA without
cleaving the target DNA site. (F) Catalytically inactive dCas9-bearing dual D10A/H840A
mutations fused to a heterologous effector domain. Cas9=CRISPR-associated protein 9
nuclease from Streptococcus pyogenes; CRISPR=clustered, regularly interspaced, short
palindromic repeat; gRNA=guide RNA; PAM (NGG)=protospacer adjacent motif (sequence
5′-NGG-3′, where “N” is any nucleobase followed by two guanine (“G”) nucleobases).
Source. Reprinted from Sander JD, Joung JK: “CRISPR-Cas Systems for Editing, Regulating
and Targeting Genomes.” Nature Biotechnology 32(4):347–355, 2014. Copyright 2014, Nature
Publishing Group. Used with permission.
PLATES 2 AND 3. (Figure 1–9) Optogenetic manipulation of
neural circuits.
(I) Direct stimulation of neuronal cell bodies is achieved by injecting virus at the target region
and then implanting a light-delivery device above the injected region. Even this simple
experiment can provide specificity with viruses that will not transduce afferent axons and
fibers of passage. (II) Additional cell-type specificity is attained either by cell-type-specific
promoters in the viral vector or via a recombinase-dependent virus, injected in a transgenic
animal expressing a recombinase such as Cre in specific cells, leading to specific expression of
the transgene only in defined cell types. (III) Projection (axonal) targeting is achieved by viral
injection at the region harboring cell bodies, followed by implantation of a light-delivery
device above the target region containing neuronal processes from the virally transduced
region; in this way, cell types are targeted by virtue of their projections. (IV) Projection
termination labeling is a more refined version of projection targeting, in which cells are
targeted by virtue of synaptic connectivity to the target region, with likely exclusion of cells
whose axons simply pass through the region. Transcellular labeling using a recombinase-
dependent system is shown. Viruses expressing Cre fused to a transneuronal tracer (lectin) are
delivered at the synaptic target site, and a Cre-dependent virus is injected into the region with
cell bodies. Cells that project to the Cre-injected area express the Cre-dependent virus and
become light sensitive. This can also be achieved with axon terminal–transducing viruses,
although without control over the postsynaptic cell type. (V) Expression of two opsins with
different characteristics in one brain region using a combination of promoter- or Cre-based
approaches. Light delivery to the somata is performed using two different wavelengths
designed to minimize cross-activation. (VI) Projections from two different brain regions are
differentially stimulated with two wavelengths matched to the respective opsins expressed
upstream.
Source. Reprinted from Yizhar O, Fenno LE, Davidson TJ, et al.: “Optogenetics in Neural
Systems.” Neuron 71(1):9–34, 2011. Copyright 2011, Elsevier, Inc. Used with permission.
PLATE 4. (Figure 2-1) Major receptor subtypes in the central
nervous system.
This figure depicts the four major classes of receptors in the CNS. (A) Ionotropic receptors.
These receptors comprise multiple protein subunits that are combined in such a way as to
create a central membrane pore through this complex, allowing the flow of ions. This type of
receptor has a very rapid response time (milliseconds). The consequences of receptor
stimulation (i.e., excitatory or inhibitory) depend on the types of ions that the receptor
specifically allows to enter the cell. Thus, for example, Na+ entry through the NMDA (N-
methyl-D-aspartate) receptor depolarizes the neuron and brings about an excitatory response,
whereas Cl– efflux through the γ-aminobutyric acid type A (GABAA) receptor hyperpolarizes
the neuron and brings about an inhibitory response. Illustrated here is the NMDA receptor
regulating a channel permeable to Ca2+, Na+, and K+ ions. The NMDA receptors also have
binding sites for glycine, Zn2+, phencyclidine, MK801/ketamine, and Mg2+; these molecules
are able to regulate the function of this receptor. (B) G protein–coupled receptors (GPCRs).
The majority of neurotransmitters, hormones, and even sensory signals mediate their effects
via seven transmembrane domain–spanning receptors that are G protein–coupled. The amino
terminus of the G protein is on the outside of the cell and plays an important role in the
recognition of specific ligands; the third intracellular loop and carboxy terminus of the
receptor play an important role in coupling to G proteins and are sites of regulation of receptor
function (e.g., by phosphorylation). All G proteins are heterotrimers (consisting of α, β, and γ
subunits). The G proteins are attached to the membrane by isoprenoid moieties (fatty acid) via
their γ subunits. Compared with the ionotropic receptors, GPCRs mediate a slower response
(on the order of seconds). Detailed depiction of the activation of G protein–coupled receptors
is given in Figure 2–2. Here we depict a receptor coupled to the G protein Gs (the s stands for
stimulatory to the enzyme adenylyl cyclase [AC]). Activation of such a receptor produces
activation of AC and increases in cyclic adenosine monophosphate (cAMP) levels. G protein–
coupled pathways exhibit major amplification properties, and, for example, in model systems
researchers have demonstrated a 10,000-fold amplification of the original signal. The effects
of cAMP are mediated largely by activation of protein kinase A (PKA). One major
downstream target of PKA is CREB (cAMP response element–binding protein), which may be
important to the mechanism of action of antidepressants. (C) Receptor tyrosine kinases. These
receptors are activated by neurotrophic factors and are able to bring about acute changes in
synaptic function, as well as long-term effects on neuronal growth and survival. These
receptors contain intrinsic tyrosine kinase activity. Binding of the ligand triggers receptor
dimerization and transphosphorylation of tyrosine residues in its cytoplasmic domain, which
then recruits cytoplasmic signaling and scaffolding proteins. The recruitment of effector
molecules generally occurs via interaction of proteins with modular binding domains SH2 and
SH3 (named after homology to the src oncogenes–src homology domains); SH2 domains are a
stretch of about 100 amino acids that allow high-affinity interactions with certain
phosphotyrosine motifs. The ability of multiple effectors to interact with phosphotyrosines is
undoubtedly one of the keys to the pleiotropic effects that neurotrophins can exert. Shown here
is a tyrosine kinase receptor type B (TrkB), which upon activation produces effects on the Raf,
MEK (mitogen-activated protein kinase/ERK), extracellular response kinase (ERK), and
ribosomal S6 kinase (RSK) signaling pathway. Some major downstream effects of RSK are
CREB and stimulation of factors that bind to the AP-1 site (c-Fos and c-Jun). (D) Nuclear
receptors. These receptors are transcription factors that regulate the expression of target genes
in response to steroid hormones and other ligands. Many hormones (including glucocorticoids,
gonadal steroids, and thyroid hormones) are able to rapidly penetrate into the lipid bilayer
membrane, because of their lipophilic composition, and thereby directly interact with these
cytoplasmic receptors inside the cell. Upon activation by a hormone, the nuclear receptor–
ligand complex translocates to the nucleus, where it binds to specific DNA sequences, referred
to as hormone responsive elements (HREs), and regulates gene transcription. Nuclear
receptors often interact with a variety of coregulators that promote transcriptional activation
when recruited (coactivators) and those that attenuate promoter activity (corepressors).
However, nongenomic effects of neuroactive steroids have also been documented, with the
majority of evidence suggesting modulation of ionotropic receptors. This figure illustrates
both the genomic and the nongenomic effects. ATF1=activation transcription factor 1;
BDNF=brain-derived neurotrophic factor; CaMKII=Ca2+/calmodulin–dependent protein
kinase II; CREM=cyclic adenosine 5′-monophosphate response element modulator;
D1=dopamine1 receptor; D5=dopamine5 receptor; ER=estrogen receptor; GR=glucocorticoid
receptor; GRK=G protein–coupled receptor kinase; P=phosphorylation; PR=progesterone
receptor.
Lithium
Masoud Kamali, M.D.
Venkatesh Basappa Krishnamurthy, M.D.
Raman Baweja, M.D.
Erika F.H. Saunders, M.D.
Alan J. Gelenberg, M.D.
Structure–Activity Relations
Lithium is the lightest alkali metal and a monovalent cation, and it shares some
properties with sodium, potassium, and calcium. It is the third element of the
periodic table. Substitution of or competition with other cations may contribute
to its effects (Baldessarini 1996; Ward et al. 1994).
Pharmacological Profile
Lithium is minimally protein bound, does not undergo biotransformation, and is
renally eliminated (Kilts 2000). Its narrow therapeutic index necessitates careful
drug monitoring. Lithium appears to affect multiple neurotransmitter systems
(see “Neurotransmitter Effects” subsection under “Mechanisms of Action”), and
it alters second-messenger systems such as cyclic adenosine monophosphate
(cAMP) and cyclic guanosine monophosphate (cGMP) (Ward et al. 1994).
Mechanism of Action
Despite extensive research, the exact mechanism of lithium’s action as a mood
stabilizer has yet to be elucidated. Multiple theories, based on animal models and
on limited studies in humans, have been proposed. In the following pages we
review theories centering on lithium’s effects on various neurotransmitter
systems, on intracellular second-messenger systems, and on signal transduction,
as well as a unifying theory focused on lithium’s neuroprotective effects.
Neurotransmitter Effects
Lithium brings about changes in several of the major neurotransmitter systems in
the brain, with the overall effect being stimulation of inhibitory transmission and
inhibition of excitatory signals (Malhi et al. 2013). Chronic administration of
lithium in mice increases and stabilizes glutamate uptake. This modulatory
action could, in part, explain lithium’s antimanic effect because it results in
overall reduction of an excitatory neurotransmitter (Dixon and Hokin 1998).
Lithium also normalizes low cerebrospinal fluid (CSF) levels of γ-aminobutyric
acid (an inhibitory neurotransmitter) in bipolar subjects (see Berrettini et al.
1983, 1986; Brambilla et al. 2003).
Lithium enhances norepinephrine and serotonin function in the central
nervous system, which could explain its antidepressant effects (Price et al. 1990;
Schildkraut et al. 1969; Stern et al. 1969). Of particular interest is lithium’s
confirmed antagonistic action at serotonin 1A (5-HT1A) and serotonin 1B (5-
HT1B) autoreceptors (Haddjeri et al. 2000; Massot et al. 1999); such action
would have the effect of increasing serotonin availability in the synaptic cleft
(Shaldubina et al. 2001). Clinically, 5-HT1A receptors may be involved in
alleviation of depression, and 5-HT1B receptors may play a role in the regulation
of sleep, sensorimotor inhibition, and locomotor activity (Monti et al. 1995;
Sipes and Geyer 1996).
Inositol Depletion
There has been much focus on the role of the inositol cycle in the clinical effects
of lithium. Lithium is a noncompetitive inhibitor of inositol monophosphatase,
depleting free inositol within 5 days of treatment initiation (Berridge et al. 1989).
These changes last for 3–4 weeks after lithium is discontinued (Moore et al.
1999). Depletion of free inositol can lead to effects on neurotransmitter and
intracellular second-messenger systems linked to the inositol cycle. For example,
adrenergic, serotonergic, and cholinergic receptor subtypes are coupled to the
cycle via G proteins, and the cycle in turn regulates protein kinase C action,
which appears to be influenced by lithium treatment in mania (Hahn et al. 2005).
Of note, depression is associated with low CSF levels of inositol in humans
(Barkai et al. 1978). Exogenous inositol can alleviate depression (Levine et al.
1993, 1995) and panic attacks (Benjamin et al. 1995). Belmaker et al. (1996)
suggested a complex “pendulum” relationship between inositol and lithium that
may provide a basis for understanding lithium’s antimanic and antidepressant
effects.
Bipolar Disorder
Acute Mania
Cade (1949) first published data on the efficacy of lithium in mania more than
60 years ago. As we approach the end of the second decade of the twenty-first
century, lithium remains one of the most efficacious treatments for bipolar
disorder.
Psychotic Mania
Lithium is equally effective in psychotic and nonpsychotic mania, and early
improvement in psychotic symptoms was found to predict higher remission and
response rates (de Sousa et al. 2012).
Bipolar Depression
Lithium is considered a first-line treatment for acute bipolar depression
(Compton and Nemeroff 2000). Goodwin and Jamison (1990) analyzed placebo-
controlled trials in bipolar depression and found that 79% of bipolar patients had
either a complete or a partial response to lithium. Placebo-controlled trials
showing the efficacy of lithium in bipolar depression include those by Baron et
al. (1975), Donnelly et al. (1978), Fieve et al. (1968), Goodwin et al. (1969,
1972), Greenspan et al. (1970), Mendels (1975), and Noyes et al. (1974). These
studies generally were small (involving between 3 and 40 patients [Goodwin et
al. 1972]).
A recent meta-analytic summary of the above-listed short studies showed a
significant advantage for lithium over placebo in bipolar disorder versus unipolar
depression (Selle et al. 2014). In a study in which in 802 patients were randomly
assigned to 8 weeks of treatment with lithium (600–1,800 mg/day), quetiapine
(300 mg/day or 600 mg/day), or placebo (Young et al. 2010), lithium failed to
separate significantly from placebo on the main efficacy measure (Montgomery-
Åsberg Depression Rating Scale [MADRS] score); however, the study was
powered to show an effect for quetiapine, and the mean serum level in lithium-
treated subjects was low (0.6 mmol/L).
In the Bipolar CHOICE (Clinical Health Outcomes Initiative in Comparative
Effectiveness) trial, 482 patients with bipolar I or II disorder, the majority
(>88%) of whom were experiencing depressive symptoms at study entry
(Nierenberg et al. 2016), were randomly assigned to receive lithium plus
adjunctive personalized treatment (APT, n=240) or quetiapine plus APT (n=242)
for 6 months. In this study, which used new clinical trials methodology,
participants in the lithium group were not given a second-generation
antipsychotic, and those in the quetiapine group were not given lithium;
however, other adjunctive treatments were provided in accordance with best-
practice guidelines (Nierenberg et al. 2013). Both groups showed improvement,
with 20% achieving sustained response over the study period, and no differences
in outcome were detected between the lithium and quetiapine groups
(Nierenberg et al. 2013).
In the Lithium Treatment Moderate-dose Use Study (LiTMUS) study
(Nierenberg et al. 2013), 283 bipolar I and II patients were randomly assigned to
receive optimized personalized treatment (OPT; evidence-based, guideline-
informed care) alone or OPT plus lithium at a moderate dosage. The lithium
dosage was fixed at 600 mg/day for the first 2 months of the study but was
allowed to change based on clinical need after that. Over the 6 months of the
trial, the two groups had similar scores on clinical outcome measures, with a
sustained remission rate of 27%. Although the addition of lithium conferred no
advantage over OPT alone, fewer patients in the lithium-plus-OPT group than in
the OPT-only group received second-generation antipsychotics.
In 2004, an expert consensus report recommended lithium as monotherapy for
mild to moderate depression in bipolar I disorder and as a component of an
initial medication regimen in severe nonpsychotic and psychotic depression
(Keck et al. 2004).
Rapid Cycling
In 1974, Dunner and Fieve observed that bipolar patients who had not responded
to long-term lithium prophylaxis were more likely to have had four or more
mood episodes per year, giving rise to the belief that lithium is not effective in
treating rapid cycling. However, subsequent studies have shown that rapid-
cycling bipolar disorder responds poorly to most available treatments and that
treatment with lithium does improve the burden of illness. In a study examining
lithium’s efficacy in rapid-cycling bipolar disorder, Dunner et al. (1977) found
that patients who had received lithium for at least 1 year had a higher percentage
of “well time” relative to baseline and reported that their mood episodes were
shorter and less severe. In an analysis of retrospective and prospective data from
51 patients with rapid-cycling bipolar disorder, Wehr et al. (1988) showed that
even among patients with continuous rapid cycling, the manic phases were
abbreviated and attenuated. A long-term prospective study of open-label
treatment with lithium found a higher rate of recurrence among rapid cyclers
versus non–rapid cyclers but similar improvement in symptoms and morbidity
(as measured by percentage of time ill, episode frequency, and time to
recurrence) (Baldessarini et al. 2000). Finally, a meta-analysis of clinical studies
comparing subjects with rapid-cycling and non-rapid-cycling bipolar disorder
showed that although lithium was less effective in preventing recurrence among
rapid cyclers, it did have beneficial effects on severity and duration of episodes
(Kupka et al. 2003). In a 20-month double-blind, parallel-group comparison
study, Calabrese et al. (2005) evaluated lithium versus divalproex monotherapy
for maintenance treatment in rapid-cycling patients who had been stabilized on a
combination of lithium and divalproex. The rates of relapse were similar for
lithium-treated and divalproex-treated patients.
The Elderly
Lithium has shown effectiveness in elderly patients. In a retrospective trial,
significantly more patients age 55 years or older improved with lithium than
with valproate, especially in cases of classic mania, whereas the two drugs
showed similar response rates when the analysis considered only the cases of
mixed mania (S.T. Chen et al. 1999). The lithium serum-level range associated
with improvement in elderly patients was similar to the therapeutic range in
younger adults: ≥0.8 mmol/L.
Medical comorbidity may be a particular consideration in elderly patients.
Volume depletion, use of nonsteroidal anti-inflammatory drugs, or use of
thiazide diuretics can increase lithium levels (Stoudemire et al. 1990). The
lithium dosage required to achieve therapeutic serum concentrations decreases
threefold from middle to old age, with this trend continuing into the ninth and
tenth decades of life (Rej et al. 2014b). In a population-based retrospective
cohort study involving 1,388 bipolar patients ages 66 years and older, medical
hospitalizations, 1-year acute medical health utilization outcomes, and medical
comorbidity rates were not different among lithium users as compared with
valproate users or nonlithium/nonvalproate users during 1-year follow-up (Rej et
al. 2015).
Meta-analyses show that lithium is associated with increased risk of reduced
urinary concentrating ability, but there is little evidence for a clinically
significant reduction in renal function in most patients, and the risk of end-stage
renal failure is low (McKnight et al. 2012). Lithium use is associated with an
increased risk of renal failure among the older (ages 50 years and above) age
group (Close et al. 2014; Rej et al. 2014a). However, chronic lithium use at
lower dosages did not affect renal function in elderly patients with mild
cognitive impairment and dementia over a 4-year study period (Aprahamian et
al. 2014). Because lithium is cleared almost exclusively by the kidneys, patients
with end-stage renal disease receiving hemodialysis cannot eliminate lithium
other than through dialysis. Lithium should be given only after a dialysis
treatment and need not be given daily (Stoudemire et al. 1990).
Because lithium appears to have neuroprotective effects that may reduce
oxidative damage, its potential role in prevention of neurocognitive decline in
aging and prevention of Alzheimer’s disease has been suggested (Bachmann et
al. 2005; Chen et al. 2000; Cui et al. 2007; Engel et al. 2006;
Mohammadianinejad et al. 2014; Phiel et al. 2003; Shao et al. 2005; Su et al.
2004; Tsaltas et al. 2007; Yoshida et al. 2006). A Danish study that followed
more than 4,800 patients with newly diagnosed bipolar disorder over 10 years
found that long-term treatment with lithium, but not with other
psychopharmacological agents, was associated with a reduced risk of developing
dementia (Kessing et al. 2010). A study that analyzed data from a national health
insurance database in Taiwan concluded that lithium use was significantly
related to a reduced risk of stroke in patients with bipolar disorder. The
association between lithium use and reduced stroke risk was strongest for
patients who received the highest lithium dosages, experienced the longest
durations of lithium treatment, and had the highest rates of lithium exposure
(Lan et al. 2015).
Laboratory Monitoring
Before lithium therapy is started, a medical history should be obtained, as well
as baseline renal laboratory tests (blood urea nitrogen, creatinine level), thyroid
function tests, and an electrocardiogram for patients older than 40 years
(American Psychiatric Association 2002, McKnight et al. 2012). The American
Psychiatric Association practice guideline for the treatment of bipolar disorder
suggests that renal function should be assessed every 2–3 months and thyroid
function should be tested once or twice during the first 6 months of treatment.
After the first 6 months, renal laboratory tests and thyroid function tests should
be monitored every 6–12 months or as clinically indicated (American Psychiatric
Association 2002; McKnight et al. 2012; Shine et al. 2015).
Neurotoxicity
Neurotoxicity, delirium, and encephalopathy have been reported with lithium
use. Specific populations with underlying neurological vulnerability have been
noted to be at higher risk. Also, certain circumstances, such as concomitant
electroconvulsive therapy or use of other psychotropics—especially first-
generation antipsychotics—have been found to increase the risk of neurotoxic
adverse effects from lithium treatment.
Neurotoxic reactions are potentially irreversible. Permanent neurological
deficits reported after episodes of lithium intoxication (Apte and Langston 1983;
Donaldson and Cuningham 1983) have included deficits in recent memory,
ataxia, and movement disorders. Early hemodialysis may help prevent
permanent sequelae in these cases. Donaldson and Cuningham (1983) also
reported persistent neurological sequelae of lithium toxicity involving multiple
sites within the nervous system. In a case series of 90 patients, Adityanjee et al.
(2005) reported that the most common sequela was cerebellar dysfunction. The
typical neurological signs of irreversible lithium neurotoxicity include cerebellar
dysfunction, extrapyramidal symptoms, brainstem dysfunction, and dementia
(Ivkovic and Stern 2014). Himmelhoch et al. (1980) found a greater incidence of
lithium-induced neurotoxicity in the elderly. Other risk factors include longer
duration of exposure to higher lithium levels and presence of medical
comorbidities, including nephrogenic diabetes insipidus, abnormal thyroid
function and impaired renal function, preexisting neurological disease, and drug
combinations including antipsychotics (Ivkovic and Stern 2014; Netto and
Phutane 2012; Oakley et al. 2001).
Tremor
A fine postural tremor affects between 4% and 65% of patients who receive
lithium (Gelenberg and Jefferson 1995). A severe tremor may indicate toxicity.
Elimination of caffeine may actually worsen tremor because renal lithium
clearance can be reduced with reduction of caffeine intake (Jefferson 1988).
Lithium tremor, which resembles essential tremor, may worsen with age.
Thyroid Abnormalities
In a chart review of 135 patients who received maintenance treatment with
lithium, 38% had abnormal values on thyroid function tests (thyroid-stimulating
hormone and/or free thyroxine index), with an association between laboratory
abnormalities and length of time on lithium (Fagiolini et al. 2006). In a
systematic review and meta-analysis, McKnight et al. (2012) reported that in
comparison with placebo-treated subjects, lithium-treated patients had a sixfold
higher risk of hypothyroidism and increased levels of thyroid-stimulating
hormone. In a retrospective study of 209 patients who received lithium, Kirov
(1998) found that 14.9% of the females and 3.4% of the males developed
hypothyroidism. Female patients and patients older than 50 years were more
likely to develop hypothyroidism (Kirov 1998; Shine et al. 2015). Other reports
have suggested that subclinical hypothyroidism during lithium therapy is much
more common than previous cross-sectional studies had indicated (Lombardi et
al. 1993). A family history of thyroid disease may lead to earlier onset of the
hypothyroidism that occurs with lithium use (Kusalic and Engelsmann 1999).
Female patients with high serum lithium concentrations should have regular
thyroid function testing (Shine et al. 2015).
Parathyroid Abnormalities
Lithium has been associated with hypercalcemia and hyperparathyroidism
(Saunders et al. 2009). A meta-analysis by McKnight et al. (2012) found that
lithium-treated patients showed a 10% increase in levels of parathyroid hormone
and calcium (McKnight et al. 2012) compared with control subjects. Similar
increases in parathyroid hormone (Albert et al. 2013) and calcium (Albert et al.
2013; Shine et al. 2015) in lithium-treated patients have been reported in other
studies as well. Monitoring of calcium levels at baseline and yearly, or more
frequently in the presence of clinical symptoms, is suggested (McKnight et al.
2012).
Renal Complications
Lithium has multiple renal effects, including those that occur early in treatment
and those that occur with chronic use. Lithium can induce tubular dysfunction
early in treatment, with reduced urinary concentrating capacity developing over
the first 8 weeks of treatment. Nephrogenic diabetes insipidus occurs in 20%–
87% of patients on lithium (Azab et al. 2015; Markowitz et al. 2000; Stone
1999). These effects may be partially mediated by lithium’s action on water and
sodium channels in the kidney (Grünfeld and Rossier 2009); thus, there has been
renewed interest in using amiloride, a sodium channel–blocking diuretic, in an
attempt to modify lithium’s toxicity (Azab et al. 2015; Bedford et al. 2008).
Another important renal effect of lithium is chronic kidney disease, which
tends to occur after 10–20 years of lithium treatment (Presne et al. 2003) at an
estimated prevalence of 1.2% (Bendz et al. 2010) to 21% (Lepkifker et al. 2004),
depending on the definition of renal insufficiency used. However, the risk of
progressing to end-stage renal disease is small (0.5%–1%) (Bendz et al. 2010;
Tredget et al. 2010). The clearest risk factors are duration of lithium use (Bendz
et al. 2010; Bocchetta et al. 2015; Castro et al. 2016; Presne et al. 2003), dosing
of lithium more than once a day (Castro et al. 2016), and higher serum lithium
levels (Castro et al. 2016; Shine et al. 2015); however, additional possible risk
factors are older age (Bendz et al. 2010; Bocchetta et al. 2015; Castro et al.
2016; Close et al. 2014; Presne et al. 2003), female sex (Castro et al. 2016; Shine
et al. 2015), previous episodes of lithium toxicity, and presence of comorbid
disorders (Castro et al. 2016; Lepkifker et al. 2004). The potential for chronic
renal disease is the reason that close laboratory monitoring is required for
patients on long-term lithium treatment (Shine et al. 2015). Once-daily dosing
and maintaining low lithium levels when possible may be helpful in preventing
long-term renal damage (Castro et al. 2016; Malhi and Tanious 2011). The
decision of whether to stop lithium in the setting of renal impairment must be
made collaboratively by the patient, the psychiatrist, and the nephrologist.
Chronic kidney disease can progress to renal failure even after lithium is
stopped; however, with mild or moderate renal dysfunction, there may be
improvement if a change is made (Grünfeld and Rossier 2009).
Cardiac Changes
Lithium intoxication has been reported to cause cardiac alterations, including
sinus bradycardia and sinus node dysfunction (Steckler 1994). Sinus node
dysfunction was found to be more prevalent among patients who had been taking
lithium for at least a year than among age-matched control subjects, although
clinically significant dysfunction was uncommon (Rosenqvist et al. 1993). Also,
cases of atrioventricular block in patients with therapeutic lithium levels have
been reported (Martin and Piascik 1985). Electrocardiographic T-wave changes,
as well as ventricular irritability, may occur (Mitchell and Mackenzie 1982). In
patients with clinical indications for lithium use, the presence of cardiovascular
disease does not constitute a contraindication to lithium use. Dosage adjustment
and frequent cardiac monitoring are essential for the safe use of lithium in
patients with cardiac disease (Tilkian et al. 1976). Because of the risk of sinus
node dysfunction and other cardiac effects, careful monitoring of the pulse and
electrocardiographic monitoring are recommended in patients older than 50
years (Roose et al. 1979).
Drug–Drug Interactions
Conclusion
Lithium is an important option in the evidence-based rational treatment of
bipolar disorder. Bipolar disorder affects between 1% and 5% of the population
(Akiskal et al. 2000) and causes significant morbidity and mortality, and the
diagnosis of bipolar disorder carries a high risk for suicide. A summary
published in 1990 estimated that 25%–50% attempt suicide and 19% complete
suicide (Goodwin and Jamison 1990); however, a recent analysis estimated that
the pooled suicide rate for bipolar disorder was 164 per 100,000 person-years,
with individuals with bipolar disorder accounting for 3.4%–14% of all suicide
deaths (Schaffer et al. 2015).
Lithium has been shown to be effective for acute mania and bipolar
depression and as a prophylactic treatment for bipolar disorder. Some data
suggest that conditions such as comorbid neurological illness and mixed
episodes may be indicators of illness that is more responsive to mood stabilizers
other than lithium. Evidence also suggests that lithium can play a role in the
treatment of refractory unipolar depression in patients at risk for suicide. Lithium
may be less risky than anticonvulsants in pregnancy. Although we continually
seek new treatments and hope that they will be more efficacious and better
tolerated than older medications, for now lithium remains an important treatment
option.
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CHAPTER 37
Valproate
Charles L. Bowden, M.D.
Pharmacological Profile
Valproic acid (dipropylacetic acid; Figure 37–1) is an eight-carbon, branched-
chain carboxylic acid that is structurally distinct from other antiepileptic and
psychotropic compounds (Bocci and Beretta 1976; Levy 1984). Its three-
dimensional structure overlays that of naturally occurring fatty acids (e.g., oleic
and linolenic acids). Valproate binds in a saturable manner to the neuronal
membrane sites to which these longer-chain fatty acids attach. Some of
valproate’s molecular mechanisms are likely a consequence of this
physiochemical property.
Mechanism of Action
Valproate stimulates extracellular signal-regulated kinase (ERK) and indirectly
inhibits glycogen synthase kinase 3 (GSK-3) (Cournoyer and Desrosiers 2009).
Valproate also stimulates the activity of bcl-2, a neuroprotective substance (Gray
et al. 2003). Valproate inhibits histone deacetylase, and many of the drug’s
subcellular effects (e.g., increasing brain-derived neurotrophic factor) are likely
a consequence of this action (Harwood and Agam 2003; Perova et al. 2010).
Co-Therapy in Schizophrenia
Adjunctive use of valproate in the treatment of schizophrenia has increased, with
one report indicating that more than one-third of psychiatric inpatients with a
diagnosis of schizophrenia received valproate during hospitalization (Citrome et
al. 2000). In a 4-week randomized, double-blind study, 242 schizophrenic
patients were assigned to receive either monotherapy with an antipsychotic
(risperidone or olanzapine) or adjunctive treatment with divalproex plus the
antipsychotic drug. Compared with patients receiving monotherapy, those who
received combination therapy showed significantly greater improvement on
Positive and Negative Syndrome Scale (PANSS)–Total and PANSS positive
symptom subscale scores from day 3 through day 21, but not at day 28. Platelet
counts decreased with combination therapy. Cholesterol levels increased with
olanzapine or risperidone monotherapy compared with the significantly lower
levels seen with the combination treatment. Weight gain did not differ for
patients receiving olanzapine versus patients receiving divalproex plus
olanzapine; however, weight gain was greater for divalproex plus risperidone
(7.5 lbs) than for risperidone (4.2 lbs) (Casey et al. 2003).
Mixed Mania
Patients with mixed manic presentations experienced greater symptom
improvement with divalproex than with lithium treatment in two randomized
studies (Freeman et al. 1992; Swann et al. 1997), one of which (Swann et al.)
was placebo controlled (reviewed in Bowden 1995). Patients with mixed manic
symptoms and patients with pure manic symptoms showed equivalent
improvement with divalproex, a finding that indicates the drug’s broad efficacy
across mania subtypes (Swann et al. 1997). By contrast, during maintenance
treatment, patients with mixed mania had equivalent responses to divalproex and
lithium, with evidence of higher rates of adverse effects as a function of illness
features of mixed mania, compared with rates of adverse effects in patients with
euphoric mania (Bowden et al. 2005; Singh et al. 2013). These results suggest
that effective long-term management of mixed manic states requires medication
regimens that are more complex than monotherapy.
Gastrointestinal Effects
Common gastrointestinal effects of valproate include nausea, vomiting, diarrhea,
dyspepsia, and anorexia. These are dose dependent, are usually encountered at
the start of treatment, and are often transient (DeVane 2003). Immediate-release
formulations of valproic acid are more likely than ER and enteric-coated
formulations to cause adverse events (Horne and Cunanan 2003; Zarate et al.
1999).
Tremor
Tremor consequent to valproate resembles benign essential tremor and may
respond to a reduction in dosage. Use of the ER or enteric-coated formulation
may lessen the frequency of tremor (Wilder 1992; Zarate et al. 1999).
Sedation
Mild sedation is common at initiation of valproate treatment. This adverse effect
is dose dependent and may be minimized by dosage reduction, slower titration,
use of ER formulations, or taking all medication at bedtime.
Pancreatitis
Idiosyncratic acute pancreatitis is an infrequent adverse event associated with
valproate. In clinical trials, rates of amylase elevation with valproate were
similar to those with placebo (Pellock et al. 2002), suggesting that precautionary
amylase levels offer little benefit in predicting pancreatitis. Therefore, clinicians
should routinely assess patients’ clinical symptoms to identify possible signs of
pancreatitis.
Hematological Effects
Leukopenia and thrombocytopenia are directly related to higher valproate serum
levels, usually 100 μg/mL or greater (Acharya and Bussel 1996; Bowden et al.
2000). Thrombocytopenia is usually mild and rarely associated with bleeding
complications. Management consists of dosage reduction. Platelet counts below
75,000/mm3 should be monitored and regularly reassessed, because counts lower
than this level are more frequently associated with bruising or bleeding (Zarate
et al. 1999).
Hepatotoxicity
None of the longer-term studies of the past decade and a half has found evidence
of hepatic dysfunction or significant worsening of hepatic indices in valproate-
treated patients compared with placebo-treated or comparator-treated patients
(Bowden et al. 2000; Tohen et al. 2002; Zajecka et al. 2002).
The risk of liver toxicity from valproate is largely limited to patients younger
than 2 years, in whom hepatic function is still immature (Tohen et al. 2003). In a
long-term study of divalproex (versus lithium) in adult outpatients with bipolar I
disorder, full-dosage regimens for 1 year were associated with improvements in
laboratory indices of hepatic function, and no hepatotoxicity was reported in the
187 patients taking divalproex (Bowden et al. 2000). A 47-week placebo-
controlled study of olanzapine augmentation of divalproex or lithium in
outpatients with bipolar disorder likewise found no evidence of adverse hepatic
effects among patients who received divalproex (Tohen et al. 2003).
One risk factor for the development of hepatotoxicity is concomitant
administration of other anticonvulsants (e.g., carbamazepine, phenytoin) that
cause induction of enzymes involved in the metabolism of valproate, leading to
increased concentrations of an active and hepatotoxic metabolite, 2-propyl-4-
pentenoic acid.
Weight Gain
Weight gain of 3–24 lbs is seen in 3%–20% of patients taking valproic acid for
periods ranging from 3 to 12 months (Bowden 2003b). Weight gain has been
consistently less with valproate than with olanzapine in comparison studies (1.22
kg vs. 2.79 kg) (Tohen et al. 2003; Zajecka et al. 2002). Valproate serum levels
greater than 125 μg/mL are more likely than lower levels to cause weight gain
(Bowden 2000). If increased appetite and weight gain occur with valproate, the
dosage should be lowered so long as clinical effectiveness is maintained;
alternatively, valproate should be discontinued and replaced with a regimen
without risk of weight gain.
Cognitive Effects
Valproate infrequently produces adverse effects on cognitive functioning, and it
improves cognition in some patients (Prevey et al. 1996). In a 20-week
randomized, observer-blinded, parallel-group trial, the addition of valproate to
carbamazepine resulted in improvement in short-term verbal memory
(Aldenkamp et al. 2000). No adverse cognitive effects associated with use of
valproate were seen in a group of elderly patients (mean age=77 years) (Craig
and Tallis 1994).
Breast Feeding
Valproate is minimally present in breast milk. Piontek et al. (2000) reported that
among six mother–infant pairs, serum valproate levels in the infants ranged from
0.9% to 2.3% of the mother’s serum levels, with absolute serum levels of 0.7–
1.56 μg/mL. The valproate concentration in an infant was 1.5% of the maternal
concentration (Wisner and Perel 1998).
Overdose
Recovery from overdose-induced coma has occurred with serum valproate
concentrations greater than 2,000 μg/mL. In addition, serum valproate
concentrations have been reduced by hemodialysis and hemoperfusion, and
valproate-induced coma has been reversed with naloxone (Rimmer and Richens
1985).
Drug–Drug Interactions
Because valproate is highly protein bound and extensively metabolized by the
liver, a number of potential interactions may occur with other protein-bound or
extensively metabolized drugs (Fogel 1988; Rimmer and Richens 1985). Thus,
free fraction concentrations of valproate in serum can be increased, and
valproate toxicity can be precipitated, by coadministration of other highly
protein-bound drugs (e.g., aspirin) that can displace valproate from its protein-
binding sites.
In the context of coadministration, valproate’s competitive inhibition of
lamotrigine excretion via glucuronidation requires that lamotrigine be started at a
lower dosage—usually 25 mg every other day—with increases implemented
cautiously. Lamotrigine’s steady-state plasma concentrations are also generally
lower when the drug is used with valproate, although not in all patients.
Conclusion
Valproate’s broad spectrum of efficacy in bipolar and related disorders and
generally good tolerability make it a foundation of treatment for many patients
with bipolar disorders. For optimal results, most patients should be treated with
the formulation that permits once-daily dosing and has the lowest peak-to-trough
serum level, which in the United States currently is divalproex ER. Although
onset of action of valproate occurs quickly with use of loading-dose strategies,
gradual dosage titration is the preferred method of treatment initiation for all but
the most severe manic states. Medication tolerability is of paramount importance
in fostering patient adherence to long-term treatment regimens.
During maintenance treatment, it is often necessary to reduce the dosage if
adverse effects persist. Valproate is principally effective in and prophylactic for
manic symptoms, although its prophylactic benefits in depression are now
relatively well established. A history of multiple affective episodes or a current
presentation characterized by irritability may be a particularly strong indicator of
a favorable response to valproate. Although some patients may achieve acute
and sustained remission with valproate monotherapy, many patients are more
effectively treated with combinations, including other mood stabilizers and
adjunctive medications. All current medications with established or putative
roles in bipolar disorder can be combined with valproate.
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10221283
CHAPTER 38
Carbamazepine, Oxcarbazepine,
and Licarbazepine
Po W. Wang, M.D.
Terence A. Ketter, M.D.
Robert M. Post, M.D.
Pharmacological Profiles
CBZ and OXC have preclinical anticonvulsant profiles similar to that of
phenytoin and less broad than that of valproate or lamotrigine. CBZ and OXC,
like phenytoin, valproate, and lamotrigine, are effective in the maximal
electroshock model of generalized tonic and/or clonic seizures and in blocking
seizures resulting from amygdala kindling (a model of partial seizures). CBZ and
OXC, like phenytoin but unlike valproate and lamotrigine, are not effective in
the pentylenetetrazole model of absence seizures and, like phenytoin and
lamotrigine but unlike valproate, fail to block kindling development (a model of
epileptogenesis).
As expected from their preclinical profiles, CBZ and OXC, like phenytoin,
valproate, and lamotrigine, are effective in partial seizures with and without
secondary generalization and, like phenytoin but unlike valproate and
lamotrigine, are ineffective in absence seizures. CBZ and OXC also have
analgesic effects in paroxysmal pain syndromes and thus are effective in
trigeminal neuralgia.
ESL, which shares a common active metabolite with OXC, has a similar
preclinical anticonvulsant profile. Thus, ESL, like OXC, is effective in the
maximal electroshock model of generalized tonic and/or clonic seizures and
effective in blocking seizures resulting from amygdala kindling (Almeida and
Soares-da-Silva 2007).
Carbamazepine
CBZ is available in the United States as a proprietary product (Tegretol; Novartis
Pharmaceuticals Corporation) supplied as a 100 mg/5 mL suspension; 100-mg
chewable tablets; 200-mg tablets; and 100-, 200-, and 400-mg extended-release
(Tegretol-XR) tablets (Physicians’ Desk Reference 2015). An additional
proprietary beaded extended-release capsule formulation—Carbatrol (Shire US
Inc.), marketed for epilepsy, and Equetro (Validus Pharmaceuticals), marketed
for bipolar disorder—is supplied in 100-, 200-, and 300-mg strengths
(Physicians’ Desk Reference 2015). Intramuscular and depot formulations are
not available. CBZ is also available in generic formulations.
CBZ is extensively metabolized, with only about 3% being excreted
unchanged in the urine. The main metabolic pathway of CBZ (to its active
10,11-epoxide, CBZ-E) appears to be primarily via cytochrome P450 (CYP)
3A3/4 (Figure 38–1, top), with a minor contribution by CYP2C8 (Kerr et al.
1994). This epoxide pathway accounts for about 40% of CBZ disposition, and an
even greater percentage in patients with induced epoxide pathway metabolism
(Faigle and Feldmann 1995). The frequency distribution of CBZ kinetic
parameters is unimodal, consistent with CYP3A3/4 being the crucial isoform.
With enzyme induction (of the epoxide pathway, presumably via CYP3A3/4
induction), formation of CBZ-E triples, and thus the CBZ-E/CBZ ratio increases
(Eichelbaum et al. 1985). Other pathways include aromatic hydroxylation (25%),
which is apparently via CYP1A2 and is not induced concurrently with epoxide
formation, and glucuronide conjugation of the carbamoyl side chain (15%) by
uridine diphosphoglucuronosyltransferase (UGT), presumably primarily by
UGT2B7 (Staines et al. 2004). These other pathways yield inactive metabolites.
CBZ has erratic absorption and a bioavailability of about 80%. Tablets should
not be exposed to humidity, because moisture can cause solidification and
decrease the drug’s bioavailability (Nightingale 1990). CBZ is about 75% bound
to plasma proteins and has a moderate volume of distribution of about 1 L/kg.
Before autoinduction of the epoxide pathway, the half-life of CBZ is about 24
hours, and clearance is about 25 mL/min. However, after autoinduction (2–4
weeks into therapy), the half-life falls to about 8 hours, and clearance rises to
about 75 mL/min. This may require dosage adjustment to maintain adequate
blood concentrations and therapeutic effects. The active CBZ-E metabolite has a
half-life of about 6 hours and is converted to an inactive diol (CBZ-D) by
epoxide hydrolase. The extended-release CBZ formulations given twice daily
yield steady-state CBZ concentrations similar to those seen with the immediate-
release formulation given four times daily (Garnett et al. 1998; Thakker et al.
1992).
When CBZ is used in the treatment of acute mania, two divergent clinical
needs influence the rate of dosage titration. The need for rapid control of the
manic syndrome should be balanced against the need to minimize adverse effects
(which can be worsened with overly aggressive escalation of CBZ dosage).
Thus, although a loading-dose strategy may be tolerated and effective in the
treatment of mania with valproate (Keck et al. 1993), the potential for neurotoxic
adverse effects (i.e., CNS symptoms such as dizziness, somnolence, cognitive
slowness, tremors, ataxia, and slurred speech) limits the use of such an approach
with CBZ.
Nonetheless, in the inpatient therapy of mania, CBZ is commonly started at
400–800 mg/day in divided doses and increased as tolerated (by 200 mg/day
every 1–4 days) to provide clinical efficacy. In controlled studies, the beaded
extended-release capsule formulation was started at 200 mg twice per day and
increased daily by 200 mg to a final dosage as high as 1,600 mg/day (Weisler et
al. 2004, 2005). Managing dosage titration against adverse effects is more
important than targeting a specific blood concentration range. The usual dosage
range is 800–1,600 mg/day given in up to three or four divided doses with the
immediate-release formulation. Sustained-release formulations permit two
divided doses per day and may even allow most or all of the daily dosage to be
taken at bedtime in mood disorder patients. Although this strategy is convenient,
it may not be feasible in some individuals because of neurotoxicity at the peak
serum concentration, which occurs about 4–8 hours after ingesting a dose. CBZ
has a fairly rapid onset of antimanic efficacy. Thus, if clinical improvement has
not occurred after 7–10 days, the clinician should consider augmentation or
alternative strategies.
In a 6-month open-label extension of controlled studies in acute mania,
beaded extended-release capsule CBZ was started at 200 mg twice per day and
increased by 200 mg every 3 days (versus every day in the acute studies) to a
final dosage as high as 1,600 mg/day (Ketter et al. 2004). This approach
decreased the incidence of central nervous system (CNS; dizziness, somnolence,
ataxia), digestive system (nausea, vomiting), and dermatological (pruritus)
adverse effects by about 50%.
In less acute situations, CBZ is often started at 100–200 mg/day and increased
as necessary and tolerated by 200 mg/day every 4–7 days. Even more gradual
initiation strategies may be necessary to alleviate adverse effects. Thus, starting
with 50 mg (half of a chewable 100-mg tablet) at bedtime and increasing by 50
mg every few days can result in a better-tolerated initiation. Often, initial
dosages of CBZ may be better tolerated after 1 month of therapy, once
autoinduction of CBZ metabolism has decreased the serum CBZ concentrations
(Cereghino 1975) and accommodation and tolerance to adverse effects such as
sedation have occurred. In two CBZ-versus-lithium maintenance studies, trough
serum CBZ concentrations were maintained at 4–12 μg/mL, with a mean of 6.4
μg/mL (Greil et al. 1997) and 7.7 μg/mL (Denicoff et al. 1997).
Because CBZ dosage and serum and cerebrospinal fluid (CSF) concentrations
do not correlate with its psychotropic efficacy (Post 1989; Post et al. 1983,
1984a), clinical management involves gradual uptitration of CBZ dosages until
adequate therapeutic efficacy is achieved, adverse effects supervene, or serum
concentrations exceed 12 μg/mL. The 4–12 μg/mL serum CBZ concentration
range used in epilepsy may be considered as a broad target, with CBZ serum
concentrations used as checks for pharmacokinetic problems. The active CBZ-E
metabolite can yield therapeutic and adverse effects similar to those of CBZ, but
it is not detected in conventional CBZ assays. Thus, the unwary clinician may
misinterpret the significance of therapeutic or adverse effects associated with
low or moderate serum CBZ concentrations.
In responders, a dose–response relationship may be evident, so slowly
increasing CBZ dosages to maximize response in the absence of significant
adverse effects would be an appropriate clinical strategy. However, if there is no
hint of therapeutic response at moderate dosages, it is unlikely that pushing to
very high dosages would be beneficial.
Oxcarbazepine
OXC is available in the United States as a proprietary product (Trileptal;
Novartis Pharmaceuticals Corporation) supplied as a 300 mg/5 mL suspension
and as 150-, 300-, and 600-mg tablets (Physicians’ Desk Reference 2015). A
novel once-daily extended-release formulation of OXC (Oxtellar XR; Supernus
Pharmaceuticals Inc.) has also been approved for the adjunctive treatment of
partial seizures in adults and in children ages 6–17 years. Limited data suggest
that this formulation has enhanced tolerability (Chung et al. 2016). Intramuscular
and depot formulations of OXC are not available.
OXC is 96% absorbed, and the modest effect of food on OXC kinetics does
not appear to be of therapeutic consequence (Degen et al. 1994). OXC is 60%
bound to plasma proteins. Like CBZ, OXC has a complex metabolism (Figure
38–1, bottom). Thus, OXC is rapidly reduced to an active monohydroxy
derivative (MHD) by cytosol arylketone reductase. The MHD form (also called
licarbazepine) is 40% bound to plasma proteins, has a moderate volume of
distribution of about 0.8 L/kg, and has a half-life of about 9 hours. OXC is
eliminated primarily in the form of MHD (70%) and MHD glucuronide
conjugates (20%), with a small proportion (10%) eliminated in the form of OXC
glucuronide conjugates and CBZ-D. OXC does not cause autoinduction, and it
causes substantially less heteroinduction than does CBZ. Thus, as described later
in this chapter (see section “Drug–Drug Interactions”), medication interactions
are less problematic with OXC than with CBZ (Baruzzi et al. 1994).
OXC is started at 150 mg/day and increased every other day by 150 mg to a
target of 1,200–1,600 mg/day in two to three divided doses. Further dosage
increases up to 2,400 mg/day may be clinically indicated. In small trials of OXC
in acute mania, mean OXC dosages were 1,400–2,400 mg/day (Emrich 1990;
Emrich et al. 1983). As with CBZ, when used to treat patients with bipolar
disorder, OXC is titrated to the desired clinical effect as tolerated, with the serum
concentration range used in epilepsy considered as a broad target, and with OXC
serum concentrations used a checks for pharmacokinetic problems. Equipotent
doses of OXC range from 1.2 to 1.5 times the CBZ dose.
Eslicarbazepine Acetate
ESL is available in the United States as a proprietary product (Aptiom; Sunovion
Pharmaceuticals Corporation) supplied in 200-, 400-, 600-, and 800-mg tablets
(Physicians’ Desk Reference 2015). Extended-release, intramuscular, and depot
formulations are not available.
Licarbazepine is the active MHD product of OXC, and eslicarbazepine is the
S-isomer of licarbazepine (Figure 38–2). ESL is a prodrug of eslicarbazepine.
Licarbazepine is 40% bound to plasma proteins, has a moderate volume of
distribution (about 0.8 L/kg), and has a half-life of about 20–24 hours (Zaccara
et al. 2015). Elimination is mainly through the kidneys, unchanged or
glucuronidated (Zaccara et al. 2015). ESL pharmacokinetics do not appear to be
affected in patients with moderate hepatic impairment (Almeida et al. 2008).
Mechanisms of Action
CBZ and OXC have both structural and mechanistic similarities. However, these
agents have such a diversity of biochemical effects that linking these
mechanisms to their varying clinical actions presents a considerable challenge.
Carbamazepine
Although CBZ has a tricyclic structure like that of imipramine, the two agents
have markedly different neurochemical, hepatic, and clinical effects. CBZ lacks
imipramine’s major effects on monoamine reuptake and high affinity for
histaminergic, cholinergic, adrenergic β, and dopamine receptors. However, CBZ
has a wide range of other cellular and intracellular effects.
One useful way of considering CBZ’s diverse mechanisms is from the
perspective of onset of action (Post 1988). CBZ cellular actions with acute onset
that might parallel the time course of clinical anticonvulsant effects include
decreasing sodium influx and glutamate release, increasing potassium
conductance, and interacting with peripheral benzodiazepine and α2-adrenergic
receptors. Acute or subchronic actions—such as increasing striatal cholinergic
neurotransmission; decreasing adenylate cyclase activity stimulated by
dopamine, norepinephrine, and serotonin; and decreasing turnover of dopamine,
norepinephrine, and γ-aminobutyric acid (GABA)—may be pertinent to CBZ’s
clinical antimanic effects. Finally, the actions requiring chronic administration—
include increasing serum and urinary free cortisol, free tryptophan, substance P
sensitivity, and adenosine A1 receptors and decreasing cerebrospinal
somatostatin—may be those that are most closely related to CBZ’s clinical
antidepressant effects.
Oxcarbazepine
Compared with the knowledge base on CBZ’s mechanisms of action, less is
known about OXC (and thus ESL, given their common active molecules). Most
evidence thus far suggests that OXC’s structural similarity to CBZ is paralleled
by mechanistic similarity (Ambrósio et al. 2002). For example, OXC, like CBZ,
appears to decrease sodium (Benes et al. 1999; Wamil et al. 1994) and calcium
(Stefani et al. 1995) influx, glutamate release (Ambrósio et al. 2001), and serum
thyroxine concentrations (Isojärvi et al. 2001b); to increase potassium
conductance (McLean et al. 1994) and dopaminergic (Joca et al. 2000)
neurotransmission; and to block adenosine A1 receptors (Deckert et al. 1993).
However, there may be some mechanistic dissimilarities, particularly given the
marked difference between OXC and CBZ in degree of hepatic enzyme
induction. For example, OXC appears to be a less potent modulator of voltage-
gated calcium channels than is CBZ (Schmutz et al. 1994; Stefani et al. 1997).
The general OXC–CBZ mechanistic overlap is consistent with the hypothesis
that OXC and CBZ have similar effects in bipolar disorder, which in turn is
consistent with preliminary clinical observations; however, these similarities
remain to be established in large controlled clinical studies.
Eslicarbazepine Acetate
ESL and OXC likely have a similar mode of action because they share the same
main active metabolite, licarbazepine (although the oxcarbazepine metabolite is
racemic licarbazepine, whereas the ESL metabolite is exclusively the S-isomer
of licarbazepine) (Almeida and Soares-da-Silva 2007; Schütz et al. 1986). Thus,
ESL behaves as a blocker of the voltage-gated sodium channel (VGSC; Almeida
and Soares-da-Silva 2007). However, whereas ESL reduces VGSC availability
through enhancement of slow inactivation, CBZ acts by altering fast inactivation
of VGSC (Hebeisen et al. 2015). Eslicarbazepine and CBZ also differ with
regard to submaximal GABA currents, Kv7.2 outward currents, and high- and
low-affinity Cav3.2 inward currents (Keating 2014). OXC and ESL may have
some mechanistic differences as well, with CBZ and OXC enhancing excitatory
synaptic transmission via antagonism of the adenosine A1 receptor at therapeutic
doses, whereas ESL does so only at supratherapeutic high dosages (Booker et al.
2015).
Acute Mania
The FDA approved a proprietary CBZ beaded extended-release capsule
formulation (Equetro) for the treatment of acute manic and mixed episodes in
patients with bipolar disorder in late 2004, but CBZ and OXC are still
considered alternative agents in the management of bipolar disorder (American
Psychiatric Association 2002). Twenty-six controlled studies have investigated
the efficacy of CBZ, OXC, and ESL in acute mania (summarized in Table 38–1).
In these studies, there is more compelling evidence for the efficacy of CBZ (18
studies encompassing 594 patients receiving CBZ) than for the efficacy of OXC
(5 studies including 119 patients receiving OXC) or ESL (2 studies
encompassing 146 patients receiving ESL).
PBO
monotherapy
Response CBZ/OXC
ratesa adjunctive
FGA adjunctive
Li adjunctive
PBO adjunctive
Eslicarbazepine Acetate
In two 3-week studies of ESL in acute mania, ESL did not separate from placebo
on the primary outcome measure of Young Mania Rating Scale change;
however, Global Clinical Impression changes were suggestive of efficacy in one
of the two studies (Grunze et al. 2015). High rates of placebo response and poor
study recruitment (leading to premature study termination) may have contributed
to failure in the second study (Grunze et al. 2015).
Acute Depression
Limited controlled data exist regarding the acute antidepressant effects of CBZ,
and there are no published controlled studies of the antidepressant effects of
OXC or ESL (Table 38–2). Although CBZ appears to have weaker
antidepressant than antimanic properties, some evidence suggests that it may
provide antidepressant benefit in about one-third of patients with treatment-
resistant depression (Neumann et al. 1984; Post et al. 1986; Small 1990),
whereas in a Chinese study, CBZ produced a response rate closer to two-thirds in
patients with non-treatment-resistant depression (Zhang et al. 2007).
Unfortunately, most of these studies are limited by their use of small samples of
heterogeneous (both bipolar and unipolar) patients with highly treatment-
resistant depression.
PBO 32%
In one study, the overall analysis suggested that maintenance treatment was
more effective with lithium than with CBZ (Greil et al. 1997). However,
subgroup differences may exist, such that lithium may be more effective in
patients with “classical” bipolar disorder (i.e., bipolar I disorder with no mood-
incongruent delusions or comorbidity), whereas CBZ may be more effective in
patients with “nonclassical” bipolar disorder (e.g., bipolar II disorder, DSM-IV
[American Psychiatric Association 1994] bipolar disorder not otherwise
specified, bipolar disorder with mood-incongruent delusions or comorbidity)
(Greil et al. 1998).
In another study, lithium maintenance treatment appeared to be more effective
than CBZ in patients with no more than 6 months’ prior exposure to either agent
(Hartong et al. 2003). However, this advantage was offset by more early
discontinuations in the lithium group, so that similar proportions (about one-
third) of patients completed 2 years with no episode. Patients taking lithium
versus CBZ tended to have somewhat greater risk of episodes in the first 3
months and markedly less risk of episodes after the first 3 months, with a
recurrence risk of only 10% per year with lithium after the first 3 months.
Patients taking CBZ had a more consistent rate of relapse or recurrence of about
40% per year.
Some CBZ relapse-prevention trials have been criticized for their
methodological limitations (Murphy et al. 1989), although such difficulties are
common in maintenance studies. (For example, divalproex and lithium failed to
separate from placebo on the primary efficacy measure in a 1-year maintenance
study [Bowden et al. 2000], a result at least partially due to methodological
problems.) Taken together, this collection of randomized placebo-controlled,
placebo–drug–placebo, and lithium comparator studies and trials in rapid-
cycling and lithium-resistant populations provides substantial evidence for the
preventive efficacy of CBZ (Prien and Gelenberg 1989). CBZ may be effective
in some individuals with valproate-resistant illness (Post et al. 1984b), and the
CBZ-plus-valproate combination may be effective in patients with little or no
response to either agent alone (Keck et al. 1992; Ketter et al. 1992).
In a retrospective study, although 22 of 34 (65%) patients with treatment-
resistant bipolar disorder responded to primarily adjunctive open CBZ acutely,
when patients were assessed 3–4 years later, only 7 of 34 (21%) and 2 of 34
(6%) were considered probable and clear responders, respectively (Frankenburg
et al. 1988). Post et al. (1990; Post and Weiss 2011) have suggested that loss of
CBZ prophylactic efficacy over time may be related to a unique form of
contingent tolerance. In these instances, techniques such as switching to another
treatment regimen with a different mechanism of action or returning later to
CBZ (after a period of not taking CBZ) are worth considering, based on case
reports and anecdotal observations.
Eslicarbazepine Acetate
A 6-month continuation study investigated the efficacy of three different dosages
of ESL (300 mg/day, 900 mg/day, and 1,800 mg/day) in preventing symptom
recurrence in the bipolar patients who had participated in the earlier placebo-
controlled studies of ESL in acute mania. Of the 85 patients who had responded
during acute treatment and were randomly assigned to one of the three dosage
groups, at least 50% did not show any clinical worsening, although there was no
significant difference between dosage groups (Grunze et al. 2015).
Response Predictors
Predictors of CBZ and OXC response have not been adequately elucidated. CBZ
can be effective in patients with a history of lithium unresponsiveness or
intolerance (Okuma et al. 1979; Post et al. 1987). Nonclassical bipolar disorder
(Greil et al. 1998; Small et al. 1991) and stable or decreasing episode frequency
(Post et al. 1990) may be associated with CBZ response. Patients with a history
of affective illness in first-degree relatives may preferentially respond to lithium,
whereas the converse may be the case for CBZ (Ballenger and Post 1978; Post et
al. 1987). Patients with comorbid neurological or substance abuse problems and
inadequate lithium responses may respond to CBZ or valproate (Himmelhoch
1987; Himmelhoch and Garfinkel 1986). Preliminary observations indicate that
baseline cerebral (left insula) hypermetabolism may be a marker of CBZ
response (Ketter et al. 1999).
Reports vary with respect to the relationships between CBZ response and
dysphoric manic presentations (Lusznat et al. 1988; Post et al. 1989) and illness
severity (Post et al. 1987; Small et al. 1991). Antidepressant responses to CBZ
may be seen in patients with more severe depression, more discrete depressive
episodes, less chronicity, and greater decreases in serum thyroxine
concentrations with CBZ (Post et al. 1986, 1991).
Although the initial studies of Post et al. (1987) and Okuma et al. (1981;
Okuma 1983) indicated that some rapid-cycling patients were responsive to
CBZ, other investigators found less robust results (Dilsaver et al. 1993; Joyce
1988). As with lithium, later studies by Okuma and associates reported a lower
CBZ maintenance response rate in rapid cycling compared with non-rapid-
cycling illness (Okuma 1993). However, even these rapid-cycling patients had a
CBZ response rate (40%) that was higher than rates reported with other agents in
other studies. Denicoff et al. (1997) also observed that patients with a history of
rapid cycling had a lower response rate to maintenance CBZ (as with
maintenance lithium) compared with those without such as history (19% vs.
54%), but rapid cyclers did well on the combination of lithium and CBZ.
Carbamazepine
Adverse effects appear to have substantial impact on the utility of CBZ in the
treatment of bipolar disorder. In a pooled analysis of two multicenter acute
mania FDA registration studies of a proprietary extended-release capsule
formulation of carbamazepine (Equetro), the number needed to harm for
somnolence was 6, and for at least 7% weight gain, the number was 23 (Ketter et
al. 2011), suggesting that neurocognitive adverse effects more than weight gain
might limit CBZ utility (Ketter 2015). Some patients may tolerate CBZ better
than other agents, particularly during longer-term treatment, because CBZ
appears to have a low propensity to cause adverse effects such as weight gain
and metabolic disturbance that can limit the utility of some other agents (Akiskal
et al. 2005; Ketter 2015).
CBZ has several common dose-related adverse effects that generally can be
minimized by attention to drug–drug interactions and gradual titration of dosage
or reversed by decreasing dosage. At high dosages, patients can develop
neurotoxicity with sedation, ataxia, diplopia, and nystagmus, particularly early in
therapy, before the autoinduction process is complete and tolerance develops to
the CNS adverse effects of CBZ. Because there is wide interindividual variation
in susceptibility to adverse effects at any given concentration, it is most useful
clinically to titrate doses against each patient’s adverse effects rather than
targeting a fixed dosage or serum concentration range.
Neurotoxic effects that emerge 1–2 hours after an individual dose often signal
that the adverse-effect threshold has been exceeded and that dose redistribution
(spreading out the doses or giving more of the dose at bedtime) or dosage
reduction may be required. Use of extended-release formulations may attenuate
CBZ peak serum concentrations, enhancing tolerability.
CBZ commonly causes benign hematological (leukopenia,
thrombocytopenia), dermatological (rash), electrolyte (asymptomatic
hyponatremia), and hepatic (transaminase elevations) problems. Analogous
serious problems are much less common. For example, mild leukopenia and
benign rash occur in up to 1 in 10 patients, with the slight possibility that these
usually benign phenomena are heralding malignant aplastic anemia and Stevens-
Johnson syndrome, seen in about 1 in 100,000 patients (Kramlinger et al. 1994;
Tohen et al. 1995).
In view of the risk of rare but serious decreases in blood counts, which
warrant a black box warning in the CBZ prescribing information, it is important
to alert patients to seek immediate medical evaluation if they develop signs and
symptoms of possible hematological reactions, such as fever, sore throat, oral
ulcers, petechiae, and easy bruising or bleeding. Hematological monitoring
needs to be intensified in patients with low or marginal leukocyte counts, and
CBZ is generally discontinued if the leukocyte count falls below 3,000/μL or the
granulocyte count below 1,000/μL. In the instance of benign leukopenia, the
addition of lithium can increase the neutrophil count back toward normal
(Kramlinger and Post 1990), but this strategy is not likely to be helpful for the
suppression of red cells or platelets, which is likely to indicate a more
problematic process.
Serious rash may occur in about 1 in 100,000 patients. The risk of serious and
sometimes fatal dermatological reactions, including toxic epidermal necrolysis
and Stevens-Johnson syndrome, may be increased tenfold in certain Asian
populations and has been strongly linked to the human leukocyte antigen (HLA)
B*1502 allele (Physicians’ Desk Reference 2015). Thus, the U.S. prescribing
information includes a black box warning that individuals of Asian ancestry
should be genetically tested for HLA-B*1502 and that carriers of this allele
should not be treated with CBZ. A twelvefold increased risk of drug-induced
hypersensitivity syndrome (DIHS; also called drug rash with eosinophilia and
systemic symptoms [DRESS]) has also been linked to HLA-A*3101 in whites of
northern European descent (McCormack et al. 2011). Given the risk of serious
rash, patients should be alerted to seek medical attention immediately if a rash
develops. In particular, rash in patients presenting with systemic illness or
involvement of the eyes, mouth, or bladder (dysuria) constitutes a medical
emergency: carbamazepine should be immediately discontinued, and the patient
should be assessed emergently (Scaparrotta et al. 2011). For more benign
presentations, CBZ is generally discontinued, because there is little ability to
predict which cases will progress to more severe, potentially life-threatening
problems. However, in rare instances of resistance to all medications except
CBZ, a repeat trial of CBZ with a course of prednisone has usually been well
tolerated (Murphy et al. 1991; Vick 1983). A substantial number of patients with
CBZ-induced rash may not develop a rash on reexposure (even without
prednisone coverage), but if a rash develops again, it usually appears more
rapidly than the first occurrence. Only 25%–30% of patients who develop a rash
with CBZ also develop a rash (cross-sensitivity) with OXC.
CBZ, in common with multiple other anticonvulsant medications (including
OXC and ESL), may increase the risk of suicidality, including suicidal behavior
or ideation. Data from controlled trials of anticonvulsant medications compared
with placebo found a 1.5-fold increased risk from 0.57% to 0.85% for
psychiatric patients (Physicians’ Desk Reference 2015).
Because of the risk of rare hepatitis, patients should be advised to seek
medical evaluation immediately if they develop malaise or abdominal pain or
other marked gastrointestinal symptoms. In general, CBZ (like other
anticonvulsants) should be discontinued if liver function values exceed three
times the upper limit of the normal range (Martínez et al. 1993).
CBZ may affect cardiac conduction and should be used with caution in
patients with cardiac disorders such as heart block. A baseline electrocardiogram
is worth considering if there is a positive cardiac history.
Conservative laboratory monitoring during CBZ therapy includes baseline
studies and evaluation of complete blood count, differential, platelets, and
hepatic indices initially and at 2, 4, 6, and 8 weeks and then every 3 months
(American Psychiatric Association 1994, 2002). Most of the serious
hematological reactions occur within the first 3 months of therapy (Tohen et al.
1995). In contemporary clinical practice, clinically indicated monitoring (e.g.,
when a patient becomes ill with a fever) is emphasized over scheduled
monitoring. Patients who have abnormal or marginal indices at any point merit
careful scheduled and clinically indicated monitoring. The U.S. prescribing
information for the beaded extended-release capsule CBZ formulation
recommends a baseline complete blood count including platelets, possibly
reticulocytes, possibly serum iron, and hepatic function tests; closely monitoring
patients with low or decreased white blood cell counts or platelets; and
considering discontinuation of CBZ if evidence indicates bone marrow
depression (Physicians’ Desk Reference 2015). Serum CBZ concentrations are
typically assessed at steady state and then as indicated by inefficacy or adverse
effects. An important clinical note is that because of autoinduction, CBZ
concentrations may decrease during the first 2–3 weeks after treatment initiation
(Eichelbaum et al. 1975), thus potentially requiring readjustment of steady-state
dosing.
Dividing or reducing dosages, rescheduling individual doses in relation to
mealtimes, and changing formulations can attenuate CBZ-induced
gastrointestinal disturbance. The CBZ oral suspension formulation may have
more proximal absorption and thus may exacerbate upper gastrointestinal
adverse effects (nausea and vomiting) or attenuate lower gastrointestinal effects
(diarrhea). The reverse holds for extended-release preparations.
Weight gain and obesity are important clinical concerns in the management of
bipolar disorder. Medications and the hyperphagia, hypersomnia, and anergy
commonly seen in bipolar depression can contribute to this important obstacle to
optimal outcomes. CBZ is less likely than lithium (Coxhead et al. 1992;
Denicoff et al. 1997) or valproate (Mattson et al. 1992) to cause weight gain. In
one study, CBZ caused weight gain in depressed (but not manic) patients, which
seemed to be related to the degree of relief of depression (Joffe et al. 1986).
Nevertheless, in view of its relatively benign effect on weight, CBZ may provide
an important alternative to other mood stabilizers for patients who struggle with
weight gain and obesity.
CBZ can induce hyponatremia, which may be tolerated well by some younger
patients but can be particularly problematic in the elderly. If confusion develops
in an elderly patient, serum sodium should be assessed. In rare instances, water
intoxication and seizures can occur. In some cases, hyponatremia can be
effectively counteracted with the addition of lithium or the antibiotic
demeclocycline (Ringel and Brick 1986).
CBZ increases plasma high-density lipoprotein (HDL; O’Neill et al. 1982)
and total cholesterol (Brown et al. 1992) concentrations. However, the HDL–to–
total cholesterol ratio does not change (O’Neill et al. 1982), and thus, CBZ-
induced increases in total cholesterol are not likely to be clinically problematic
in relation to atherosclerosis (Brown et al. 1992).
CBZ appears to reduce serum concentrations of both female and male sex
hormones (Verrotti et al. 2011). In common with several other anticonvulsants,
CBZ may adversely affect bone density (Verrotti et al. 2010).
CBZ is teratogenic (former FDA pregnancy category D) and is associated with
low birth weight, craniofacial deformities, digital hypoplasia, and, in
approximately 3% of births, spina bifida (Jones et al. 1989; Rosa 1991). Folate
supplementation may attenuate the risk of spina bifida, and fetal ultrasound
studies may allow early detection. In one study of children born to women with
epilepsy, in utero exposure to CBZ or valproate, but not to lamotrigine, had a
detrimental effect on child neurodevelopment, although CBZ appeared less
likely than valproate to cause major developmental delays (Cummings et al.
2011).
CBZ is present in breast milk at concentrations about half those in maternal
blood, but it may not accumulate in fetal blood (Froescher et al. 1984; Kuhnz et
al. 1983; Pynnönen et al. 1977; Shimoyama et al. 2000). Clinicians may prefer to
avoid the risk of exposing infants to CBZ in breast milk (Frey et al. 2002) and
may wish to discourage breast feeding in women taking CBZ (Physicians’ Desk
Reference 2015).
Oxcarbazepine
As with CBZ, adverse effects may limit OXC therapy. However, OXC may have
tolerability advantages compared with CBZ (Dam et al. 1989), in part perhaps
related to the absence of the CBZ-E metabolite. Of note, OXC lacks black box
warnings regarding serious rash, blood dyscrasias, or tissue typing, although
OXC still has the class warning regarding increased risk of suicidality.
Compared with CBZ, OXC appears to have a lower propensity to cause
neurotoxicity and rash. About 75% of patients who develop a rash with CBZ will
tolerate OXC. OXC does not appear to require hematological monitoring.
OXC, like CBZ, may cause transaminase elevations and gastrointestinal
adverse effects, but there is less weight gain than with valproate (Rättyä et al.
1999) and less impact on lipids than with CBZ (Isojärvi et al. 1994).
Hyponatremia occurs more commonly with OXC (Friis et al. 1993) than with
CBZ (Isojärvi et al. 2001a). However, clinically significant hyponatremia is less
common than asymptomatic hyponatremia (Reinstein et al. 2002).
Compared with CBZ, OXC has less impact on female hormone blood
concentrations, likely due to its less marked hepatic enzyme induction. However,
OXC induction of female hormone metabolism may still decrease the efficacy of
hormonal contraceptives (Fattore et al. 1999; Krämer et al. 1992). OXC, in
common with CBZ and several other anticonvulsants, may adversely affect bone
density (Verrotti et al. 2010).
OXC, in contrast to CBZ, has not to date been associated with congenital
malformations in humans (former FDA pregnancy category C). Whether this is
due to fewer OXC exposures or the absence of the CBZ-E metabolite (rendering
OXC less teratogenic) is unknown. OXC is present in breast milk; therefore, as
with CBZ, clinicians may prefer to avoid the risk of exposing infants to OXC in
breast milk and may wish to discourage breast feeding in women taking OXC
(Physicians’ Desk Reference 2015).
Eslicarbazepine Acetate
Adverse effects may limit OXC therapy, as with CBZ, but owing to structural
advantages, tolerability may be better with ESL (Almeida and Soares-da-Silva
2007). The most commonly reported adverse effects from two epilepsy
registration studies included somnolence, dizziness, vertigo, ataxia, abnormal
coordination, diplopia, fatigue, and headache (Physicians’ Desk Reference
2015). The risk of rash was low (about 1%). The risk of hyponatremia with ESL
is unknown, with rates ranging from 0.6% to 1.3% in premarketing trials
(Zaccara et al. 2015) and rates as high as 3% in postmarketing studies (Massot et
al. 2014). Significant decreases in sodium levels (≥10 mEq/L) were more
common with ESL than with placebo (Physicians’ Desk Reference 2015). ESL
may increase QT interval on electrocardiogram (Vaz-Da-Silva et al. 2012).
Importantly, ESL, similar to OXC, lacks black box warnings for serious rash,
blood dyscrasias, or tissue typing, although ESL still has the (non–black box)
class warning regarding increased risk of suicidality.
ESL, like OXC, has not to date been associated with congenital malformations
in humans (former FDA pregnancy category C), and ESL is excreted in breast
milk (Physicians’ Desk Reference 2015).
Drug–Drug Interactions
Combination therapy is common in bipolar disorder, with up to two-thirds of
patients taking more than one medication concurrently (Kupfer et al. 2002).
Patients with treatment-resistant illness may require a stepped-care approach
(Figure 38–3), and they appear to be receiving increasingly complex medication
regimens (Frye et al. 2000). CBZ, and to a lesser extent OXC, has clinically
significant drug–drug interactions that increase the complexity of managing
patients with bipolar disorder.
FIGURE 38–3. Stepped-care approach to bipolar depression.
Composite schema of results from three different studies in which patients with bipolar
depression received carbamazepine (CBZ) monotherapy (Post et al. 1986), lithium (Li) added
to CBZ (Kramlinger and Post 1989b), or a monoamine oxidase inhibitor (MAOI) added to
CBZ±Li (Ketter et al. 1995b). Each successive intervention resulted in additional efficacy.
Carbamazepine
The pharmacokinetic properties of CBZ are typical of older enzyme-inducing
anticonvulsants but are atypical among medications prescribed by psychiatrists.
CBZ necessitates special care when treating patients concurrently with other
medications (Ketter et al. 1991a, 1991b). Three major principles appear to make
important contributions to CBZ drug–drug interactions:
Oxcarbazepine
In comparison with CBZ, OXC has fewer clinically significant drug–drug
interactions. Differences in three major areas appear to contribute importantly to
differences between OXC and CBZ with regard to drug–drug interactions:
Eslicarbazepine Acetate
ESL, which shares the same active metabolite as OXC, also has fewer clinically
significant drug–drug interactions compared with CBZ. ESL is modestly protein
bound, without significant related interactions. ESL does not have significant
effects on most CYP enzyme pathways, including 1A2, 2A6, 2B6, 2C9, 2D6,
2E1, and 4A9/11 (Almeida and Soares-da-Silva 2007). Its three main
pharmacokinetic effects are weak induction of CYP3A4, weak induction of
UDP-glucuronyl transferases, and weak inhibition of CYP2C19 (Zaccara et al.
2015).
Interactions With Mood Stabilizers
Similar to OXC and in contrast to CBZ, ESL does not significantly induce
valproate metabolism. Moreover, ESL does not have significant interactions with
lamotrigine or topiramate metabolism (Bialer and Soares-da-Silva 2012). ESL
may increase phenytoin levels by up to 35%, presumably because of CYP2C19
inhibition (Bialer and Soares-da-Silva 2012). When used concurrently with
CBZ, however, ESL levels may be decreased by up to 33%, presumably because
of CBZ-induced glucuronidation, potentially requiring ESL dosage adjustments
(Bialer and Soares-da-Silva 2012).
Conclusion
In the past, because of the lack of an FDA indication, complexity of use, and
methodological concerns regarding earlier efficacy studies, CBZ was generally
considered an alternative rather than a first-line intervention in bipolar disorder.
However, the approval of a proprietary CBZ beaded extended-release capsule
formulation (Equetro) for the treatment of acute manic and mixed episodes in
patients with bipolar disorder and the low propensity of CBZ to cause the weight
gain and metabolic problems seen with some other agents may lead clinicians to
reassess the role of CBZ in the management of bipolar disorder (Ketter 2015).
OXC, compared with CBZ, has more limited evidence of efficacy in bipolar
disorder, but it has enhanced tolerability and fewer drug–drug interactions. MHD
(the active metabolite of OXC) and ESL (the prodrug to the S-enantiomer of
MHD) likewise have enhanced tolerability and fewer drug–drug interactions, but
their efficacy in bipolar disorder remains to be established. Thus, with CBZ (but
not OXC), common benign leukopenia needs to be distinguished from rare
serious aplastic anemia, and patients and caregivers need to be alert to symptoms
of this adverse effect. In addition, CBZ (and to a lesser extent OXC) in
combination therapy induces the metabolism of other drugs, potentially
undermining their efficacy if the dosage is not adjusted for this lowering effect.
Also, other drugs (e.g., erythromycin, verapamil) can inhibit CBZ (but not OXC)
metabolism, causing CBZ toxicity. Instructing patients to alert their other
caregivers and their pharmacist that they are receiving CBZ may help avoid drug
interactions. Informing patients of several of the common interactions can
further assist in the warning process, because other practitioners may
inadvertently introduce commonly used drugs such as erythromycin with the
attendant risk of CBZ toxicity.
CBZ is an important treatment option for patients with bipolar disorder who
experience inadequate response or unacceptable adverse effects with lithium and
valproate. Awareness of CBZ and OXC pharmacology and potential drug–drug
interactions will enable clinicians to provide the safest and most effective care
for their patients with bipolar disorder.
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CHAPTER 39
Gabapentin
Early observations of enhanced general well-being in epileptic patients treated
with anticonvulsants, as well as various early hypotheses of kindling and
sensitization proposed as models of affective illness progression (Weiss and Post
1998), have promoted controlled investigations of anticonvulsant drugs as
potential mood-stabilizing agents.
Gabapentin is U.S. Food and Drug Administration (FDA)–approved for the
adjunctive treatment of complex partial epilepsy in pediatric patients ages 3–12
years and in patients older than 12 years (with and without secondary
generalization) and for the management of postherpetic neuralgia in adults. A
retrospective review of five placebo-controlled trials of gabapentin in more than
700 patients with refractory partial seizure disorder additionally supported the
concept of improvement in general well-being, prompting controlled
investigation of the drug in primary psychiatric conditions (Dimond et al. 1996).
Structure–Activity Relations
Gabapentin, 2-[1-(aminomethyl)cyclohexyl]acetic acid, is a synthetic analog of
γ-aminobutyric acid (GABA) (Figure 39–1).
Anxiety Disorders
Gabapentin produces a dose-dependent anxiolytic response in animal models
(Singh et al. 1996). Open-trial investigations have reported positive results with
add-on gabapentin in the treatment of generalized anxiety disorder (GAD)
(Pollack et al. 1998) and panic disorder (Pollack et al. 1998), as well as in
refractory obsessive-compulsive disorder (Corá-Locatelli et al. 1998). Findings
from controlled investigations of gabapentin in social phobia (Pande et al. 1999)
and in panic disorder (Pande et al. 2000b) suggested that gabapentin has
anxiolytic activity.
The first study was a 14-week randomized, double-blind, placebo-controlled
two-site study of 69 outpatients with DSM-IV (American Psychiatric
Association 1994)–confirmed social phobia (Pande et al. 1999). All patients
were required to have a score of 50 or greater on the Liebowitz Social Anxiety
Scale (LSAS) at baseline. Reductions in the LSAS score served as the primary
outcome measure. In the intent-to-treat analysis, gabapentin was more effective
than placebo in reducing social anxiety symptoms. The dosage range for
gabapentin was 900–3,600 mg/day, with 56% of patients responding to and
tolerating the maximum daily dosage of 3,600 mg. Dizziness and dry mouth
were significantly more common in patients treated with gabapentin.
The second study was an 8-week randomized, placebo-controlled six-site
monotherapy study of 103 patients with DSM-IV–confirmed panic disorder with
or without agoraphobia (Pande et al. 2000b). Gabapentin was dosed flexibly
between 600 and 3,600 mg/day. The primary outcome measure was a decrease in
the Panic and Agoraphobia Scale (PAS) score. There were no differences in
dropout rate. In the intent-to-treat analysis, no difference in PAS score reduction
was seen between patients randomly assigned to receive gabapentin and those
receiving placebo. In a post hoc stratification between high (≥20) and low (<20)
PAS symptom severity, patients with high symptom severity who were randomly
assigned to receive gabapentin had a greater baseline-to-endpoint decrease in
PAS score than did those who were randomly assigned to receive placebo.
Somnolence, headache, dizziness, infection, asthenia, and ataxia were more
common with gabapentin than with placebo.
Bipolar Disorder
Numerous case reports on and open trials of gabapentin as a mood stabilizer,
encompassing more than 400 patients with a pooled response rate between 65%
and 70%, have been reviewed elsewhere (Frye et al. 2000; Yatham et al. 2002).
One double-blind, placebo-controlled outpatient study evaluated add-on
gabapentin for the treatment of bipolar I disorder with manic, hypomanic, or
mixed symptoms (Pande et al. 2000a). The first phase of the study involved a 2-
week single-blind, placebo lead-in wherein dosages of the subject’s primary
mood stabilizer (lithium or valproate) could be adjusted to maximal clinical
benefit and minimum threshold of therapeutic level (i.e., lithium level of 0.5
mmol/L, valproate level of >50 μg/mL). The second phase was a 10-week
double-blind trial in which subjects were randomly assigned to receive
gabapentin, at flexible dosages between 600 and 3,600 mg/day (three-times-a-
day dosing), or placebo. In the intent-to-treat population, 117 subjects were
randomized; no differences in demographic profile or dropout rate were found
between the two groups. The primary outcome measure—total decreased score
on the Young Mania Rating Scale—was significantly different between groups
in favor of add-on placebo. In a post hoc analysis, lithium adjustments in the
single-blind placebo lead-in phase were made more frequently in the placebo
group than in the gabapentin group; most of these adjustments (9 of 12; 75%)
consisted of a dosage increase. This fact suggests either a strong placebo
response or the effect of maximizing lithium blood levels to achieve a greater
antimanic response. Of the gabapentin-treated patients who had drug levels
measured, nearly 20% had plasma gabapentin levels that were undetectable.
The second controlled study was a 6-week double-blind, placebo-controlled
crossover comparative trial of gabapentin monotherapy, lamotrigine
monotherapy, and placebo in 35 inpatients with refractory mood disorder (Frye
et al. 2000; Obrocea et al. 2002). In the preliminary analysis (Frye et al. 2000)
and final analysis (Obrocea et al. 2002), gabapentin demonstrated no better
treatment response than placebo in a group of patients with highly refractory
bipolar (primarily rapid-cycling) disorder.
There appears to be a marked contrast between the pooled results of the
uncontrolled observations (generally positive) and the results of the controlled
studies (generally negative). Important limitations of the controlled
investigations included maximizing lithium response in the single-blind placebo
run-in phase, lack of rigorous compliance assessment, and use of a monotherapy
study design in a cohort of patients with primarily rapid-cycling, treatment-
refractory illness.
Substance-Related Disorders
Mood-stabilizing anticonvulsants such as divalproex sodium and carbamazepine
may be useful in the treatment of alcohol abuse in bipolar disorder (Malcolm et
al. 2001). Gabapentin has been shown to reduce excitability and convulsions in
animal models of alcohol withdrawal (Watson et al. 1997). Its lack of hepatic
metabolism, CYP enzyme induction, protein binding, and addictive potential
makes gabapentin a potentially useful compound in this patient population.
Gabapentin’s potential utility in the treatment of alcohol withdrawal was
examined after initial positive reports emerged (Bozikas et al. 2002). One study
demonstrated that gabapentin had efficacy comparable to that of phenobarbital in
treating alcohol withdrawal (Mariani et al. 2006), although another controlled
trial did not substantiate gabapentin’s benefit over placebo (Bonnet et al. 2003).
In a post hoc analysis (Bonnet et al. 2007), there was a significant increase in the
Profile of Mood States (POMS) vigor subscore in the gabapentin group versus
the placebo group; this response was particularly robust in patients with
comorbid mild depression.
Despite the conflicting findings regarding gabapentin’s efficacy in alcohol
withdrawal, its therapeutic benefit in the sleep-disturbance component of alcohol
withdrawal syndrome is now recognized. In outpatients with DSM-IV alcohol
dependence experiencing persistent insomnia, low-dose gabapentin (mean
dose=900 mg at bedtime), in comparison with trazodone, was associated with
greater improvement in sleep problems, as assessed with the Sleep Problems
Questionnaire (Karam-Hage and Brower 2003). In another study, gabapentin, in
comparison with lorazepam, was associated with significant reductions in self-
reported sleep disturbances and daytime sleepiness in outpatients being treated
for alcohol withdrawal (Malcolm et al. 2007).
A 4-week randomized, placebo-controlled, double-blind study evaluated
gabapentin’s utility in the prevention of relapse to alcohol use (Furieri and
Nakamura-Palacios 2007). After detoxification, 60 men with DSM-IV alcohol
dependence who had been consuming, on average, 17 drinks per day for the
preceding 3 months were randomly assigned to receive gabapentin (300 mg
twice daily) or placebo. The gabapentin group showed significant reductions in
number of drinks per day, percentage of heavy drinking days, and craving for
alcohol (specifically automaticity of drinking) as well as an increase in
percentage of days abstinent. In a more recent study in 150 individuals with
DSM-IV alcohol dependence, the addition of gabapentin to naltrexone was
reported to significantly improve drinking outcomes in comparison with
naltrexone alone or placebo (Anton et al. 2011). The largest clinical trial to date
examined linear dose effects of gabapentin on alcohol-related insomnia,
dysphoria, and craving in patients with DSM-IV alcohol dependence (Mason et
al. 2014). In this 12-week randomized, double-blind trial (n=150), evidence of a
linear dose response (1,800 mg gabapentin > 900 mg gabapentin > placebo) was
found for abstinence, absence of heavy drinking (defined as ≥4 and ≥5
drinks/day for women and men, respectively), mood (i.e., improvement), sleep
(i.e., sleep quality), and craving (i.e., reduction).
Finally, in a proof-of-concept randomized controlled study in 50 treatment-
seeking outpatients with DSM-IV cannabis dependence, gabapentin at 1,200
mg/day was significantly more effective than placebo in reducing cannabis use
and decreasing withdrawal symptoms (Mason et al. 2012).
Drug–Drug Interactions
Given its lack of hepatic metabolism, absence of CYP autoinduction, and
minimal plasma protein binding, gabapentin does not affect levels of
anticonvulsant drugs; similarly, gabapentin’s pharmacokinetic characteristics do
not change when the drug is coadministered with hepatically metabolized
anticonvulsants (Medical Economics Company 2006). However, gabapentin’s
renal excretion does pose a potential risk when the drug is used concomitantly
with lithium.
Although the therapeutic index for gabapentin is large, the safety window for
lithium is not. In a pharmacokinetic study examining the effect of gabapentin
versus placebo on a single 600-mg dose of lithium, there was no difference in
maximal lithium concentration (Li Cmax), time to reach Cmax, or area under the
curve in 13 patients receiving steady-state gabapentin (mean
dose=3,645.15±931.5 mg) compared with those receiving steady-state placebo
(Frye et al. 1998). It is important to emphasize that this study was in a patient
population with normal renal function; cases of reversible renal impairment
associated with gabapentin have been reported (Grunze et al. 1998).
Pregabalin
Pregabalin is an anticonvulsant drug approved by the FDA for the adjunctive
treatment of partial-onset seizures in adults. It is also approved for the treatment
of neuropathic pain associated with diabetic peripheral neuropathy, postherpetic
neuralgia, and fibromyalgia. Like many of the newer anticonvulsant agents,
pregabalin has been evaluated in carefully controlled studies for possible utility
in neurological and psychiatric conditions other than primary epilepsy.
Structure–Activity Relations
Pregabalin, (3S)-3-(aminomethyl)-5-methylhexanoic acid, is a synthetic analog
of GABA (Figure 39–2).
Fibromyalgia
Pregabalin is the first medication to receive an FDA indication for the treatment
of fibromyalgia. Fibromyalgia is a common chronic pain disorder characterized
by widespread diffuse musculoskeletal pain and tenderness frequently
accompanied by significant psychiatric comorbidity, including fatigue, sleep
disturbance, and mood and anxiety disorders. Classifications of disease severity
for fibromyalgia have been published by the American College of Rheumatology
(Wolfe et al. 1990). The prevalence of fibromyalgia in the U.S. population is
estimated at 2%, with rates higher in adult women than in men (Arnold et al.
2007).
Three placebo-controlled studies—two focused on acute treatment (Crofford
et al. 2005; Mease et al. 2008) and one focused on relapse prevention (Crofford
et al. 2008)—have evaluated pregabalin’s efficacy in the treatment of patients
with fibromyalgia. In the first study, an 8-week double-blind, randomized,
placebo-controlled investigation of pregabalin (150, 300, and 450 mg/day)
versus placebo, pregabalin at the 450-mg daily dosage significantly reduced the
average severity of pain in comparison with placebo (Crofford et al. 2005). Sleep
improvement was noted at both the 300-mg and the 450-mg daily dosages.
Dizziness and somnolence were the most frequent adverse events. Arnold et al.
(2007), in recognition of the large overlap of psychiatric comorbidity in
fibromyalgia, conducted a post hoc analysis of the Crofford et al. (2005) study to
assess symptoms of anxiety and depression and their impact on pregabalin
treatment. Of 529 patients who had enrolled in pregabalin treatment for
fibromyalgia, significantly more patients endorsed anxiety symptoms (71%) than
endorsed depressive symptoms (56%). Improvement in pain symptoms with
pregabalin versus placebo did not depend on baseline anxiety or depression; in
fact, 75% of the pain reduction was not explained by improvements in mood
and/or anxiety.
In the second study, a 13-week double-blind, placebo-controlled multicenter
trial, 748 patients with fibromyalgia were randomly assigned to receive either
placebo or pregabalin at dosages of 300, 450, or 600 mg/day (twice-daily
dosing) (Mease et al. 2008). The primary outcome measure was symptomatic
relief of pain associated with fibromyalgia, as measured by a mean pain score
from an 11-point numeric rating scale (0=no pain; 10=worst possible pain) from
patients’ daily diaries. Patients in all pregabalin groups showed statistically
significant improvement in endpoint mean pain scores as well as in sleep.
In the third study, the Fibromyalgia Relapse Evaluation and Efficacy for
Durability Of Meaningful Relief (FREEDOM) trial, pregabalin was evaluated in
nearly 600 patients with fibromyalgia (Crofford et al. 2008). This study included
an initial 6-week open-label phase followed by 26 weeks of double-blind
treatment with pregabalin or blind substitution with placebo. The primary
outcome measure was time to loss of therapeutic response, defined as less than a
30% reduction in pain or worsening of symptoms of fibromyalgia. Time to loss
of therapeutic response was significantly greater for the pregabalin group than
for the placebo group, with Kaplan-Meier estimates of time to event showing
that half of the placebo group had relapsed by day 19, whereas half of the
pregabalin group had still not lost response by trial end.
Finally, pregabalin was investigated as an adjunct to antidepressant
medication in fibromyalgia patients with comorbid depression (Arnold et al.
2015). In this randomized, placebo-controlled, double-blind crossover study,
patients on stable treatment with selective serotonin reuptake inhibitor (SSRI) or
serotonin–norepinephrine reuptake inhibitor (SNRI) antidepressants were
randomly assigned to adjunctive pregabalin or placebo for 6 weeks, followed by
a 2-week taper/washout phase and a crossover to the opposite adjunctive
condition for another 6 weeks. Mean scores on measures of pain, anxiety,
depression, and fibromyalgia impact all significantly improved with adjunctive
pregabalin compared with placebo.
Anxiety Disorders
Substance-Related Disorders
As previously noted, pregabalin has no hepatic metabolism and is excreted
essentially unchanged in the urine. This pharmacokinetic profile is ideal for
patients with alcohol abuse or dependence who have elevated transaminases but
need safe, efficacious treatment for symptoms of alcohol withdrawal.
Pregabalin’s anticonvulsant, analgesic, and anxiolytic properties and potential
utility in alcohol-related disorders were examined in a preclinical study using a
mouse model of alcohol dependence (Becker et al. 2006). Controlled clinical
studies of pregabalin in alcohol-dependent patients are needed.
A study in patients with GAD indicated that pregabalin was efficacious in
facilitating discontinuation of long-term benzodiazepine therapy (Hadley et al.
2012).
Conclusion
There is increasing interest in the use of anticonvulsant drugs in mood and
anxiety disorders. Both gabapentin and pregabalin have demonstrated efficacy
for pain, fibromyalgia, and specific anxiety disorders. Gabapentin also appears
to have potential use in cannabis and alcohol use disorders. Gabapentin’s and
pregabalin’s use in bipolar disorder have not been demonstrated in controlled
clinical trials.
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CHAPTER 40
Lamotrigine
David E. Kemp, M.D., M.S.
Marc L. van der Loos, M.D., Ph.D.
Keming Gao, M.D., Ph.D.
Joseph R. Calabrese, M.D.
Mechanism of Action
The mechanism by which lamotrigine achieves its therapeutic effect in the
treatment of bipolar disorder is unknown. The inhibition of voltage-activated
sodium channels (Xie and Hagan 1998) may best characterize lamotrigine’s
mechanism of action. In addition to sodium channel inhibition, lamotrigine
antagonizes N-type calcium channels (Stefani et al. 1996; von Wegerer et al.
1997). Interestingly, one of the most replicated susceptibility genes for bipolar
disorder (ANK3) codes for a protein that regulates the assembly of voltage-gated
sodium channels (Schulze et al. 2009). These genetic findings, coupled with the
action of lamotrigine on sodium and calcium channels, suggest that
channelopathies may be involved in the pathophysiology of bipolar disorder.
Antiglutamatergic action is another means by which lamotrigine may affect
mood. Presynaptic inhibition of voltage- and use-sensitive sodium channels,
calcium channels, and potassium channels (Grunze et al. 1998) is believed to
result in decreased release of the excitatory amino acid glutamate. The reduction
of glutamate may occur through suppression of postsynaptic α-amino-3-
hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (Lee et al.
2008). In addition, lamotrigine may increase brain levels of N-acetylaspartate, a
mechanism believed to enhance neuronal viability, as deficits in N-
acetylaspartate contribute to excessive glutamatergic tone and subsequent cell
death (Croarkin et al. 2015).
Additional Uses
Maintenance Treatment of Rapid-Cycling Bipolar Disorder
Calabrese et al. (2000) conducted a maintenance study with lamotrigine in rapid-
cycling bipolar disorder. The difference between the lamotrigine and placebo
treatment groups in time to additional pharmacotherapy for a developing or fully
developed mood episode did not achieve statistical significance. However,
overall survival time in the study (i.e., time to dropout for any reason) was
significantly different between the treatment groups in favor of lamotrigine
(P=0.036). When patients with bipolar I and II subtypes were compared,
lamotrigine-treated bipolar II disorder patients had a significantly longer median
survival of 17 weeks compared with a median of 7 weeks for placebo-treated
patients (P=0.015).
Dosing Recommendations
The recommended dosing schedule for lamotrigine in adults involves initiating
therapy with 25 mg daily for the first 14 days and then advancing to 50 mg daily
for the third and fourth weeks of treatment. During the fifth week of treatment,
lamotrigine can be increased to 100 mg daily, followed by titration to 200 mg
daily during the sixth and seventh weeks of treatment. When lamotrigine is used
to augment valproate therapy in adult patients, the recommended titration
schedule begins with 25 mg every other day for 14 days, advances to 25 mg
daily for 14 days, and then increases to 50 mg daily and 100 mg daily beginning
at each of the fifth and sixth weeks of treatment, respectively (Table 40–1). The
titration process for lamotrigine used as an adjunct to treatment with an enzyme-
inducing antiepileptic drug begins with 50 mg daily for 14 days, advances to 100
mg daily (taken in divided doses) for 14 days, and eventually increases to a
target maintenance dosage of 400 mg/day (Table 40–2). No published data
support improved efficacy for lamotrigine in the treatment of bipolar disorder at
dosages greater than 200 mg/day in the absence of an enzyme inducer.
Additionally, there is no clear association between serum levels of lamotrigine
and measures of affective response.
TABLE 40–1. Recommended titration schedule for lamotrigine for
patients with bipolar disorder taking valproate
Week Dosage
Weeks 1 and 2 25 mg every other day
Weeks 3 and 4 25 mg daily
Week 5 50 mg daily
Week 6 100 mg daily
Week 7 100 mg daily
Note. The usual maintenance dosage when lamotrigine is added to valproate is
100 mg/day.
Source. Adapted from GlaxoSmithKline 2015.
Skin Reactions
In early epilepsy trials, rash led to hospitalization and treatment discontinuation
or Stevens-Johnson syndrome in 0.3% of the adults taking lamotrigine
(Calabrese et al. 2002). The annual incidence of serious drug-based skin
reactions associated with lamotrigine—such as Stevens-Johnson syndrome,
DRESS (drug rash with eosinophilia and systemic symptoms), and toxic
epidermal necrolysis—was highest in 1993 (4.2%) but steadily declined and had
stabilized by 1998 (0.02%). This reduction in incidence was likely attributable to
the manufacturer’s dosage revision in 1994, which advised a more protracted
titration schedule (Calabrese et al. 2002; Messenheimer et al. 1998). It is well
documented that the risk of rash is heightened by exceeding the recommended
initial dosage or the rate of dosage escalation of lamotrigine, and by
coadministering lamotrigine with valproic acid. The risk is also greater in
children younger than 12 years. Nearly all cases of life-threatening rashes caused
by lamotrigine have occurred within 2–8 weeks of treatment initiation
(GlaxoSmithKline 2015).
The most common lamotrigine-associated rash is an exanthematic
maculopapular or morbilliform eruption that is benign. However, a clinically
similar eruption may be associated with more rare and serious systemic
hypersensitivity reactions (Guberman et al. 1999). Figure 40–2 presents a
decision-making algorithm for the management of benign and serious rashes
(Calabrese et al. 2002). A serious lamotrigine rash is usually confluent with
prominent facial and neck involvement. The rash may be tender or have a
purpuric or hemorrhagic appearance. It may be accompanied or preceded by
fever, malaise, pharyngitis, anorexia, or lymphadenopathy (Guberman et al.
1999). Thus, all patients who develop a rash during the first few months of
lamotrigine therapy should be instructed to hold the next dose and immediately
seek medical consultation. The greatest risk of rash appears to be during the first
8 weeks of treatment. A rash during the first 5 days of therapy is usually due to a
nondrug cause. Because immune tolerance to lamotrigine is lost following
interruption of dosage for more than 1 week, patients should be instructed to
resume lamotrigine at the prior initial start-up dose and to gradually titrate
upward whenever therapy has been interrupted for more than a few days.
FIGURE 40–2. Clinical management of rash related to
lamotrigine treatment.
CBC=complete blood count; LFT=liver function test.
Source. Reprinted from Calabrese JR, Sullivan JR, Bowden CL, et al.: “Rash in Multicenter
Trials of Lamotrigine in Mood Disorders: Clinical Relevance and Management.” Journal of
Clinical Psychiatry 63:1012–1019, 2002. Copyright 2000, Physicians Postgraduate Press.
Used with permission.
Aseptic Meningitis
Rare cases of aseptic meningitis in association with lamotrigine have occurred
(Boot 2009; Kilfoyle et al. 2005; Lam et al. 2010). Clinical manifestations
include meningismus, photophobia, headache, vomiting, and fever. Symptoms
were reported to appear within 1 day to 1.5 months following initiation of
treatment. In several cases, sudden and severe symptoms of meningitis have
occurred within minutes of reintroducing lamotrigine. In most cases of drug-
induced aseptic meningitis, there is complete recovery once the offending agent
has been discontinued (Moris and Garcia-Monco 1999).
Weight-Neutral Effects
In comparison with other agents used in the management of bipolar disorder, a
distinctive feature of lamotrigine is its weight-neutral tolerability profile (Sachs
et al. 2006). A post hoc analysis found that nonobese patients taking lamotrigine
are unlikely to experience a change in weight. However, obese patients are
significantly more likely to lose weight with lamotrigine and to gain weight with
lithium (Bowden et al. 2006).
Safety in Overdose
Among 493 cases of lamotrigine toxicity in overdose, the majority of patients
(52.1%) experienced no toxic clinical effects (Lofton and Klein-Schwartz 2004).
Common symptoms included drowsiness, vomiting, nausea, ataxia, dizziness,
and tachycardia. Rare cases of coma, seizures, heart conduction delay, and
respiratory depression have been reported in overdose. Some ingestions of
lamotrigine involving quantities up to 15 grams have been fatal.
Drug–Drug Interactions
Lamotrigine is not known to inhibit the activity of the cytochrome P450 2D6
enzyme. However, the addition of adjunctive lamotrigine to enzyme inducers
such as carbamazepine, phenytoin, primidone, and phenobarbital decreases
lamotrigine plasma concentrations by approximately 40%–50% (Hahn et al.
2004). The inducing effect of oxcarbazepine is approximately half that of
carbamazepine (Weintraub et al. 2005). Because lamotrigine is nearly
exclusively metabolized by glucuronidation, the introduction of adjunctive
valproate (an enzyme inhibitor) results in immediate and successful competition
for metabolism, with resultant increases in half-life.
Evidence has emerged that oral contraceptives containing estrogen have the
potential to decrease serum concentrations of lamotrigine by up to 64% (Sabers
et al. 2001, 2003). Progestins, however, are not associated with a decrease in
lamotrigine levels (Reimers et al. 2005). During the long-term treatment of
bipolar disorder, use of ethinyl estradiol–containing compounds may require an
increase in the maintenance dosage of lamotrigine of as much as twice the
recommended target maintenance dose. Conversely, stopping estrogen-
containing oral contraceptives, including during the “pill-free” week, may
increase lamotrigine levels to a clinically significant range.
Conclusion
Although initial results from trials of lamotrigine in the treatment of mania were
unfavorable, subsequent maintenance studies have provided compelling data to
show that lamotrigine prevents the recurrence of mood episodes and possesses
antidepressant efficacy, albeit most convincingly for prophylaxis against
depression recurrence as opposed to acute resolution of depression. Even with its
ability to stabilize mood, lamotrigine appears to have a low propensity to trigger
affective switches to mania or hypomania, with a switch risk similar to that of
placebo. Lamotrigine’s neutral effects on body weight and favorable side-effect
profile make it appealing for use in patients who have comorbid metabolic
syndrome or those who are unable to tolerate other treatments. At present,
lamotrigine remains the only antiepileptic drug mood stabilizer with more
established efficacy in the depressed illness phase than in mania or hypomania.
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CHAPTER 41
Topiramate
Susan L. McElroy, M.D.
Paul E. Keck Jr., M.D.
Pharmacological Profile
Topiramate (Figure 41–1) has multiple pharmacological properties that may
contribute to its anticonvulsant and neuropsychiatric effects (Langtry et al. 1997;
Rho and Sankar 1999; Rosenfeld 1997; Shank et al. 2000; White 2002, 2005;
White et al. 2007). First, topiramate inhibits voltage-gated sodium channels in a
voltage-sensitive, use-dependent manner and thus suppresses action potentials
associated with sustained repetitive cell firing (Kawasaki et al. 1998; Shank et al.
2000). Second, topiramate increases brain γ-aminobutyric acid (GABA) levels,
possibly by activating a site on the GABAA receptor, thereby enhancing the
inhibitory chloride ion influx mediated by the GABAA receptor and potentiating
GABA-evoked currents (Kuzniecky et al. 1998; Petroff et al. 2001; Simeone et
al. 2006). Because this action is not blocked by the benzodiazepine antagonist
flumazenil, it is thought that topiramate exerts this effect via an interaction with
the GABAA receptor that is not modulated by benzodiazepines (White et al.
2000).
Mechanism of Action
Although the mechanism of topiramate’s anticonvulsant action is unknown, it
has been hypothesized to be due to some combination of the drug’s multiple
pharmacological properties (Rho and Sankar 1999; Shank et al. 2000; White
2002, 2005; White et al. 2007). For example, the drug’s anticonvulsant profile,
as well as its benefits in substance use and eating disorders, has been
hypothesized to be due to its dual actions on the GABAergic and glutamatergic
systems (Johnson et al. 2003, 2005; McElroy et al. 2003, 2007; Rho and Sankar
1999; Schiffer et al. 2001).
Other Indications
Topiramate is not approved by the FDA for use in the treatment of any
psychiatric disorder. Because the drug was widely used off-label in the treatment
of bipolar disorder after it came to market (see subsection “Bipolar Disorder”
below), Johnson & Johnson Pharmaceutical Research and Development, the
discoverer of topiramate, conducted a large study program of topiramate in
adults with acute bipolar mania. These placebo-controlled studies failed to
demonstrate significant benefit from topiramate versus placebo on Young Mania
Rating Scale (YMRS) scores (Kushner et al. 2006; McElroy and Keck 2004). By
contrast, findings from randomized, placebo-controlled trials suggest that
topiramate may be efficacious in major depressive disorder, schizophrenia,
binge-eating disorder (BED), bulimia nervosa, alcohol use disorder,
psychotropic-induced weight gain, and obesity.
Bipolar Disorder
Five randomized, placebo-controlled studies have shown that topiramate
monotherapy is not efficacious in the short-term treatment of acute manic or
mixed episodes in adults with bipolar I disorder (Kushner et al. 2006; McElroy
and Keck 2004). All five studies used week 3 as the primary endpoint; in
addition, three of the studies had a week 12 secondary endpoint, two studies had
lithium comparator groups, and all trials measured weight as a secondary
outcome. In each trial, the primary efficacy outcome—the change from baseline
to week 3 in the YMRS score—failed to show a statistically significant
separation between topiramate and placebo. There was also no drug-versus-
placebo separation in the three trials with week 12 data. By contrast, in the two
trials in which lithium was used, lithium did show statistical superiority to
placebo.
Similarly, in the only placebo-controlled study of adjunctive topiramate in
bipolar disorder, 287 outpatients experiencing a manic or mixed episode (by
DSM-IV [American Psychiatric Association 1994] criteria) and a YMRS score
of 18 or higher while taking therapeutic levels of valproate or lithium showed
similar reductions (40%) in baseline YMRS scores for both topiramate and
placebo after 12 weeks (Roy Chengappa et al. 2006). In the only placebo-
controlled study of topiramate in pediatric bipolar I disorder, 56 children and
adolescents (ages 6–17 years) experiencing a manic or mixed episode were
randomly assigned to topiramate or placebo for 4 weeks (DelBello et al. 2005).
Initially designed to enroll approximately 230 subjects, the study was
prematurely discontinued when results from the adult mania trials were negative.
Decrease in mean YMRS score from baseline to final visit using last observation
carried forward (LOCF) analysis was not statistically different between
treatment groups. However, a post hoc repeated-measures linear regression
model of the primary efficacy analysis showed a statistically significant
difference in the slopes of the linear mean profiles (P=0.003).
No placebo-controlled study of topiramate has yet been done in acute bipolar
depression. Results from an 8-week single-blind comparison trial in which 36
outpatient adults with bipolar depression were randomly assigned to receive
either topiramate (mean dosage=176 mg/day; range=50–300 mg/day) or
bupropion sustained release (mean dosage=250 mg/day; range=100–400
mg/day) suggested that the drug might have antidepressant properties in some
bipolar patients (McIntyre et al. 2002). The percentage of patients meeting a
priori response criteria (≥50% decrease from baseline in mean total score on the
17-item Hamilton Rating Scale for Depression [Ham-D]) was significant for
both topiramate (56%) and bupropion sustained release (59%).
Depressive Disorders
Two randomized, placebo-controlled studies of topiramate in patients with major
depressive disorder have been conducted. In the first, 64 females with DSM-IV
recurrent major depressive disorder were randomly assigned to receive
topiramate or placebo for 10 weeks (C. Nickel et al. 2005a). Topiramate was
superior to placebo in reducing depressive and anger symptoms. All subjects
tolerated topiramate well, and there were no suicidal events. In the second study,
53 patients with DSM-IV major depressive disorder that had been inadequately
responsive to an 8-week trial of a selective serotonin reuptake inhibitor (SSRI)
were randomly assigned to receive adjunctive topiramate (100–200 mg/day) or
placebo for 8 weeks (Mowla and Kardeh 2011). Topiramate recipients had a
32% mean decrease in Ham-D score, whereas placebo recipients had a mean
decrease of 5.5%. Topiramate augmentation also produced significantly greater
global improvement in depressive symptoms compared with placebo
augmentation. Six patients discontinued topiramate because of side effects,
which included loss of appetite, gastric disturbance, memory problems, and
akathisia. No suicidal events were reported.
Psychotic Disorders
Case reports. There are several case reports of the successful use of
topiramate to treat catatonia in patients with chronic psychotic disorders
(McDaniel et al. 2006). By contrast, there are also reports of the emergence of
psychotic symptoms with topiramate treatment (Duggal and Singh 2004; Miller
et al. 2010).
Eating Disorders
Five positive randomized, placebo-controlled studies involving subjects with
bulimia nervosa (two studies) or BED (three studies) have demonstrated that
topiramate reduces binge eating.
Bulimia nervosa. In the first bulimia nervosa study, a 10-week trial with 69
subjects, topiramate (median dosage=100 mg/day; range=25–400 mg/day) was
superior to placebo in reducing the frequency of binge and purge days (days
during which at least one binge-eating or purging episode occurred; P=0.004)
(Hedges et al. 2003; Hoopes et al. 2003). Binge-eating/purging remission rates
were 32% for topiramate and 6% for placebo (P=NS). Dropout rates were 34%
for topiramate and 47% for placebo. In the second study, subjects with DSM-IV
bulimia nervosa received 10 weeks of topiramate (titrated to 250 mg/day in the
sixth week) (n=30) or placebo (n=30) (C. Nickel et al. 2005b). Topiramate was
associated with significant decreases in binge/purge frequency (defined as a
>50% reduction; 37% for topiramate and 3% for placebo), body weight
(difference in weight loss between the two groups=3.8 kg), and all of the Short
Form 36-Item Health Survey (SF-36) scales (all Ps< 0.001).
Binge-eating disorder. In the first controlled study in BED, 61 subjects
with DSM-IV BED and obesity received topiramate or placebo for 14 weeks
(McElroy et al. 2003). Topiramate was significantly superior to placebo in
reducing binge frequency, as well as global severity of illness, obsessive-
compulsive features of binge-eating symptoms, body weight, and BMI. The
dropout rate, however, was high: 14 (47%) subjects receiving topiramate and 12
(39%) subjects receiving placebo did not complete the trial.
The second controlled study of topiramate in BED was a multicenter trial in
which subjects with DSM-IV BED and at least three binge-eating days per week,
a BMI ranging from 30 kg/m2 to 50 kg/m2, and no current psychiatric disorders
or substance abuse were randomly assigned to receive topiramate or placebo for
16 weeks (McElroy et al. 2007). Of 407 subjects enrolled, 13 did not meet
inclusion criteria; 195 topiramate and 199 placebo subjects were therefore
evaluated for efficacy. Topiramate significantly reduced binge-eating days per
week, binge episodes per week, weight, and BMI compared with placebo (all
Ps< 0.001). The drug also significantly decreased measures of obsessive-
compulsive symptoms, impulsivity, hunger, and disability. Fifty-eight percent of
topiramate-treated subjects achieved remission compared with 29% of placebo-
treated subjects (P<0.001). Discontinuation rates were 30% in each group;
adverse events were the most common reason for topiramate discontinuation
(16%; placebo, 8%).
The third controlled study of topiramate in BED was another multicenter trial
in which 73 patients with BED and obesity were randomly assigned to 19
sessions of cognitive-behavioral therapy (CBT) in conjunction with topiramate
or placebo for 21 weeks (Claudino et al. 2007). Compared with patients given
placebo, patients given topiramate showed a significantly greater rate of
reduction in weight, the primary outcome measure, over the course of treatment
(P<0.001). Topiramate recipients also showed a significant weight loss (−6.8 kg)
relative to placebo recipients (−0.9 kg). A greater percentage of topiramate-
treated patients (31 of 37) than of placebo-treated patients (22 of 36) attained
remission of binge eating (P=0.03). There was no difference between groups in
completion rates, although one topiramate recipient withdrew because of an
adverse effect.
Other eating disorders. There are no randomized controlled studies of
topiramate in anorexia nervosa. However, there are reports of topiramate
triggering or worsening anorexia nervosa as well as reports of eating disorder
patients misusing the drug to lose weight (McElroy et al. 2008). In contrast,
there are case reports of the successful treatment of night eating syndrome with
topiramate (Kucukgoncu et al. 2015).
Obsessive-Compulsive Disorder
Four placebo-controlled trials have evaluated adjunctive topiramate in subjects
with obsessive-compulsive disorder (OCD), with mixed results. In the first
study, 41 subjects with OCD that had not improved after at least 12 weeks of
treatment with an SSRI were randomly assigned to receive topiramate or placebo
plus their current OCD regimen for 12 weeks. Topiramate recipients had a mean
decrease of 32% in Yale-Brown Obsessive Compulsive Scale (Y-BOCS) scores,
whereas placebo recipients had a decrease of 2.4% (Mowla et al. 2010). In the
second study, adjunctive topiramate (mean endpoint dosage 179 mg/day)
significantly reduced the Y-BOCS Compulsions subscale score (P=0.014), but
not the Obsessions subscale score or the total score, in 36 adult subjects with
OCD receiving SSRIs (Berlin et al. 2011). In the third study, 39 inpatients with
OCD and bipolar mania were randomly assigned to receive the addition of
topiramate or placebo to their current regimen of lithium, olanzapine, and
clonazepam was associated with significantlyfor 4 months (Sahraian et al. 2014).
Y-BOCS scores showed a greater numeric decline for patients receiving placebo
than for those receiving topiramate. By contrast, among the 32 completers, there
were significantly more responders (defined as >34% reduction in Y-BOCS
scores) among topiramate recipients than among placebo recipients (53% and
12.5%, respectively; P<0.01). However, in the fourth study, involving 38
patients with refractory OCD, topiramate (mean dosage=137.5 mg/day) was not
superior to placebo in reducing Y-BOCS scores after 12 weeks of treatment
(Afshar et al. 2014).
Obesity
At least nine randomized, placebo-controlled trials have evaluated topiramate
(Astrup et al. 2004; Bray et al. 2003; Eliasson et al. 2007; Stenlöf et al. 2007;
Tonstad et al. 2005; Toplak et al. 2007; Tremblay et al. 2007; Wilding et al.
2004) or a controlled-release formulation of topiramate (Rosenstock et al. 2007)
for weight loss in subjects with obesity. In all nine studies, topiramate was
superior to placebo for weight loss at all dosages (range=64–400 mg/day) and at
all endpoints (ranging from 28 weeks to 1 year) evaluated. The four long-term
studies (duration ranging from 40 weeks to 1 year) found that topiramate was
associated with weight loss that continued for up to 1 year without plateauing
(Astrup et al. 2004; Eliasson et al. 2007; Stenlöf et al. 2007; Wilding et al. 2004).
In a study of subjects with comorbid obesity and hypertension, there were
significant decreases in diastolic but not systolic blood pressure in the two
groups receiving topiramate (either 96 mg/day or 192 mg/day) compared with
the placebo group (Tonstad et al. 2005). In four studies of topiramate in subjects
with comorbid obesity and type 2 diabetes, topiramate-treated subjects showed
significant decreases in glycosylated hemoglobin (HbA1c) compared with
placebo-treated subjects (Eliasson et al. 2007; Rosenstock et al. 2007; Stenlöf et
al. 2007; Toplak et al. 2007). In the pivotal studies leading to the FDA approval
of topiramate extended release plus phentermine for chronic weight
management, topiramate monotherapy was superior to placebo for weight loss,
and the drug combination was superior to either topiramate or phentermine
monotherapy (Alfaris et al. 2015).
Use in Pregnancy
Topiramate can cause fetal harm when given to pregnant women. Prenatal
exposure to topiramate is associated with an increased risk of oral clefts (Hunt et
al. 2008).
Drug–Drug Interactions
The clearance of topiramate can be increased by the coadministration of hepatic
enzyme–inducing drugs (Bialer et al. 2004; Gidal 2002; Langtry et al. 1997;
Rosenfeld et al. 1997; van Passel et al. 2006). Thus, carbamazepine and
phenytoin may substantially decrease topiramate levels.
Conversely, topiramate has mild enzyme-inducing properties and may
enhance the metabolism of ethinyl estradiol. Available data suggest that at
topiramate dosages of 200 mg/day or lower, this induction is insignificant, but at
dosages greater than 200 mg/day, induction becomes dose dependent and occurs
to a great extent (Bialer et al. 2004). Therefore, women taking combination oral
contraceptive agents need to be counseled about this potential interaction.
Although there have been reports of topiramate causing increased lithium
levels (Abraham and Owen 2004), this effect appears to be rarely clinically
significant (Bialer et al. 2004).
Conclusion
In sum, although topiramate does not have regulatory approval for a psychiatric
disorder, considerable data suggest that the drug may be helpful in a wide range
of psychiatric conditions. In particular, topiramate appears efficacious in BED,
bulimia nervosa, alcohol use disorder, and psychotropic-associated weight gain.
It might also be efficacious for major depressive disorder, schizophrenia, and
borderline personality disorder. Data on topiramate’s efficacy in cocaine or
methamphetamine use disorders, smoking cessation, and OCD have been mixed.
Of note, there is no evidence to suggest that topiramate has acute anti-manic or
long-term mood-stabilizing effects in bipolar disorder. The use of topiramate in
psychiatric disorders, however, is limited by its adverse event profile.
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Other Agents
CHAPTER 42
Cholinesterase-Related Therapies
Impairment of cholinergic neurotransmission, especially in the hippocampus and
cerebral cortex (temporoparietal), has been clearly established over the past 40
years as a significant factor in the clinical signs of cognitive impairment,
including those of Alzheimer’s disease (Davies and Maloney 1976; Mesulam
2004; Whitehouse et al. 1982). Butyrylcholinesterase (BChE) and
acetylcholinesterase (AChE) are the two main types of cholinesterase present in
the brain. The development of AChE inhibitors (AChEIs) to increase
acetylcholine levels in the brain for enhanced synaptic transmission has been
successful, with marginal positive clinical outcomes to date (Birks 2006; Tan et
al. 2014; Thompson et al. 2004). Four AChEIs have been marketed in the United
States for cognitive therapy: tacrine, donepezil, rivastigmine, and galantamine.
These pharmaceuticals are primarily for symptomatic relief and have limited
current value in stopping or reversing the disease process. A significant number
of AChEI nonresponders exist (Jones 2003). Improvements in cognitive
functioning have been shown with AChEIs without major differences in their
efficacy (Birks 2006; Colović et al. 2013; Seltzer 2006; Thompson et al. 2004).
There are limited data to support the use of these agents in mild neurocognitive
disorder (Cooper et al. 2013). The major side effects of AChEIs are
gastrointestinal.
Recommendations
Tacrine is no longer recommended for routine clinical use. Donepezil,
rivastigmine, and galantamine are recommended with or without other cognitive
enhancers (e.g., memantine). Tolerability is improved by slow dosage titration.
All cholinesterase inhibitors have significant potential for side effects; it is
difficult to determine whether one AChEI has a significantly better side-effect
profile than another AChEI, given individual patients’ variability. Switching
AChEIs can be a reasonable treatment strategy if lack of efficacy or tolerability
is an issue.
Donepezil
Donepezil, a piperidine-based, reversible, noncompetitive AChEI with a plasma
half-life of about 70 hours, was approved for the treatment of mild to moderate
Alzheimer’s disease in the United States in 1996 and for severe Alzheimer’s
disease in 2006. Donepezil is given once daily in 5-mg, 10-mg, or 23-mg doses;
5-mg therapy is only slightly less effective than 10-mg therapy and is an
appropriate regimen for mild to moderate Alzheimer’s disease, especially when
tolerability is an issue (Birks and Harvey 2006). For moderate to severe
Alzheimer’s disease, 10-mg or 23-mg therapy is indicated; the 23-mg dose is
generally initiated after a patient has been stable for at least 3 months on the 10-
mg dose. Donepezil is also available as an orally disintegrating tablet in 5-mg
and 10-mg doses. A formulation combining memantine extended-release and
donepezil is now available.
Donepezil has shown benefit in treating mild, moderate, and severe
Alzheimer’s disease (Birks and Harvey 2006; Wallin et al. 2007) and has been
studied for efficacy in patients with mild neurocognitive disorder (Chen et al.
2006; Pa et al. 2013; Seltzer 2007). A meta-analysis of pooled data on the use of
donepezil indicated that caution is warranted in its use to treat mild
neurocognitive disorder due to modest treatment effects with significant side
effects (Birks and Flicker 2006). In another review of 41 studies, donepezil and
other AChEIs were not recommended for use in mild neurocognitive disorder
(Cooper et al. 2013).
Rivastigmine
Rivastigmine, a carbamyl derivative, is a slowly reversible AChEI and BChE
inhibitor (BChEI) with an elimination half-life of about 2 hours. It was approved
in 2000 for use in the United States and is indicated for the treatment of mild to
moderate dementia of Alzheimer’s disease and Parkinson’s disease.
Rivastigmine inhibits the G1 isoenzyme of AChE selectively up to four times
more potently than it does the G4 isoenzyme (Enz et al. 1993). This unique
compound with its BChEI properties has been postulated to be of greater benefit
than other AChEIs in the treatment of Alzheimer’s disease because BChE
activity increases in the hippocampus and cortex while AChE activity diminishes
(Tasker et al. 2005); to date, this has not been conclusively shown to be of
clinical significance (Noetzli and Eap 2013). However, as a therapy involving
multiple target receptor sites, this agent does have a theoretical advantage over
single-target approaches. A recent Cochrane review noted that rivastigmine
appears to be beneficial for the treatment of mild to moderate Alzheimer’s
disease (Birks and Grimley Evans 2015). Rivastigmine capsules are available in
1.5-mg, 3-mg, 4.5-mg, and 6-mg doses. A rivastigmine skin patch received U.S.
Food and Drug Administration approval in 2007; gastrointestinal side effects are
reduced in frequency with this drug delivery system. An oral solution is also
available.
For Alzheimer’s disease, rivastigmine is initiated at 1.5 mg taken orally twice
daily. If tolerated, the dosage is increased every 2 weeks, first to 3 mg twice
daily and then to 4.5 mg twice daily, up to a maximum dosage of 6 mg twice
daily. Transdermal therapy is initiated at one 4.6-mg skin patch applied daily for
at least 4 weeks, at which time the dosage may be increased to the 9.5-mg daily
patch. For Parkinson’s disease, the oral rivastigmine dosage is increased as done
in Alzheimer’s disease, except that the minimum interval is extended to every 4
weeks (rather than every 2 weeks), up to a maximum dosage of 6 mg twice daily.
Galantamine
Galantamine hydrobromide, a tertiary alkaloid, is a specific, competitive, and
reversible AChEI with a plasma half-life of 6–8 hours that was first marketed in
the United States in 2001 as a treatment for mild to moderate dementia of
Alzheimer’s disease. Galantamine is unique in that it modulates neuronal
nicotinic receptors (Coyle and Kershaw 2001). Whether this nicotinic receptor
modulation imparts any significant clinical benefit in disease modification
remains unknown. Oral dosing is initiated at 4 mg twice daily, with an increase
after a minimum of 4 weeks to 8 mg twice daily as tolerated. The optimal dosage
range is 16–24 mg/day. The extended-release galantamine formulation for once-
daily dosing has efficacy and side effects similar to those of the twice-daily
dosing formulation; it is generally initiated at a dosage of 8 mg/day (taken in the
morning), increased to 16 mg/day after a minimum interval of 4 weeks, and (if
tolerated after a minimum of 4 additional weeks) increased to 24 mg/day. An
oral suspension is available as well. Pooled data from early trials in patients with
mild cognitive impairment showed significantly higher rates of death due to
bronchial carcinoma, cerebrovascular disorder/syncope, myocardial infarction,
and suicide in the galantamine treatment groups (Cusi et al. 2007; Loy and
Schneider 2006), although the use of cholinesterase inhibitors, including
galantamine, was found to reduce the risk of myocardial infarction and death in a
different study (Nordström et al. 2013). One double-blind, placebo-controlled
trial of galantamine with antipsychotic medication in the treatment of subjects
with schizophrenia did not show significant benefit, although there was a trend
toward improvement in several cognitive domains (Lee et al. 2007).
Galantamine combined with memantine is being actively studied for its potential
to improve cognition in schizophrenia (Koola 2016; Koola et al. 2014).
Other Agents
Physostigmine, a reversible inhibitor of BChE and AChE, is poorly tolerated due
to multiple gastrointestinal side effects, especially nausea and vomiting, and has
a very short half-life.
Huperzine alpha (more commonly known as huperzine A) is sold in the
United States as a dietary supplement for cognitive enhancement and is a slow,
reversible inhibitor of AChE. Huperzine A is believed to have neuroprotective
effects by reducing neuronal cell death caused by glutamate (Ved et al. 1997).
The combination of other AChEIs with huperzine A may exacerbate
gastrointestinal side effects; patients’ usage of this over-the-counter supplement
should be monitored, especially if other AChEIs are considered for treatment.
ZT-1, a novel huperzine A analogue, is being investigated as an alternative to
huperzine A (Jia et al. 2013).
Metrifonate, a long-acting irreversible cholinesterase inhibitor, was tested in
clinical trials, but further development was discontinued after a higher-than-
expected incidence of neuromuscular dysfunction and respiratory paralysis was
found.
Selective and nonselective neuronal nicotinic receptor agonists have shown
statistically significant cognitive enhancement in young, healthy subjects and
mixed results in subjects with Alzheimer’s disease (Dunbar et al. 2007; Frölich
et al. 2011; Lombardo and Maskos 2015; Newhouse et al. 1997; Potter et al.
1999; Sunderland et al. 1988). More recent studies have found potential
neuroprotective effects from analogues of nicotine and cotinine, a nicotine
metabolite with fewer side effects than nicotine (Gao et al. 2014).
N-Methyl-D-Aspartate–Related Therapies
Glutamate is an agonist of kainate, NMDA, and α-amino-3-hydroxy-5-methyl-4-
isoxazole propionic acid (AMPA) receptors. Neuronal plasticity of memory and
learning is influenced by glutamate’s direct modulation of the NMDA
postsynaptic receptor; glutamate acts as an excitatory neurotransmitter activating
the NMDA receptor. Glutamate excess results in neurotoxicity, affecting
cognitive functioning (Koch et al. 2005).
Recommendations
Memantine appears to reduce the level of cognitive impairment in patients with
moderate to severe Alzheimer’s disease. Memantine in combination with an
AChEI is an appropriate consideration for improvement in cognition and
behavior.
Memantine
Memantine is a noncompetitive NMDA receptor antagonist approved in the
United States for treating moderate to severe Alzheimer’s disease. The NMDA
receptor modulates memory function. Memantine’s low-affinity antagonism of
glutamate (which has been linked to neurodegeneration and excitotoxicity) may
protect against neurotoxicity (Lipton and Rosenberg 1994). Memantine has been
shown to be effective in reducing the level of cognitive impairment in patients
with moderate to severe Alzheimer’s disease (Bullock 2006; Nakamura et al.
2014; Reisberg et al. 2003).
Memantine is available in tablets, in extended-release capsules, and as an oral
solution; dosing should be adjusted for patients with moderate or severe renal
impairment (target of 14 mg/day). It is recommended that memantine tablets be
initiated at a dosage of 5 mg/day for 1 week, and increased weekly by 5 mg/day
up to a target dosage of 20 mg/day. Memantine tablets are generally given in
twice-daily doses, although the elimination half-life ranges from 60 to 80 hours.
Memantine is available as an extended-release capsule (7 mg, 14 mg, 21 mg, and
28 mg); it is recommended that memantine capsules be initiated at a dosage of 7
mg/day for 1 week, increasing by 7 mg after a minimum of 1 week to 14 mg/day
up to a target dosage of 28 mg/day. Memantine extended-release capsules are
given in once-daily dosing. Memantine capsules may be opened and the contents
sprinkled on applesauce.
Recommendations
AChEIs appear to have a valid role in the treatment of vascular cognitive
impairment. Combination therapy is an important consideration, especially with
other known vascular risk modifiers, including aspirin, other nonsteroidal anti-
inflammatory drugs (NSAIDs), and cytidine 5′-diphosphocholine (CDP-choline).
Randomized controlled trials do not currently support the use of aspirin or other
NSAIDs for the treatment of vascular cognitive impairment (Jaturapatporn et al.
2012). The active use of statins for the prevention and treatment of vascular
cognitive impairment is currently not well supported by the literature; however,
research with statins remains very active in this pursuit (McGuinness et al.
2016). Aspirin remains a cornerstone first-line intervention for decreasing
potential cardiovascular comorbidity; aspirin may have a future role as a
combination therapy with cognitive enhancers.
Other Therapies
Antioxidant-related treatment for cognitive impairment remains poorly
supported by placebo-controlled, double-blind studies. Ginkgo biloba could be
classified within several potential treatment categories, including antioxidants,
nutraceuticals, cholinergic agents, and vasodilators; most studies have shown no
to only marginal benefit for this agent (Laws et al. 2012). Vitamin E (including
tocopherols and tocotrienols), vitamin C, and carotenoids have antioxidant
properties; however, reports of benefit in treating patients with cognitive
impairment are mixed. Although antioxidants may have potential as a
combination therapy modality, further research is required before endorsing
specific treatment recommendations with current antioxidants.
Various other agents have been tested and studied for their potential to
improve cognitive impairment; these include secretase inhibitors, tramiprosate,
modafinil, hormone replacement therapy, nutraceuticals (Rubia cordifolia, Salvia
lavandulaefolia, Rosmarinus officinalis, and Melissa officinalis), dehydro-3-
epiandrosterone (DHEA), aniracetam, piracetam, latrepirdine, and unifiram.
Currently, no recommendations can be made for use of any of these agents as
monotherapy or combination therapy.
Antiamyloid immunization may provide one of the greatest opportunities to
prevent amyloid-β deposition. Immunization strategies generally focus on active
or passive immunization and direct central nervous system delivery of anti–
amyloid-β antibodies. Active immunization with β-amyloid antibodies can
reduce plaque formation (Lemere et al. 2006; Singh et al. 2012; Solomon 2006).
Passive immunization with monoclonal antibodies, preparations of
immunoconjugates, or entire Alzheimer’s disease–associated immunogenes
shows promise for treating cognitive impairment due to Alzheimer’s disease and
may be safer than active immunization (Geylis and Steinitz 2006; Marciani
2015; Solomon 2007). Active and passive immunization may cause
microhemorrhages, and further research continues to seek safer vaccines.
Conclusion
The molecular pathogenesis of nerve cell death remains elusive, especially as it
relates to the onset and progression of cognitive impairment. Alzheimer’s
disease and other types of cognitive impairment represent a wide spectrum of
neurosystem dysfunction, and no single treatment modality yet found is
sufficient to address the global apoptosis and degeneration that occur. Due to the
multiple types of neurochemical and substructure dysfunction occurring in
cognitive impairment, multiple-drug interventions will likely be required
(Campos et al. 2016; Siskou et al. 2007; Sunderland et al. 1992).
Future studies will explore second-messenger modulation, inhibition of the
synthesis of amyloid-β using a mimic of the prion protein to inhibit β-secretase
cleavage of the amyloid precursor protein, amyloid plaque sheet breakers,
AMPA receptor modulators, hyperactive signaling pathway blockers, epigenetic
drug candidates, and the role of σ1-receptor agonists and selective neuronal
nicotinic receptor agonists (Crews and Masliah 2010; Parkin et al. 2007; Rose et
al. 2005; Sarter 2006). Currently, the AChEIs and memantine are appropriate
choices for slowing the progression of cognitive impairment. Several other
promising agents are likely to become available within the next decade.
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CHAPTER 43
Sedative-Hypnotics
Seiji Nishino, M.D., Ph.D.
Noriaki Sakai, D.V.M., Ph.D.
Kazuo Mishima, M.D., Ph.D.
Emmanuel Mignot, M.D., Ph.D.
William C. Dement, M.D., Ph.D.
Structure–Activity Relations
The term benzodiazepine refers to the portion of the structure composed of
benzene rings (A in top portion of Figure 43–2) fused to a seven-membered
diazepine ring (B). However, most of the older benzodiazepines contain a 5-aryl
substituent (C) and a 1,4-diazepine ring, and the term has come to mean the 1,4-
benzodiazepines.
Pharmacological Profile
Benzodiazepines share anticonvulsant and sedative-hypnotic effects with the
barbiturates. In addition, they have a remarkable ability to reduce anxiety and
aggression (Cook and Sepinwall 1975). In the mammalian CNS, two subtypes of
benzodiazepine omega (ω) receptors have been pharmacologically recognized.
Benzodiazepine ω1 receptors are sensitive to β-carbolines, imidazopyridines
(e.g., zolpidem), and triazolopyridazines. Benzodiazepine ω2 receptors have low
affinity for these ligands but relatively high affinity for benzodiazepines.
Benzodiazepine ω1 sites are enriched in the cerebellum, whereas ω2 sites are
mostly present in the spinal cord, and both receptor subtypes are found in the
cerebral cortex and hippocampus. Benzodiazepine ω1 and ω2 receptor subtypes
are also located peripherally in adrenal chromaffin cells.
Another benzodiazepine subtype, ω3, was identified and is commonly labeled
as the peripheral benzodiazepine receptor subtype because of its distribution on
glial cell membranes in non-nervous tissues such as adrenal, testis, liver, heart,
and kidney. This subtype was later detected in the CNS, especially on the
mitochondrial membrane, and not in association with GABAA receptors (Gavish
et al. 1992). The ω3 receptor subtype has high affinity for benzodiazepines and
isoquinoline carboxamides (Awad and Gavish 1987). The functional role of this
receptor subtype is unknown, but it may be involved in the biosynthesis and
mediation of the sedative-hypnotic effects of certain neuroactive steroids (e.g.,
pregnenolone, dehydroepiandrosterone [DHEA], allopregnanolone, tetrahydro-
deoxycorticosterone) (Edgar et al. 1997; Friess et al. 1996; Rupprecht et al.
1996). Neurosteroids modulate GABAA-mediated transmission through an
allosteric mechanism that is distinct from the modulation mechanism of
benzodiazepines and barbiturates. By stimulation of ω3 receptors with agonists,
cholesterol is transferred from intracellular stores in mitochondria and becomes
available to the mitochondrial cytochrome P450 cholesterol side-chain cleavage
enzyme (P450scc), and neurosteroid biosynthesis begins (Papadopoulos et al.
2001). Benzodiazepine ω3 receptor subtypes also may serve as mitochondrial
membrane stabilizers and protect against pathologically induced mitochondrial
and cell toxicity (Papadopoulos et al. 2001).
The GABAA receptor is a ligand-gated ion channel that mediates fast synaptic
neurotransmission in the CNS. When the GABAA receptor is occupied by
GABA or GABA agonists such as muscimol, the chloride channels open and
chloride ions diffuse into the cell. Early research established that diazepam (and
related benzodiazepines) does not act directly through GABA but instead
modulates inhibitory transmission through the GABAA receptor in some other
way. It was subsequently discovered that benzodiazepines bind specifically to
neural elements in the mammalian brain with high affinity and that an excellent
correlation exists between drug affinities for these specific binding sites and in
vivo pharmacological potencies (Möhler and Okada 1977; Squires and Brastrup
1977).
The binding of a benzodiazepine to the GABAA receptor site is enhanced in
the presence of GABA or a GABA agonist, suggesting that a functional (but
independent) relationship exists between the GABAA receptor and the
benzodiazepine receptor binding sites (Tallman et al. 1978). Barbiturates (and to
some extent alcohol) also seem to produce anxiolytic and sedative effects at least
partly by facilitating GABAergic transmission (see “Barbiturates” section later
in this chapter). This common action for chemically unrelated compounds can be
explained by the shared ability of these compounds to stimulate specific sites on
the GABAA receptor.
The benzodiazepines bind with high affinity to their binding sites so that the
action of GABA at its receptor site is allosterically enhanced. GABA can
produce stronger postsynaptic inhibition in the presence of a benzodiazepine.
Benzodiazepine agonists are assumed to potentiate only ongoing physiologically
initiated actions of GABA (at GABAA receptors), whereas barbiturates are
thought to cause inhibition at all GABA-ergic synapses regardless of their
physiological activity. In addition, barbiturates appear to increase the duration of
the open state of the chloride channel, whereas benzodiazepines increase the
frequency of channel openings but have little effect on duration (Twyman et al.
1989). These fundamental differences between the allosteric effects of
benzodiazepines within the GABAA receptor and the conducive effects of
barbiturates on the chloride ion channel may explain why low doses of
barbiturates have a pharmacological profile similar to that of benzodiazepines,
whereas high doses of barbiturates cause a profound and sometimes fatal
suppression of brain synaptic transmission. It is notable that selective GABAA
receptor agonists, such as muscimol, have no sedative or anxiolytic properties;
thus, the entire GABAA–benzodiazepine receptor complex must be involved for
expression of sedative-hypnotic properties.
Nonbenzodiazepine Hypnotics
Regarding the pharmacokinetics of nonbenzodiazepine hypnotics, no (or only
weak) active metabolites exist for the compounds currently available.
Benzodiazepines Barbiturates
Total sleep time ↑ tolerance with short-acting ↑ rapid tolerance
agents
Stage 2, % ↑ ↑
Slow-wave sleep ↓ ↓ (slight)
(stages 3 and 4), %
REM latency ↑ ↑
REM, % ↓ (slight) ↓
Withdrawal Rebound insomnia with REM rebound
short-acting agents Rebound decrease in
Carryover effectiveness with stage 2 and total
long-acting agents sleep time
REM rebound (slight)
Note. REM=rapid eye movement sleep; ↑=increased; ↓=decreased.
Most benzodiazepines increase REM latency. The time spent in REM sleep is
usually shortened; however, the reduction in percentage of REM sleep is
minimal because the number of cycles of REM sleep usually increases late in the
sleep time. Despite the shortening of SWS and REM sleep, the net effect of
administration of benzodiazepines is usually an increase in total sleep time, so
that the individual feels that the quality of sleep has improved. Furthermore, the
hypnotic effect is greatest in subjects with the shortest baseline total sleep time.
If the benzodiazepine is discontinued after 3–4 weeks of nightly use, a
considerable rebound in the amount and density of REM sleep and SWS may
occur. However, this is not a consistent finding.
Because long-acting benzodiazepine hypnotics impair daytime performance
and increase the risk of falls in geriatric patients, several shorter-acting
benzodiazepines are the preferred choice for elderly individuals (see section
“General Considerations in the Pharmacological Treatment of Insomnia” later in
this chapter). However, it has been found that short-acting benzodiazepines can
induce rebound insomnia (a worsening of sleep difficulty beyond baseline levels
on discontinuation of a hypnotic) (Kales et al. 1979), rebound anxiety,
anterograde amnesia, and even paradoxical rage (Figure 43–7). Many other
factors, such as the subtype of insomnia being treated and the dosage and
duration of treatment, are also important in explaining the occurrence of these
specific side effects, which also may occur with longer-acting benzodiazepines.
Nevertheless, enthusiasm for shorter-acting compounds has been tempered by
the discovery of these adverse effects.
Overdose
The benzodiazepines are very widely prescribed, so it is not surprising that they
are used in many suicide attempts. For adults, overdoses of benzodiazepines
reportedly are not fatal unless alcohol or other psychotropic drugs are taken
simultaneously. Typically, the patient falls asleep but is arousable and wakes
after 24–48 hours. Treatment is supportive. A stomach pump is usually more
punitive than therapeutic, and dialysis is usually ineffective because of high
plasma binding.
Barbiturates
History and Discovery
Barbital, one of the derivatives of barbituric acid, was introduced in 1903 and
soon became extremely popular in clinical medicine because of its sleep-
inducing and anxiolytic effects (Maynert 1965). In 1912, phenobarbital was
introduced as a sedative-hypnotic. Since then, more than 2,500 barbiturate
analogs have been synthesized, about 50 of which have been made commercially
available and only 20 of which remain on the market.
The success of the partial separation of anticonvulsant from sedative-hypnotic
properties led to the development of nonsedative anticonvulsants such as
phenytoin in the late 1930s and trimethadione in the early 1940s. The success of
barbiturates as sedative-hypnotics was largely overshadowed by the discovery of
the benzodiazepines in the late 1960s. With pharmacological properties very
similar to those of barbiturates, the benzodiazepines have a much safer
pharmacological profile. Thus, benzodiazepines have replaced barbiturates in
many instances, especially for psychiatric conditions in which suicide is a
possibility.
Structure–Activity Relations
Derivatives of barbituric acid, the parent compound of all barbiturates, do not
dissolve readily in water but are quite soluble in nonpolar solvents. In general,
structural changes that increase liposolubility also decrease these compounds’
duration of action, decrease the latency to onset of activity, accelerate metabolic
degradation, and often increase hypnotic potency.
Compared with barbituric acid derivatives with methyl groups at position 5,
those with large aliphatic groups at this position have greater activity but shorter
duration of action. However, when aliphatic groups have more than seven
carbons, they lose their hypnotic activity and tend to exhibit convulsant activity.
Methylation of the 1-N atom increases liposolubility and shortens duration of
action, and desmethylation may increase the duration of action (Rall 1990).
Overdose
An overdose of barbiturates leads to fatal respiratory and cardiovascular
depression. Suicide attempts frequently involve overdoses of barbiturates, taken
either alone or in combination with alcohol or other psychotropic drugs,
particularly tricyclic antidepressants. These suicide attempts, unfortunately, are
often successful. Depending on local factors such as proximity to a hospital and
expertise of staff in intensive emergency care, death occurs in 0.5%–10% of
these cases. Severe poisoning results at 10 times the hypnotic dose, and twice
that amount may be fatal.
Drug–Drug Interactions
Barbiturates used with other CNS depressants can cause severe depression.
Ethanol is the drug most frequently used in combination with barbiturates, and
interactions with antihistaminic compounds are also common. Monoamine
oxidase inhibitors and methylphenidate also increase the CNS depressant effect
of barbiturates.
Barbiturates may increase the activity of hepatic CYP enzymes two- to
threefold. Clinically, this change is particularly important for patients who are
also receiving metabolic competitors such as warfarin or digitoxin, for which
careful control of plasma concentrations is vital (Rall 1990).
Other Sedative-Hypnotic Compounds
Alcohol-Type Hypnotics
The alcohol-type hypnotics include the chloral derivatives, of which chloral
hydrate (0.5–1.0 g), clomethiazole (192 or 384 mg), and ethchlorvynol (0.5–1.0
g) are still used occasionally in the elderly. Chloral hydrate is metabolized to
another active sedative-hypnotic—trichloroethanol. These drugs have short half-
lives (∼4–6 hours) and decrease sleep latency and number of awakenings; SWS
is slightly depressed, but overall REM sleep time is largely unaffected. Chloral
hydrate and its metabolite have an unpleasant taste and frequently cause
epigastric distress and nausea. Undesirable side effects include light-headedness,
ataxia, and nightmares. Chronic use of these drugs can lead to tolerance and
occasionally to physical dependence. As with barbiturates, overdosage can lead
to respiratory and cardiovascular depression, and therapeutic use of these drugs
has largely been superseded by the use of benzodiazepines.
Gamma-Hydroxybutyrate/Sodium Oxybate
γ-Hydroxybutyrate (GHB) is a hypnotic agent that has been used mostly in the
treatment of insomnia in narcoleptic patients (Scrima et al. 1990). A small
amount of GHB also exists naturally in the CNS (Bessman and Fishbein 1963).
The drug is rarely used in other indications and is frequently abused. GHB was
classified as a Schedule I controlled substance in March 2000 in the United
States, but in July 2002, the drug’s sodium salt form, sodium oxybate (Xynem),
was approved for the treatment of narcolepsy. Nighttime administration of GHB
(20–40 mg/kg) reduces excessive daytime sleepiness associated with narcolepsy.
The compound promotes SWS and REM sleep (Lapierre et al. 1990), but its
effects on sleep architecture are short-lasting, and repeated administration
usually is necessary during the night. GHB also is used for the treatment of
cataplexy in narcolepsy, although the mechanisms of GHB’s effect on cataplexy
remain unknown. The physiological significance of a brain GHB signaling
pathway and the detailed mechanisms of many actions of exogenous GHB
remain unclear. Exogenously administered GHB induces a wide range of
neuropharmacological effects, including sedation, memory impairment, an
increase in sleep, seizures, dependence/abuse, and coma (Wong et al. 2004).
GHB has long been known to have an effect on dopamine systems in the brain
and likely inhibits dopamine release (Vayer et al. 1987).
Most of the effects of exogenous GHB have been shown to be mediated
(either fully or in part) by GABAB receptors (Castelli et al. 2004; Maitre 1997;
Wong et al. 2004). In 2003, the cloning of a putative GHB receptor was reported
(Andriamampandry et al. 2003).
Despite this progress, there is an urgent need for a well-validated functional
assay for GHB receptors. Moreover, because GHB can also be metabolized to
GABA, it remains to be seen whether the many GABAB receptor–mediated
actions of GHB are caused by GHB itself acting directly on GABAB receptors or
by a GHB-derived GABA pool (or both) (Wong et al. 2004).
Antihistamines
Antihistamines such as promethazine (25–50 mg), diphenhydramine (25–50
mg), and doxylamine (25 mg) are sometimes prescribed as sleep inducers. They
decrease sleep latency but do not increase total sleep time (see Reite et al. 1997).
These compounds are especially useful for patients who cannot sleep well
because of acute allergic reactions or itching. Because sedative antihistamines
lack abuse potential, they also may be a good choice for individuals with
substance use disorders. However, rapid tolerance is a problem.
In April 2008, doxepin hydrochloride (marketed under the trade name
Silenor), a tricyclic antidepressant with histamine 1 (H1) receptor antagonism,
received FDA approval for the treatment of insomnia. Doxepin (as Sinequan) (3
and 6 mg) reduces wake after sleep onset and prolongs total sleep time (Markov
and Doghramji 2010). Several other selective H1 receptor blockers and H1
receptor reverse agonists are also under development for use as hypnotics.
Melatonin and Melatonin Receptor Agonists
Melatonin
Melatonin is a neurohormone produced by the pineal gland during the dark
phase of the day–night cycle. In animals, melatonin has been implicated in the
circadian regulation of sleep and in the seasonal control of reproduction. Studies
suggest that melatonin administration may have some therapeutic effects in
various disturbances of circadian rhythmicity, such as those related to jet lag
(Arendt et al. 1987), shift work (Folkard et al. 1993), non-24-hour sleep–wake
cycle in blind individuals (Arendt et al. 1988), and delayed-sleep-phase insomnia
(Dahlitz et al. 1991), with few side effects (e.g., headaches or nausea). High
doses of melatonin (3–100 mg), which increase serum melatonin levels far
beyond the normal nocturnal range, have been suggested to produce hypnotic
effects in humans (Dollins et al. 1994). Lower and more physiological doses of
melatonin (e.g., 0.3 mg) might also be active (Zhdanova et al. 2001).
In humans, the production of melatonin during the dark period declines with
age; this effect parallels declines in sleep quantity and quality (van Coevorden et
al. 1991), especially in elderly persons with insomnia (Haimov et al. 1994;
Mishima et al. 2001). These findings appear to suggest that deficiencies in
nocturnal melatonin secretion might contribute to disrupted sleep in the elderly;
thus, melatonin may be particularly beneficial for insomnia in this population.
Indeed, some studies reported favorable effects with supplementary
administration of melatonin in elderly persons with disturbances in sleep
maintenance (Garfinkel et al. 1995; Haimov et al. 1995). However, several
studies reported contradictory findings indicating no significant relation between
physiological melatonin secretion levels and sleep-maintenance parameters
(Hughes et al. 1998; Lushington et al. 1998; Youngstedt et al. 1998; Zeitzer et al.
1999), as well as no significant therapeutic effect of melatonin replacement on
sleep maintenance in elderly persons with insomnia (Hughes et al. 1998).
One of the difficulties in establishing the therapeutic efficacy of melatonin is
its short half-life (20–30 minutes). Bedtime melatonin administration (1–3 mg)
reduces sleep latency but has few objective effects on sleep architecture. It is
also unclear whether the hypnotic effect from a physiological or
pharmacological dose represents a direct effect on sleep, an indirect effect on
circadian timing that subsequently gates the release of sleep, or both. Finally,
very few double-blind, placebo-controlled studies have been done, and most
current reports are confounded by strong placebo effects in the context of a
melatonin fad. Melatonin might be an effective hypnotic in some indications, but
better-controlled studies are needed to establish its efficacy in specific
indications. The purity of the products sold in health food stores is also a
problem, and the long-term effects of melatonin administration in humans are
unknown.
A prolonged-release formulation of melatonin (marketed under the trade name
Circadin) was approved by the European Commission in June 2007 as
monotherapy (2 mg) for the short-term treatment of primary insomnia
characterized by poor-quality sleep in patients 55 years and older (Lemoine et al.
2007).
Conclusion
The mechanism of action of most currently available hypnotics
(benzodiazepines, barbiturates, alcohol, and nonbenzodiazepine hypnotics)
involves a modulatory effect on GABAergic activity. These compounds
stimulate GABAergic transmission by acting on the GABAA–benzodiazepine–Cl
− macromolecular complex, which is known to contain multiple modulatory
binding sites and many receptor subtypes. This recently discovered molecular
diversity within the macromolecular complex suggests that new GABAergic
hypnotic compounds, including newly developed nonbenzodiazepine hypnotics
with subtype selectivity, may have more favorable side-effect profiles.
Other non-GABAergic hypnotics, including sedative antidepressants,
antihistamines, melatonin and melatonin receptor agonists, and (most recently)
orexin receptor antagonists, are useful strategies in the treatment of insomnia,
especially because these hypnotics may lack some of the hampering side effects
often seen with classical GABAergic hypnotics, such as abuse potential and
amnesic effects. Prescription of these non-GABAergic hypnotics, as with the
prescription of other regular benzodiazepine-like hypnotic compounds, should
be guided by the knowledge that insomnia is a heterogeneous condition that
must be explored clinically before any pharmacological treatment is initiated.
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11600532
CHAPTER 44
Psychostimulants and
Wakefulness-Promoting Agents
Charles DeBattista, D.M.H., M.D.
Abuse
Agent Schedule Approved for Medication type potential
Amphetamine II ADHD, Anorexiant/stimulant Black box
narcolepsy warning
Lisdexamfetamine II ADHD Stimulant Black box
warning
Methylphenidate II ADHD, Anorexiant/stimulant Black box
narcolepsy (“Mild stimulant”) warning
Amphetamines
Structure–Activity Relations
Structurally, amphetamine is phenylisopropylamine. Ultimate pharmacological
action is determined by alterations to any of the three basic parts of the
amphetamine molecule.
Amine Changes
In terms of affecting clinical utility, substitution at the amine group is the most
common alteration. Methamphetamine (both L and D isomers), which is
characterized by an additional methyl group attached to the amine, making it a
secondary substituted amine, is more potent than amphetamine. Usefully, one
may think of the amine group as enhancing stimulant-like properties.
Isopropyl Changes
An intact isopropyl side chain appears to be needed in order to maintain the
potency of amphetamine. For example, changing the propyl to an ethyl chain
creates phenylethylamine, an endogenous neuroamine (a metabolite of the
monoamine oxidase inhibitor [MAOI] phenelzine) that has mood- and energy-
enhancing properties but less potency and a much shorter half-life than
amphetamine (Janssen et al. 1999).
Aromatic Changes
Substitutions on the phenyl group are associated with a decrease in
amphetamine-like properties. Interestingly, reduction of the phenyl to a
cyclohexyl ring reduces the potency, but not the efficacy, of amphetamine
properties. Unlike changes at the amine or isopropyl level, additions to the
aromatic ring substantially alter the effects of the compound. The most common
changes at the aromatic ring are of the methoxy type and are associated with
hallucinogenic properties.
Stereospecificity
In recent years there has been renewed interest in drugs that are pure
stereoisomers, as opposed to racemic mixtures, especially with the release of
dexmethylphenidate (the dextro isomer of methylphenidate) and escitalopram
(the levo isomer of citalopram). In amphetamine isomers, it is true that the
dextro form (i.e., dextro isomer, or dextroamphetamine) is almost twice as potent
as the levo form (i.e., levo isomer, or levoamphetamine) in promoting
wakefulness, but they are of equal potency in reducing cataplexy and rapid eye
movement (REM) sleep (Nishino and Mignot 1997). The effect on dopamine
reuptake is stereospecific; inhibition in rat brain, striatum, and hypothalamus has
been found to be markedly different between the two isomers (Ferris and Tang
1979).
The clinical utility of stereospecificity is unclear. Urine levels of the levo
isomer have been used to measure compliance in amphetamine-addicted patients
prescribed dextroamphetamine for maintenance or detoxification; the logic is
that the more levo isomer present in urine, the less compliance (George and
Braithwaite 2000).
Perhaps the most clinically useful difference between amphetamine isomers
involves their differential effects on reinforcement. Studies in rats have shown
that the dextro isomer is four times more potent than the levo isomer in
promoting lever pressing for intracranial stimulation (Hunt and Atrens 1992).
However, that pure dextroamphetamine is better for the treatment of ADHD
than, for example, the mixed salts of dextroamphetamine/amphetamine is neither
obvious nor conclusively shown. In addition, the overall greater potency of the
dextro form for central actions suggests that this form may have a higher
potential for abuse.
Pharmacological Profile
Amphetamines are noncatecholamine, sympathomimetic amines with central
nervous system (CNS) stimulant activity that causes catecholamine efflux and
inhibits the reuptake of these neurotransmitters (see subsection “Mechanism of
Action” later in this section).
Mechanism of Action
The classic mechanism of action of amphetamine involves rapid diffusion
directly into neuron terminals; through dopamine and norepinephrine
transporters, amphetamine enters vesicles, causing release of dopamine and
norepinephrine. The release of these neurotransmitters into the synapse mediates
some of the psychological and motoric effects of amphetamine, including
euphoria, increased energy, and locomotor activation.
Drug–Drug Interactions
A comprehensive review found that drug interactions with amphetamine were
mostly pharmacodynamic in nature (Markowitz and Patrick 2001); however,
because a small portion of amphetamine metabolism occurs via the cytochrome
P450 (CYP) 2D6 isoenzyme, those drugs that inhibit 2D6 metabolism can,
theoretically, have the effect of increasing the plasma level of amphetamine.
Lisdexamfetamine
Lisdexamfetamine dimesylate, a prodrug that on absorption is metabolized to
dextroamphetamine and L-lysine, was approved in 2007 for the treatment of
ADHD. Food does not affect absorption of lisdexamfetamine, but acidification
of the urine results in more rapid clearance.
Two small studies in children found good efficacy and tolerability for
lisdexamfetamine in the treatment of ADHD. A 4-week randomized, double-
blind, forced-dose, parallel-group study compared lisdexamfetamine 30, 50, or
70 mg/day with placebo in children (ages 6–12 years) with ADHD (Biederman
et al. 2007b). Efficacy, as measured by scores on the ADHD Rating Scale—
Version IV (ADHD-RS-IV), the Conners Parent Rating Scale (CPR), and the
Clinical Global Impression–Improvement (CGI-I) scale, was statistically
superior to that of placebo for all dosages tested. A randomized, double-blind,
placebo-controlled crossover study compared lisdexamfetamine with placebo
and extended-release mixed amphetamine salts (Adderall XR) in 52 children
(ages 6–12 years) with ADHD in an analog classroom setting (Biederman et al.
2007a). The study found comparable efficacy and safety for the active
medications and superiority over placebo as measured by scores on the CGI-I
scale and the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP)–
Deportment subscale.
In 420 adults, a 4-week forced-dose (30, 50, or 70 mg/day) study found
lisdexamfetamine to have significantly greater efficacy over placebo as
measured by ADHD-RS scores. Human liability studies have also found lower
abuse-related drug-liking scores compared with immediate-release D-
amphetamine at equivalent dosages (Najib 2009).
In 2014, lisdexamfetamine was approved for the treatment of binge-eating
disorder in adults. The registration trials involved more than 700 patients with
moderate to severe binge-eating disorder. In a Phase II trial, subjects were
randomly assigned to 30, 50, or 70 mg/day lisdexamfetamine or placebo for 3
weeks and maintained at this dosage for an additional 8 weeks. Compared with
placebo, the 50-mg/day and 70-mg/day dosages were more effective in reducing
the total number of binge-eating days, were more likely to result in a a remission
of symptoms, and produced greater global improvement (McElroy et al. 2015a).
Subsequent to that study, two Phase III trials have evaluated the efficacy and
safety of lisdexamfetamine (target dosage of 50 or 70 mg/day as tolerated)
versus placebo in adults ages 18–55 years with binge-eating disorder.
Lisdexamfetamine at both dosages was more effective than placebo in reducing
the total number of binge days. The active-treatment groups showed a reduction
in binge-eating days from an average of 5 days/week to 1 day/week (versus a
reduction to about 2 days/week in the placebo group). Compared with subjects
who received placebo, those who received active treatment experienced greater
overall improvement, as measured by the CGI–I score (McElroy et al. 2016).
Several preliminary studies suggested that lisdexamfetamine might be useful
as an adjunctive treatment for major depressive disorder. Trivedi et al. (2013)
found that 20–50 mg of lisdexamfetamine added to escitalopram for 6 weeks
was superior to placebo in treating residual symptoms of depression. However,
two subsequent Phase III randomized controlled trials failed to demonstrate a
significant benefit for lisdexamfetamine over placebo in the adjunctive treatment
of major depressive disorder. Still, there is some evidence that lisdexamfetamine
may be more effective than placebo in treating executive function deficits in
patients with major depressive disorder (Madhoo et al. 2014) and that it may
have a role in the treatment of bipolar depression (McElroy et al. 2015b).
Methylphenidate
Structure–Activity Relations
Although methylphenidate has two chiral centers, only one contributes to its
clinical effect. The D- and L-threo enantiomers are in a racemic mixture,
although a single-isomer form of methylphenidate, dexmethylphenidate [(R,R)-
(+)], is currently being marketed under the brand name Focalin. There are some
differences in the pharmacological parameters of the two isomers, as described
in the following subsection.
Mechanism of Action
Although it is both a norepinephrine and a dopamine reuptake inhibitor,
methylphenidate appears to exert its effects primarily through its action on
dopamine neurobiology. It blocks the dopamine transporter (DAT) and increases
extracellular dopamine. The amount of extracellular dopamine increase varies
greatly among individuals depending on the extent of both DAT blockade and
baseline dopamine release.
Drug–Drug Interactions
Although theoretically a substrate of CYP2D6, methylphenidate was found not
to have any significant metabolism in humans via this enzyme (DeVane et al.
2000). The prescribing information (Novartis 2007) does cite methylphenidate’s
potential ability to inhibit the metabolism of warfarin, some antiepileptic agents,
and tricyclic antidepressants (TCAs), and therefore caution should be observed.
However, a review found that methylphenidate is relatively safe and has minimal
drug–drug interactions, with the exception of concomitant MAOI use
(Markowitz and Patrick 2001).
Modafinil
Modafinil is the first U.S. Food and Drug Administration (FDA)–designated
“wakefulness-promoting agent”; it is approved by the FDA for the treatment of
excessive sleepiness associated with narcolepsy, sleep apnea, and residual
sleepiness after standard treatment for shift-work sleep disorder (Cephalon Inc.
2008). As described below, modafinil does little to prevent or alter sleep when
one is trying to do so; however, it appears to permit more stable wakefulness
(i.e., reduced sleep propensity) when one is attempting to stay awake in the
presence of elevated sleep pressure.
Structure–Activity Relations
Modafinil (2-[(diphenylmethyl)sulfinyl]acetamide) exists in racemic form. Both
stereoisomers appear to have the same activity in animals.
Mechanism of Action
The precise mechanism by which modafinil exerts its wakefulness-promoting
effect in patients with excessive sleepiness due to narcolepsy is not yet known.
Modafinil, given its efficacy in narcolepsy, is not surprisingly observed to
increase c-fos activity of hypocretin cells, as well as in the tuberomammillary
nucleus (which is primarily histaminergic), striatum, and cingulate cortex at
higher dosages (Scammell et al. 2000). Additionally, in rats, an increase in
histamine release in the anterior hypothalamus is seen (Ishizuka et al. 2003).
However, modafinil’s wakefulness-promoting effects were not decreased in
histamine knockout mice (Bonaventure et al. 2007).
What may be an important aspect of the pharmacology of modafinil is its lack
of effect on the neuroendocrine system. A comparison of healthy volunteers who
were sleep deprived for 36 hours with those who received modafinil during sleep
deprivation found no difference in cortisol, melatonin, or growth hormone levels
(Brun et al. 1998).
Armodafinil
Armodafinil, properly l-(R)-modafinil (or [−]-[R]-modafinil), is the longer-
acting isomer of racemic modafinil. In 2007, it received FDA approval for the
same indications as modafinil—specifically, excessive sleepiness associated with
narcolepsy, obstructive sleep apnea/hypopnea syndrome (OSAHS) as an adjunct
to standard treatment, and shift-work sleep disorder (SWSD).
Armodafinil and racemic modafinil produce comparable peak plasma
concentrations, although the peak for armodafinil occurs later than that for
modafinil and is maintained for 6–14 hours postdose (Dinges et al. 2006).
Published data on armodafinil are still limited. Two 12-week double-blind
studies using armodafinil 150 mg as an adjunct to continuous positive airway
pressure (CPAP), both in patients who were otherwise stable except for some
residual sleepiness (Hirshkowitz et al. 2007) and in patients who were still
symptomatic (Roth et al. 2006), found improvements in wakefulness measures.
Armodafinil also significantly improved the quality of episodic secondary
memory (i.e., the ability to recall unrehearsed information). Whether this effect
was due directly to the medication, to improved wakefulness, or to decreased
hypoxia (as a function of being more awake) is unclear. However, armodafinil
did not adversely affect the CPAP or any other physiological parameters.
A 12-week double-blind study of armodafinil in narcolepsy found
improvements similar to those seen with modafinil. These included improved
wakefulness (as measured by the Maintenance of Wakefulness Test), improved
Clinical Global Impression of Change (CGI-C) scores, and improvement in
memory and attention. Armodafinil 150 mg/day and 250 mg/day were similarly
effective (Harsh et al. 2006).
In SWSD, armodafinil 150 mg/day was tested against placebo in a 12-week
study, showing significant prolongation of time to sleep onset and an
improvement in overall clinical condition by CGI-C. Armodafinil had no effect
on daytime sleep polysomnography (Roth et al. 2005).
Attention-Deficit/Hyperactivity Disorder
Multiple double-blind, placebo-controlled studies have shown the efficacy of
stimulants for ADHD, and their use is well investigated in both adults and
children (Greenhill et al. 2002; Wilens et al. 2002). Some studies are aimed at
showing the superiority of one preparation relative to another, although this
approach is not always fruitful; for example, one study comparing various
single-dose amphetamine preparations with one another and with placebo over 8
weeks found that they were all superior to placebo. However, immediate-release
amphetamines had a faster onset but shorter duration of action; spansules,
although much slower to take effect than the others, lasted several hours longer
(James et al. 2001).
With respect to individual stimulants, all appear to be equally efficacious in
the treatment of ADHD, but they have been reported to have different time
courses. In a double-blind, double-control (placebo and methylphenidate) study,
the mixed amphetamine salts of Adderall were found to exert their effects
rapidly but to dissipate quickly over the course of the day, although Adderall
lasted longer than methylphenidate (Swanson et al. 1998). Interestingly, higher
doses of Adderall lasted longer than lower doses, indicating a dose-dependent
effect in duration of action not found with methylphenidate. Thus, although
stimulants may appear to be of equal efficacy overall, there is considerable
variability in individual response to each stimulant.
The decision to choose amphetamines or methylphenidate for the treatment of
ADHD is often based on the clinician’s preference and degree of experience with
the medication. At least one important blinded crossover study found that in
performance tasks, both drugs were generally equally efficacious (Efron et al.
1997).
Modafinil is not FDA approved for the treatment of ADHD. A 4-week double-
blind study with an 8-week open-label extension found modafinil to be
efficacious across all ADHD rating subscales for the duration of the open-label
extension (Boellner et al. 2006). Interestingly, 10% of the 220 children studied
lost an average of 3 kg, while 4% gained the same amount. Another such double-
blind study found significant efficacy with dosages of 300 mg/day, although
heavier children (≥30 kg) required 400 mg/day (Biederman et al. 2006). A
pooled analysis of three trials (638 patients) found that modafinil produced
similar and impressive improvements in ADHD rating scales between stimulant-
naive and prior-stimulant subgroups relative to placebo (Wigal et al. 2006). As in
other studies, insomnia and headache were the most common, but infrequent,
side effects. A 9-week trial (Biederman et al. 2005) found that almost half of
patients (mean age 10 years, mean dosage 368 mg/day) were much or very much
improved, and efficacy was seen in both inattentive and hyperactive subgroups
and both school and home ratings. Some small but controlled trials (Rugino and
Samsock 2003; Turner et al. 2004) found efficacy with modafinil, and in one
study (Taylor and Russo 2000), equivalence to dextroamphetamine was shown.
Modafinil is currently indicated only for the treatment of excessive sleepiness
associated with narcolepsy, OSAHS, and SWSD.
Stroke and Traumatic Brain Injury
The results from studies on the effects of stimulants in patients who had strokes
or traumatic brain injury are mixed. Although small early studies showed some
superiority of amphetamine to placebo in improving motor function poststroke
(Crisostomo et al. 1988; Walker-Batson et al. 1995), a double-blind study found
that 10 mg/day of amphetamine combined with physiotherapy in geriatric stroke
patients was not superior to placebo plus physiotherapy in improving activities
of daily living or motor function 5 weeks later (Sonde et al. 2001). Neither was
amphetamine found to be superior to placebo in improving somatosensory
training outcomes (Knecht et al. 2001). Modafinil also has not been consistently
effective in the treatment of fatigue associated with traumatic brain injury (Jha et
al. 2008). In contrast, relative to placebo, dextroamphetamine 10 mg/day
significantly improved language recovery in poststroke aphasic patients when
immediately coupled with a session of speech therapy; this effect was seen as
quickly as within 1 week (Walker-Batson et al. 2001). A review lamented the
lack of good data in brain-injured patients but did note that available data
suggest that the bulk of stimulant efficacy may lie with its improvements in
mood and cognitive processing (Whyte et al. 2002).
Although there is a dearth of placebo-controlled studies, there are some
interesting reports in which stimulants were compared with antidepressants in
patients with poststroke depression. One such study, comparing methylphenidate
with TCAs, found similar and significant response to both drugs, although the
stimulant worked faster (Lazarus et al. 1994).
Modafinil has been reported to have some therapeutic efficacy in some types
of brain injury. Two double-blind studies by the same group (Saletu et al. 1990,
1993) found modafinil effective in improving cognition and accelerating
improvement in patients with alcoholic brain syndrome. In addition, there is
some evidence that modafinil may help with cognition in patients with traumatic
brain injury (Dougall et al. 2015; Maksimowski and Tampi 2016).
Narcolepsy
Stimulants have traditionally been used for the treatment of excessive sleepiness
associated with narcolepsy. Narcolepsy is characterized by excessive sleepiness
that is typically associated with cataplexy and other REM sleep phenomena such
as sleep paralysis and hypnagogic hallucinations. Modafinil’s approval for
treatment of excessive sleepiness in narcolepsy was based on substantial
evidence from large multicenter clinical trials (Broughton et al. 1997; U.S.
Modafinil in Narcolepsy Multicenter Study Group 1998, 2000). Modafinil is less
disruptive of sleep than amphetamines and is rated as having a lower abuse
potential (Shelton et al. 1995) (see Table 44–1). One study found that taking an
extra dose (200 mg) at midday improved wakefulness in patients with
narcolepsy without causing insomnia at night (Schwartz et al. 2004).
Importantly, cataplexy—the sudden occurrence of muscle weakness in
association with experiencing laughter, anger, or surprise—is responsive to
amphetamines but not to modafinil (Shelton et al. 1995).
Fatigue
The use of stimulants for the treatment of fatigue syndromes may seem intuitive,
but evidence from large-scale controlled clinical trials to warrant this use is
scant. In one of the only double-blind, placebo-controlled studies, men with HIV,
depression, and fatigue had significantly less fatigue with dextroamphetamine
(73% response) (Wagner and Rabkin 2000). Tolerance, dependence, and abuse
were not observed, even across a 6-month open phase. A double-blind study of
methylphenidate and pemoline in a similar group of 144 patients with HIV who
had severe fatigue found both stimulants effective in improving fatigue and
quality of life (Breitbart et al. 2001). Rabkin et al. (2011) found that a significant
majority of HIV patients—including those with comorbid hepatitis C—reported
an improvement in fatigue with armodafinil. Likewise, in a Phase III trial of
modafinil treatment in 631 patients with cancer-related fatigue, Jean-Pierre et al.
(2010) found that modafinil was more effective than placebo in helping patients
with severe fatigue. However, modafinil did not separate from placebo in cancer
patients with mild or moderate fatigue at baseline. Similarly, in a Phase III study
of armodafinil 150 mg/day for 8 weeks in the treatment of cancer-related fatigue
in multiple myeloma patients, armodafinil failed to separate from placebo
(Berenson et al. 2015). In addition, no advantage was found for armodafinil in a
controlled study of the treatment of brain radiation–related fatigue (Page et al.
2015).
Two controlled trials (Adler et al. 2003; Högl et al. 2002) found modafinil
effective in reducing excessive sleepiness in Parkinson’s disease. Findings from
open-label studies of modafinil for fatigue in multiple sclerosis (Rammohan et
al. 2002) and myotonic dystrophy (Damian et al. 2001) suggest modafinil’s
utility in management of fatigue. A small double-blind crossover study of
modafinil in myotonic dystrophy found a reduction in fatigue but no
improvement on activity measures (Wintzen et al. 2007). This result would be
consistent with modafinil’s rather selective effect on wakefulness and minimal
impact on motor or autonomic parameters. In the same vein, studies of modafinil
in patients with fibromyalgia (Schwartz et al. 2007) and of armodafinil in
patients with sarcoidosis (Lower et al. 2013) did find that the medications were
useful in treating the fatigue associated with these disorders.
Obesity
That amphetamines are anorectic is well known; however, the extent of the effect
may be overstated. Bray and Greenway (1999) summarized the studies of
obesity treatments, wherein they cited a large review of more than 200 short-
term (3-month) double-blind studies of various noradrenergic agents, including
amphetamine and amphetamine derivatives. Patients taking stimulants were
twice as likely as those taking placebo to lose 1 lb/week; however, the
percentage of patients who lost 3 lb/week was quite small (10%). A small study
found that high doses of amphetamine (30 mg) decreased overall caloric intake
but did so primarily through a decrease in fat consumption; carbohydrate
consumption actually increased (Foltin et al. 1995). This mild effect on appetite
is important when considering the use of stimulants in elderly patients who lack
both energy and motivation and have poor appetite.
Depression
As described earlier in this chapter, the only large-scale randomized controlled
trials of a stimulant in the treatment of depression have involved
lisdexamfetamine. Whereas early controlled studies suggested a benefit from
adjunctive lisdexamfetamine (Trivedi et al. 2013) in the treatment of depression,
subsequent Phase III trials failed to demonstrate the efficacy of
lisdexamfetamine in the treatment of residual depressive symptoms after
selective serotonin reuptake inhibitor (SSRI) treatment.
Beyond the lisdexamfetamine data, the bulk of the evidence for the utility of
stimulants in the treatment of depression derives from case series by Feighner et
al. (1985) and Fawcett et al. (1991), which suggested the efficacy of stimulants
combined with MAOIs and MAOI/TCA combinations as well as their safety in
not causing hypertensive or hyperthermic crises, and case series by Stoll et al.
(1996) and Metz and Shader (1991), in which a combination of stimulant and
SSRI was used. Another case series argued for amphetamine’s ability to augment
an antidepressant effect in patients with only partial response, although the
effects were, not unexpectedly, primarily in improving fatigue and apathy
(Masand et al. 1998).
In an open-label trial of depressed cancer patients, both amphetamine and
methylphenidate were reported to improve depressive symptoms to the same
extent, and effects were seen within 2 days. In this series, stimulants did not
cause anorexia; in fact, they improved appetite in more than half of the patients
studied (Olin and Masand 1996), suggesting that these agents are not
contraindicated solely on the basis of concerns about anorexia.
In a review, Orr and Taylor (2007) noted the paucity of high-quality data and
suggested a possible role for stimulants in depression, particularly as adjunctive
agents, in specific patient subgroups.
The utility of modafinil in depressive states is still not well characterized, the
majority of evidence being either anecdotal or retrospective. More work is likely
forthcoming, but there are two studies that bear some examination. The mood-
altering properties of modafinil were studied in 32 normal volunteers in a
double-blind crossover inpatient study (Taneja et al. 2007). Modafinil had
positive results on general mood, especially on alertness and energy measures,
but also had a negative effect on feeling calm (i.e., increased anxiety).
A double-blind, placebo-controlled trial (Dunlop et al. 2007) examining the
effects of modafinil initiated at the outset of treatment with an SSRI in depressed
patients with fatigue found no difference in the primary outcome measure of the
Epworth Sleepiness Scale but found some improvement in the hypersomnia
items of the 31-item Hamilton Rating Scale for Depression. Two other controlled
trials (DeBattista et al. 2003; Fava et al. 2005) and two open-label trials
(DeBattista et al. 2001; Menza et al. 2000) suggest that modafinil may have
some utility as an augmentation agent to antidepressants in depressed patients
with fatigue or excessive sleepiness.
Both modafinil and armodafinil have shown some preliminary benefit in the
treatment of bipolar depression. Frye et al. (2007) found that the addition of
modafinil at dosages of 100–200 mg/day for 6 weeks to a standard mood
stabilizer was more effective than the addition of placebo in 85 patients with
bipolar depression. In a larger randomized controlled multicenter study
(Calabrese et al. 2010), 257 patients with bipolar depression on either lithium or
valproate were randomly assigned to receive augmentation treatment with 150
mg/day armodafinil or placebo. Armodafinil appeared to help some—but not all
—patients with bipolar depression, and the differences between groups did not
reach statistical significance. Likewise, a study of 399 bipolar depressed patients
randomly assigned to receive adjunctive armodafinil or placebo for 8 weeks
failed to demonstrate armodafinil’s benefit on the primary outcome measure
(mean change from baseline on the 30-Item Inventory of Depressive
Symptomatology—Clinician-Rated [IDS-C30] total score) (Frye et al. 2015).
However, armodafinil was efficacious on a number of secondary measures,
including IDS-C30 remission and Global Assessment of Functioning.
Conclusion
The safety and efficacy of stimulants for the treatment of ADHD have been
established. Modafinil and armodafinil are also firmly established as efficacious
wakefulness-promoting agents in narcolepsy, sleep apnea, and shift work sleep
disorder. The utility of these drugs in other areas is being examined. Although
there is intense interest in the potential use of stimulants and modafinil in other
psychiatric and neurobehavioral conditions, controlled studies on their safety and
efficacy are limited. It is unclear why stimulants have not been extensively
investigated for clinical utility for indications other than the treatment of ADHD.
The approval of armodafinil, as the newest of the wakefulness-promoting
compounds, may perhaps spur further research. Well-designed large-scale
controlled trials are needed to define and characterize the role of stimulants and
modafinil in various psychiatric illnesses. It is hoped that this will be an area of
continued interest and development, from the elucidation of the molecular
mechanisms of stimulants and modafinil to the demonstration through controlled
trials of their potential clinical safety and benefits.
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_____________
This chapter is an update and revision of Ballas CA, Evans DL, Dinges DF:
“Psychostimulants and Wakefulness-Promoting Agents,” in The American
Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition. Edited by
Schatzberg AF, Nemeroff CB. Washington, DC, American Psychiatric
Publishing, 2009, pp. 843–860.
CHAPTER 45
Over the past several decades, electroconvulsive therapy (ECT) has been
proven to be perhaps the most effective somatic treatment for mood disorders
(Kellner et al. 2012). The continued use of ECT spurred more systematic
research on its indications, techniques to maximize efficacy and minimize side
effects, and understanding ECT’s mechanism of action. In this chapter, we
review the history of ECT, the preclinical and clinical data on the mechanism of
action of ECT, and the relevant literature related to the efficacy and side-effect
burden of ECT. We also offer practical guidelines for the administration of ECT
in treating various psychiatric disorders, including appropriate patient selection,
stimulus settings and electrode placement, pretreatment medical evaluation, and
management of the patient during acute, continuation, and maintenance courses
of ECT. Finally, we discuss recent developments with nonconvulsive therapies
such as transcranial magnetic stimulation (TMS) in relation to their efficacy in
depression treatment and their utility as part of the neuromodulatory treatments.
Electroconvulsive Therapy
History
The development of ECT occurred at a time when few somatic treatments were
available for psychiatric disorders and physicians were attempting to find
treatments for severely ill psychotic patients. In 1935, Manfred Sakel (1900–
1957) induced hypoglycemic episodes in psychiatric patients (using insulin
shock therapy), and in the same year Lazlo Meduna (1896–1964) injected
patients with pentylenetetrazol to induce convulsions in order to treat psychosis.
Three years later, the Italian psychiatrists Ugo Cerletti (1877–1963) and Lucio
Bini (1908–1964) used electroshock treatments to induce seizures. This
treatment proved safer and easier to administer than chemically induced seizures
and replaced other methods of inducing seizures.
Modern psychopharmacology began with the discovery of lithium (1949) and
iproniazid (1957) for the treatment of mood disorders and the synthesis of the
first antipsychotic, chlorpromazine (1952); the first tricyclic antidepressant,
imipramine (1959); and the first benzodiazepine, chlordiazepoxide (1960). The
development of psychotropic medications was associated with a decline in the
use of ECT from the 1960s to the 1980s, at which point the use of ECT began to
increase, with data showing that more than 36,000 U.S. patients received ECT in
1986 (Thompson et al. 1994). However, the percentage of U.S. hospitals
providing ECT declined by an estimated 43% between 1993 and 2009 (Case et
al. 2013). Studies in Canada and Denmark have reported relatively stable rates of
ECT use over the last 15–30 years (Munk-Olsen et al. 2006; Rapoport et al.
2006), whereas decreasing rates of use have been reported in the United
Kingdom and Australia (Plakiotis et al. 2012; Scott 2012). The results of the
Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study
(Rush et al. 2009) and the Clinical Antipsychotic Trials of Intervention
Effectiveness (CATIE) program (Lieberman et al. 2005) confirmed the limited
effectiveness of psychopharmacology for major mental disorders and supported
the continued clinical relevance of ECT for those patients whose symptoms do
not respond to medication management (Insel and Wang 2009; McCall 2007).
Since the 1980s, the safety of ECT has improved significantly with the
introduction of sophisticated cardiopulmonary and electroencephalographic
monitoring, the development of better anesthetic agents, and the adoption of the
brief-pulse stimulus machine. Today, ECT is arguably the fastest, most effective
treatment for mood disorders. ECT is also one of the safest procedures
performed under general anesthesia, with a mortality rate reported at 0.002% or
less (Watts et al. 2011).
Mechanism of Action
Anticonvulsant Hypothesis
One of the most popular theories on the mechanism of action of ECT is that the
antidepressant efficacy is directly correlated with the anticonvulsant effect of
ECT. That is, the therapeutic effect of ECT is proportional to an increase in the
seizure threshold during ECT. This theory is based on the fact that a course of
ECT results in an increase in seizure threshold and a decrease in seizure duration
(Sackeim 1999) and focuses on changes in neurotransmitter systems and
intracellular biochemical processes related to the seizure threshold.
γ-Aminobutyric acid (GABA) is the predominant inhibitory transmitter in the
brain and is a target for multiple anticonvulsant drugs (e.g., barbiturates,
benzodiazepines). Data from animal studies indicated increases in the threshold
for bicuculline- and pentylenetetrazol-induced seizures following a series of
electroconvulsive shock (ECS) treatments (Nutt et al. 1981; Płaźnik et al. 1989).
Because bicuculline and pentylenetetrazol act by inhibiting GABAA receptors,
these findings suggest that ECT results in changes in GABAergic inhibition.
Additionally, GABA levels increase in certain central nervous system (CNS)
regions after ECS in laboratory animals (Green et al. 1982), and evidence from
magnetic resonance spectroscopy indicates that ECT increases GABA levels in
the occipital cortex in humans (Sanacora et al. 2003). These changes in GABA
levels suggest that there may be an increase in tonic inhibition after repeated
seizures, and effects on GABA-mediated tonic inhibition are increasingly
recognized as an important aspect of several neuroactive drugs (Farrant and
Nusser 2005). In line with this research is the finding that the most consistent
biological marker for ECT response has been increased frontal delta activity
(i.e., postictal depression) shown on the electroencephalogram (EEG) after ECT
(Azuma et al. 2007; Mayur 2006), which is associated with decreased cerebral
blood flow in the immediate postictal period (Nobler et al. 1993).
Mania
Anecdotal reports and case studies suggest that ECT is beneficial in the
treatment of mania associated with bipolar disorder (Fink 2001, 2006). In a
prospective controlled trial, Small et al. (1988) compared the efficacy of ECT
with that of lithium in the treatment of mania. Patients who received ECT
improved more during the first 8 weeks of treatment than did patients who
received lithium. Nevertheless, after 8 weeks of treatment, ECT and lithium
were comparable in efficacy.
A double-blind RCT of bifrontal and bitemporal ECT in acute mania also
confirmed the efficacy of ECT in mania (Hiremani et al. 2008). In addition,
patients with mixed symptoms of depression and mania responded particularly
well to ECT (Gruber et al. 2000; Medda et al. 2010, 2014; Valentí et al. 2008;
Vieta 2005). Given the benefit of anticonvulsant medications in treating mania
and the evidence that ECT may exert its therapeutic effect by raising the seizure
threshold (Sackeim 1999), the efficacy of ECT for mania is not surprising.
Catatonia secondary to mania represents another clinical scenario in which ECT
may offer advantages in efficacy and rapidity of response compared with
pharmacotherapy (Taylor and Fink 2003).
Challenges specific to treating mania with ECT include the following:
Schizophrenia
With the introduction of clozapine and the atypical antipsychotics, ECT has
become a third-line treatment for schizophrenia in the United States, but ECT
may be a first-line treatment for schizophrenia in some Eastern Hemisphere
countries such as India and China (e.g., McDonald 2012). ECT continues to have
an important role in the treatment of acute psychotic episodes, catatonic
schizophrenia, and neuroleptic malignant syndrome (Matheson et al. 2010;
Pompili et al. 2013; Tharyan and Adams 2005). Case reports of ECT in more
chronic and treatment-resistant cases support the role of ECT in the treatment of
schizophrenia (Biedermann et al. 2011; Chanpattana and Kramer 2003;
Chanpattana and Sackeim 2010; Cupina et al. 2013; Pawelczyk et al. 2014;
Pompili et al. 2013).
ECT is particularly beneficial in the treatment of positive symptoms of
schizophrenia and is less effective in decreasing negative symptoms
(Chanpattana and Sackeim 2010; Pawelczyk et al. 2014). ECT also has been
shown to be effective in augmenting antipsychotic treatment in treatment-
resistant schizophrenia (Painuly and Chakrabarti 2006; Ravanić et al. 2009). A
randomized trial found bilateral ECT to be effective as an add-on to clozapine
for treatment-refractory psychosis in schizophrenia, with a 50% response rate in
this difficult-to-treat population (Petrides et al. 2015).
ECT combined with antipsychotic therapy also may be effective in the
management of aggressive behavior in patients with schizophrenia (Hirose et al.
2001) as well as for maintenance treatment of schizophrenia (Chanpattana et al.
1999).
There has been research to support bifrontal (as opposed to bitemporal)
electrode placement as providing better treatment response and tolerability in
schizophrenia, although the data are limited (Phutane et al. 2013).
Catatonic schizophrenia is very responsive to ECT (Fink 2013; van Waarde et
al. 2010), and ECT can be an important treatment when benzodiazepines are
ineffective and symptoms do not respond to antipsychotics or when
antipsychotics are relatively contraindicated because of an unclear diagnosis of
catatonia versus neuroleptic malignant syndrome (Rosebush and Mazurek 2010).
The recommendations of the American Psychiatric Association Task Force on
Electroconvulsive Therapy (American Psychiatric Association 2001) state that
ECT is an effective treatment for schizophrenia in the following clinical
conditions: 1) during acute onset of symptoms, 2) when the catatonic subtype of
schizophrenia is present, and 3) when there is a history of a positive response to
ECT.
Stimulus Waveform
Given that a convulsive stimulus is necessary for the antidepressive effects of
ECT, a nearly infinite number of variations are available for formulating the
stimulus waveform. The earliest ECT devices delivered a sinusoidal stimulus.
Other waveforms available on early ECT devices included the “chopped” sine
wave, the unidirectional pulse square wave, and the alternating brief-pulse
square wave. Although some investigators suspected that sine wave stimuli
might produce slightly better antidepressive effects compared with brief-pulse
stimuli, that idea became untenable when a randomized study showed that sine
wave ECT produced more memory side effects than brief-pulse ECT,
irrespective of the placement of the stimulating electrodes (Weiner et al. 1986b).
This finding of greater cognitive side effects with sine wave ECT was
replicated in an efficacy study using a prospective cohort design, which showed
that compared with brief-pulse stimulation, sine wave stimulation was associated
with a slowing of reaction time that persisted for at least 6 months after ECT
(Sackeim et al. 2007). The more severe cognitive side effects produced by
sinusoidal stimuli may be explained by the slower rise time for each sine wave
cycle as compared with the brief-pulse cycle. Consequent to the slower rise time,
much of the sine wave stimulus is subconvulsive and thus presumably adds
nothing to the therapeutic effect of ECT, adding only to cognitive side effects.
The steep rise in the brief-pulse waveform allows for the entire stimulus to be
above the convulsive threshold (suprathreshold). Because much of the sine wave
stimulus is nonproductive, being in the subconvulsive range, it would be
predicted that brief-pulse stimuli would be more efficient, requiring a stimulus of
smaller magnitude to produce a seizure. Standard brief-pulse stimuli are defined
by a pulse duration of 1–2 milliseconds, whereas ultrabrief-pulse stimuli are
defined by a pulse duration of less than 0.50 millisecond. In 1980, Weiner
showed that standard brief-pulse stimuli could induce a seizure with only one-
third of the energy required with sine wave stimuli. Standard brief-pulse ECT
devices have currently replaced sine wave devices in the United States (Farah
and McCall 1993).
Devices using ultrabrief-pulse stimuli have the advantage of improving the
efficiency of seizure induction. Abrams (2002) estimated that it takes only about
0.25 millisecond to initiate neuronal depolarization, and that longer pulse widths
are inefficient and waste electrical charge. The total energy output of these
ultrabrief-pulse modalities is the same as the total energy output of the standard
brief-pulse widths; thus, as the stimulus pulse widths are shortened, the stimulus
trains are lengthened. Ultrabrief-pulse widths may have an advantage because
shorter pulse widths and longer pulse trains have been shown to elicit seizures
with a smaller electrical charge and therefore may have fewer cognitive side
effects (Sackeim et al. 2008).
Several recent studies have assessed the efficacy and side-effect profile of
brief-pulse versus ultrabrief-pulse width right-unilateral ECT. In a prospective
study comparing ultrabrief-pulse right-unilateral ECT (0.3 millisecond; n=74)
versus brief-pulse right-unilateral ECT (1.0 millisecond; n=22) in depressed
patients, Loo et al. (2008) found similar depression response rates in the two
groups (albeit a slower rate of response in the ultrabrief-pulse right-unilateral
ECT group), with better cognitive outcomes in the ultrabrief group. In a
prospective randomized trial of high-dose right-unilateral ECT in 87 depressed
inpatients, Spaans et al. (2013b) found that patients receiving ultrabrief-pulse
ECT were significantly less likely to achieve remission—and required
significantly more treatments to do so—compared with patients receiving brief-
pulse ECT. A retrospective study in 150 subjects pooled from three research
samples found that fewer treatments were needed with brief-pulse than with
ultrabrief-pulse right-unilateral ECT and that remission rates were significantly
higher with brief-pulse ECT (Loo et al. 2013). Generally, researchers have found
that ultrabrief-pulse right-unilateral ECT produced fewer neurocognitive effects
(specifically on autobiographical memory) compared with brief-pulse treatment
(Loo et al. 2008; Mayur et al. 2013; Verwijk et al. 2012) or that side effects for
the two types were similar (Spaans et al. 2013b).
The data on pulse width and bilateral ECT are also evolving. In a retrospective
study of bilateral ECT in which 65 patients with major depressive disorder
received a pulse width of either 0.5 millisecond (brief) or 0.25 millisecond
(ultrabrief), the two groups had similar response and remission rates
(Niemantsverdriet et al. 2011). In a prospective randomized trial in which 64
patients received treatment with a course of either bifrontal ultrabrief-pulse (0.3
millisecond) ECT at 1.5 times the seizure threshold or right-unilateral ultrabrief-
pulse ECT at 6 times the seizure threshold, the two patient groups showed
equivalent response rates, with no changes in cognition in either group (Sienaert
et al. 2010).
However, a randomized trial of 90 depressed patients who were treated with
either right-unilateral ECT at 6 times the seizure threshold or bilateral ECT at 2.5
times the seizure threshold, using either a traditional brief pulse (1.5
milliseconds) or an ultrabrief pulse (0.3 millisecond), found that the remission
rate with ultrabrief-pulse bilateral ECT was significantly lower than that with
brief-pulse bilateral ECT (35% vs. 65%). Ultrabrief- and brief-pulse right-
unilateral ECT (remission rates of 73% and 59%, respectively) were as effective
as brief-pulse bilateral ECT (65%) but produced fewer cognitive side effects. Of
the four treatment groups, ultrabrief-pulse right-unilateral ECT was associated
with the fewest cognitive side effects (Sackeim et al. 2008).
A recent systematic review concluded that brief-pulse right-unilateral ECT
was “slightly” more efficacious than ultrabrief-pulse right-unilateral ECT in
treating depression and required fewer treatment sessions but was also associated
with more cognitive side effects (Tor et al. 2015). Other groups have reviewed
the data and argued against the use of ultrabrief-pulse right-unilateral ECT,
stating that the evidence does not support its selection over brief-pulse right-
unilateral ECT (Spaans et al. 2013a) or over brief-pulse bilateral ECT at 2.5
times the initial seizure threshold (McCormick et al. 2009) as the first-line
treatment. Clinicians considering the use of brief-pulse right-unilateral versus
ultrabrief-pulse right-unilateral ECT versus bilateral ECT should take into
account clinical factors such as baseline cognitive or neurological status and the
severity of psychiatric symptoms, as well as practical issues such as the potential
for increased length of the treatment course with brief-pulse treatments (Galletly
et al. 2012, 2014).
The picture with ultrabrief-pulse bilateral ECT is less clear, and further
research may be needed to determine the relative efficacy of ultrabrief-pulse
versus standard brief-pulse bilateral ECT. Some have argued that brief-pulse
right-unilateral ECT should be used when a faster speed of response is required,
and that brief-pulse bilateral ECT should be used until more research data has
accumulated in support of the efficacy of ultrabrief-pulse bilateral ECT (Loo et
al. 2012).
Seizure Morphology
The report of Sackeim et al. (1993) that threshold right-unilateral ECT produced
seizures of 25 seconds or longer without antidepressant efficacy cast into doubt
the clinical wisdom that the stimulus dose was therapeutic if the electrographic
seizure lasted at least 25 seconds. Investigators have sought to find a
physiological marker of treatment adequacy to replace seizure duration. The
most promising candidate is seizure morphology. Ottosson (1962) reported that
lidocaine changed the shape of ECT seizures, as well as shortening their
duration. Lidocaine-modified seizures, in addition to being less efficacious than
standard ECT seizures, were characterized by loss of spike activity and poor
postictal suppression.
Seizure morphology varies according to ECT technique. That is, greater
seizure intensity correlates with ECT techniques that progress from lower
efficacy (with right-unilateral electrode placement and low stimulus intensity) to
higher efficacy (with bilateral placement and high stimulus intensity) (Krystal et
al. 1993). Electrode placement and stimulus intensity have independent and
additive effects on seizure morphology. Seizures of greater intensity are
characterized by higher peak ictal amplitudes, greater stereotypy of the ictal
discharge, greater symmetry and coherence between the left and the right
cerebral hemispheres, and more profound postictal suppression. Preliminary
evidence suggests that greater seizure intensity is predictive of a greater
likelihood of response and/or a faster response (McCall et al. 1993; Nobler et al.
1993).
The natural extension of this reasoning leads to the hope that seizure
morphology could guide decisions about stimulus intensity as the course of ECT
progresses. For example, if seizure intensity is low in the middle of the treatment
course, then the treatment technique should be changed (by switching electrode
placement and/or increasing the stimulus intensity) in order to optimize the
clinical outcome. Manufacturers of ECT devices now incorporate automated
measures of seizure intensity into the ECT chart recorder, and the accompanying
owner’s manual instructs the practitioner to increase the stimulus intensity if the
seizure morphology appears to be degraded. The unstated implication is that
degraded seizure morphology is a problem and that increasing the stimulus
intensity will fix the problem. This instruction might have merit if stimulus
intensity were the primary determinant of seizure morphology, but other factors,
such as age, baseline convulsive threshold, and other intrinsic patient
characteristics, likely play an equal role in determining seizure expression
(McCall et al. 1996, 1998). For example, greater seizure durations coupled with
greater seizure regularity as shown by electroencephalography at the second
ECT session are predictive of a better antidepressive outcome at the conclusion
of the ECT course, and this relation is independent of the choice of stimulus
electrode placement (Kimball et al. 2009).
Seizure morphology is little influenced by increasing the stimulus intensity
above 2.5 times the seizure threshold. Therefore, it is premature to recommend
stimulus dosing on the basis of seizure morphology. The importance of seizure
morphology in predicting clinical outcome is far from being understood, and
more work is needed if seizure morphology is to become a practical tool for
governing ECT technique. Peak heart rate has been proposed as an alternative
physiological measure of treatment adequacy, with higher heart rates perhaps
indicating better clinical outcomes (Swartz 2000). Again, this approach has yet
to be widely accepted.
When treating high-risk patients with ECT, clinicians must evaluate the effects
of ECT on cerebral and cardiac physiology and review data from the extant ECT
literature to help develop individual risk–benefit ratios (American Psychiatric
Association 2001; Saito 2005; Sundsted et al. 2014). All patients should undergo
a thorough medical and neuropsychiatric review before beginning a course of
ECT. Particular emphasis should be placed on diseases affecting the CNS and
the cardiovascular system. The pre-ECT evaluation should include a physical
examination, a detailed neurological examination, a mental status examination, a
medical history, and a review of systems. The patient’s mental status should be
evaluated before initiation of ECT and monitored closely before administration
of ECT at every session thereafter.
Interictal Delirium
Interictal delirium that develops during a course of ECT can persist on days
when the patient does not receive a treatment. This side effect is observed
primarily in elderly patients and increases in incidence with advancing age
(Figiel et al. 1990). ECT-induced interictal delirium is associated with prolonged
hospitalization and an increased risk of falls. Among the elderly, additional risk
factors for interictal delirium are 1) Parkinson’s disease, 2) Alzheimer’s disease,
3) one or more cardiovascular risk factors, and 4) preexisting structural changes
in the caudate nucleus observed on brain scans. Patients who develop postictal
confusion are likely to have greater retrograde amnesia in the weeks and months
after ECT (Sobin et al. 1995).
The incidence of delirium during a course of ECT can vary dramatically
depending on the ECT technique used. As a rule, ECT-induced interictal
delirium is a short-lived, reversible side effect if identified early. Once delirium
has been identified, ECT treatments should be withheld until it resolves.
Subsequent treatments should be administered less frequently and/or at a lower
electrical charge.
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PART III
Psychopharmacological Treatment
CHAPTER 46
Treatment of Depression
William V. Bobo, M.D., M.P.H.
Richard C. Shelton, M.D.
Epidemiology
Neurobiology of Depression
Current evidence suggests that there is no single, unifying etiopathophysiology
for MDD (Kupfer et al. 2012). However, certain neurobiological alterations have
been consistently observed in animal models of MDD and in human patients,
many of which are modifiable through antidepressant or other biological
treatments for MDD. These neurobiological markers of MDD are discussed
below.
Dysregulation of Neurotransmitter
Functioning
For several decades, drug development and biological treatment models for
MDD were based primarily on the hypothesis that abnormalities in monoamine
neurotransmitter signaling caused the psychological and neurovegetative signs
and symptoms of the disorder (Owens 2004). Indeed, all known orally
administered antidepressant medications interact with monoamine transporters
or receptors or with enzymes responsible for their degradation (Li et al. 2012).
Although this hypothesis has added profoundly to our understanding of the
pathophysiology of MDD and the mechanisms of antidepressive treatment
response, it alone cannot explain the wide variation in phenotypic presentation
across large numbers of affected patients, nor can it explain the tremendous
interindividual variability in clinical response to antidepressants (Hindmarch
2001).
As our understanding of the mechanism of action of antidepressant therapies
has grown, more attention has been given to other neurotransmitter systems.
Converging evidence from postmortem genetic in vivo neuroimaging studies has
implicated glutamate abnormalities in the pathophysiology of mood disorders,
including MDD (Duman 2014; Sanacora et al. 2012). Moreover,
pharmacotherapies that target glutamatergic N-methyl-D-aspartate (NMDA)
receptors have shown considerable promise as putative antidepressants. For
example, subanesthetic doses of ketamine, an NMDA receptor antagonist, have
been shown to induce rapid (within hours) antidepressant activity that may
persist over several days to weeks in patients with pharmacotherapy-resistant
MDD and bipolar depression (Newport et al. 2015). However, rates of
antidepressant response to ketamine therapy vary widely, and not all
glutamatergic compounds—or even all NMDA receptor antagonists—produce
antidepressant effects.
Neuroimmune Mechanisms
Psychosocial stressors are known to activate not only the HPA axis but also pro-
inflammatory responses, which may represent another link between the effects of
stress and the onset of MDD (Haroon et al. 2012). Compared with healthy
subjects, depressed patients have been found to have higher levels of
inflammatory biomarkers, including higher circulating pro-inflammatory
cytokines, such as interleukin 6 (IL-6), IL-1, and tumor necrosis factor–alpha
(TNF-α) (Dantzer et al. 2008; Hiles et al. 2012). Exposure to interferon-α (INF-
α), an inflammatory cytokine used to treat chronic hepatitis C and neoplastic
diseases, can induce depressive symptoms that overlap with MDD (Capuron et
al. 2009) and that can be reduced or prevented by antidepressants (Baraldi et al.
2012; Udina et al. 2014). Pro-inflammatory cytokines have been shown to
activate the HPA axis and to alter the metabolism of monoamine
neurotransmitters and gluatamate (Haroon et al. 2012). Antidepressant treatment
of depressed patients has been shown to reduce plasma levels of cytokines (IL-
1β and possibly IL-6) in some studies but not others (Hannestad et al. 2011;
Hiles et al. 2012), and decreases in pro-inflammatory cytokine levels over time
have not always correlated with improvement in depressive symptoms (Brunoni
et al. 2014b). For this reason, a neuroimmune mechanism cannot account for all
cases of clinically significant depression or serve as a unified explanation of
antidepressant activity.
Treatment Options
Antidepressant Medications
Pharmacotherapy with antidepressants is an important component of a
comprehensive biopsychosocial treatment plan for managing MDD. The
pharmacological profiles of individual antidepressants are extensively reviewed
in Chapters 8–23 of this volume. Our focus in this chapter is the practical aspects
of antidepressant use and the broader range of treatments for MDD and other
depressive disorders.
Somatic Therapies
ECT is the best studied of the somatic interventions. It is a clearly one of the
treatments of choice for individuals with TRD, and it is effective for MDD with
psychotic or catatonic features and for other situations in which a rapid
antidepressive effect is needed and lag times to therapeutic benefit with
conventional antidepressants are unacceptable (e.g., persons with MDD who are
at high suicide risk or those who are nutritionally compromised because of food
refusal). Although the mechanism of action of ECT is still not well understood, it
is a safe and effective treatment. In repeated studies, ECT has been found to be
more effective than placebo (sham ECT) and pharmacotherapy in patients with
TRD (UK ECT Review Group 2003). Adverse cognitive effects and relapses
following a successful course (even with ongoing pharmacotherapy) are the
main limitations of ECT (Jelovac et al. 2013; UK ECT Review Group 2003).
Relapse rates can be reduced with maintenance ECT. Cognitive side effects may
be limited by the use of alternative electrode placements (unilateral instead of
bitemporal) and by the use of ultrabrief-pulse (instead of brief-pulse) ECT (Tor
et al. 2015). For a review of recent advances in ECT and other somatic therapies,
see Chapter 45 in this volume, “Electroconvulsive Therapy and Other
Neuromodulation Therapies,” by McDonald et al.
Vagus nerve stimulation (VNS) was initially developed for the treatment of
epilepsy. In 2005 it was approved by the U.S. Food and Drug Administration
(FDA) for use in TRD. One of the key findings to emerge from studies of VNS
is that its effects may be cumulative, with the full benefits usually not evident
until 9–12 months after treatment initiation (Sackeim et al. 2007; Schlaepfer et
al. 2008). VNS is generally available only in specialized settings with adequate
surgical capabilities.
Transcranial magnetic stimulation (TMS) was first identified as a treatment
for depression in 1995 by a group of National Institute of Mental Health
researchers (George et al. 1995). Since that time, several smaller studies have
supported the efficacy of TMS for the treatment of MDD (Allan et al. 2011). At
present, TMS is FDA approved for the treatment of MDD in individuals whose
depressive episode has been unresponsive to one adequate medication trial. A
number of related neurostimulation treatments are in development, including
magnetic seizure therapy, transcranial direct current stimulation, low-field
magnetic stimulation, and cranial electrical stimulation (Rosa and Lisanby
2012).
Deep brain stimulation (DBS) is an FDA-approved treatment for severe,
intractable Parkinson’s disease, essential tremor, dystonia, and obsessive-
compulsive disorder (under a humanitarian device exemption). In a large
multisite study of DBS therapy in 20 individuals with TRD, the initial 6-month
response and remission rates were 60% and 30%, respectively (Lozano et al.
2008). Significant reductions in depressive symptoms and high remission rates
have subsequently been demonstrated in small open studies of DBS therapy for
severely treatment-resistant depression (Anderson et al. 2012). Despite these
encouraging results, there is still an inadequate understanding of the precise
mechanisms underlying the therapeutic effects of DBS for TRD, and its use in
the treatment of MDD is still considered to be investigational. Furthermore,
larger trials of DBS in TRD have not confirmed its efficacy (Dougherty et al.
2015). As with VNS, longer periods of exposure to DBS may yield better effects
(Holtzheimer et al. 2012).
Bright light therapy appears to be an effective augmentation therapy for
certain types of depressive disorders (Oldham and Ciraulo 2014). Light has been
best studied in patients with seasonal affective disorder (i.e., DSM-5 major
depressive episode with seasonal pattern), although it also appears to be effective
for some patients with nonseasonal depression (Even et al. 2008). Light therapy
for up to 90 minutes per day has been shown to effectively treat—and also to
prevent the development of—depressive disorders (Even et al. 2008; Westrin and
Lam 2007), especially those with a seasonal pattern. Light therapy has also been
shown to improve depressive symptoms in pregnant and postpartum women
(Corral et al. 2007; Wirz-Justice et al. 2011).
In summary, ECT is clearly effective for TRD and severe forms of depression,
including MDD with psychotic features. VNS and TMS are also approved for
the treatment of MDD that has not responded to at least one antidepressant trial.
Additional neuromodulatory treatments such as DBS are under clinical
development and show considerable promise but are likely to be available only
in highly specialized treatment settings. It is clear that more work needs to be
done in investigating somatic options for patients with TRD.
Psychotherapies
Cognitive-Behavioral Therapy
Cognitive-behavioral therapy (CBT) is a time-limited psychotherapy that aims to
help patients systematically assess and modify distorted (depression promoting)
automatic thoughts and assumptions about themselves, their current situation,
and their future. These cognitive techniques are coupled with behavioral
interventions designed to combat passive disengagement from life activities,
including social withdrawal. CBT has been shown to be effective in reducing
active symptoms of depression and preventing depressive relapses (Lynch et al.
2010). Although practice guidelines have preferentially recommended
antidepressant pharmacotherapy over psychotherapy for severe episodes of
MDD, recent evidence has suggested that for patients with nonpsychotic MDD,
baseline depression severity may not moderate differences in antidepressive
efficacy between CBT and antidepressant pharmacotherapy (Weitz et al. 2015).
The combination of CBT with antidepressant pharmacotherapy may be more
effective than medication alone in reducing depressive symptoms and improving
recovery rates and adherence to treatment (Hollon et al. 2014). CBT also appears
to be just as effective as continuation medication in preventing relapse after
recovery from a depressive episode (Hollon et al. 2005).
Interpersonal Therapy
Interpersonal psychotherapy (IPT) is a time-limited individual psychotherapy
that focuses on four problem areas—grief, role transitions, role disputes, and
interpersonal deficits—during acute treatment of depression. IPT has been
demonstrated to be an efficacious acute treatment for patients with MDD, both
alone and in combination with antidepressant pharmacotherapy (Cuijpers et al.
2011).
Both IPT and CBT are recommended as first-line psychotherapies for treating
patients with MDD, and there is no clear evidence that one is more efficacious
than the other (Jakobsen et al. 2012). However, IPT appears to be effective in
reducing relapse only while it is continued (Frank et al. 2007).
Lifestyle Interventions
A variety of lifestyle interventions have been systematically evaluated, mainly as
adjuncts to core depression treatments. Beneficial effects have been observed for
increasing physical activity and exercise; making dietary modifications;
maintaining adequate relaxation and sleep practices; practicing mindfulness-
based meditation; and reducing or eliminating recreational substance use,
including nicotine, drugs, and alcohol (Sarris et al. 2014). In general, nearly all
of these interventions can be recommended for improving general health and
well-being in most patients with little risk of harm.
Conclusion
Over the past decade, there have been remarkable advances in our knowledge
about the neurobiology, course and prognosis, and treatment of MDD and other
unipolar depressive illnesses. Some patients with MDD have an episodic course
with relatively normal functioning between discrete mood episodes. The
majority of patients, however, have a more chronic and persisting course.
Fortunately, there are a large number of first-line treatments for MDD,
including a wide variety of antidepressants. Although many patients benefit from
treatment with antidepressants, a significant percentage of patients do not
respond to a degree that leads to symptomatic remission and full functional
recovery. Furthermore, a substantial number of patients do not benefit even after
multiple therapeutic trials of antidepressants. For those who respond but do not
achieve remission, options for management include implementing dosage
increases as tolerated, initiating pharmacological augmentation regimens
(combination pharmacotherapy), integrating pharmacotherapy with psychosocial
treatments (including CBT or IPT), and switching treatments. For patients with
TRD, the same general approaches can be used, although older antidepressants
(such as TCAs and MAOIs) and ECT are higher-priority treatment options. Most
patients with MDD with psychotic features will require combination
pharmacotherapy with an antidepressant and an antipsychotic drug. Seasonal
forms of depression may respond well to light therapy. Adoption of healthy
lifestyle habits can be recommended for nearly all patients.
Although the field has made significant progress with regard to depression
treatment, many challenges remain, particularly for patients with TRD, for
which treatment options are the most limited. However, advances in basic
biological investigations of depression are greatly expanding our knowledge, and
new psychotherapies and biological treatments continue to be developed. Future
research will be focused on integrating findings across multiple neuroscientific
disciplines to better elucidate the roles of and interactions between the variety of
neurotransmitter-, neuroendocrine-, immune-, neurohormonal-, neurotrophic-,
and circuitry-based systems implicated in the pathogenesis of depression.
Advances in translational research will identify novel biological targets for
depression treatment and will allow us to develop better and more personalized
approaches for our patients.
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_____________
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CHAPTER 47
Lithium
Lithium has been a mainstay of treatment for acute mania for more than 50
years, with superior efficacy compared with placebo (reviewed in Goodwin and
Jamison 2007) and equivalent efficacy compared with divalproex (Bowden et al.
1994), carbamazepine (Lerer et al. 1987; Small et al. 1991), risperidone (Segal et
al. 1998), olanzapine (Berk et al. 1999), quetiapine (Bowden et al. 2005),
aripiprazole (Keck et al. 2003a), and typical antipsychotics (Garfinkel et al.
1980; Johnson et al. 1971; Platman 1970; Prien et al. 1972; Shopsin et al. 1975;
Spring et al. 1970; Takahashi et al. 1975). Lithium produced improvement in
psychotic as well as manic symptoms in these trials.
Lithium response for acute mania can be maximized by titrating to plasma
concentrations at the upper end of the therapeutic range (1.0–1.4 mmol/L) as
tolerated (Stokes et al. 1976). In randomized controlled trials, significant clinical
improvement usually was reported within 7–14 days among responders (Keck
and McElroy 2001). Common side effects associated with acute treatment with
lithium include nausea, vomiting, tremor, somnolence, weight gain, and
cognitive slowing. Lithium also may interfere with thyroid function and
exacerbate renal disease; thus, monitoring of thyroid and renal function tests is
an important part of lithium administration.
Antiepileptics
Divalproex
Divalproex and related formulations of valproic acid had superior efficacy
compared with placebo (Bowden et al. 1994, 2006; Brennan et al. 1984; Emrich
et al. 1981; Pope et al. 1991) and equivalent efficacy compared with lithium
(Bowden et al. 1994; Freeman et al. 1992), haloperidol (McElroy et al. 1996),
and olanzapine (Zajecka et al. 2002) in randomized controlled treatment trials of
acute bipolar manic or mixed episodes. Olanzapine was superior to divalproex as
measured by mean reduction of manic symptoms and proportion of patients in
remission at study completion in a second head-to-head comparison trial (Tohen
et al. 2002a). Müller-Oerlinghausen et al. (2000) found that valproate
augmentation of typical antipsychotics led to significantly lower mean
antipsychotic dosages and higher response rates compared with placebo added to
typical antipsychotics in patients with acute mania.
Acute antimanic response is correlated with divalproex plasma concentrations
between 50 and 125 mg/L, with some evidence of greater response at the upper
end of the therapeutic range (Allen et al. 2006; Zajecka et al. 2002). Some
patients may require plasma concentrations greater than 125 mg/L, but side
effects become progressively more prevalent above this level. Divalproex
administered at a therapeutic starting dosage of 20–30 mg/kg/day has shown
good tolerability in inpatients, and some evidence indicates a more rapid
response than with gradual titration from a lower (e.g., 750 mg/day) starting
dosage (Hirschfeld et al. 1999; Keck et al. 1993).
Divalproex is generally well tolerated during treatment of acute manic or
mixed episodes. Common side effects include somnolence, nausea, vomiting,
tremor, weight gain, and cognitive slowing. Enteric-coated and extended-release
formulations (the latter requiring a 20% dosage increase to yield plasma
concentrations equivalent to those with immediate-release formulations) have
improved tolerability compared with valproic acid formulations. Rare serious
adverse events include pancreatitis, thrombocytopenia, significant hepatic
transaminase elevation, hyperammonemic encephalopathy in patients with urea
cycle disorders, and hepatic failure.
Antipsychotics
Typical (First-Generation) Antipsychotics
Chlorpromazine (Klein 1967) and haloperidol (McIntyre et al. 2005) were
superior to placebo in randomized controlled trials. Typical antipsychotics bear
the burden of neurological and neuroendocrinological side effects and may carry
an increased risk of postmanic depressive episodes (Kukopulos et al. 1980).
Atypical (Second-Generation)
Antipsychotics
The atypical antipsychotics olanzapine, risperidone, quetiapine, ziprasidone,
aripiprazole, asenapine, and cariprazine have all shown efficacy in the treatment
of acute bipolar mania in at least two randomized, placebo-controlled trials.
Olanzapine was found to be superior to placebo (Tohen et al. 1999, 2000),
superior or equal in efficacy to divalproex (Tohen et al. 2002a; Zajecka et al.
2002), and comparable in efficacy to lithium (Berk et al. 1999; Niufan et al.
2008), risperidone (Perlis et al. 2006), and haloperidol (Tohen et al. 2003a) in
mean reduction of manic and mixed symptoms in 3- to 4-week monotherapy
trials. Adjunctive treatment with olanzapine was superior to placebo in patients
whose symptoms were inadequately responsive to lithium or divalproex
monotherapy (Tohen et al. 2002b). In short-term studies, the most common side
effects associated with olanzapine were somnolence, constipation, dry mouth,
increased appetite, weight gain, and orthostatic hypotension.
Risperidone was superior to placebo (Hirschfeld et al. 2004; Khanna et al.
2005) and comparable to olanzapine (Perlis et al. 2006), haloperidol (Smulevich
et al. 2005), and lithium (Segal et al. 1998) in mean reduction of manic and
mixed symptoms as monotherapy in 3- to 4-week trials. Risperidone was
superior to placebo as an adjunctive therapy with lithium or divalproex in one
placebo-controlled trial (Sachs et al. 2002), but not in a second placebo-
controlled trial in combination with lithium, divalproex, or carbamazepine
(Yatham et al. 2003). The rate of extrapyramidal side effects (EPS) associated
with risperidone was low when the drug was administered at average dosages up
to 4 mg/day (Hirschfeld et al. 2004; Sachs et al. 2002; Yatham et al. 2003), but
not when administered at average dosages of 6 mg/day or greater (Khanna et al.
2005; Segal et al. 1998). In short-term trials, other commonly occurring side
effects included prolactin elevation, akathisia, somnolence, dyspepsia, and
nausea.
Quetiapine was superior to placebo as monotherapy in two 12-week studies in
adult patients (Bowden et al. 2005; McIntyre et al. 2005) and was comparable to
lithium in a 4-week study in adult patients (Li et al. 2008). Similarly, quetiapine
was superior to placebo as adjunctive treatment with lithium or divalproex
(Sachs et al. 2004; Yatham et al. 2004). The mean modal dosage of quetiapine
associated with antimanic efficacy in most studies was approximately 600
mg/day (Vieta et al. 2005b). Quetiapine was also superior to placebo in the
reduction of hypomanic or mild manic symptoms among outpatients in an 8-
week trial (McElroy et al. 2010a). The most common side effects from
quetiapine in monotherapy trials were headache, dry mouth, constipation, weight
gain, somnolence, and dizziness.
Ziprasidone was superior to placebo (mean dosage=120–130 mg/day) in two
3-week monotherapy trials in adult patients (Keck et al. 2003b; Potkin et al.
2005) and comparable to haloperidol in a 12-week trial (Ramey et al. 2003).
Ziprasidone was not superior to placebo as an adjunctive treatment with lithium
in a study designed to prove superior onset of action by 2 weeks of treatment
(Weisler et al. 2004a). Ziprasidone-related side effects in monotherapy trials
included headache, somnolence, EPS, akathisia, and dizziness.
Aripiprazole had significantly greater efficacy in the reduction of manic
symptoms compared with placebo in three 3-week trials (Keck et al. 2003a,
2007; Sachs et al. 2006) and equivalent efficacy compared with haloperidol
(Vieta et al. 2005a) and lithium (Keck et al. 2009) in adequately powered 12-
week comparison trials. Aripiprazole was initiated at 15 or 30 mg/day. Common
side effects associated with aripiprazole in the placebo-controlled trials were
headache, nausea, vomiting, constipation, insomnia, and akathisia.
Asenapine was superior to placebo in mean reduction of manic symptoms in
two 3-week trials (McIntyre et al. 2009, 2010). Common side effects attributed
to asenapine were EPS and mild weight gain.
Cariprazine, a dopamine D3 and D2 receptor partial agonist, was superior to
placebo in reduction of manic symptoms in three randomized controlled trials
(Calabrese et al. 2015; Durgam et al. 2015; Sachs et al. 2015). The most
common side effects associated with cariprazine (occurring in ≥10% of subjects
and at twice the rate with placebo) were akathisia, EPS, tremor, dyspepsia, and
vomiting.
In the studies of atypical antipsychotics reviewed in this section, no significant
differences in response were seen between patients with and patients without
psychotic features or between patients with manic episodes and patients with
mixed episodes among all agents, with the exception of trials of quetiapine,
many of which excluded patients with mixed episodes. The prototypical atypical
agent clozapine was reported to have substantial efficacy in several large case
series of patients with treatment-refractory mania (Calabrese et al. 1996; Green
et al. 2000) but has not been studied in placebo-controlled trials in mania.
Electroconvulsive Therapy
Electroconvulsive therapy (ECT) is an important treatment option for manic
patients with severe, psychotic, or catatonic symptoms. ECT was superior in
efficacy both to lithium (Small et al. 1988) and to the combination of lithium and
haloperidol (Mukherjee et al. 1994) in prospective comparison studies. In
addition, ECT in combination with chlorpromazine was superior to sham ECT
and chlorpromazine (Sikdar et al. 1994). Although these were small studies, their
findings are consistent with those of other naturalistic studies of ECT in the
treatment of acute mania (Black et al. 1987; Thomas and Reddy 1982). There is
a risk of neurotoxicity in patients receiving ECT while also receiving lithium;
thus, lithium should be discontinued when ECT is administered (Hirschfeld et al.
2002).
Novel Treatments
In two short-term monotherapy pilot trials (Yildiz et al. 2008; Zarate et al. 2007)
and one adjunctive therapy trial (Amrollahi et al. 2011), the protein kinase C
inhibitor tamoxifen was superior to placebo in reduction of manic symptoms.
Placebo-controlled trials of the extended-release formulation of the atypical
antipsychotic paliperidone in acute mania have thus far yielded mixed findings
(Berwaerts et al. 2011, 2012b; Vieta et al. 2010).
Lithium
Eight of nine placebo-controlled trials conducted in the 1960s and 1970s in
patients with bipolar I and II disorders found lithium superior to placebo in acute
bipolar depression (reviewed in Zornberg and Pope 1993). In an analysis of five
studies in which it was possible to distinguish “unequivocal” lithium responders
from patients who had partial but incomplete improvement in depression,
Zornberg and Pope (1993) reported that 36% had an unequivocal response,
compared with 79% who had partial but incomplete benefit.
Atypical Antipsychotics
Quetiapine
Quetiapine (300 mg/day and 600 mg/day) was superior to placebo in reduction
of depressive symptoms in four large 8-week multicenter trials involving
outpatients with bipolar I and II depression (Calabrese et al. 2005a; McElroy et
al. 2010b; Thase et al. 2006; Young et al. 2010). No significant difference in
efficacy was found between the two quetiapine dosage groups. However, the rate
of side effects was lower in the 300 mg/day groups compared with the 600
mg/day groups. Switch rates were low across all treatment groups and were not
significantly different among the quetiapine and placebo groups.
Antiepileptics
Lamotrigine
In an initial large 7-week randomized, placebo-controlled trial, lamotrigine (at
50 mg/day and 200 mg/day) was superior to placebo in patients with bipolar I
depression (Calabrese et al. 1999). Switch rates (3%–8%) were not significantly
different among the three groups. A second large placebo-controlled, parallel-
group, flexible-dose trial involving patients with bipolar I and II depression did
not find a significant advantage for lamotrigine over placebo (Bowden 2001). In
a double-blind crossover trial, Frye et al. (2000) found lamotrigine superior to
placebo in improving depression in patients with treatment-refractory rapid-
cycling bipolar I or II disorder. Lamotrigine was superior to placebo when added
to lithium treatment in an 8-week trial in patients with breakthrough depressive
episodes (van der Loos et al. 2009). Common side effects of lamotrigine in these
studies included headache, nausea, infection, and xerostomia. The risk of serious
rash from lamotrigine can be reduced by carefully adhering to recommended
titration schedules (GlaxoSmithKline 2016), but patients should be warned of
the risk of rash and of the need to report any such symptoms immediately.
Carbamazepine
In two small controlled trials in patients with treatment-refractory bipolar
depression, response to carbamazepine was superior to that seen with placebo
(Post et al. 1986) or lithium (Small 1990). The results of these initial intriguing
findings have not been followed by large placebo-controlled, parallel-group
studies.
Divalproex
Two small randomized, placebo-controlled trials of divalproex in the treatment
of acute bipolar depression yielded opposite findings. Sachs and Collins (2001)
did not find divalproex to be superior to placebo in one pilot trial, whereas Davis
et al. (2005) found divalproex superior to placebo in reduction of depressive and
anxiety symptoms in a later pilot study.
Antidepressants
Because of the meager evidence base, current recommendations regarding the
use of antidepressants in conjunction with mood stabilizers for acute bipolar I
depression tend toward the conservative (i.e., avoid antidepressants if possible).
However, some general impressions can be gleaned from the available clinical
trials. First, switch rates associated with newer antidepressants in short-term
trials, in general, appear to be lower than those associated with tricyclic
antidepressants (TCAs) in older studies (Thase and Sachs 2000). Second, among
all of the antidepressants studied, the most substantial evidence for efficacy rests
with the monoamine oxidase inhibitor (MAOI) tranylcypromine (Himmelhoch et
al. 1991), but safety concerns often eliminate this agent from first-line therapy
choices (Hirschfeld et al. 2002). Bupropion (Sachs et al. 1994) and selective
serotonin reuptake inhibitors (SSRIs) (Nemeroff et al. 2001) are common first-
line agents administered in conjunction with mood stabilizers.
Electroconvulsive Therapy
ECT had significantly greater efficacy than MAOIs, TCAs, or placebo in several
randomized controlled trials in patients with bipolar depression (reviewed in
Zornberg and Pope 1993). ECT may be particularly indicated for patients with
severe, psychotic, or catatonic symptoms.
Psychotherapy
Very few randomized controlled trials of any form of psychotherapy for patients
with acute bipolar depression have been conducted. Cognitive-behavioral and
interpersonal therapy have demonstrated efficacy in the treatment of unipolar
major depression, but these modalities have been examined only in very small
preliminary studies in patients with bipolar depression, thus far without
conclusive findings (Cole et al. 2002; Zaretsky et al. 1999).
Novel Treatments
Two preliminary placebo-controlled trials found the dopamine D2 and D3
receptor agonist pramipexole superior to placebo in the adjunctive treatment of
depression in patients with bipolar I or bipolar II disorder (Goldberg et al. 2004;
Zarate et al. 2004). Switch rates with pramipexole did not differ significantly
from those with placebo.
In a 1-week placebo-controlled trial, Watson et al. (2012) examined the
efficacy of mifepristone in improvement in spatial working memory in 60
patients with bipolar depression. They found that mifepristone (600 mg/day)
treatment was associated with sustained improvement in spatial working
memory as an independent variable apart from improvement in depressive
symptoms.
Maintenance Treatment
Bipolar disorder is a recurrent lifelong illness in more than 90% of the patients
who experience a manic episode (Goodwin and Jamison 2007). Because of the
high risk of recurrence and morbidity associated with mood episodes and
interepisode symptoms, maintenance treatment is usually recommended after a
single manic episode (Hirschfeld et al. 2002). The goals of maintenance
treatment include prevention of syndromal relapse and subsyndromal symptoms,
optimization of functioning, and prevention of suicide.
Lithium
Lithium is the most extensively studied medication in the maintenance treatment
of bipolar disorder. Data from randomized, placebo-controlled trials conducted
in the 1960s and 1970s indicated that lithium protected against relapse, with a
fourfold lower risk compared with placebo at 6-month and 1-year follow-up
(Keck et al. 2000). Lithium was superior to placebo in preventing relapse into
mania in two randomized controlled parallel-group trials lasting 18 months
(Bowden et al. 2003; Calabrese et al. 2003).
The optimal maintenance lithium serum concentration is an important
consideration in successful maintenance treatment. Maintenance lithium serum
concentrations usually are lower than those required to produce acute antimanic
efficacy. However, studies by Gelenberg et al. (1989) and Keller et al. (1992)
found a serum level–response relationship, with levels of 0.4–0.6 mEq/L being
associated with 2.6 times the relapse rate and a significantly greater likelihood of
experiencing subsyndromal symptoms compared with levels of 0.8 mEq/L or
higher. There was also a serum level–side effect relationship, with patients at
higher levels experiencing significantly higher rates of side effects, often leading
to discontinuation. Perlis et al. (2002), in yet another reanalysis of the Gelenberg
et al. (1989) data, reported that an abrupt drop in serum lithium levels, whether
due to random reassignment or to nonadherence, was the most powerful
predictor of relapse. The optimal lithium level for many patients will be the level
that balances relapse prevention and suppression of subsyndromal symptoms
against minimization of bothersome day-to-day side effects.
Antiepileptics
Two large 18-month placebo-controlled maintenance trials comparing
lamotrigine (200–400 mg/day) with lithium (0.8–1.1 mEq/L) found lamotrigine,
but not lithium, superior to placebo in preventing depressive episodes (Bowden
et al. 2003; Calabrese et al. 2003). In contrast, lithium, but not lamotrigine, was
superior to placebo in preventing manic episodes. Of the nearly 1,200 patients
who received lamotrigine in these trials, 9% developed a benign rash
(morbilliform or exanthematous eruptions), compared with 8% of the 1,056
patients receiving placebo. When patients who received lamotrigine during the
open-label run-in phase of the studies were included in the analysis, the total
incidence of rash was 13%, with two cases of serious rash requiring
hospitalization (Calabrese 2002).
Calabrese et al. (2000) conducted a 6-month placebo-controlled relapse
prevention study of lamotrigine (mean dosage=288 mg/day) in 182 patients with
rapid-cycling bipolar I or II disorder. There was no significant difference
between the lamotrigine and the placebo treatment groups in time to need for
additional medications for recurrent mood symptoms.
The only randomized, placebo-controlled maintenance study of divalproex in
bipolar I disorder found no significant difference in time to development of any
mood episode among patients receiving divalproex, lithium, or placebo (Bowden
et al. 2000). A number of unforeseen methodological limitations in this trial
complicated interpretation of its results. Among patients who received
divalproex for treatment of the index manic episode in an open treatment period
prior to randomization, divalproex was superior to placebo on rates of early
termination due to any mood episode (29% vs. 50%) during the subsequent year.
Divalproex was also compared with olanzapine in a 47-week blinded
maintenance trial (Tohen et al. 2003b). Calabrese et al. (2005b) compared
divalproex with lithium in a 20-month study of patients with rapid-cycling
bipolar disorder and found comparable relapse rates in both treatment groups.
There are no data regarding the optimal maintenance valproic acid
concentration in bipolar disorder. Current practice usually consists of titrating to
therapeutic serum concentrations (50–125 μg/mL) and, as with lithium,
balancing relapse and subsyndromal symptom prevention against minimization
of side effects (Hirschfeld et al. 2002). Treatment with valproate appears to pose
an increased risk of polycystic ovarian syndrome (PCOS), although the
relationship between PCOS and weight gain as a possible mechanism is unclear
(Hirschfeld et al. 2002).
Although a number of studies have examined the efficacy of carbamazepine in
the maintenance treatment of bipolar disorder, most of these studies yielded
results that were difficult to reliably interpret on methodological grounds
(Dardennes et al. 1995).
Atypical Antipsychotics
Olanzapine was comparable to divalproex in a 47-week comparison trial (Tohen
et al. 2003b) and to lithium in a 1-year comparison trial (Tohen et al. 2005).
Olanzapine received an indication for maintenance treatment in bipolar disorder
based on superiority over placebo in prevention of manic and depressive
episodes over 48 weeks (Tohen et al. 2006). The combination of olanzapine and
lithium or divalproex was superior to placebo and lithium or divalproex in
relapse prevention over 18 months in patients who had initially responded to the
active combination acutely (Tohen et al. 2002b) and then were re-randomized
(Tohen et al. 2004). However, patients in the combination therapy group had
twice the weight gain of patients in the monotherapy group.
Aripiprazole was superior to placebo in preventing manic relapse over a 6-
month follow-up period in patients with bipolar disorder who were initially
stabilized on aripiprazole monotherapy for an acute manic or mixed episode
(Keck et al. 2006, 2007). By contrast, no significant difference between
aripiprazole and placebo was found for rates of depressive relapse. However, the
overall low rate of depressive relapse in this trial may have been due to the
inclusion of patients whose index episodes were manic or mixed rather than
depressive.
Two 104-week adjunctive placebo-controlled trials found quetiapine in
combination with lithium or divalproex to be superior to placebo with lithium or
divalproex in prolonging time to recurrence of a mood episode (Suppes et al.
2009; Vieta et al. 2008). The quetiapine combination groups also had lower
proportions of patients experiencing a mood event.
In a 6-month maintenance trial, ziprasidone was superior to placebo in
combination with lithium or divalproex in prolonging time to intervention for a
mood episode and in proportion of patients requiring an intervention during the
length of the trial (Bowden et al. 2010).
In two randomized controlled trials, risperidone (long-acting injectable
formulation) was found to be superior to placebo in prevention of relapse, both
as monotherapy and as adjunctive therapy (Quiroz et al. 2010; Vieta et al. 2012).
Evidence from one placebo-controlled trial suggests that paliperidone
extended release may be efficacious as a maintenance treatment in patients with
bipolar disorder (Berwaerts et al. 2012a).
Electroconvulsive Therapy
The use of ECT in the maintenance treatment of bipolar disorder has never been
studied systematically in a randomized controlled trial. However, several
naturalistic studies suggest that maintenance ECT may be a useful treatment
alternative for patients whose symptoms are inadequately responsive to
pharmacotherapy (Schwarz et al. 1995; Vanelle et al. 1994).
Psychotherapy
Most patients with bipolar disorder experience a common cluster of
psychological problems stemming directly from the illness. A number of specific
psychosocial interventions as adjuncts to mood stabilizer therapy have been
shown to improve the long-term outcome of bipolar disorder (reviewed in Rizvi
and Zaretsky 2007). The best-studied interventions include educational,
interpersonal, family, and cognitive-behavioral therapies. Randomized controlled
trials conducted over 1- to 2-year follow-up periods support the efficacy of
cognitive-behavioral therapy (Lam et al. 2005), family-focused and related
forms of therapy (Clarkin et al. 1990, 1998; Miklowitz et al. 2003; Rea et al.
2003), interpersonal and social rhythm therapies (Frank et al. 2005), and group
psychoeducation (Colom et al. 2003) in reducing or delaying mood episode
recurrence, increasing treatment adherence, and improving functioning. Family-
focused, interpersonal, and social rhythm therapies were all associated with
delaying time to depressive episode relapse compared with brief treatment
(Miklowitz et al. 2007).
Conclusion
There have been substantial advances in the pharmacological treatment of
bipolar disorder in the past two decades. A number of medications have
demonstrated efficacy in the treatment of acute mania in placebo-controlled
trials, either as monotherapy or as an adjunct to mood stabilizers. In addition,
available data indicate that combination therapy with an antipsychotic and a
mood stabilizer is more rapidly effective, with better overall response rates in
acute mania, than either mood stabilizers or antipsychotics alone.
The treatment of bipolar depression remains one of the least-studied aspects of
the illness. The “mood stabilizer first” strategy and the combined use of mood
stabilizers and antidepressants in moderate to severe bipolar depression are
common approaches.
Most patients with bipolar disorder require treatment with more than one
medication during the course of their illness. The efficacy of combination
strategies is only now receiving close scrutiny. Recent studies suggest that for
some patients, the use of combinations of antidepressants and mood stabilizers
as maintenance treatment may be important to prevent depressive relapse.
The role and efficacy of different types of psychotherapy at different phases of
illness management in bipolar disorder are now becoming clearly established.
These components of treatment are important in educating patients and families,
improving insight and treatment adherence, enhancing coping skills, and dealing
with the sequelae of mood symptoms and episodes—and, it is hoped, improving
functioning and outcome. Treatment advances in bipolar disorder are finally
occurring rapidly. Bringing these treatments to patients with bipolar disorder is
both the challenge and the reward of helping people manage this illness.
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8120153
CHAPTER 48
Over the past two decades, there has been substantial progress in the
treatment of anxiety and related disorders. In this chapter, we review the main
findings from double-blind and some open-label trials in each disorder.
Panic Disorder
Treatment outcome in panic disorder can be measured with the Panic Disorder
Severity Scale (PDSS), which can be administered both as a clinician-rated and
as a self-rated scale (Shear et al. 1997). Other widely used measures include the
Sheehan Panic and Anticipatory Anxiety Scale (PAAS; Sheehan 1986) and the
self-rated Marks-Mathews Fear Questionnaire (FQ; Marks and Mathews 1979).
Although not always attainable, the desired endpoint is full remission. Effective
treatment results in reduced emergency department and laboratory resource
utilization (Roy-Byrne et al. 2001).
First-Line Drug Treatments
Selective Serotonin Reuptake Inhibitors
In 1995, Boyer reported that selective serotonin reuptake inhibitor (SSRI) drugs
were more effective than imipramine and alprazolam in treating panic disorder,
although a meta-analysis by Otto et al. (2001) failed to confirm these findings.
Evidence is now available in support of citalopram (Wade et al. 1997),
escitalopram (Stahl et al. 2003), fluoxetine (Michelson et al. 1998, 2001),
fluvoxamine (Asnis et al. 2001; Black et al. 1993), paroxetine (Ballenger et al.
1998; Oehrberg et al. 1995; Sheehan et al. 2005), and sertraline (Londborg et al.
1998), and also the nonselective serotonin reuptake inhibitor clomipramine
(Lecrubier and Judge 1997). Fluoxetine, paroxetine, and sertraline have been
approved by the U.S. Food and Drug Administration (FDA) for treatment of
panic disorder.
Patients with panic disorder are often extremely sensitive to activating effects
of antidepressants; have poor tolerance of symptoms such as palpitations,
sweating, and tremor; and frequently discontinue treatment or drop out. This
problem can almost always be prevented by coprescribing a benzodiazepine
(Goddard et al. 2001; Pollack et al. 2003) or by starting with low dosages of an
SSRI and increasing them gradually as tolerated. Physician availability and
thorough preparation and education of patients are crucial. Other common side
effects of SSRIs include weight gain, sexual dysfunction, impairment of sleep,
and potential drug–drug interactions.
Discontinuation of treatment can lead to relapse, which mimics panic
symptoms and is quite distressing. Gradual dosage reduction is recommended, as
are patient education, physician availability, and coping strategies, including
behavior therapy (Otto et al. 1993). Switching to a long-acting SSRI such as
fluoxetine may be considered. Serotonin 2 (5-HT2) or serotonin 3 (5-HT3)
receptor antagonists, such as mirtazapine, nefazodone, and ondansetron, may be
used to limit some of the symptoms that are mediated through these pathways
(e.g., insomnia, agitation, gastrointestinal distress).
Benzodiazepines
The Cross-National Collaborative Panic Study (1992) showed that alprazolam,
along with imipramine, was more effective than placebo in panic disorder;
Lydiard et al. (1992) showed that alprazolam 2 mg/day was more effective than
placebo. Efficacy for clonazepam was also demonstrated in panic disorder
(Davidson and Moroz 1998; Rosenbaum et al. 1997; Tesar et al. 1991), and its
use for this indication is now FDA approved.
Alprazolam is now regarded as a second-line treatment. Problems include
sedation at higher dosages, abuse liability, and discontinuation-related distress.
Comparable efficacy and tolerability have been demonstrated for the sustained-
release formulation of alprazolam (Pecknold et al. 1994; Schweizer et al. 1993),
with decreased likelihood of adverse discontinuation effects.
Clonazepam has an advantage over alprazolam due to its longer half-life;
however, it can also produce sedation, depression, and discontinuation
symptoms. Bandelow et al. (1995) showed that reduction of panic attacks is an
unsatisfactory marker of treatment benefits and therefore should not be relied on
as the principal outcome measure. Substantial improvement of quality of life and
work productivity were demonstrated in the clonazepam trials compared to
placebo (Jacobs et al. 1997). A recent review supports a role for clonazepam
alone or in combination with SSRIs and/or cognitive-behavioral therapy (CBT)
in the management of panic disorder (Nardi et al. 2013).
A particular concern with benzodiazepines is their use in the elderly, who are
more prone to sedation and falls that can result in fractures and potential head
injury, and who are also more likely to experience discontinuation problems.
Other Drugs
The extended-release (XR) formulation of venlafaxine, a serotonin–
norepinephrine reuptake inhibitor (SNRI), demonstrated greater efficacy than
placebo in patients with panic disorder in a 10-week trial (Bradwejn et al. 2005),
was as effective as paroxetine in a 12-week placebo-controlled trial (Pollack et
al. 2007), and has received FDA approval for the treatment of panic disorder.
The drug is well tolerated, with an adverse-effect profile comparable to that of
the drug in depression and other anxiety disorders.
Mirtazapine, a noradrenergic and specific serotonergic antidepressant,
demonstrated possible benefit in panic disorder in open trials (Boshuisen et al.
2001; Sarchiapone et al. 2003) and in a double-blind comparison with fluoxetine
(Ribeiro et al. 2001); however, double-blind, placebo-controlled trials have yet
to be conducted. It is noteworthy that mirtazapine has been associated with the
induction of panic attacks in depressed patients undergoing dosage escalation
and discontinuation (Berigan 2003; Klesmer et al. 2000).
Reboxetine, a selective noradrenergic reuptake inhibitor, has been found to
produce greater improvement than placebo in patients with panic disorder
(Versiani et al. 2002), and in general to be well tolerated. In a more recent
randomized, single-blind study comparing reboxetine with paroxetine,
paroxetine was more effective for panic attacks, but no differences between the
treatments were noted for anticipatory anxiety and avoidance (Bertani et al.
2004). These findings suggest perhaps different roles of norepinephrine and
serotonin in the treatment of panic disorder. However, the selective
noradrenergic reuptake inhibitor maprotiline appears to be ineffective in panic
disorder (Den Boer and Westenberg 1988), whereas the data for bupropion are
inconclusive (Sheehan et al. 1983; Simon et al. 2003).
Trazodone was less effective than imipramine and alprazolam in the treatment
of panic disorder (Charney et al. 1986). The 5-HT1A partial agonist buspirone
and the anticonvulsant gabapentin were generally ineffective in panic disorder
(Pande et al. 2000; Sheehan et al. 1990). Possible benefit has been reported in
open-label trials for other anticonvulsant drugs, including levetiracetam,
tiagabine, and valproic acid (Keck et al. 1993; Papp 2006; Zwanzger et al.
2001). A small double-blind, placebo-controlled trial with tiagabine did not show
clinical benefits, although cholecystokinin-tetrapeptide (CCK-4)–induced
sensitivity to panic attacks decreased (Zwanzger et al. 2009).
Preliminary data suggest improvement in refractory panic disorder when
atypical antipsychotics are used as augmentation of SSRI treatment (olanzapine:
Sepede et al. 2006; risperidone: Simon et al. 2006) or in higher dosages as
monotherapy (olanzapine: Hollifield et al. 2005). A single-blind comparison trial
comparing paroxetine and low-dose risperidone found the low-dose risperidone
to be as effective as paroxetine in the treatment of panic attacks (Prosser et al.
2009); however, double-blind, placebo-controlled trials are needed. In a recent
randomized, placebo-controlled monotherapy trial of quetiapine XR versus
divalproex extended release in bipolar patients with comorbid panic disorder or
generalized anxiety disorder, quetiapine XR at a dosage range of 50–300 mg/day
showed rapid and sustained effects in reducing anxiety symptoms (Sheehan et al.
2013).
Metabotropic glutamate type 2 receptor agonists have shown promise in
preclinical models of anxiety but have yet to demonstrate clinical efficacy in
panic disorder (Bergink and Westenberg 2005). Similarly, the effect of a
cholecystokinin-B receptor antagonist was no different from placebo in patients
with panic disorder (Pande et al. 1999a).
Long-Term Management
Maintenance treatment is recommended for at least 12–24 months, if not longer.
In a controlled trial of paroxetine, clomipramine, and placebo, 84% of the
paroxetine-treated patients eventually became panic free over the 9-month
period (Lecrubier and Judge 1997). In a 4-year naturalistic follow-up study of
367 patients with panic disorder, greater improvements in panic attacks, phobic
avoidance, and daily functioning were observed in those who received
continuation treatment for 4 years, compared with 1 year (Katschnig et al. 1995),
suggesting that recovery continues over several years.
Long-term randomized controlled trials have reported efficacy for citalopram
(Lepola et al. 1998), clomipramine (Fahy et al. 1992), fluoxetine (Michelson et
al. 1999), paroxetine (Lecrubier and Judge 1997; Lydiard et al. 1998), and
sertraline (Rapaport et al. 2001). In a relapse prevention trial following 3 months
of successful open-label treatment, Ferguson et al. (2007) showed that over the
course of 7 months, relapse on venlafaxine XR was 22%, compared with 50% on
placebo.
Discontinuation
Even though there is some similarity between symptoms of relapse and
symptoms of drug withdrawal, the existence of discontinuation symptoms is
unarguable. A slow taper is recommended (for some benzodiazepines, it may be
necessary to taper the drug over weeks or months). Timing of the taper may be
important—it is best done when other variables in a patient’s life are as stable as
possible. Switching to a longer-acting benzodiazepine such as clonazepam,
adding an anticonvulsant such as carbamazepine or valproate (Pages and Ries
1998), and utilizing behavior therapy (Otto et al. 1993) have all been used to
ameliorate discontinuation symptoms.
Various elaborations of CBT have demonstrated consistent efficacy for panic
disorder, with the common elements being education, cognitive strategies, and
exposure to feared sensations and situations (Clum et al. 1993; Royal Australian
and New Zealand College of Psychiatrists Clinical Practice Guidelines Team for
Panic Disorder and Agoraphobia 2003). CBT is a first-line choice, and even
when pharmacotherapy is given as the main treatment, principles of CBT should
be incorporated into the management plan. It can be of benefit during the process
of drug discontinuation, and perhaps in lessening the chance of relapse
afterwards.
Pharmacotherapy
Most clinicians consider SSRIs as the first choice for generalized SAD and β-
blockers or benzodiazepines as the first choice for nongeneralized SAD. Second-
line drugs for generalized SAD comprise the benzodiazepines, venlafaxine (an
SNRI), and perhaps other antidepressants, including nefazodone, mirtazapine,
and MAOIs. Bupropion and TCAs have been generally disappointing.
Serotonergic Drugs
Van Vliet et al. (1994) showed fluvoxamine’s superiority over placebo, with
response rates of 46% and 7%, respectively. Stein et al. (1999) confirmed the
efficacy of fluvoxamine relative to placebo on all symptom domains (i.e., fear,
avoidance, and physiological arousal). Controlled-released (CR) fluvoxamine
was likewise found to be superior to placebo (Davidson et al. 2004c; Westenberg
et al. 2004), and a study in Japan also found fluvoxamine to be effective versus
placebo in reducing SAD symptoms and psychosocial disability (Asakura et al.
2007).
Sertraline also has been studied (Blomhoff et al. 2001; Katzelnick et al. 1995;
Liebowitz et al. 2003; Van Ameringen et al. 2001; Walker et al. 2000). In the
study by Van Ameringen et al. (2001), 53% of patients responded to sertraline as
compared with 29% to placebo, and sertraline-treated patients showed
improvement on all three symptom domains of the Brief Social Phobia Scale. In
a primary care setting, Haug et al. (2000) showed that cognitive therapy and
sertraline could be effectively delivered, although the combination did not show
any superiority over treatment with drug alone.
Paroxetine’s superiority relative to placebo in SAD has been shown in both
short-term efficacy and relapse prevention studies. In the short-term studies by
Stein et al. (1998), Allgulander (1999), and Baldwin et al. (1999), rates of
response to paroxetine were 55%, 70%, and 66%, respectively, as compared with
placebo response rates of 24%, 8%, and 32%. All subjects in the paroxetine trials
fulfilled criteria for generalized SAD and showed benefit on the LSAS within 2–
4 weeks. Paroxetine CR was also shown to be effective (using LSAS as the
primary outcome measure) and well tolerated in a 12-week double-blind,
placebo-controlled trial (Lepola et al. 2004).
Fluoxetine, while superior to placebo on primary outcomes in one study
(Davidson et al. 2004c), failed to separate from placebo in another study (Kobak
et al. 2002), showing a relatively high placebo response rate (30%). Another
study found cognitive therapy to be superior to both fluoxetine plus exposure
exercises and placebo plus exposure exercises on SAD measures, with no
difference between the latter two groups (Clark et al. 2003). Another
serotonergic agent, nefazodone, also failed to separate from placebo on most
outcome measures (Van Ameringen et al. 2007).
Trials with escitalopram have shown it to be superior to placebo in short-term,
long-term, and relapse prevention studies of generalized SAD (Kasper et al.
2005; Lader et al. 2004; Montgomery et al. 2005). Venlafaxine XR has also
shown superiority over placebo in two double-blind trials of generalized SAD
(Allgulander et al. 2004; Liebowitz et al. 2005).
A double-blind, placebo-controlled trial of mirtazapine in women showed
statistically significant superiority for drug over placebo (Muehlbacher et al.
2005). However, a more recent double-blind, placebo-controlled trial in 60
outpatients with generalized SAD who received mirtazapine at dosages of 30–45
mg/day failed to find evidence of efficacy (Schutters et al. 2010).
Paroxetine, paroxetine CR, sertraline, fluvoxamine CR, and venlafaxine XR
are currently FDA approved for SAD treatment.
Benzodiazepines
Three major placebo-controlled trials have shown efficacy for benzodiazepines
in SAD. Gelernter et al. (1991) showed a modest effect for alprazolam over
placebo (38% vs. 20% response rate) at a mean daily dosage of 4.2 mg, although
it was generally inferior to phenelzine. Davidson et al. (1993) found a substantial
70% clonazepam response rate compared with a 20% placebo response rate in 75
subjects. Bromazepam was also found to be more effective than placebo
(Versiani et al. 1997). A recent double-blind, placebo-controlled trial of
augmentation and switch strategies for refractory SAD found that clonazepam
augmentation of sertraline treatment (up to 3 mg/day) was superior to placebo
augmentation and also to a switch to venlafaxine, with a higher percentage of
patients achieving remission (Pollack et al. 2014).
Benzodiazepines provide significant benefits yet are not considered first-line
drugs because of their more limited spectrum of action and potential withdrawal
difficulties. However, they work rapidly, are well tolerated, and may be
particularly useful for individuals with periodic performance-related social
anxiety or treatment-resistant SAD.
Anticonvulsants
Gabapentin and pregabalin produce significant effects in SAD. Pande et al.
(1999b) found a superior effect for gabapentin over placebo in a trial using
flexible dosing (ranging from 900 mg/day to 3,600 mg/day, with 2,100 mg/day
being the most common final gabapentin dosage), with response rates of 39%
and 17%, respectively. Baseline symptom scores were comparatively high and
overall response rates relatively low, suggesting a degree of treatment-resistant
illness in the study population. Pregabalin also has shown benefit in generalized
SAD (Feltner et al. 2003; Pande et al. 2003). Although pregabalin at a dosage of
150 mg/day was no different from placebo, 600 mg/day produced greater effects
than placebo, with response rates of 43% and 22%, respectively. A 26-week
double-blind, placebo-controlled maintenance trial of pregabalin at a fixed
dosage of 450 mg/day showed that pregabalin not only was superior to placebo
in maintaining symptomatic improvement but also was relatively well tolerated
(Greist et al. 2011). Levetiracetam failed to differentiate from placebo (Stein et
al. 2010). Further work with anticonvulsants is needed, given that these agents
are generally well tolerated, safe, and less likely to produce discontinuation
symptoms compared with many SSRIs and benzodiazepines.
Other Drugs
Olanzapine yielded greater improvement than placebo in a small (n=12) double-
blind, placebo-controlled monotherapy trial (Barnett et al. 2002), suggesting that
atypical antipsychotics may deserve further investigation in SAD, although their
benefits will need to be weighed against their potential metabolic effects.
Ondansetron, while producing a statistically significant effect relative to placebo,
seems to be of limited clinical benefit (Bell and DeVeaugh-Geiss 1994;
Davidson et al. 1997b), although it may be used adjunctively in some cases.
Buspirone was ineffective in a double-blind trial, with a 7% response rate (van
Vliet et al. 1997).
Despite their intuitive appeal, β-blockers have shown poor effect in treating
generalized SAD. For example, atenolol failed to separate from placebo in two
trials (Liebowitz et al. 1992; Turner et al. 1994). β-Blockers do show some value
in performance-related social anxiety, perhaps by virtue of their ability to reduce
peripheral autonomic arousal and block negative feedback. A double-blind trial
of mirtazapine failed to show benefit (Schutters et al. 2010). Nefazodone,
bupropion, and selegiline have not shown impressive results in open-label
reports (Emmanuel et al. 1991; Simpson et al. 1998; Van Ameringen et al. 1999).
A novel therapeutic approach is suggested by the findings of Hofmann et al.
(2006), who administered a single dose of D-cycloserine or placebo to patients
with social anxiety disorder treated with CBT. The drug was given prior to each
CBT session and enhanced the benefit of CBT to a greater extent than did
placebo. The postulated mechanism of action relates to drug-facilitated
extinction of learned fear via glutamatergic pathways. However, a recent
placebo-controlled multisite trial of CBT augmentation with D-cycloserine in
generalized SAD by the same authors found that although D-cycloserine
augmentation was associated with approximately a 30% faster rate of
improvement, there was no difference in response or remission rate compared
with placebo (Hofmann et al. 2013).
A study comparing the neurokinin-1 antagonist GR205171 against citalopram
and placebo in 36 social phobia patients found response rates of 41.7%, 50%,
and 8.3%, respectively, as well as a significant reduction in regional cerebral
blood flow (rCBF) in the rhinal cortex, amygdala, and parahippocampal–
hippocampal regions during a stressful public speaking task with the active
agents (Furmark et al. 2005).
Connor et al. (2006) reported benefit for one-time intradermal bilateral
axillary injections of 50 units of botulinum toxin type A for subjects with SAD
and troublesome axillary hyperhidrosis. Effects persisted over 8 weeks and were
superior to those of placebo for sweating, daily function, and activities. All
subjects received concomitant paroxetine for other aspects of SAD.
Other Issues
CBT is efficacious in SAD, being comparable to pharmacotherapy (Davidson et
al. 2004b; Fedoroff and Taylor 2001), but little is known as to whether adding
CBT to medication lowers the relapse rate, and so far the limited evidence does
not suggest any potentiating effects when the treatments are combined
(Davidson et al. 2004b), except in children (Walkup et al. 2008). In a
comparative study of drug and psychotherapy, Heimberg et al. (1998) showed
that phenelzine and CBT were approximately similar, although phenelzine had
an edge in more severely symptomatic patients. On the other hand, when
subjects who had discontinued treatment were followed up, rates of relapse
tended to be lower in those who had received CBT than in those who had taken
phenelzine. A later study by the same group (Blanco et al. 2010) showed
superior outcomes for combined phenelzine and CBT over each treatment given
alone.
Specific Phobia
Specific phobia is among the most common psychiatric disorders, with a lifetime
prevalence of 8%–12.5% (Alonso et al. 2004; Kessler et al. 2005b) and 12-
month prevalence of 3.5%–9% (Alonso et al. 2004; Kessler et al. 2005a).
Although the disorder is characterized by an early onset (median age at onset is 7
years) (Kessler et al. 2005b), most individuals are unimpaired by their symptoms
and rarely seek treatment (Magee et al. 1996; Stinson et al. 2007; Zimmerman
and Mattia 2000). However, for a minority of individuals, specific phobia causes
significant disability and requires treatment. The generally accepted treatment of
choice is exposure therapy, which is uniformly and rapidly effective, with
techniques including virtual reality as well as in vivo exposure and muscle
tension exercises (for blood–injury phobia) (Swinson et al. 2006). Few studies
have evaluated the efficacy of pharmacological approaches, and no drug has yet
been approved by the FDA for treating specific phobia. No standard ratings exist
for this disorder, although the Marks-Mathews FQ is quite suitable for blood–
injury phobia and some other fears. A modification of this scale, the Marks-
Sheehan Main Phobia Severity Scale (MSMPSS; Sheehan 1986), can be
recommended.
Serotonergic drugs have shown efficacy in treating symptoms of fear and
avoidance in a variety of anxiety disorders and thus would seem logical choices
in specific phobias. In a small (n=11) 4-week double-blind controlled trial,
subjects receiving paroxetine (up to 20 mg/day) showed a 60% response rate,
compared with 17% for subjects receiving placebo (Benjamin et al. 2000). A
more recent randomized double-blind pilot trial compared escitalopram versus
placebo over 12 weeks in 12 adults with specific phobia (Alamy et al. 2008). No
difference was observed on the primary outcome; however, 60% of
escitalopram-treated subjects showed response (based on a Clinical Global
Impression Scale [CGI] Improvement score of 1 or 2), compared with 29% of
subjects receiving placebo (effect size=1.13). The findings from these two small
trials require validation in larger controlled trials. In contrast, in a controlled trial
of the serotonergic and noradrenergic TCA imipramine in 218 phobic subjects
(agoraphobic, mixed phobic, or simple phobic) receiving 26 weeks of behavior
therapy, no difference was observed between imipramine and placebo (Zitrin et
al. 1983).
In a long-term controlled study of clonazepam in social phobia, Davidson et
al. (1994) observed that clonazepam was superior in reducing symptoms of
anxiety related to blood–injury phobia as measured by changes in the blood–
injury phobia subscale of the Marks-Mathews FQ. Intermittent use of
benzodiazepines also may be helpful in the acute treatment of the somatic
anxiety that accompanies specific phobia, although this usage has not been an
area of active investigation.
Using a novel approach, Ressler et al. (2004) investigated the effect of a
cognitive enhancer, D-cycloserine, as an adjunct to psychotherapy. D-Cycloserine
is an N-methyl-D-aspartate (NMDA) receptor partial agonist that has
demonstrated improvement in extinction in rodents. Subjects with acrophobia
(n=28) were randomly assigned to receive a single dose of D-cycloserine or
placebo prior to each of two virtual reality exposure therapy sessions. The
combination of D-cycloserine and exposure therapy was associated with greater
improvement in the virtual reality setting, as well as on a variety of anxiety
domains. These changes were noted early in treatment and were maintained at 3-
month follow-up. A recent small (n=35) double-blind, placebo-controlled
randomized trial of D-cycloserine enhancement of prolonged exposure therapy in
dog- or spider-phobic children showed that D-cycloserine helped children to
better retain their fear extinction learning (Byrne et al. 2015).
Specific phobia tends to be a chronic condition. Although psychotherapeutic
approaches can be beneficial in the short term, evidence suggests that the initial
gains noted with treatment may not be sustained over the long term (Lipsitz et al.
1999). Pharmacological augmentation may help to extend the benefits of
exposure therapy over time.
Anxiolytics
Benzodiazepines
Benzodiazepines have been widely used to treat acute and chronic anxiety since
their introduction in the 1960s. Their activity is mediated through potentiation of
the inhibitory neurotransmitter γ-aminobutyric acid (GABA) at the GABAA
receptor. The efficacy and relative safety of benzodiazepines in short-term use
(i.e., several weeks or months) are well established (Rickels et al. 1983; Shader
and Greenblatt 1993). However, the longer-term use of these drugs is more
controversial and can be associated with the development of tolerance,
physiological dependence, and withdrawal (if abruptly discontinued), as well as
troublesome side effects, including ataxia, sedation, motor dysfunction, and
cognitive impairment. Furthermore, these drugs should be avoided in patients
with a history of substance use disorders, and long-term use may infrequently
lead to the development of major depression (Lydiard et al. 1987).
Benzodiazepines have been shown to be effective in GAD, as reported by
Rickels et al. (1993). The appeal of these drugs lies in their rapid onset of action,
ease of use, tolerability, and relative safety. Findings from several 6- to 8-month
trials of maintenance treatment for chronic anxiety have indicated continued
efficacy of benzodiazepines over time (Rickels et al. 1983, 1988a, 1988b;
Schweizer et al. 1993). Because GAD tends to be a chronic disorder, many
patients may need to continue pharmacotherapy with benzodiazepines (or other
drugs) for many years, and long-term use of benzodiazepines may lead to the
complications listed above.
Approximately 70% of patients with GAD will respond to an adequate trial of
a benzodiazepine (Greenblatt et al. 1983), which corresponds to the equivalent
of a 3- to 4-week treatment course of up to 40 mg/day of diazepam or 4 mg/day
of alprazolam (Schweizer and Rickels 1996). Discontinuation should be
managed by slow taper to minimize withdrawal symptoms, rebound anxiety, and
relapse potential. Some evidence suggests that benzodiazepines may be more
effective in treating the autonomic arousal and somatic symptoms of GAD but
less effective for the psychic symptoms of worry and irritability (Rickels et al.
1982; Rosenbaum et al. 1984).
As our understanding of the phenomenology of GAD has grown, there has
been a greater emphasis on the psychic component of the disorder (DSM-5;
American Psychiatric Association 2013). Given these changes, along with the
high rates of comorbid depression in GAD and the anxiolytic activity of many of
the newer classes of antidepressants, the use of benzodiazepines as a primary
treatment for GAD is less recommended.
Azapirones
The azapirones are believed to exert their anxiolytic effect through partial
agonism of 5-HT1A receptors. Several trials have indicated that buspirone is
superior to placebo and comparable to benzodiazepines in treating GAD, with
fewer side effects and without concerns for abuse, dependence, and withdrawal
(Cohn et al. 1986; Enkelmann 1991; Petracca et al. 1990; Rickels et al. 1988b;
Strand et al. 1990), although other studies have reported conflicting results
(Fontaine et al. 1987; Olajide and Lader 1987; Ross and Matas 1987). Buspirone
appears to be more effective in treating the psychic component of anxiety
(Rickels et al. 1982), and possibly anxiety with mixed depressive symptoms
(Rickels et al. 1991), than in treating the somatic and autonomic symptoms of
anxiety (Schweizer and Rickels 1988; Sheehan et al. 1990). An adequate trial of
buspirone in GAD would be 3–4 weeks of treatment at a dosage of up to 60
mg/day, in divided doses. Treatment-limiting effects of the drug include greater
potential for side effects at higher dosages, slower onset of action, more variable
antidepressant effects, and possibly reduced effectiveness in patients with a prior
favorable response to benzodiazepines (Schweizer et al. 1986).
Tricyclic Antidepressants
In a 6-week trial comparing imipramine and alprazolam, similar improvement
was observed with both treatments by week 2; however, imipramine appeared to
be more effective in treating the psychic anxiety component, whereas alprazolam
was more effective in attenuating somatic symptoms (Hoehn-Saric et al. 1988).
In an 8-week double-blind, placebo-controlled trial of imipramine, trazodone,
and diazepam (Rickels et al. 1993), diazepam showed an early-onset effect by
week 2, primarily on somatic symptoms. Over the next 6 weeks, however,
psychic anxiety symptoms were more responsive to the antidepressants. Overall,
imipramine was more efficacious than diazepam, trazodone was comparable to
diazepam, and all treatments were superior to placebo. In a controlled trial
comparing imipramine, paroxetine, and 2′-chlordesmethyldiazepam, early onset
of action was again noted with the benzodiazepine by week 2, but overall greater
improvement was noted with the antidepressants by week 4, especially in
psychic symptoms (Rocca et al. 1997).
Hydroxyzine
Hydroxyzine blocks histamine1 (H1) and muscarinic receptors. In three
controlled trials, hydroxyzine was superior to placebo (Ferreri and Hantouche
1998; Lader and Scotto 1998; Llorca et al. 2002). Recent reports of hydroxyzine-
related ventricular arrhythmias have led to cautionary labeling in Europe in the
use of this drug and restriction of the maximum dosage to 100 mg/day
(European Medicines Agency 2015).
Anticonvulsants
The α2δ calcium channel antagonist pregabalin was superior to placebo in four
studies of GAD (Feltner et al. 2003; Pande et al. 2003; Pohl et al. 2005; Rickels
et al. 2005). Efficacy was noted early in treatment, but the ability of this drug to
successfully treat some of the comorbid disorders associated with GAD is
unknown. A recent review of six short-term double-blind, placebo-controlled
pregabalin trials in GAD showed that pregabalin treatment significantly
improved both psychic and somatic Ham-A-rated GAD symptoms, with a dose–
response effect that plateaued at 300 mg/day (Lydiard et al. 2010). Pregabalin
has shown efficacy and reasonably good tolerability in elderly patients with
GAD (Montgomery 2006). In a long-term trial in 624 GAD patients, responders
to 8 weeks of open-label pregabalin at 450 mg/day were randomly assigned to
receive pregabalin or placebo for 24 weeks (Feltner et al. 2008). Relapse rates
were significantly lower for pregabalin (42%) than for placebo (65%), although
attrition rates for pregabalin were higher (21.4% vs. 15.3%).
The GABA reuptake inhibitor tiagabine failed to separate from placebo on key
measures in three placebo-controlled multicenter trials (Pollack et al. 2008b).
Antipsychotics
Evidence for antipsychotic monotherapy in GAD is limited for some agents and
more robust for others. An open-label trial suggested benefit for ziprasidone
(Snyderman et al. 2005). Flupenthixol is approved for the treatment of
depression in some countries and was shown in one controlled study to be
superior to amitriptyline, clotiazepam, and placebo in subjects with refractory
GAD (Wurthmann et al. 1995). Sulpiride is also used in similar situations
(Bruscky et al. 1974; Chen et al. 1994).
The strongest evidence supporting atypical antipsychotic use in GAD at
present is for quetiapine XR, which was shown to be effective and superior to
placebo in a multicenter trial, and at 150 mg/day was effective for both psychic
and somatic anxiety symptoms, with improvement being noted as early as 4 days
(Bandelow et al. 2010). The active comparator in this trial, paroxetine 20
mg/day, showed a lesser effect on somatic anxiety and a higher prevalence of
sexual side effects. Remission rates were 42.6%, 38.8%, and 27.2% for
quetiapine XR, paroxetine, and placebo, respectively. A longer-term double-
blind, placebo-controlled multicenter maintenance trial with quetiapine XR at
50–300 mg/day in 432 patients found it to be effective in preventing recurrence
of anxiety symptoms (Katzman et al. 2011).
Long-term use of atypical antipsychotics carries some concerns about
tolerability and safety, especially in regard to weight gain and metabolic adverse
effects, and these concerns need to be balanced against the long-term benefits in
GAD in terms of reduction of disability and improved functionality.
Other Drugs
Riluzole, a presynaptic glutamate release inhibitor, showed promise in a small
open-label study at a daily dosage of 100 mg (Mathew et al. 2005).
Agomelatine, a serotonin 5-HT2C antagonist and melatonin1/2 receptor
agonist, is efficacious in GAD (Stein et al. 2008).
Complementary treatments have had mixed results in GAD. Homeopathy was
found to be ineffective in one trial (Bonne et al. 2003). The herbal remedy kava
did not separate from placebo in one trial (Connor and Davidson 2002), although
Sarris et al. (2009) showed some evidence supporting the benefit of a water-
soluble formulation of kava in subjects with short-term GAD-like symptoms.
Liver damage remains a potentially devastating concern, however, and even the
preferred aqueous extract cannot be regarded as entirely safe, particularly at kava
dosages above 250 mg/day (Teschke and Schulze 2010). Two small placebo-
controlled trials suggested that chamomile and Ginkgo biloba may have modest
anxiolytic effects in patients with mild to moderate GAD (Amsterdam et al.
2009; Woelk et al. 2007). Kasper et al. (2014) demonstrated that lavender oil
extract at dosages of 80 mg/day and 160 mg/day was superior to placebo and
was better tolerated than paroxetine in a four-arm trial of subjects with DSM-5
GAD. Later studies by these researchers showed that the compound reduced 5-
HT1A receptor binding in the hippocampus, anterior cingulate cortex, and
fusiform and temporal gyri.
A meta-analysis of GAD studies by Hidalgo et al. (2007) showed that the
effect sizes (in diminishing order from strongest to weakest) for each drug or
drug group versus placebo were as follows: pregabalin, 0.50; hydroxyzine, 0.45;
venlafaxine XR, 0.42; benzodiazepines, 0.38; SSRIs, 0.36; buspirone, 0.17; and
homeopathy and herbal treatment, −0.31.
Drugs that have been approved in the United States for treating GAD or
historical forerunners of the disorder include a large number of benzodiazepines,
buspirone, paroxetine IR, escitalopram, venlafaxine XR, and duloxetine.
Pregabalin is not approved in the United States but is approved for GAD in
Europe.
There is also convincing evidence in favor of efficacy for CBT in GAD, with
sustained benefit over 2 years of follow-up. These findings have been well
reviewed by Swinson et al. (2006). There are no clinically informative studies to
compare, or combine, CBT and pharmacotherapy in GAD, but on pragmatic
grounds, one may consider their combination in patients who have shown only a
partial response to a thorough course of either CBT or medication alone.
Obsessive-Compulsive Disorder
Although obsessive-compulsive disorder (OCD) has moved to a new disorder
category—Obsessive-Compulsive and Related Disorders—in DSM-5, we have
retained it in this chapter because of its similarities to anxiety disorders in
presentation and treatment approaches.
According to the National Comorbidity Survey Replication (NCS-R), the
lifetime and 12-month prevalence rates for OCD are 1.6% and 1.0%,
respectively (Kessler et al. 2005a, 2005b). OCD has been recognized as the tenth
leading cause of disability worldwide (Murray and Lopez 1996). Treatment can
be grouped broadly into psychosocial and psychopharmacological approaches,
the latter being our focus here. The chief rating scale for treatment studies of
OCD remains the Yale-Brown Obsessive Compulsive Scale (Y-BOCS; Goodman
et al. 1989), a 10-item observer-rated measure.
Monotherapy
A series of placebo-controlled studies completed in the late 1980s and the early
1990s led to the first approved treatment of OCD in the United States and other
countries (Clomipramine Collaborative Study Group 1991). Clomipramine is a
potent serotonin reuptake inhibitor (SRI) but is not selective for serotonin,
because its demethylated metabolite is a norepinephrine reuptake inhibitor
(NRI). The anti-OCD effect of clomipramine correlates with the plasma level of
the SRI parent drug, suggesting that reuptake inhibition of serotonin is the
critical factor underlying the drug’s benefit. Moreover, selective noradrenergic
reuptake inhibitors such as nortriptyline and desipramine have been shown to
lack efficacy in OCD (Leonard et al. 1988; Thorén et al. 1980).
In the Clomipramine Collaborative Study Group (1991) trial, the Y-BOCS
score was reduced by about 40% in the active-drug group compared with a
reduction of about 5% in the placebo group, consistent with findings by Huppert
et al. (2004) that OCD has a remarkably low placebo response rate.
Clomipramine and SSRIs are equivalent in the treatment of OCD (Koran et al.
1996); however, because of its side effects, clomipramine is considered a
second-line treatment.
Today, SSRIs are considered the first-line treatment for OCD, and
fluvoxamine, fluoxetine, sertraline, and paroxetine have been approved by the
FDA for that indication (Greist et al. 1995a, 1995b; Tollefson et al. 1994).
Clomipramine, fluvoxamine, fluoxetine, and sertraline are also effective and
indicated for treating OCD in children (Flament et al. 1985; Liebowitz et al.
2002; March et al. 1998; Riddle et al. 2001), although CBT and the combination
of CBT with an SSRI may be more effective (Ivarsson et al. 2015). When an
SSRI drug is to be used in the treatment of OCD, it may need to be given at
higher dosages, and it may take a longer time to work effectively (Ninan et al.
2006; Stein et al. 2007). Most clinicians believe that treatment should be long-
term to reduce the chance of relapse (Pato et al. 1990), although the dosage
might be lowered without loss of benefit (Ravizza et al. 1996).
Antidepressants
The TCAs and MAOIs were among the first pharmacological agents studied in
controlled trials of PTSD. More recently, several controlled multicenter trials
have shown efficacy for the SSRIs and SNRIs. With the documented
antidepressant and anxiolytic effects of these agents and the high rates of
comorbid depression in PTSD (Kessler et al. 1995), antidepressants would seem
a logical choice for PTSD treatment.
Anxiolytics
Benzodiazepines are often prescribed to treat acute anxiety in the aftermath of a
trauma; however, findings have been disappointing. An open-label study of
alprazolam and clonazepam in 13 outpatients with PTSD found reduced
hyperarousal symptoms but no change in intrusion or avoidance/numbing
(Gelpin et al. 1996). In a crossover design, subjects received 5 weeks of
treatment with either alprazolam or placebo followed by 5 weeks of the
alternative therapy (Braun et al. 1990). Minimal improvement was observed in
anxiety symptoms overall, with no improvement in core PTSD symptoms.
Clonazepam 2 mg was not different from placebo in controlling nightmares in a
2-week single-blind crossover study in which the test drug was added to
preexisting treatment (Cates et al. 2004). Thus, the evidence does not support the
use of benzodiazepines in the management of core PTSD symptoms, even
though they appear to be widely used for that purpose (Mellman et al. 2003).
Furthermore, a recent meta-analysis of the efficacy of benzodiazepines in the
treatment of PTSD found them to be not only ineffective but also potentially
harmful, in terms of increasing the risk of developing PTSD if prescribed after
recent trauma as well as worsening aggression, depression, and comorbid
substance use (Guina et al. 2015), Benzodiazepines should therefore be
considered relatively contraindicated for use in PTSD or after recent trauma
exposure.
Anticonvulsants
Lipper et al. (1986) proposed that the pathophysiology of PTSD may involve
sensitization and kindling processes and, to this end, that anticonvulsants might
be of therapeutic benefit. In testing this hypothesis, Lipper and colleagues found
that 7 of 10 Vietnam War veterans who received open-label carbamazepine
(600–1,000 mg/day) for 5 weeks reported improvement, particularly in intrusion
and hyperarousal symptoms. Three subsequent open-label studies, two with
sodium valproate in combat veterans (Clark et al. 1999; Fesler 1991) and one
with adjunctive topiramate in a civilian PTSD sample (Berlant and van Kammen
2002), also reported positive effects. However, two more recent double-blind,
placebo-controlled trials of divalproex monotherapy in combat veterans with
PTSD were negative (Davis et al. 2008a, n=85; Hamner et al. 2009, n=29).
Topiramate has received mixed reports in PTSD. An initial trial was negative
(Tucker et al. 2007); however, a more recent double-blind, placebo-controlled
trial in 70 civilians (men and women) showed positive effects on re-experiencing
and numbing/avoidance symptoms for topiramate at a mean dosage of 102.9
mg/day (Yeh et al. 2011). Topiramate at dosages up to 300 mg/day in a
prospective 12-week, randomized, placebo-controlled, flexible-dose trial also
decreased alcohol consumption and cravings and improved hyperarousal
symptoms in 30 veterans diagnosed with PTSD and alcohol use disorder (Batki
et al. 2014).
The largest placebo-controlled trial of an anticonvulsant to date found no
difference between tiagabine (at a dosage of up to 16 mg/day) and placebo in a
12-week multicenter trial in 232 patients (Davidson et al. 2007). In a small
placebo-controlled trial of lamotrigine (200–500 mg/day) in 15 outpatients
(Hertzberg et al. 1999), a response rate of 50% was noted with lamotrigine,
compared with a placebo response rate of 25%.
Other Treatments
Conclusion
Twenty years ago, few would have thought that one class of drugs, the SSRIs, all
of which were initially introduced for depression, would have established
primacy in most major anxiety (or anxiety-related) disorders. Their position is
based on numerous placebo-controlled trials, and they are considered first-line
drugs for treatment of these disorders, followed closely by the SNRIs. There is
evidence that these drugs also offer some protection against relapse. However,
they are not 100% successful, they carry some limiting side effects, and they
may require supplementation with, or substitution by, drugs from other
categories. We have reviewed the main clinical trials of these other drugs and
expect further progress in the pharmacotherapy of anxiety and related disorders,
with both established drugs and novel categories. Among many unexplored
areas, we need to know more about the treatment of resistant and comorbid
anxiety disorders, combined psychotherapy and pharmacotherapy interventions,
the comparative efficacy of pharmacotherapy and psychosocial treatments, and
possible early interventions that may help prevent and/or alleviate the severity
and chronicity of these conditions.
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CHAPTER 49
Treatment of Schizophrenia
Tsung-Ung W. Woo, M.D., Ph.D.
Carla M. Canuso, M.D.
Joanne D. Wojcik, Ph.D., P.M.H.C.N.S.-B.C.
Douglas Noordsy, M.D.
Mary F. Brunette, M.D.
Alan I. Green, M.D.
Negative Symptoms
Negative symptoms represent a “loss” of functions or abilities that people
without schizophrenia normally possess. They include anhedonia, affective
flattening, alogia, avolition, and asociality. Negative symptoms are somewhat
associated with intellectual and neurocognitive impairment (Dickerson et al.
1996; Harvey and Keefe 1998), and they are better predictors of long-term
functional outcome and psychosocial functioning of schizophrenia patients than
are positive symptoms (Buchanan et al. 1994; Dickerson et al. 1996; Harvey and
Keefe 1998). However, neurocognitive deficits in schizophrenia (see subsection
with that name later in this chapter) remain the strongest predictors of outcome
(Green 1996). It is important to remember that EPS produced by antipsychotic
medications can sometimes resemble negative symptoms of schizophrenia.
The concept of primary versus secondary negative symptoms may provide a
useful framework for assessing symptoms (Carpenter et al. 1988). According to
this construct, primary negative symptoms represent the core negative symptoms
reflecting the schizophrenia disease process. Secondary negative symptoms, on
the other hand, are caused by or are secondary to positive symptoms of
psychosis or the antipsychotic medications themselves. A reduction in
medication dosage may alleviate some secondary negative symptoms, but this
strategy is unlikely to have a beneficial effect on primary negative symptoms.
Diagnosis of Schizophrenia
According to DSM-5 (American Psychiatric Association 2013), to make the
diagnosis of schizophrenia, there must be evidence of continuous symptomatic
disturbance for at least 6 months accompanied by a decline from the premorbid
level of functioning. Thus, in line with the Kraepelinian concept (Kraepelin
1919/1971), DSM-5 emphasizes the longitudinal course of deterioration of the
illness. This 6-month period can include functional deterioration occurring
during the prodromal phase before the onset of overt psychosis. Within the 6-
month period, the patient must have experienced two or more of the following
symptoms for at least 1 month: delusions, hallucinations, disorganized speech,
grossly disorganized or catatonic behavior, and negative symptoms; and one of
these symptoms must be a positive symptom (delusions, hallucinations, or
disorganized speech). If the duration of psychotic symptoms is less than 1 month
because of successful treatment with antipsychotic medication, a diagnosis of
schizophrenia may still be made. In DSM-IV-TR (American Psychiatric
Association 2000), only one of the five symptoms was required if delusions were
bizarre or if Schneiderian first-rank auditory hallucinations (i.e., a voice keeping
up a running commentary on the person’s behavior or thoughts or two or more
voices conversing with each other) were present. However, because of the poor
specificity of Schneiderian symptoms and bizarre delusions, this special
designation was removed in DSM-5. Another major change in DSM-5 was the
removal of the subtypes of schizophrenia because of their limited reliability and
validity.
Course of Schizophrenia
Schizophrenia is a chronic illness, with the onset of psychotic symptoms usually
occurring around late adolescence or early adulthood (Lewis and Lieberman
2000). The age at onset is approximately 5 years later in women than in men
(Angermeyer et al. 1990; Faraone et al. 1994; Hambrecht et al. 1992; Szymanski
et al. 1995). Although there may be no clear sex differences in cross-sectional
symptomatology of the illness (Häfner et al. 1993; Szymanski et al. 1995),
women in general tend to have more favorable outcomes.
Accumulating evidence suggests that schizophrenia is a neurodevelopmental
disorder (Lewis and Levitt 2002; Murray 1994; Pilowsky et al. 1993;
Waddington 1993; Weinberger 1987, 1996). It has been postulated that
disturbances in brain development during the first and second trimesters may
contribute to the pathophysiology of the illness (Waddington 1993). Other
factors such as obstetrical complications may further alter the course of brain
development (Cannon 1997; Geddes and Lawrie 1995).
For a period of 2–5 years before the onset of the first overt psychotic episode,
up to three-quarters of the patients who eventually develop schizophrenia show a
wide spectrum of “prodromal” symptoms and reduced functioning (Docherty et
al. 1978; Freedman and Chapman 1973; Häfner et al. 1992, 1993, 1994; Huber
et al. 1980; Lieberman 2006; Simon et al. 2007; Varsamis and Adamson 1971;
Yung and McGorry 1996a, 1996b). Prodromal symptoms are usually affective or
cognitive in nature (e.g., depressed mood, social withdrawal, decreased
concentration and attention, decreased motivation, agitation, anxiety, and sleep
disturbances) and can also include attenuated positive symptoms. After the onset
of the first episode of psychosis, the course of the illness is often characterized
by a gradual deterioration, especially over the first 2–5 years (McGlashan 1998).
Some evidence suggests that functional deterioration may be accompanied by a
gradual loss of gray matter volume in the cerebral cortex (DeLisi et al. 1997;
Kasai et al. 2003a, 2003b; Salisbury et al. 2007; van Haren et al. 2008; Zipursky
et al. 1992). In fact, increasing evidence suggests that gray matter reduction may
have already begun prior to the onset of frank illness (Moorhead et al. 2013;
Pantelis et al. 2003; Takahashi et al. 2009; Witthaus et al. 2009). Although there
has been speculation that these observations of functional and structural brain
changes around the onset of psychosis may reflect a neurodegenerative process
(DeLisi 1999; DeLisi et al. 1997; Lieberman 1999), the available evidence in
support of the neurodegeneration hypothesis of schizophrenia remains weak
(Carpenter 1998; Weinberger and McClure 2002). An alternative interpretation
of these findings is that they represent the dysregulation of late developmental
processes that involve refinement of brain circuits through pruning of synaptic
connectivities (Sekar et al. 2016).
After an initial period of functional deterioration, symptoms tend to become
more or less stabilized. Positive symptoms often respond to treatment, whereas
negative symptoms are believed to be relatively treatment resistant and may tend
to become increasingly prominent during the course of the illness (Breier et al.
1991). Most studies (Ho et al. 2000; Kane et al. 2016; Marshall et al. 2005) have
suggested that early intervention during the very first episode of psychosis could
be associated with better overall prognosis; thus, a major goal in the treatment of
schizophrenia is early recognition and timely treatment of the illness.
Management of Schizophrenia
Acute Psychosis
The acute phase of schizophrenia is characterized by psychotic symptoms and
often by agitation. Affective symptoms such as depression and mania also may
be present. Patients who are unable to care for themselves or who show a risk of
harming themselves or others may require hospitalization. Acute psychosis
requires treatment with antipsychotic medication.
Management of an acutely agitated and psychotic patient may require physical
restraint and parenterally administered antipsychotic medication. Many
physicians still use a high-potency first-generation antipsychotic either alone or
in conjunction with a benzodiazepine (such as lorazepam) and/or an
anticholinergic drug (such as benztropine) for acute symptom management.
Additionally, intramuscular administration of a second-generation antipsychotic,
such as olanzapine or ziprasidone, is also increasingly common.
If the patient has a history of treatment with antipsychotic medications, the
clinician must ascertain whether the current psychosis is the result of
nonadherence to the medication regimen or a “breakthrough” episode due to loss
of therapeutic response to the medications. Noncompliance with antipsychotic
medications is common and is one of the major causes of symptom exacerbation
or full-blown relapse (Crow et al. 1986; Lieberman et al. 1993; Robinson et al.
1999). Causes of noncompliance vary, but the most common reasons are
unpleasant side effects, lack of insight into the illness, delusional interpretations
about medication, substance use, and lack of a supportive environment
(Kampman and Lehtinen 1999). With noncompliant patients, it is imperative to
focus on improving adherence by providing psychoeducation to the patient (and
family, if available), discussing with the patient the reasons for nonadherence,
and developing a plan for improved adherence (which may include daily support
and monitoring of medication dosages). Depot or long-acting injectable
medications also should be considered if noncompliance is a persistent or
recurring problem. In the case of apparent breakthrough psychosis, a change in
the patient’s medication regimen may be indicated. Other causes of exacerbation
of psychosis include comorbid substance use disorders and comorbid depression,
as well as psychosocial stressors such as difficulties with housing, employment,
benefits, insurance, disability, family, or friends. Therefore, although
medications are undoubtedly the mainstay of initial treatment of psychosis, other
interventions such as psychotherapy, group therapy, family therapy, dual-
diagnosis treatment, social skills training, and case management are important
adjuncts to pharmacological management.
First-Episode Psychosis
Emphasis on the early diagnosis and treatment of the first psychotic episode of
schizophrenia arises from evidence suggesting that longer durations of untreated
psychosis may be associated with poorer long-term outcomes (Birchwood 1992;
Cechnicki et al. 2014; Harris et al. 2005; Loebel et al. 1992; Marshall et al.
2005; Penttilä et al. 2014; Perkins et al. 2005; Wyatt 1991). Unfortunately, the
average time between onset of symptoms and initiation of treatment in the
United States is a year and a half (Addington et al. 2015). Coordinated specialty
care provided to patients and their families as early as possible in the course of
illness improves outcomes and may reduce disability (Kane et al. 2016).
Because of their more favorable neurological side-effect profiles (mainly the
reduced risks of adverse neurological events such as parkinsonism, akathisia,
and tardive dyskinesia), the second-generation antipsychotics are often used in
the initial treatment of first-episode psychosis. Because patients are likely to
require long-term treatment, clinicians often choose medications with the lowest
risk for cardiometabolic side effects (weight gain, hyperlipidemia, and glucose
intolerance), monitor all side effects regularly in accordance with published
guidelines (American Diabetes Association et al. 2004), and adjust medication
types and dosages on the basis of efficacy and tolerability. In general, a
conservative titration schedule is appropriate for first-episode patients, in part to
minimize side effects but also to take into account that these patients may require
only low dosages for the control and remission of symptoms (Remington et al.
1998; Robinson et al. 1999; Schooler et al. 2005; Wyatt 1995).
After remission of an initial episode of psychosis, discontinuation of
medication, even if done very gradually, is controversial and often not attempted.
Any such decision should be made in light of studies showing that the relapse
rate is very high after medication discontinuation in first-episode schizophrenia
(Crow et al. 1986; Johnson 1985; Kane et al. 1982; Robinson et al. 1999). Gitlin
et al. (2001), using a low threshold to define recurrence of symptoms, reported
that the relapse rate in the first year after medication discontinuation was 78%,
and this rate had increased to 98% by the end of the second year.
Choice of Antipsychotics
Since the early 1990s, second-generation antipsychotics have been used widely.
The National Institute of Mental Health (NIMH) sponsored the Clinical
Antipsychotic Trials of Intervention Effectiveness (CATIE) study (Lieberman et
al. 2005), which was designed to compare the effectiveness of four second-
generation antipsychotics (olanzapine, quetiapine, risperidone, ziprasidone) and
a representative first-generation antipsychotic (perphenazine) in “real-world”
schizophrenia patients. The primary outcome measure was treatment
discontinuation. Of the 1,432 subjects who received at least one dose of
medication, 74% discontinued the study medication before 18 months: 64% of
the subjects taking olanzapine discontinued, compared with 74%–82% of those
taking perphenazine, quetiapine, risperidone, or ziprasidone. More subjects
receiving olanzapine discontinued because of weight gain and metabolic effects,
whereas more subjects assigned to perphenazine discontinued because of EPS
(Lieberman et al. 2005). Of interest, individuals assigned to olanzapine or
risperidone who were continuing with their baseline medication had significantly
longer times until discontinuation than did those assigned to switch
antipsychotics (Essock et al. 2006).
Phase II of the CATIE study involved two treatment pathways—efficacy and
tolerability—with randomized follow-up medication based on the reason for
discontinuation of the previous antipsychotic drug (McEvoy et al. 2006; Stroup
et al. 2006). For patients who failed to improve with an atypical antipsychotic,
clozapine was more effective than switching to another atypical antipsychotic
(McEvoy et al. 2006), and in patients who failed to respond to perphenazine,
olanzapine or quetiapine was more effective than risperidone (Stroup et al.
2006). Moreover, in subjects who discontinued a second-generation agent for
tolerability or efficacy reasons but who were unwilling to be randomly assigned
to clozapine, risperidone or olanzapine was more effective than quetiapine or
ziprasidone (Stroup et al. 2006). (Note: Since the CATIE study was published,
several new antipsychotics—asenapine, brexpiprazole, cariprazine, iloperidone,
lurasidone, and paliperidone—have been approved by the U.S. Food and Drug
Administration [FDA]. A very limited number of direct comparison studies
appear to suggest that these new antipsychotics are neither more nor less
efficacious compared with older second-generation antipsychotics (Fu et al.
2014a, 2014b), but little is known about the effectiveness of these newer agents
relative to the older agents.) Finally, although the CATIE cost-effectiveness
analysis found perphenazine to be less costly than—and similar in effectiveness
(based on quality-adjusted life-years) to—each of the atypical antipsychotics
tested, the investigators noted that their results could not be generalized to all
patient populations; they therefore concluded that the study findings did not
warrant policies that would unconditionally restrict access to a particular
medication (Rosenheck et al. 2006).
Similar to the NIMH-sponsored CATIE study, the United Kingdom’s National
Health Service funded the Cost Utility of the Latest Antipsychotic Drugs in
Schizophrenia Study (CUtLASS). This study of 227 schizophrenia-spectrum
patients randomly assigned to first- and second-generation antipsychotics (other
than clozapine) found no difference between the groups in quality of life,
symptoms, or health care costs at 1 year (Jones et al. 2006).
Neither the CATIE nor the CUtLASS study addressed the comparative effects
of oral versus long-acting injectable antipsychotics. Mirror-image studies in
which patients served as their own control subjects provide evidence of
substantial benefit for first-generation long-acting injectable antipsychotics over
oral antipsychotic medications (Kane et al. 2013; Kishimoto et al. 2014;
Schooler 2003), although this putative superiority is in general not supported by
findings from randomized controlled trials (Kishimoto et al. 2014; Rosenheck et
al. 2011). At present, risperidone, paliperidone, olanzapine, and aripiprazole are
the only second-generation antipsychotics available in long-acting injectable
formulations.
Taken together, the CATIE and the CUtLASS studies indicate that
antipsychotic medications are generally effective but have a variety of
shortcomings. Physicians need to be well informed about the differential
tolerability profiles among the antipsychotics. Several of the first-generation
agents clearly have a high risk of EPS and tardive dyskinesia (Glazer 2000b;
Jeste et al. 1998; Tollefson et al. 1997). Risperidone and paliperidone tend to
elevate serum prolactin levels and may cause EPS at higher dosages. Iloperidone
may elevate serum prolactin to a lesser degree. Akathisia and other EPS also
may be common with aripiprazole, brexpiprazole, cariprazine, and lurasidone.
Although weight gain and metabolic disturbances are associated with most of the
second-generation agents, olanzapine and clozapine appear to have the highest
likelihood of causing these side effects (Allison et al. 1999; American Diabetes
Association et al. 2004). Sedation is most commonly observed in patients
receiving asenapine, quetiapine, olanzapine, ziprasidone, or clozapine.
Ziprasidone, paliperidone, and iloperidone carry product labeling for QTc
prolongation and should be used with caution in patients at risk for QTc
prolongation. Finally, clozapine, because of its side effects of agranulocytosis,
seizures, and myocarditis, is generally reserved for patients with treatment-
resistant illness or suicidality. Table 49–1 lists the available formulations for the
most commonly used first-generation antipsychotic medications and all of the
second-generation agents.
Olanzapine X X X X
Paliperidone X X
Risperidone X X X X
Ziprasidone X X
Maintenance Treatment
The major goals of maintenance treatment are prevention of relapse and
improvement in psychosocial and vocational functioning. The primary methods
used to achieve these goals consist of an integration of optimal
psychopharmacological and psychosocial treatments. Treatment and prevention
of other psychiatric comorbidities, such as substance use disorders, are important
aspects of maintenance treatment. Also, prevention and treatment of medical
comorbidities that may be associated with second-generation antipsychotics, as
well as those that may result from the lifestyles of some patients with
schizophrenia who are given these drugs, have become a very important part of
long-term management.
Prevention of relapse improves long-term clinical outcomes (Wyatt et al.
1998) and reduces the associated economic burden of the illness (Bernardo et al.
2006). With each relapse, the time required to regain clinical stability lengthens,
with the possible consequence of ultimate unresponsiveness to treatment
(Lieberman et al. 1993; Wyatt et al. 1998). Nonadherence to medication is a
significant predictor of relapse (Schooler 2006); long-acting injectable
antipsychotics may have the potential to improve medication adherence and thus
improve long-term outcomes.
Treatment-Resistant Schizophrenia
At least 30% of patients with schizophrenia have an incomplete to poor response
to antipsychotics, with persistent psychotic symptoms (Kane et al. 1988, 2007;
Tamminga 1999). For research purposes, Kane et al. (1988) operationally
defined treatment resistance as 1) lack of significant response to at least three
adequate trials of antipsychotics from at least two different chemical classes in
the past 5 years and 2) persistently poor social and occupational functioning.
Most of the available data suggest that clozapine is the most effective drug for
treatment-resistant schizophrenia (Kane et al. 2001; Lewis et al. 2006; McEvoy
et al. 2006). However, because of the serious side effects that may be associated
with clozapine and the requirement for frequent white blood cell count
monitoring, some patients and some psychiatrists are reluctant to use it, and
some patients are unable to tolerate it. Whether the other second-generation
agents even approach the effectiveness of clozapine for the treatment of these
chronically ill patients is also unclear. Evidence regarding whether either
risperidone (Bondolfi et al. 1998; Breier et al. 1999; Volavka et al. 2002) or
olanzapine (Buchanan et al. 2005; Tollefson et al. 2001; Volavka et al. 2002) is
as effective as clozapine is mixed. Other preliminary data also suggest the
possible utility of quetiapine, aripiprazole, and ziprasidone in treatment-resistant
illness (Emsley et al. 2000; Kane et al. 2006, 2007).
Multiple controlled trials have assessed whether combining two antipsychotics
is more effective than antipsychotic monotherapy. Thus far, the evidence is
mixed and inconclusive (Barbui 2008; Correll et al. 2009; Evins et al. 2005), and
many patients taking two antipsychotics are able to switch back to a single agent
without destabilization (Essock et al. 2011). In summary, clozapine remains the
primary medication for treatment-resistant schizophrenia, although some studies
suggest that other second-generation agents also may have a role in the
management of this disorder. Clinically, judicious addition of adjunctive agents,
such as mood stabilizers, may be beneficial. Clearly, more research is needed to
guide treatment in patients with severe and resistant symptoms.
Neurocognitive Deficits
Neurocognitive deficits, especially disturbances in executive functioning,
memory, and attention (Green 1996; Green et al. 2000), are closely associated
with the long-term functional outcome of patients with schizophrenia. It appears
that second-generation antipsychotics may improve some aspects of cognition in
schizophrenia, as found in meta-analysis reports (Bilder et al. 2002; Désaméricq
et al. 2014; Woodward et al. 2005). The therapeutic effects of the newer
antipsychotics are most notable in measures of verbal fluency and executive
functioning, whereas improvement in memory may be more limited. However,
data obtained from the CATIE trial showed that at 18 months of treatment,
perphenazine was actually more effective than any of the second-generation
drugs in improving all domains of neurocognitive deficits (Keefe et al. 2007).
The investigators postulated that several factors might potentially explain this
unexpected finding, such as sample size, differences between midpotency drugs
such as perphenazine and high-potency drugs (e.g., haloperidol) that were
commonly used in prior studies, the real-world features of the CATIE sample,
and prior drug trials before entering the study (Keefe et al. 2007). Interestingly, a
meta-analysis of 34 studies found that first-generation antipsychotics do appear
to have some cognition-enhancing properties, although effect sizes tend to be
quite small (Mishara and Goldberg 2004). Finally, it is not clear whether any of
the apparent statistically significant improvements in neurocognitive deficits
measured in the laboratory can actually be translated into improved functional
outcomes, for example, in terms of employment, school performance, or social
role (see Green 2002).
Psychosocial Treatment of
Schizophrenia
Despite the proven efficacy of antipsychotics in the treatment of schizophrenia,
most patients continue to have some degree of residual positive symptoms,
negative symptoms, and cognitive deficits, and many have difficulty attaining or
regaining their desired level of social and occupational functioning. To address
functional goals, treatment is ideally offered by a multidisciplinary team that
includes, at a minimum, a medication prescriber and a clinician skilled in
psychosocial rehabilitation but also may include employment and housing
specialists. Programs that use clinical case managers to directly assist patients in
accessing services and to provide the psychosocial interventions are ideal (Rapp
and Goscha 2004). In the first episode of psychosis, specialized programs are
tailored for young people and their families to maximize engagement, rapid
stabilization, and return to psychosocial functioning (Mueser et al. 2015). To
date, several different types of psychosocial interventions have been empirically
shown to reduce rates of relapse and rehospitalization, and a variety of
treatments may assist patients in acquiring social and vocational skills and
possibly in managing residual psychotic symptoms (Bustillo et al. 2001;
Lauriello et al. 1999; Penn and Mueser 1996). Initial studies have shown that
psychosocial treatments can be effective when delivered via technology (Ben-
Zeev et al. 2014; Brunette et al. 2011b; Gottlieb et al. 2013; Rotondi et al. 2010),
potentially increasing their reach while maintaining quality and lowering the cost
of psychosocial treatment. Importantly, the interaction between pharmacological
and psychosocial treatments appears to be more than additive, because each can
enhance the effects of the other and affect different domains of outcome (Marder
2000).
Relapse Prevention
It has long been noted that patients with highly critical or overinvolved family
members (so-called high-expressed-emotion [EE] families) have a higher risk of
relapse (Brown and Rutter 1966). In a classic study, Goldstein et al. (1978)
reported that a 6-week therapy focusing on teaching families more effective
communication and dispute-resolution skills reduced relapse rates for up to 6
months. Many other studies have since confirmed the efficacy of family
psychoeducational interventions (involving education and training in problem-
solving techniques and/or cognitive and behavioral management strategies) to
prevent relapse and to improve other outcomes (Falloon et al. 1982; Pilling et al.
2002; Pitschel-Walz et al. 2001; Tarrier et al. 1988). In addition, the positive
effect of family interventions seems to persist beyond the time of intervention
(Sellwood et al. 2001) and is independent of either the specific form or the
intensity of the intervention (Bustillo et al. 2001).
Another psychosocial intervention that has been shown to be effective in
preventing relapse or rehospitalization in schizophrenia is assertive community
treatment (ACT). This intervention, which involves intensive multidisciplinary
team management and service delivery in both community and inpatient settings,
is designed for individuals who experience intractable symptoms and high levels
of functional impairment. At least 30 studies of ACT have shown advantages
over standard community treatment in reducing symptoms, family burden, and
hospitalization and in improving independent living, housing stability, and
quality of life (McFarlane et al. 2015; Mueser et al. 1998; Phillips et al. 2001;
Stein and Test 1980). However, it appears that the advantages of ACT do not
persist after discontinuation of the program, even after prolonged delivery of
services.
Hyperprolactinemia
Antipsychotic medications—particularly some of the typical agents, as well as
risperidone, paliperidone, and lurasidone—can produce an increase in serum
prolactin levels (Dickson and Glazer 1999; Marder et al. 2004). It is well known
that hyperprolactinemia secondary to medical disorders (e.g., pituitary tumor)
can produce galactorrhea, hypogonadism, and osteoporosis, all of which have
also been reported in patients with schizophrenia (Abraham et al. 1996;
Ghadirian et al. 1982; Riecher-Rössler et al. 1994; Windgassen et al. 1996;
Yazigi et al. 1997). Yet the relations between antipsychotic-induced
hyperprolactinemia and these conditions, perhaps with the exception of
galactorrhea (Windgassen et al. 1996), remain unclear, with conflicting reports in
the literature (Canuso et al. 2002; Costa et al. 2007; Hummer et al. 2005; Kinon
et al. 2006; Kleinberg et al. 1999; O’Keane and Meaney 2005).
Clinicians should ask patients about possible symptoms of
hyperprolactinemia. If a patient is symptomatic, prolactin levels should be
obtained and medical causes of hyperprolactinemia ruled out. Prolactin
elevation–associated symptoms of galactorrhea or of sexual or menstrual
dysfunction may be minimized through a dosage reduction or through a
medication change to an atypical antipsychotic with less prolactin-elevating
potential (Canuso et al. 1998; Dickson and Glazer 1999).
Substance-Related Disorders
Nearly one-half of the patients with schizophrenia are reported to have a lifetime
history of an alcohol or a substance use disorder, compared with 16% of the
general population (Regier et al. 1990). Alcohol is the most commonly abused
substance in chronically ill patients, followed by cannabis and cocaine (Selzer
and Lieberman 1993; Sevy et al. 1990). As in the general population, men with
schizophrenia are more likely to abuse substances than are women (Mueser et al.
1995).
Comorbid substance use has a deleterious effect on the course of
schizophrenia (Grech et al. 1999); use of even small amounts can produce
negative effects (Drake et al. 2001; D’Souza et al. 2005). Patients with
schizophrenia and substance use disorders are at increased risk for infectious
diseases such as HIV, hepatitis B, and hepatitis C (Rosenberg et al. 2001); in
addition, alcohol and substance use are associated with clinical worsening, poor
functioning, and increased rates of hospitalizations and homelessness (Dixon et
al. 1990; Drake and Mueser 1996; Hurlburt et al. 1996a; Negrete et al. 1986;
Soni and Brownlee 1991). In some studies, more than 50% of the first-episode
patients were reported to have cannabis use disorder (Rolfe et al. 1999), which
often complicates the diagnosis of a psychotic disorder (Addington 1999).
Although obtaining information from patients about their use of substances of
abuse should be a standard part of a medical history, problematic alcohol or
substance use is often underrecognized and undertreated in mental health
settings (Ananth et al. 1989). Because patients often deny use of alcohol and
drugs, clinicians also should pursue collateral reports from family members, case
managers, and others involved in the delivery of services to patients. Patients
with schizophrenia and a comorbid alcohol or substance use disorder require
treatment for both disorders (Bellack and DiClemente 1999), optimally in
programs that provide long-term comprehensive services along with integrated
mental health and substance abuse treatment, including medication management
(Drake and Mueser 2001; Minkoff 1989; Osher and Kofoed 1989).
Although there is no agreed-on pharmacological treatment approach for
patients with schizophrenia and comorbid alcohol or substance use disorders
(Green et al. 2007, 2008; Wilkins 1997), some investigators have been interested
in the potential role of atypical antipsychotics in reducing substance use in these
patients. The atypical antipsychotic that has been studied most in this population
is clozapine. Preliminary studies of clozapine have reported promising results for
reducing alcohol and drug use (Brunette et al. 2006; Buckley et al. 1999; Drake
et al. 2000; Green et al. 2003; Lee et al. 1998; Zimmet et al. 2000). A small
randomized trial provided some confirmation of these preliminary studies
(Brunette et al. 2011a).
Data concerning the potential effects of other atypical antipsychotics on
substance use reduction and relapse prevention are even more preliminary.
Findings have been mixed for risperidone (Albanese 2000; Green et al. 2003;
Petrakis et al. 2006; Rubio et al. 2006; Smelson et al. 2000), olanzapine (Littrell
et al. 2001; Noordsy et al. 2001; Sayers et al. 2005; Smelson et al. 2006),
quetiapine (Brown et al. 2003; Potvin et al. 2006), and aripiprazole (Beresford et
al. 2005; Brown et al. 2005). No research has assessed the effects of
brexpiprazole, cariprazine, ziprasidone, asenapine, iloperidone, or lurasidone on
substance craving or use.
Other possible pharmacological options with evidence for efficacy in the
treatment of substance use disorders in schizophrenia include the following: 1)
disulfiram for co-occurring alcohol use disorder (note that use requires
monitoring in patients with schizophrenia) (Kofoed et al. 1986; Mueser et al.
2003; Petrakis et al. 2005); 2) naltrexone for co-occurring alcohol use disorder
(Petrakis et al. 2004, 2005); 3) the tricyclic antidepressants desipramine and
imipramine for comorbid cocaine use disorder (Siris et al. 1993; Ziedonis et al.
1992); and 4) bupropion, nicotine replacement therapy, and varenicline for
tobacco use disorder (Evins et al. 2005; George et al. 2002; Nino-Gomez et al.
2010). Acamprosate, although shown to be effective for alcohol use disorder in
placebo-controlled trials, has yet to be studied in patients with schizophrenia.
Depression
Schizophrenia is often associated with depressive states ranging from dysphoria
to major depressive disorder (Blum et al. 2015). The Epidemiologic Catchment
Area study suggested that individuals with schizophrenia have a 14-fold greater
risk of depression compared with the general population (Fenton 2001). At
various times, depression has been viewed as an aspect of schizophrenia
(McGlashan and Carpenter 1976; Sax et al. 1996), as a response to psychosis
(McGlashan and Carpenter 1976; Sax et al. 1996), or as a state occurring after
the cessation of frank psychotic symptoms (Birchwood et al. 2000). The DSM-5
Psychotic Disorders Work Group recommended that depressive symptoms that
do not meet full criteria for an episode of major depressive disorder be
considered a component of schizophrenia, and in accordance with this view,
depression was included as one of eight Clinician-Rated Dimensions of
Psychosis Symptom Severity (American Psychiatric Association 2013;
Malaspina et al. 2013).
Depression in patients with schizophrenia must be differentiated from
negative symptoms and EPS; the presence of a core depressed mood and related
neurovegetative symptoms should be distinguished from flatness of affect,
parkinsonism, and anhedonia (McGlashan and Carpenter 1976). Depression
occurring during an exacerbation of psychosis may remit with treatment of the
psychosis (Birchwood et al. 2000; Koreen et al. 1993; Tollefson et al. 1999).
However, postpsychotic depression classically develops after the resolution or
improvement of psychotic symptoms (see Birchwood et al. 2000; Koreen et al.
1993). Dysphoria and demoralization (Iqbal et al. 2000; Siris 2000a) may occur
as patients struggle with illness-related disability (Bartels and Drake 1988).
Treatment of depression in patients with schizophrenia may include both
psychopharmacological and psychosocial components (A. Hasan et al. 2015;
Siris 2000b). Because depression may presage an increase in psychosis, the
pharmacological treatment of psychotic symptoms should be optimized.
Treatment of depression in acute psychosis may be accomplished through the
use of antipsychotic medication alone, especially second-generation
antipsychotics (Banov et al. 1994; Levinson et al. 1999; Marder et al. 1997;
Tollefson et al. 1998). However, an episode of major depressive disorder that
develops after the remission of psychosis often requires the addition of
antidepressants to the medication regimen (Hogarty et al. 1995; Kirli and
Caliskan 1998; Levinson et al. 1999; Siris et al. 1987). Psychosocial
interventions can help with demoralization and dysphoria (Siris 2000b). Severe
depression also may be treated with electroconvulsive therapy (ECT; Pompili et
al. 2013).
Suicide
Suicide is one of the leading causes of premature death in patients with
schizophrenia, who have a 10% lifetime risk of suicide. Nearly 50% of the
patients with schizophrenia attempt suicide during their lifetime (Black et al.
1985; Tsuang et al. 1999). Risk factors include depression and the diagnosis of
schizoaffective disorder (Harkavy-Friedman et al. 2004; Radomsky et al. 1999),
social isolation (Drake et al. 1986; Goldstein et al. 2006; Potkin et al. 2003), and
feelings of hopelessness and disappointment over failure to meet high self-
expectations (Kim et al. 2003; Westermeyer et al. 1991). Patients with a higher
level of insight and awareness of their illness may be at increased risk (Amador
et al. 1996; Bourgeois et al. 2004; Crumlish et al. 2005), as may patients with a
low level of functioning (Kaplan and Harrow 1996).
A history of suicide attempts is one of the strongest predictors of suicide in
patients with schizophrenia (Potkin et al. 2003; Rossau and Mortensen 1997;
Roy 1982). A meta-analysis of 29 case–control and cohort studies indicated that
suicide risk factors included previous depressive disorders, substance use
disorders, agitation or motor restlessness, fear of mental disintegration, poor
adherence to treatment, and recent loss (Hawton et al. 2005).
An increased risk of suicide is present in the early phase of the illness (Drake
et al. 1985; Kuo et al. 2005; Nordentoft et al. 2015). Suicide risk peaks
immediately after admission and shortly after discharge (Qin and Nordentoft
2005; Rossau and Mortensen 1997). Patients in an active phase of the illness
(Heilä et al. 1997) or with positive symptoms (Kelly et al. 2004) may be at
particular risk, especially if they have prominent symptoms of suspiciousness
and delusions (Fenton et al. 1997).
The treating clinician should regularly evaluate the patient’s condition, assess
for suicide risk factors, and aim to enhance protective factors such as social
support and positive coping skills (Montross et al. 2005). Patients who present
with suicidal thoughts or behavior require close follow-up and intensive outreach
(Drake et al. 1986; Harkavy-Friedman and Nelson 1997). Improved ward safety,
effective substance use disorder therapy, treatment of mood symptoms, and
ensured medication adherence are all measures that may help prevent suicide
(Hawton et al. 2005; Hunt et al. 2006).
Psychopharmacological treatment plays a crucial role in the prevention of
suicide. In one study, more than half of the patients who committed suicide
either were noncompliant with their medication regimens or had been prescribed
inadequate dosages of antipsychotics, and 23% were estimated to be
nonresponsive to their medication (Heilä et al. 1999). Moreover, a landmark
study of nearly 1,000 patients with schizophrenia and schizoaffective disorder
who were at risk for suicide (but who were not necessarily classically treatment
resistant) indicated that treatment with clozapine was more likely to decrease
suicidality than was treatment with olanzapine (Meltzer et al. 2003). ECT also
may be helpful for suicidal symptoms among people with schizophrenia
(Pompili et al. 2013).
Obsessive-Compulsive Symptoms
Obsessive-compulsive symptoms are seen in 9%–30% of patients with
schizophrenia (Berman et al. 1995a; Byerly et al. 2005; Cassano et al. 1998;
Ongür and Goff 2005). Although obsessive-compulsive symptoms may be
difficult to distinguish from delusions (Eisen et al. 1997), they are important to
identify because they may indicate a poor prognosis yet may be responsive to
specialized treatment regimens (Byerly et al. 2005; Fenton and McGlashan
1986; Hwang et al. 2000; Ongür and Goff 2005). The obsessive-compulsive
symptoms in schizophrenia are similar to those in obsessive-compulsive disorder
(Tibbo et al. 2000), although the symptoms may not be ego-dystonic in patients
with schizophrenia.
Treatment of obsessive-compulsive schizophrenia may require the addition of
a serotonergic antidepressant to the antipsychotic regimen (Berman et al. 1995b;
Chang and Berman 1999; Poyurovsky et al. 2000). However, prescribers should
be mindful of the risk of drug interactions, because the combined use of
serotonin reuptake inhibitors with some antipsychotics, particularly clozapine,
may lead to excessive antipsychotic serum levels. CBT also may be useful for
managing obsessive-compulsive symptoms (Hagen et al. 2014).
Future Directions
Despite advances in understanding of the neurobiology of schizophrenia, and a
variety of novel-mechanism agents currently being evaluated in clinical trials, it
remains the case that all approved antipsychotic medications primarily modulate
the dopamine system. Although postsynapatic dopamine D2 antagonists and
partial D2 agonists have proven antipsychotic efficacy, these agents are mostly
prescribed in oral formulations. Because inconsistent patient adherence can limit
the utility of these agents in clinical practice, several longer-acting injectable
formulations of existing dopaminergic agents have been developed. These agents
traditionally have been dosed every 2–4 weeks, but a 3-month formulation of
paliperidone was recently approved, and a 6-week formulation of aripiprazole is
available. In earlier stages of drug development are several novel and established
dopamine-modulating agents with combined pharmacological activity at other
important neurotransmitter receptors, including serotonin, glutamate, σ2, and the
μ opioid receptor. Such agents may confer some efficacy or safety benefit over
existing medications.
Although dopaminergic drugs will continue to play a major role in treatment
of the positive symptoms of schizophrenia, more effective treatments are needed
against the functionally disabling negative and neurocognitive symptoms of the
illness. Recent drug development efforts, particularly for negative symptoms,
have targeted the glutamatergic system. Although promising Phase II findings
were reported for a metabotropic glutamate 2/3 receptor agonist (Patil et al.
2007) and a glycine transport reuptake inhibitor (Umbricht et al. 2014), later-
phase programs yielded disappointing results (Downing et al. 2014; Kinon et al.
2011; Roche 2014). Several α7-nicotinic receptor agonists also have been studied
in the treatment of cognitive impairment in schizophrenia. Other novel-
mechanism agents that are either under investigation or of theoretical interest for
the treatment of cognitive impairment in schizophrenia include α2 γ-
aminobutyric acid type A (GABAA) receptor agonists (Lewis and Gonzalez-
Burgos 2006), muscarinic agonists (Shekhar et al. 2008), serotonin 5-HT6 (Roth
et al. 2004) and 5-HT7 (Horiguchi et al. 2011; Horisawa et al. 2011; Nikiforuk et
al. 2013) receptor antagonists, and phosphodiesterase 10A inhibitors (Kehler and
Nielsen 2011).
In addition to recent pharmacological advances in the treatment of
schizophrenia, emerging evidence suggests that novel psychosocial approaches,
including computerized cognitive remediation, may be of benefit in treating
cognitive impairment in schizophrenia (Fisher et al. 2009; Lindenmayer et al.
2008, 2013). Moreover, the use of pro-cognitive medications along with
software targeted to engage specific neuronal circuits could facilitate use-
dependent plasticity. Such combined therapies, along with social and vocational
skills training, could lead to better outcomes in the functioning and quality of life
for people with schizophrenia.
The future is also likely to see further progress in the development of
treatments for prodromal schizophrenia, with the goal of improving symptoms
and delaying or preventing conversion to the full expression of the illness.
Interestingly, the risk–benefit ratio of antipsychotic therapy does not appear to be
particularly favorable in this population, with studies showing inconsistent
benefit in preventing conversion to psychosis and high side-effect burden
(McGlashan et al. 2006; McGorry et al. 2002; Yung et al. 2011). Alternatively,
promising data from studies of long-chain omega-3 fatty acids (Amminger et al.
2010) and CBT (Morrison et al. 2004) have been reported. Taken together, these
results suggest that the therapeutic targets for preventing the progression to
schizophrenia differ from the target for treating psychosis. It is hoped that as new
treatments for the negative and cognitive systems of schizophrenia emerge, these
therapeutics will also be found to have a role in the treatment of prodromal
symptoms and the prevention of schizophrenia.
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The authors would like to acknowledge the contribution of Holly L.L. Pierce in
the preparation of this chapter.
CHAPTER 50
Treatment of Substance-Related
Disorders
Brian J. Sherman, Ph.D.
Karen J. Hartwell, M.D.
Aimee L. McRae-Clark, Pharm.D.
Kathleen T. Brady, M.D., Ph.D.
Alcohol-Related Disorders
In the United States in 2014, approximately 139.7 million people ages 12 years
and older reported past-month alcohol use, and 17.0 million people met criteria
for alcohol use disorder (Center for Behavioral Health Statistics and Quality
2015). From 2006 to 2010, excessive alcohol consumption was responsible for 1
in 10 deaths annually among working-age adults (Stahre et al. 2014), yet only a
fraction (1.4 million in 2013) received any formal treatment (Substance Abuse
and Mental Health Services Administration 2014).
Pharmacotherapy for alcohol use disorder involves a two-stage approach.
Detoxification from alcohol is the first step and can be inpatient or outpatient,
depending on the severity of dependence and other risk factors such as chronic
medical conditions. Following detoxification, pharmacotherapeutic agents may
be used to prevent relapse or reduce alcohol intake by targeting different
neurotransmitter systems associated with alcohol dependence. The FDA has
approved disulfiram, naltrexone, and acamprosate for the treatment of alcohol
use disorder.
Relapse Prevention
Alcohol-Sensitizing Agents
Opioid Antagonists
Naltrexone. The opioid antagonist naltrexone was approved in 1994 for the
treatment of alcohol use disorder. Although naltrexone’s exact mechanism of
action in reducing alcohol use is unknown, preclinical trials suggest that it
reduces craving by modulating dopamine activity in the nucleus accumbens and
ventral tegmental area and by blocking the effects of endogenous opioids
following consumption of alcohol (for a review, see Johnson 2008).
Anticraving Agents
Anticonvulsants
Serotonergic Agents
Opioid-Related Disorders
Opioid use disorder is a serious and increasing public health concern. In the
United States in 2014, approximately 2.5 million people ages 12 years and older
had an opioid use disorder in the past year (Center for Behavioral Health
Statistics and Quality 2015). Opioids (primarily prescription pain relievers and
heroin) were involved in 28,647 deaths in 2014, and the rate of opioid overdose
has tripled since 2000 (Rudd et al. 2016). Opioid use has been associated with
mortality, criminality, violence, HIV, hepatitis C, and poor quality of life (Hulse
et al. 1999)
The FDA has approved three medications for the treatment of opioid use
disorder: methadone, buprenorphine, and naltrexone. All three agents bind to μ
opioid receptors, but they differ in their pharmacokinetic and pharmacodynamic
properties, intrinsic activity at the receptor, and mechanism of relapse
prevention. Of importance, most studies have been conducted in individuals who
are primarily intravenous heroin users rather than individuals who use
prescription opioids. There may be important differences between these two
groups, and more systematic treatment studies of individuals with prescription
opioid use disorders are needed.
FDA-Approved Medications
Methadone
Methadone is a full opioid agonist with high affinity for the μ opioid receptor, a
long terminal half-life, and delayed steady-state efficacy, which contributes to its
risk of fatal overdose during induction. Initial dosing should begin with 10–20
mg. If withdrawal symptoms are not adequately suppressed within 1 hour,
additional medication may be required but should not exceed 30 mg in the first
day and 40 mg in the first 3 days. Once withdrawal symptoms are stabilized,
dosing can be increased to 100 mg or higher for tolerant individuals.
With appropriate administration and adherence, methadone is generally safe.
However, methadone-associated risks of respiratory depression, QTc interval
prolongation, and sudden death require acute monitoring and led to a 2006
physician safety alert from the FDA. Methadone may be used for detoxification
or maintenance therapy.
Buprenorphine
Buprenorphine is a partial opioid agonist with high affinity for the μ opioid
receptor and slow dissociation, enabling protection for more than 24 hours in
many cases. Given its high affinity and slow dissociation, buprenorphine may
induce acute withdrawal if receptors are bound by a full agonist at the time of
administration. To avoid precipitating withdrawal, physicians should wait until
the patient is experiencing withdrawal symptoms to begin induction. Initial
dosing usually begins with 2–4 mg, which, if well tolerated, can be followed by
an additional 2–4 mg approximately 8 hours later. Some patients will require a
24- to 32-mg maintenance dose, but most patients can be adequately maintained
with 16 mg or less once stabilized.
As a partial opioid receptor agonist, buprenorphine confers a ceiling effect,
thus reducing overdose potential and euphoria from illicit opioid use. The safety
profile of buprenorphine is therefore more favorable than that of full agonists,
and it is not associated with QTc interval prolongation, respiratory depression, or
other drug interactions. Buprenorphine may be used for detoxification or in
combination with naloxone (discussed further in the “Buprenorphine–Naloxone”
subsection later in this chapter) for maintenance therapy.
Naltrexone
Naltrexone is an opioid receptor antagonist with high affinity for the μ opioid
receptor. Through competitive antagonism at the μ opioid receptor, naltrexone
blocks the euphoric effects of opioids and reduces overdose risk. Naltrexone is
long acting and may be given every 2–3 days; however, daily administration is
recommended. Naltrexone is most effective in highly motivated individuals,
because noncompliance is common, and relapse to previous levels of opioid use
is potentially fatal for individuals who have lost opioid tolerance while taking
naltrexone.
Naltrexone may be used for relapse prevention once abstinence is achieved.
Extended-release depot and implant formulations have been developed to
improve adherence; these formulations are discussed in the “Extended-Release
Injectable Naltrexone” subsection under “Relapse Prevention” later in this
chapter.
Buprenorphine
Buprenorphine was approved by the FDA for the office-based treatment of
opioid use disorder in 2002. In order to prescribe buprenorphine, physicians
must undergo an 8-hour training and be granted approval from the U.S.
Department of Health and Human Services, after which they may see 30 patients
in the first year and 100 per year thereafter.
Early trials of buprenorphine established its efficacy in treating opioid use
disorders. A 25-week RCT compared buprenorphine with methadone and found
the two medications to be equally effective in reducing opioid use and
maintaining participants in treatment (R.E. Johnson et al. 1992). A systematic
Cochrane review evaluated evidence comparing buprenorphine maintenance
with placebo and methadone maintenance (Mattick et al. 2014). Fixed-dose
results suggested that compared with placebo, buprenorphine improved
treatment retention at any dose but suppressed illicit opioid use only at doses of
16 mg or higher. Compared with methadone, buprenorphine did not differ in
treatment retention or suppression of opiate use at medium or high doses
(methadone: medium = 40–85 mg, high ≥ 85 mg; buprenorphine: medium=7–15
mg, high≥16 mg), although low-dose methadone (≤40 mg) was associated with
better retention than low-dose buprenorphine (2–6 mg). Studies that used
flexible dosing found that compared with methadone maintenance,
buprenorphine retained fewer participants, but among those retained in
treatment, no difference was seen in suppression of opioid use. In summary,
whereas methadone at low or flexible doses appears to be more effective than
buprenorphine in retaining patients in treatment, methadone at medium to high
fixed doses is no different from buprenorphine in treatment retention or opioid
use suppression.
Buprenorphine–Naloxone
Buprenorphine–naloxone was introduced to address the risks of diversion and
injection overdose associated with buprenorphine alone. Naloxone is a high-
affinity μ opioid receptor antagonist. It has high bioavailability when injected
and therefore prevents abuse and overdose by immediately counteracting the
agonist properties of buprenorphine, resulting in acute withdrawal. However,
sublingually, naloxone has low bioavailability; therefore, when the combination
is administered sublingually, as is customary, the individual experiences the
intended agonist effect of buprenorphine without experiencing withdrawal. A
buprenorphine-to-naloxone ratio of 4:1 has been established.
Fudala et al. (2003) conducted the seminal efficacy study of office-based
treatment of opioid use disorders using combination buprenorphine–naloxone
compared with buprenorphine alone or placebo. The 4-week double-blind,
randomized trial (N=326) found buprenorphine alone and buprenorphine–
naloxone to have greater efficacy than placebo, as measured by percentage of
negative opioid drug screens (20.7% vs. 17.8 vs. 5.8) and reductions in opioid
craving. The open-label phase (N=461) demonstrated that both the
buprenorphine–naloxone combination and buprenorphine alone can be safely
administered in an outpatient office-based setting. The study authors concluded
that buprenorphine–naloxone is at least as good as buprenorphine alone and
better than placebo.
Weiss et al. (2011) conducted a multisite, randomized, two-phase adaptive
treatment design examining brief and extended buprenorphine–naloxone
treatment for prescription opioid dependence (N=653). Brief treatment included
a 2-week stabilization phase, followed by a 2-week taper and an 8-week
postmedication follow-up assessment (12-week treatment), whereas the extended
treatment condition included 12 weeks of buprenorphine–naloxone treatment,
followed by a 4-week taper and an 8-week postmedication follow-up (24-week
treatment). Extended treatment produced more successful outcomes compared
with brief treatment, but only while subjects were maintained on buprenorphine–
naloxone; at 8-week postmedication follow-up, there were significant reductions
in treatment success rates.
Buprenorphine Implants
Further efforts to reduce diversion, improve adherence, and enhance outcomes
include the development of subcutaneous buprenorphine implants, which were
approved by the FDA in 2016. A randomized, placebo-controlled 6-month
multisite trial (Ling et al. 2010) found buprenorphine implants to be efficacious
as evidenced by greater mean percentage of negative opioid drug screens from
weeks 1 to 16 compared with placebo (40.4% vs. 28.3%) and for the entire 24-
week period (36.6% vs. 22.4%). The implant group also had higher retention
rates (65.7% vs. 30.9%) and fewer clinician- and patient-rated withdrawal
symptoms. A subsequent study confirmed the safety and efficacy of
buprenorphine implants in reducing opioid use, improving retention, reducing
craving and withdrawal ratings, and increasing global ratings of improvement
compared with placebo (Rosenthal et al. 2013). Importantly, the authors reported
that buprenorphine implants were noninferior to the commonly used sublingual
buprenorphine formulation on percentage of negative urine drug screens during
the 24-week study.
Relapse Prevention
Oral Naltrexone
Naltrexone has been approved by the FDA for the treatment of opioid use
disorders since 1984. It acts by blocking the μ opioid receptor for 24–72 hours
(depending on dose), preventing the individual from experiencing drug-induced
euphoria. Continued abstinence through relapse prevention allows recovery of
the endogenous opioid system and relief of protracted abstinence symptoms.
Naltrexone was introduced in addiction treatment in the 1970s as an orally
administered nonaddictive medication with hopes of wide acceptance and
effectiveness. However, numerous clinical trials have reported poor outcomes
compared with placebo, no treatment, or other pharmacological treatment
(Minozzi et al. 2011; Schottenfeld et al. 2008). Moreover, adherence rates are
generally low, and overdose due to relapse in previously tolerant opioid-
dependent individuals poses a serious risk for oral naltrexone use. To address
poor adherence and associated overdose risk of relapse, XR-NTX was developed
and approved by the FDA in 2010.
Overdose Prevention
Recently, overdose education and naloxone rescue kits have been developed and
used in various settings to address the growing opioid overdose epidemic.
Naloxone is an opioid antagonist that is capable of reversing opioid overdose by
decoupling opioids from the opioid receptor and inducing acute withdrawal. It
can be administered via injection or nasal spray. Access has increased in the past
5 years, with 44 states plus the District of Columbia passing immunity laws that
enable physicians to prescribe the drug or civilians and first responders to
administer the drug without fear of civil, criminal, or professional liability
(National Conference of State Legislatures 2017). Thirty-four states plus the
District of Columbia also have passed various types of Good Samaritan laws that
encourage individuals witnessing or experiencing an overdose to call 911 or seek
emergency medical assistance by protecting help-seeking individuals from
prosecution for minor drug-related crimes.
Tobacco-Related Disorders
According to the 2014 National Survey on Drug Use and Health, 66.9 million
people, or 25% of the population ages 12 years and older, were current users of a
tobacco product, with 21% being current cigarette smokers (Center for
Behavioral Health Statistics and Quality 2015). Approximately 4.5% were
current cigar smokers, 1% were current pipe tobacco smokers, and 3% used
smokeless tobacco. Few tobacco users are successful in permanently quitting in
their initial attempt. Most tobacco users consume tobacco for many years and
cycle through periods of abstinence and relapse. Failure to grasp the chronic
nature of tobacco use disorders can lead to discouragement in health care
providers and impede the treatment of tobacco use over time. According to data
from the 2001–2010 National Health Interview Surveys, in 2010 more than 70%
of U.S. smokers reported that they wanted to quit, and 52% reported having tried
to quit in the past year (Centers for Disease Control and Prevention 2011).
Unfortunately, most of these quit attempts are unaided, and most smokers return
to regular smoking within a few weeks (Ward et al. 1997).
Counseling Strategies
Behavioral strategies, including in-person counseling, telephone quitlines, and
self-help materials, provide a small but important effect in achieving smoking
cessation. Telephone counseling is readily available in the United States through
the publicly funded quitline 1-800-QUIT-NOW (1-800-784-8669). A pooled
estimate of 47 trials indicated that increasing the amount of behavioral support
increased the chance of successful smoking cessation by 10%–25% (Stead et al.
2015).
Pharmacotherapy
Current practice guidelines recommend the use of an effective medication at
every quit attempt unless medically contraindicated or within special
populations, such as pregnant women and adolescents, for which there is limited
evidence of effectiveness (Fiore et al. 2008). Seven first-line medications are
safe, effective, and FDA approved for smoking cessation; these include nicotine
replacement therapies (NRTs; patch, gum, lozenge, nasal spray, inhaler),
bupropion sustained release (SR), and varenicline. Generally, cessation
medications double the quit rate relative to placebo (20% vs. 10%; Cahill et al.
2013).
Bupropion SR
In the late 1990s, the SR formulation of bupropion was approved by the FDA for
smoking cessation and marketed under the trade name Zyban. Bupropion SR is
an antidepressant with noradrenergic and dopaminergic effects and antagonist
action at the nicotinic acetylcholine receptor. In a recent systematic review
(Hughes et al. 2014), bupropion was associated with a significantly higher rate
of smoking abstinence at 6 months compared with placebo (19.7% vs. 11.5%).
Bupropion may work by blocking nicotine effects, relieving withdrawal, or
decreasing depressed mood. A standard bupropion SR course begins with one
150-mg tablet taken by mouth once a day for 3 days, at which point the dosage is
increased to one tablet taken by mouth twice a day (separated by at least 8 hours)
for 7–12 weeks. The tobacco quit date is 1 week after starting medication. If the
treatment is successful, some patients benefit from continued treatment for up to
6 months to prevent relapse.
Bupropion SR is generally well tolerated. Bupropion reduces seizure
threshold, and seizures are estimated to occur in 1 out of 1,000 treated patients
(Hughes et al. 2014). Contraindications include seizure disorders, eating
disorders, and monoamine oxidase inhibitor use within 14 days.
Varenicline
Varenicline is a partial agonist at the α4β2 nicotinic receptor that relieves
symptoms of nicotine withdrawal and blocks nicotine from attaching to the
receptor, thus reducing the rewarding properties of smoking (Coe et al. 2005).
Numerous controlled studies support the efficacy of varenicline for smoking
cessation. Two early studies that included more than 2,000 participants
(Gonzales et al. 2006; Jorenby et al. 2006) were 12-week RCTs comparing
varenicline, bupropion, and placebo. Rates of continuous abstinence for the last
month of the treatment phase were 44% for varenicline, 30% for bupropion, and
18% for placebo. Continuous abstinence rates for 1 year for varenicline,
bupropion, and placebo were 23%, 14.6%, and 10.3%, respectively, in one study
(Jorenby et al. 2006). A standard course is typically 0.5 mg every day for 3 days,
then 0.5 mg twice a day for 4 days, and then 1 mg twice a day with food. The
target quit date is 1 week after starting varenicline. If clinically warranted, the
initial total 12-week course can be continued for an additional 12 weeks if initial
treatment is successful.
Combination Therapies
Previous research has indicated that combination NRT—patch and lozenge—
increased quit rates compared with either placebo or monotherapy (Piper et al.
2009).
Varenicline combined with bupropion has been investigated in several RCTs.
Of the prospective trials, one showed a greater 4-week smoking abstinence for
weeks 8–11 with combination therapy (39.8%) than with monotherapy (25.9%)
(odds ratio [OR]=1.89; 95% confidence interval [CI]=1.07–3.35). Ebbert et al.
(2014) found greater prolonged abstinence (53% vs. 43% at 12 weeks and 37%
vs. 28% at 26 weeks) in the combination group compared with varenicline plus
placebo, although results were not significant at 52 weeks. In a study by Rose
and Behm (2014), smokers who used the nicotine patch and did not reduce
smoking were randomly assigned to 12 weeks of varenicline and bupropion SR
or varenicline plus placebo. Participants receiving the combination had
significantly higher abstinence rates compared with the varenicline plus placebo
group (40% vs. 26%). The combination treatment was significantly more
effective in males and highly dependent smokers (Rose and Behm 2014).
Second-Line Medications
Second-line medications should be considered on a case-by-case basis if first-
line medications (alone or in combination) are ineffective or contraindicated.
Several medications are effective but have a more limited role because of
potential side effects and lack of FDA approval for smoking cessation.
Medications in this category include clonidine and nortriptyline (Fiore et al.
2008).
Special Populations
Women Who Are Pregnant or Who Are Trying to Conceive
The harmful effects of smoking during pregnancy are well known and include
small-for-gestational-age neonates, stillbirth, preterm birth, and placenta previa
(Jauniaux and Burton 2007). Current guidelines recommend the use of in-person
psychosocial strategies that exceed minimal advice to quit smoking. Although
quitting smoking during the first trimester will produce the greatest benefit,
quitting at any time can be beneficial. In a recent meta-analysis that excluded
potentially biased, non-placebo-controlled RCTs, NRT was no more effective
than placebo (Coleman et al. 2015). Evidence is insufficient to recommend the
use of bupropion or varenicline during pregnancy.
Stimulant-Related Disorders
The search for a pharmacotherapeutic treatment for cocaine and amphetamine
use disorders has been extremely active over the last 20 years, with controlled
trials of antidepressants, anticonvulsants, dopamine agonists and antagonists,
and many other agents. Unfortunately, many medications that show promise in
animal models of stimulant dependence and/or positive outcomes in small
uncontrolled trials fail to decrease drug use by objective measures in larger
controlled trials. In addition, many clinical trials in stimulant-dependent
individuals are flawed by high dropout rates and medication noncompliance. To
date, no medications have clearly shown efficacy in the treatment of cocaine or
amphetamine dependence; however, the medications discussed in this section
have shown promise, often in subgroups of individuals studied.
Disulfiram
In addition to its effects on alcohol metabolism, disulfiram blocks the enzymatic
degradation of both cocaine and dopamine. Investigators have hypothesized that
increased dopamine levels may help improve hedonic tone (i.e., sense of well-
being, pleasure, or contentment) in cocaine-dependent individuals, and the
increased cocaine levels have been shown to increase cocaine-related anxiety
and dysphoria in individuals pretreated with disulfiram (Hameedi et al. 1995).
Regardless of the mechanism, four clinical trials to date have reported that
disulfiram reduces cocaine use in cocaine-dependent patients (Carroll et al.
2004; George et al. 2000). Given these results, disulfiram definitely should be
considered in the treatment of cocaine dependence as long as the individual is
willing to remain alcohol-free and understands the potential for increased
toxicity with cocaine use.
Modafinil
Modafinil, a novel stimulant and glutamatergic agent that is FDA approved for
narcolepsy, has been tested in both cocaine and amphetamine dependence.
Although initial trials were positive (Dackis et al. 2005), subsequent trials found
that efficacy was limited to individuals who did not have a history of alcohol
dependence and to men (Anderson et al. 2009; Dackis et al. 2012). Trials of
modafinil are ongoing, but the medication is well tolerated and may be useful in
reducing cocaine withdrawal symptoms and helping some individuals attain
abstinence (Malcolm et al. 2002).
Topiramate
There have also been several promising studies with topiramate, an
anticonvulsant agent that has shown promise in alcohol dependence (see
“Topiramate” subsection earlier in this chapter). In one placebo-controlled trial
of cocaine dependence, topiramate-treated subjects were more likely than
placebo-treated subjects to achieve 3 weeks of continuous abstinence and to be
rated as clinically improved (Kampman et al. 2004).
Conclusion
Effective pharmacological treatments are available for alcohol, opioid, and
tobacco use disorders, but studies suggest that these treatments are underused.
The search for a medication treatment for stimulant use disorders remains an
active area of research, with a wide range of agents being tested across hundreds
of clinical trials. Given the devastating personal and societal effects of
substance-related disorders, pharmacotherapy should be considered when
appropriate as part of a comprehensive treatment plan.
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CHAPTER 51
Treatment of Personality
Disorders
Marissa Miyazaki, M.D.
Daphne Simeon, M.D.
Eric Hollander, M.D.
Models of Personality
Whereas nobody doubts the existence of personality, what constitutes its
disordered form has been controversial. There is little disagreement on the
limitations of the current categorical classification of personality disorders, but
consensus on a unified model has been lacking. Much of the debate has centered
on dimensional versus categorical models of personality disorders. The
alternative dimensional model for personality disorders in Section III of the
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5;
American Psychiatric Association 2013), has two main criteria: impairment in
personality functioning and one or more pathological personality traits.
The founder of personality psychology, Allport (1937), in one of the earliest
conceptualizations of personality disorders, theorized that “personality ‘is’
something and personality ‘does’ something” (p. 48). In the nearly 80 years since
then, research into what personality “is” (i.e., trait structural models) has
dominated the field (Ro et al. 2013). Recently there has been increased attention
on what personality “does”—that is, the functional aspects of personality and
how it serves to adapt individuals’ behaviors to their situations (Ro and Clark
2009). Distinguishing personality functioning from traits is important
conceptually, because simply having extreme traits is not necessarily
pathological. From an evolutionary perspective, Livesley and Jang (2000)
theorized that severe personality pathology reflects a failure of three adaptive
systems: a “self-system” (i.e., development of a stable concept of self and,
correspondingly, of others) and two “other-systems” (i.e., the capacity for close
personal relations and intimacy, and the ability to function effectively at a
societal level). The consequence of this system failure is an inability to handle
major life tasks—in effect, Freud’s lieben und arbeiten (to love and to work).
The heterogeneity and absence of evidence to support treatment of individual
personality disorders led researchers to largely ignore specific DSM Axis II
personality disorder categories and adopt a more parsimonious approach to
treatment, focusing instead on dimensions of psychopathology that cut across
various personality disorders. The limitations of categorical models led to the
development of a trait-based algorithm initially proposed by Siever and Davis
(1991) and further developed by Soloff (1998). This new algorithm posited that
four dimensions cutting across all personality disorder categories—affective
instability, anxiety–inhibition, cognitive–perceptual disturbances and
impulsivity–aggression—should be studied rather than individual symptom
clusters or diagnoses. This model has served as a dominant framework for
understanding the evidence regarding medication effects on personality disorders
(Bateman et al. 2015).
The diagnosis and classification of personality disorders are shifting toward a
more dimensional model of classification (Widiger and Simonsen 2005).
Although several models were proposed in DSM-IV-TR (American Psychiatric
Association 2000), the model included in Section III of the recently published
DSM-5 as an alternative to current categorical classifications is based on the
empirically supported Five-Factor Model (FFM), which includes the following
broad domains: negative affectivity (vs. emotional stability), detachment (vs.
extraversion), antagonism (vs. agreeableness), disinhibition (vs.
conscientiousness), and psychoticism (vs. lucidity) (Widiger and Costa 1994).
This model, in contrast to other models, was felt to adequately cover the full
range of personality disorder symptomatology and has amassed the most
empirical support (Widiger and Costa 1994). Compared with other models, it
was felt to more accurately reflect normal as well as abnormal personality
functioning and to better account for the symptoms and traits of DSM-IV-TR
personality disorders (Clark 2007). The aspects of personality functioning
considered to be most important to people across all cultures and languages
when they describe themselves and others pertain to interpersonal relatedness, a
domain thought to form the core of personality disorders (Pincus 2005) and
captured by the two factors of extraversion and agreeableness.
Despite the formidable challenges in understanding what constitutes
“disordered” personality features and their optimal treatment approach, reasons
for optimism exist. The traditional view that personality disorders are necessarily
chronic, stable over time, and marked by poor outcomes has been challenged in
recent years in light of the fact that the more serious epiphenomena of disorders
such as borderline personality disorder, including serious suicide attempts,
impulsive behaviors, misuse of services, and aggressive outbursts, all show
improvement with treatment. Findings from longitudinal studies of personality
disorders such as the Collaborative Longitudinal Personality Disorders Study
(CLPS) and the McLean Study of Adult Development (MSAD) have challenged
the traditional entrenched pessimism about the poor prognoses of personality
disorders such as borderline personality disorder (Gunderson et al. 2011;
Zanarini et al. 2010). Such findings have driven the removal from DSM-5 of the
separate Axis II category altogether, as well as the introduction of terms such as
remission and relapse to the conceptualization of personality disorders.
Atypical antipsychotics
Frankenburg 15 refractory Clozapine — 2–9 months
and Zanarini BPD
1993
Schulz et al. BPD Risperidone Placebo 8 weeks
1998
Schulz et al. 11 BPD (7 also Olanzapine — 8 weeks
1999 SztPD)
Zanarini and 28 BPD Olanzapine Placebo 6 months
Frankenburg
2001
Rocca et al. 15 BPD with Risperidone — 8 weeks
2002 marked
aggression
Bogenschutz 40 BPD Olanzapine Placebo 12 weeks
and
Nurnberg
2004
Villeneuve and 23 BPD Quetiapine — 12 weeks
Lemelin
2005
Nickel et al. 52 BPD Aripiprazole Placebo 12 weeks
2006
Atypical Antipsychotics
Atypical antipsychotics have received increased attention in recent years (see
Table 51–1). On the whole, BPD treatment studies using atypical antipsychotics
have shown improvements in affective instability, impulsivity, psychosis, and
interpersonal dysfunction. In clinical practice, it appears that atypical
antipsychotics are prescribed more frequently than conventional agents due to
their greater tolerability and lower risks of EPS and tardive dyskinesia. A
number of studies have examined olanzapine in the treatment of BPD (see Table
51–1). The largest study to date was conducted by Zanarini et al. (2011). In this
12-week randomized, double-blind, placebo-controlled trial, 451 outpatients
with DSM-IV (American Psychiatric Association 1994) borderline personality
disorder received olanzapine 2.5 mg/day (n=150), olanzapine 5–10 mg/day
(n=148), or placebo (n=153). Olanzapine 5–10 mg/day showed a clinically
modest advantage over placebo in the treatment of overall borderline
psychopathology. Treatment-emergent adverse events included somnolence,
fatigue, increased appetite, and weight gain (Zanarini et al. 2011). A 12-week
open-label extension of the study found sustained improvements over longer
durations (Zanarini et al. 2012). Another large-scale placebo-controlled study
comparing the efficacy and tolerability of low and moderate dosages of
extended-release quetiapine in 95 adults with BPD found that participants in the
low-dosage quetiapine (150 mg/day) group had significant improvement on
overall BPD severity measures compared with those in the placebo group.
Eighty-two percent in the low-dosage quetiapine group were rated as
“responders,” compared with 74% in the moderate-dosage (300 mg/day) group
and 48% in the placebo group. The most common adverse events with
quetiapine (which were more prominent in the high-dosage group) included
sedation, changes in appetite, and dry mouth. The overall completion rate for the
8-week double-blind treatment phase was 67% (67% for the low-dosage
quetiapine group, 58% for the moderate-dosage quetiapine group, and 79% for
the placebo group) (Black et al. 2014).
Antidepressants
Although older antidepressants including tricyclic antidepressants (TCAs) and
monoamine oxidase inhibitors (MAOIs) have shown modest efficacy in
improving affective symptoms in BPD (Cornelius et al. 1993; Cowdry and
Gardner 1988; Soloff et al. 1993), both TCAs and MAOIs pose serious risks in
overdose and carry the potential for adverse events that are of particular concern
in this unstable, impulsive population.
BPD studies with selective serotonin reuptake inhibitors (SSRIs) have yielded
mixed findings. Whereas some older studies suggested statistically significant
superiority of SSRIs over placebo in BPD (Coccaro and Kavoussi 1997;
Markovitz 1995; Salzman et al. 1995), more recent controlled studies with
SSRIs showed either no difference from placebo or additional benefit over
placebo only when SSRIs were used to augment standard treatments such as
dialectical behavior therapy (Simpson et al. 2004). SSRI monotherapy also has
demonstrated no statistical benefit over atypical antipsychotic monotherapy for
depression and impulsive aggression (Zanarini et al. 2004a).
BPD studies with serotonin–norepinephrine reuptake inhibitors (SNRIs) such
as venlafaxine (Markovitz and Wagner 1995) and the newer agent duloxetine
(Bellino et al. 2010) also showed modest efficacy in treating affective symptoms
(irritability, anger) and impulsive behaviors (self-injury), but these trials were
limited by their open-label design and small sample sizes. Studies of
antidepressant treatment in BPD are summarized in Table 51–2.
Continuation 1 year
of above
study
Mood Stabilizers
Mood stabilizers are known to calm excitatory neurotransmission, but the
various agents differ in terms of their mechanism of action and effects on γ-
aminobutyric acid (GABA)-ergic and glutamatergic signaling mechanisms. As a
class, mood stabilizers have gained increasing attention as a medication strategy
for treatment of BPD symptoms, demonstrating moderate effect sizes on
impulsive aggression, affective instability, self-injurious behaviors, and overall
functioning.
Early studies supported a role for lithium in BPD (Rifkin et al. 1972). In a
single small controlled study (Links et al. 1990), 17 subjects with BPD received
6 weeks each of lithium, the TCA desipramine, and placebo in a randomized
crossover design, and 10 subjects completed at least two medication trials.
Neither medication was better than placebo for depressive symptoms, although
lithium led to a significant decrease in anger and suicidality according to
clinician but not patient perception.
Anticonvulsants are used more widely than lithium in the treatment of BPD
symptoms. Early studies with carbamazepine reported mixed findings, with
some showing improvement in behavioral dyscontrol (Cowdry and Gardner
1988) and others showing no significant improvement with carbamazepine
treatment (de la Fuente and Lotstra 1994) compared with placebo.
More recently, anticonvulsant trials have focused on valproate and newer
anticonvulsants. In one placebo-controlled trial, 16 outpatients with BPD were
treated for 10 weeks with valproate or placebo (Hollander et al. 2001). Global
improvement was significant by two measures in patients treated with valproate,
but the small sample size and high dropout rate precluded statistically significant
findings. In another controlled study, valproate’s efficacy was examined in 30
women with comorbid BPD and bipolar II disorder over 6 months of treatment
(Frankenburg and Zanarini 2002). Valproate at an average dosage of 850 mg/day
was well tolerated and resulted in significant improvement in interpersonal
sensitivity, hostility/anger, and aggression compared with placebo.
A larger placebo-controlled multicenter trial of valproate showed some
efficacy for impulsive aggression in Cluster B personality disorders (Hollander
et al. 2003). In this study, 91 outpatients selected for the presence of prominent
impulsive aggression and the absence of bipolar I disorder or current major
depression were randomly assigned to 12 weeks of treatment with placebo or
valproate (mean dosage of 1,400 mg/day). Valproate was well tolerated overall,
with only 17% of subjects discontinuing because of valproate-related adverse
events. The main finding of the study was a significant decrease in impulsive
aggression in the last month of treatment, with valproate treatment reducing
irritability, impulsive behaviors, and overall aggression, including verbal assault,
assault against objects, and assault against others (Hollander et al. 2003).
Controlled studies have focused on lamotrigine (200 mg/day) and topiramate
(200–250 mg/day) and suggest that both agents may offer therapeutic benefits in
treating affective instability and impulsivity in BPD. Lamotrigine (at a target
dosage of 200 mg/day) has demonstrated efficacy in treating impulsivity,
affective symptoms, and aggression in BPD (Tritt et al. 2005). Long-term
follow-up studies suggest that the benefits of lamotrigine are sustained and that it
is an effective and relatively safe agent for longer-term treatment of aggression
in women with BPD (Leiberich et al. 2008). Topiramate is another agent that has
demonstrated efficacy for certain dimensions of BPD, such as anger (Loew et al.
2006; Nickel et al. 2004, 2005). Follow-up studies of topiramate support its
efficacy long-term (Loew and Nickel 2008; Nickel et al. 2006).
BPD treatment trials with mood stabilizers are summarized in Table 51–3.
TABLE 51–3. Summary of medication treatment trials with mood stabilizers in b
personality disorder (BPD)
Mood
Study Subjects stabilizer(s) Other agent(s) Duration
Rifkin et al. 21 Lithium Placebo 6 weeks
1972 emotionally
unstable
character
disorder
In almost all Cluster B personality disorder trials, BPD has been the primary
focus. Although some of these trials, as individually mentioned in the overview
above, included mixed samples of Cluster B participants, they did not present
separate analyses for non-BPD diagnoses. Therefore, the general principle to
follow in treating Cluster B disorders other than BPD would be to target
symptom clusters with medications as per the guidelines developed for BPD (see
Table 51–4). In general, narcissistic and histrionic personality disorders are not
characterized by the severe degree of either mood lability or impulse dyscontrol
seen in BPD, but for individuals in whom such features are more prominent or
problematic, medication trials can be attempted.
In regard to antisocial personality disorder, the general treatment guideline is
that individuals who meet full criteria for the disorder are generally treatment
noncompliant and nonresponsive. Very few pharmacological studies have
focused on patients with antisocial personality disorder (Coccaro 1993). Early
trials suggested a role for lithium in reducing markers of antisocial behavior,
including rule infractions and impulsive-aggressive behavior, among
incarcerated males (Wickham and Reed 1987). Studies with phenytoin 300
mg/day among prisoners and outpatients also showed some benefit for impulsive
(but not premeditated) behaviors as well as reduced measures of anxiety and
depression (Stanford et al. 2001). Finally, there is some evidence of benefit from
nortriptyline (25–75 mg/day) and bromocriptine (15 mg/day) (Powell et al.
1995) in reducing alcohol abuse among individuals with antisocial personality
disorder, a significant finding in light of the fact that men with antisocial
personality disorder have been found to be three to five times more likely than
those without the disorder to abuse alcohol and illicit drugs (Robins and Price
1991).
More recently, a report on four antisocial personality disorder inpatients in a
maximum-security facility found decreases in impulsivity, hostility,
aggressiveness, irritability, and rage reactions with quetiapine treatment at
dosages of 600–800 mg/day (Walker et al. 2003). Generally, borderline patients
who have some antisocial traits are more responsive to medication treatment
than are purely antisocial patients. Studies with the mood stabilizer valproate
suggested that individuals with antisocial personality disorder were less
responsive to the pharmacotherapy than were subjects with other Cluster B
personality disorders (Hollander et al. 2003). It has also been found, however,
that borderline patients are significantly more likely than antisocial personality
disorder patients to have received adequate medication trials with anxiolytics
and antidepressants (Zanarini et al. 1988).
Conclusion
In this chapter we reviewed the pharmacological treatment of personality
disorders, providing a conceptual framework, highlighting methodological
limitations, and summarizing medication treatment trials to date. Almost all of
these trials focused on symptom clusters, such as psychoticism, impulsivity,
hostility/aggression, mood instability, and anxiety/inhibition. This focus is
consistent with the growing conceptualization of personality disorders as
syndromes of overlapping traits arising from a complex interaction between
genetic determinants and developmental processes, influenced by adverse life
events, with the primary manifestations of the disorder represented as difficulties
with interpersonal relationships. Translation of current research into robust
clinical recommendations for the treatment of personality disorders has been
hampered by a number of methodological limitations, including heterogeneity of
study populations, selective attention to BPD, and diversity of outcome
measures. Despite these limitations, there is sufficient evidence to suggest a role
for medications as an adjunctive treatment for symptom reduction, functional
improvement, and overall adaptation for personality disorders. Progress in our
understanding of the neurobiological underpinnings of personality and their
component dimensions will help guide development of better models of
personality and its disordered forms, thereby providing a basis for rational
pharmacotherapy to complement psychosocial interventions.
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CHAPTER 52
Bulimia Nervosa
BN has its onset in adolescence or early adult life, with a prodromal period
characterized by dissatisfaction with body shape and a fear of becoming
overweight, followed by dietary restriction and weight loss. Sooner or later,
periods of dietary restriction are followed by episodes of binge eating
experienced as a loss of control over dietary intake. These, in turn, further
aggravate dissatisfaction with body shape and fears of weight gain. Ultimately,
the bulimic patient discovers purging, usually in the form of self-induced
vomiting, with or without laxative or diuretic use, excessive exercise, or (less
commonly) fasting; and in rare cases in the form of chewing food and spitting it
out.
Medical complications of BN include potassium depletion, which combined
with low weight may lead to cardiovascular complications and death. Other
complications include dental caries, salivary gland enlargement, and exercise
injuries (Mitchell and Crow 2010). Comorbid psychopathology includes major
depression; anxiety disorders, social phobia, and panic disorder; obsessive-
compulsive disorder; alcoholism; and personality disorders, particularly those in
the Cluster B spectrum.
Pharmacological Treatment
Antidepressants
The use of antidepressants in the treatment of BN was sparked by the
observation that depression is often a comorbid feature of the disorder (Pope and
Hudson 1982). In 1982, two groups of researchers conducted small-scale
uncontrolled studies indicating that both tricyclic antidepressants and
monoamine oxidase inhibitors reduced binge eating and purging (Pope and
Hudson 1982; Walsh et al. 1982). A wide range of antidepressants have been
found effective in double-blind, placebo-controlled studies, including
imipramine (Agras et al. 1987; Mitchell et al. 1990; Pope et al. 1983),
desipramine (Agras et al. 1991; Barlow et al. 1988; Blouin et al. 1989; Hughes et
al. 1986), phenelzine (Walsh et al. 1988), brofaromine (Kennedy et al. 1993),
trazodone (Pope et al. 1989), fluoxetine (Fluoxetine Bulimia Nervosa
Collaborative Study Group 1992), fluvoxamine (Milano et al. 2005), and
citalopram (Leombruni et al. 2006). Fluoxetine is the only medication approved
by the U.S. Food and Drug Administration (FDA) for the treatment of BN.
Antidepressants are prescribed for BN at the same dosages used for treating
depression, with the exception of fluoxetine, for which a dosage of 60 mg/day
was found more effective than 20 mg/day in reducing binge eating and purging
in a placebo-controlled trial involving 387 bulimic women (Fluoxetine Bulimia
Nervosa Collaborative Study Group 1992).
Overall, most antidepressants appear effective for the short-term treatment of
BN, with little difference between them (Hay and Claudino 2010). Less is
known about the long-term effectiveness of medication. In an early study
(Fichter et al. 1991), 72 patients with BN successfully treated as inpatients were
randomly assigned to receive either fluvoxamine or placebo. Those on the active
drug had a higher rate of recovery over a 15-week period. In a second study of
this issue, 147 women with BN who had decreased their vomiting by at least
50% while taking 60 mg of fluoxetine over an 8-week period were randomly
allocated to continue medication or to be switched to placebo (Romano et al.
2002). A survival analysis found that the group receiving active medication
experienced a longer time to relapse (or dropout) than did the placebo group.
However, it should be noted that at the 12-month follow-up, 83% of the
fluoxetine group and 92% of the placebo group had relapsed or dropped out. The
authors suggest that given these results, a multimodal approach to the treatment
of BN, including cognitive-behavioral therapy (CBT), should be considered.
To date, only one study has compared different lengths of antidepressant
treatment, in this case with desipramine. Patients with BN treated for 16 weeks
relapsed to pretreatment levels of binge eating when medication was withdrawn.
On the other hand, those treated for 24 weeks maintained remission after
withdrawal and at 1-year follow-up (Agras et al. 1991, 1994). This study
suggests that patients who respond to antidepressant treatment should be given a
minimum trial of 6 months on medication. For the most part, however,
controlled studies of antidepressants are of relatively short duration, as is the
assessment of bulimic symptoms. Both of these factors may somewhat
exaggerate the clinical efficacy of these medications.
In a study involving 77 BN patients (Walsh et al. 2006b) that examined the
rate of decline in bulimic symptoms with desipramine, the authors found that
patients unlikely to respond to the antidepressant could be reliably identified
after 2 weeks of treatment. This finding was replicated in a combined data set
(N=785) from two controlled trials (Sysko et al. 2010). Patients who did not
reduce binge eating or vomiting by 60% by week 2 of treatment were unlikely to
respond to fluoxetine. Identification of poor responders early in treatment allows
for the deployment of different approaches to treatment.
One problem with medication given at times other than bedtime is that a
significant amount may be purged through subsequent vomiting. Side effects and
reasons for discontinuation of the various medications are similar to those
observed in the treatment of depression. However, a study of bupropion found
that a higher-than-expected proportion of bulimic patients developed grand mal
seizures (Horne et al. 1988). The authors concluded that bupropion should not be
used for the treatment of BN.
Antiepileptics
Although considerable evidence from controlled trials indicates that most
antidepressants are useful in the treatment of BN, few controlled studies of other
pharmacological agents with a reasonable sample size have appeared in the
literature. However, topiramate (an anticonvulsant drug) has been evaluated in
two controlled trials. The reason for considering topiramate was that epileptic
patients experienced appetite reduction and weight loss on this medication. In
the first study (Hoopes et al. 2003), patients meeting criteria for DSM-IV-TR
(American Psychiatric Association 2000) bulimia nervosa were allocated at
random to treatment with either topiramate at an average dosage of 100 mg/day
(n=35) or placebo (n=34) over a 10-week period. Twenty-two (63%) of those in
the topiramate group completed the trial, and topiramate was statistically
superior in reducing binge eating and purging, with 22% of completers in
remission at the end of treatment. In the second study (Nickel et al. 2005), 30
patients with BN were randomly allocated to receive either topiramate or
placebo. Topiramate was statistically superior to placebo in reducing binge
eating and purging; however, no data on remission or recovery were reported.
Side effects commonly seen with topiramate are fatigue, cognitive blunting, and
flu-like symptoms.
Combined Treatment
CBT for BN developed in parallel with the use of antidepressants. CBT is
considered the first-line treatment for BN because it appears to be more effective
than antidepressant medication and other psychotherapies such as interpersonal
psychotherapy (Hay and Claudino 2010). There is also evidence for the
effectiveness of guided self-help CBT. The components of CBT include
psychoeducation about BN; reduction of dieting and reinstatement of normal
eating; exposure to feared foods; reduction of concerns about weight and shape;
and reduction of interpersonal triggers of binge eating. The existence of two
different and effective treatments, antidepressant medications and CBT, naturally
led to the question of whether the combined treatments would be more effective
than either treatment alone.
The largest study of combined treatment conducted to date, which involved
120 women with BN, used a medication regimen consisting of desipramine
followed by fluoxetine if the first medication was either ineffective or poorly
tolerated (Walsh et al. 1997). It is important to note that the two-medication
combination was used by two-thirds of the patients assigned to active
medication, suggesting that a two-medication combination is closer to clinical
reality than the use of a single medication. The average dosage of desipramine
was 188 mg/day, and that of fluoxetine was 55 mg/day. Forty-three percent of
the patients receiving medication dropped out of the study, compared with 32%
of those receiving psychotherapy. Patients receiving active medication (in
combination with CBT) had a significantly greater reduction in binge eating
compared with those receiving placebo. Finally, antidepressant medication
combined with CBT was superior to medication alone in reducing purging
frequency. Among patients receiving CBT plus medication, 50% were in
remission at the end of treatment, compared with 25% of those receiving
medication alone. These findings suggest that the combination of CBT plus
antidepressant medication may be the most effective approach to the treatment of
BN.
Comprehensive Treatment
Patients with BN should be treated as outpatients unless there are medical or
psychiatric reasons for hospitalization (e.g., an intercurrent physical illness or a
comorbid psychiatric disorder requiring hospitalization, such as major
depressive disorder with suicidality). One reason that outpatient treatment is
useful for the BN patient is that gains made in the hospital may not carry over to
the patient’s home environment, where more complex food stimuli and greater
stress are present than in the hospital.
The research evidence to date suggests that the combination of antidepressant
medication and CBT is likely to be somewhat more effective than either therapy
alone. Because CBT is more effective than antidepressant medication and is
associated with fewer dropouts than medication, in the ideal case, CBT should
be the first therapy offered to the patient. However, CBT is not always available,
and in such circumstances, medication will be the only choice. In addition,
patient preferences for one or the other treatment should be taken into account.
The flow chart in Figure 52–1 presents an algorithm as guidance to the overall
treatment of BN. The first decision to make is whether the patient has current
major depression, which is seen in approximately 25% of bulimic patients
presenting for treatment. Because depressive symptoms can interfere with the
conduct of CBT for BN, antidepressant medication should precede CBT in such
patients. When the patient has sufficiently recovered from depression, the eating
disorder should be reevaluated. If the patient has not recovered from the eating
disorder, then CBT should be added.
FIGURE 52–1. Flow chart depicting different treatment
sequences for bulimia nervosa (BN).
CBT=cognitive-behavioral therapy.
Binge-Eating Disorder
Although the association between binge eating and obesity had been noted from
time to time, it was not until the upsurge of research into the psychopathology
and treatment of BN that systematic attention was paid to BED. The principal
features of BED are episodes of binge eating at a frequency of at least 1 day per
week for 3 months, marked distress caused by binge eating, and binge eating that
does not occur during the course of BN or AN (American Psychiatric
Association 2013). Purging does not occur in this condition, although about 10%
of patients with BED have a history of BN.
Between 1% and 3% of women in the general population meet criteria for
BED (Hudson et al. 2007, 2012), a proportion that is little changed by the new
DSM-5 criteria, which—like those for BN—now require an average of one
binge episode per week over a 3-month period. In clinical populations, the ratio
of women to men with BED is approximately 3:2, the highest rate for men of
any eating disorder. Although obesity is not a requirement for the diagnosis of
BED, there is a substantial overlap between BED and obesity. Studies have
shown that about one-quarter of obese individuals have symptoms that meet
criteria for BED, and that the prevalence of binge eating increases as body mass
index increases (Marcus et al. 1985; Spitzer et al. 1993; Telch et al. 1988).
Because binge eating often precedes the onset of overweight, binge eating may
be a risk factor for obesity. Moreover, BED is associated with comorbid
psychopathology similar to that seen in BN and causes much distress; hence, it is
an entity deserving of treatment in its own right. A comparison of individuals
with BED with weight-matched non-binge-eating obese individuals found that
subjects with BED were significantly more likely than those without BED to
receive a diagnosis of major depressive disorder (51%), panic disorder (9%), or
borderline personality disorder (9%) (Yanovski et al. 1993).
Pharmacological Treatment
Antidepressants
Double-blind, placebo-controlled studies suggest that antidepressants are at least
as useful in the treatment of BED as they are in BN. Early placebo-controlled
studies found desipramine to be effective in reducing binge eating, with an
abstinence rate of 60% (McCann and Agras 1990). Studies of selective serotonin
reuptake inhibitors (SSRIs) have suggested moderate efficacy, with overall
remission rates of approximately 40%, compared with 20% for placebo
(Appolinario and McElroy 2004; McElroy et al. 2010). Most studies showed
some degree of weight loss, which for the most part was not clinically
significant.
Antiepileptics
Anticonvulsants such as topiramate and zonisamide also appear to be useful in
the treatment of BED (McElroy et al. 2006). A 16-week double-blind multisite
study in which 394 participants with BED were allocated at random to receive
either topiramate or placebo provided evidence for the efficacy of topiramate
(McElroy et al. 2007). The median dosage of topiramate was 300 mg/day.
Dropouts were equivalent between groups (29% topiramate; 30% placebo).
Fifty-eight percent of subjects in the topiramate group and 29% of those in the
placebo group were in remission at the end of the study period. The mean weight
loss was 4.5 kg in the topiramate group versus a small weight gain in the placebo
group. The most common side effects specific to topiramate were paresthesia
and difficulty concentrating. Hence, topiramate leads to a reasonable rate of
remission of the eating disorder combined with substantial and clinically
meaningful weight loss.
Other Medications
A recent multisite study suggested that lisdexamfetamine, a dextroamphetamine-
like drug FDA approved for the treatment of attention-deficit/hyperactivity
disorder, may be useful, at least in the short term, for the treatment of BED
(McElroy et al. 2015). Two hundred sixty individuals with BED were randomly
allocated to receive active drug (30, 50, or 70 mg/day) or placebo. Exclusion
criteria resulted in a group of subjects with very little comorbid
psychopathology; hence, results relate only to this subgroup of BED patients.
Lisdexamfetamine was administered for 8 weeks with a 1-week follow-up after
discontinuation. Results were in favor of medication, with 50% of patients in the
group receiving lisdexamfetamine 70 mg/day achieving 4 weeks without binge
eating prior to the end of treatment, compared with 21.3% of patients on
placebo. Results for patients receiving 50 mg/day were similar to those for the
70-mg/day group, but there was no difference between medication and placebo
for the 30-mg/day group. Mean weight loss was 4.3 kg for the high-dosage
group, compared with no loss for the placebo group. These results are
encouraging both for binge-eating reduction and for weight loss, although long-
term studies are now needed to examine maintenance of therapeutic gains and to
extend the findings to a more representative group of patients.
A placebo-controlled study in 50 overweight participants with BED compared
orlistat (a lipase inhibitor), given at a dosage of 120 mg three times daily, with
placebo, both groups also receiving an abbreviated form of CBT (Grilo et al.
2005). At the end of treatment, 64% of those in the orlistat group and 36% of
those in the placebo group were in remission. The proportions achieving at least
a 5% weight loss were 36% for orlistat and 8% for placebo. However, after
discontinuation of both treatments, there was no difference in abstinence rates
between groups (52% in both groups).
Although in earlier studies the serotonin–norepinephrine reuptake inhibitor
sibutramine appeared to be successful in reducing both binge eating and weight,
it is no longer available in the United States because of associated cardiovascular
effects (Grilo et al. 2014).
Comprehensive Treatment
BED presents three problems to the clinician: binge eating, overweight, and
comorbid psychopathology, particularly depression. Hence, comprehensive
treatment should address all of these problems. There are few direct comparisons
of psychotherapy and medication, and the situation is further complicated by the
larger placebo responses found in BED as compared with BN, possibly
accounting for the lack of efficacy of pharmacological agents in smaller-scale
studies. For patients who prefer medication, current evidence suggests that
topiramate has the most evidence for efficacy in reducing binge eating and
weight, although acceptability may be low due to side effects. Lisdexamfetamine
may provide an additional effective approach to treatment focused on reducing
binge eating. However, lisdexamfetamine is a Drug Enforcement
Administration–controlled medication with potential for abuse and dependence;
therefore, careful monitoring of dosage and vigilance for signs of misuse are
needed. Less is known about medications that may add to the effects of
psychotherapies such as CBT and interpersonal therapy, both of which are
associated with substantial reductions in binge eating that appear to be well
maintained, although weight losses are small. Hence, augmentation studies are
needed to guide clinical decision making. However, consideration might be
given to combining a weight-reducing agent with one of the effective
psychotherapies.
Anorexia Nervosa
AN is a relatively rare disorder characterized by marked weight loss, intense fear
of gaining weight, and disturbance in the experience of body shape (i.e., feeling
fat despite marked weight loss). It is the most lethal psychiatric disorder. A meta-
analysis of 41 cohorts from peer-reviewed studies published between 1966 and
2010 found that AN patients were 5.2 times more likely to die prematurely than
females in the general population and 18.1 times more likely to die by suicide
(Keshaviah et al. 2014). Because of the disabling nature and chronicity of the
condition and the lack of evidence-based treatments for the chronic form of the
disorder, it has become apparent that identification and treatment of the disorder
early in its course are essential.
A specific family therapy (family-based treatment [FBT]) for adolescents that
aims to help parents take charge of their child’s eating appears to be successful
in both the short and the long term, with about 50% of adolescent patients with
anorexia recovered both at the end of treatment and at follow-up (Lock et al.
2005, 2010). In the largest trial to date (Agras et al. 2014), 164 adolescents with
AN were randomly allocated to either FBT or systems family therapy (SyFT).
There were no statistically significant differences in outcome at either end-of-
treatment or 1-year follow-up, with 40% recovering with FBT. However, FBT
produced significantly faster weight gain early in treatment, which may have led
to fewer hospitalizations than SyFT and hence to lower treatment costs (FBT
$8,963, SyFT $18,005). Therefore, for adolescent AN, family therapy in general
and FBT in particular are evidence-based treatments (Hay et al. 2014).
Pharmacological Treatment
Controlled pharmacological studies in both adolescents and adults have
generally shown a lack of efficacy. Most studies of antipsychotic agents in the
treatment of AN, including chlorpromazine, pimozide, sulpiride olanzapine, and
risperidone, showed no evidence of efficacy for weight gain (Dally and Sargant
1960; Hagman et al. 2011; Kafantaris et al. 2011; Vandereycken 1984;
Vandereycken and Pierloot 1982). Similarly, antidepressants have proved
disappointing (Mitchell et al. 2013). An inpatient study found that fluoxetine
was not effective in hospitalized patients with AN (Attia et al. 1998). In this
study, 31 women hospitalized with AN participated in a 7-week randomized,
double-blind trial of fluoxetine at a mean dosage of 56 mg/day. Four patients in
each group terminated the trial early. Although all patients in the study showed
improvement, no significant differences were seen between active medication
and placebo. In addition, there was no apparent effect of medication on
depression or obsessional symptoms. This study suggested that fluoxetine had no
effect over and above that of an inpatient program and adds to the literature’s
consistent failure to show a beneficial effect of antidepressant medication during
the period of weight regain.
Despite promising findings in an earlier small-scale outpatient study (Kaye et
al. 2001), a double-blind, placebo-controlled trial in 93 adult outpatients found
no benefit for fluoxetine in either promoting weight maintenance or prolonging
time to relapse (Walsh et al. 2006a). As is usual in this population, a large
proportion of patients dropped out or terminated early from treatment (51% of
fluoxetine-treated and 63% of placebo-treated patients). A fairly high proportion
of patients were dissatisfied with treatment. The very high dropout rates make
statistical comparisons between groups difficult because of the large amount of
data being carried forward in an intent-to-treat analysis. Nonetheless, the only
difference between groups was a statistical advantage for fluoxetine in reducing
anxiety levels.
Given the finding that fluoxetine confers no benefit for adult patients with AN
either during the weight-gain period in the hospital or during outpatient
treatment, one must conclude that use of fluoxetine is not indicated in the
treatment of AN except to treat comorbid psychopathology. However, there have
been no satisfactory studies of other SSRIs in adolescents with AN, and such
studies would appear warranted, given the high priority for treatment early in the
course of AN.
Most patients with AN can be treated as outpatients. However, treatment can
be difficult because of the patient’s reluctance to gain weight. Weight should be
monitored at every outpatient visit, and it is important that weight be measured
in a hospital gown to prevent the use of lead weights to which some patients
with anorexia resort. Other methods of inflating weight are less easy to detect,
such as drinking large quantities of water before being weighed. Indications for
hospitalization include weight less than 75% of ideal body weight for age and
height, heart rate below 40 beats/minute, blood pressure below 90/60 mm Hg,
potassium levels below 3 mEq/L, temperature below 97°F, and very rapid weight
loss. In addition, because of the associated psychopathology in this disorder, the
usual indications for hospitalization for severe psychopathology should be
followed.
Conclusion
The place of psychopharmacological agents in the treatment of BN has been well
worked out. Treatment with sequential trials of different antidepressants should
result in abstinence rates of about 40%. The addition of CBT enhances the
effectiveness of antidepressants. It is becoming clear that agents such as
topiramate and similar anticonvulsants are useful in the treatment of BED, with
the added advantage of facilitating substantial weight loss in the overweight
patient. The recent FDA approval of lisdexamfetamine dimesylate recognizes the
potential benefit of this medication in BED. In the case of AN, there is little
evidence that pharmacological agents are helpful in either inpatient or outpatient
treatment of the adult patient, except to treat comorbid psychiatric disorders.
There is insufficient information regarding adolescent AN to provide guidance
regarding the use of medication at this point.
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CHAPTER 53
Treatment of Insomnia
Andrew D. Krystal, M.D., M.S.
Although there have long been agents available that differ in which of these
systems they affect, it has generally been believed that the pharmacological
mechanism of action of insomnia agents has no effect on their clinical effects
(Krystal et al. 2013b). Clinical effects have been assumed to be determined by
dose and pharmacokinetics (Krystal et al. 2013b). The higher the dosage, the
greater the clinical sleep-enhancing effect; the higher the dosage and the more
rapid the absorption, the sooner the clinical effect occurs; and the higher the
dosage and the longer the elimination half-life, the longer the duration of sleep
enhancement (Krystal et al. 2013b). This model emerged when the
pharmacological management of insomnia was dominated by a group of agents
—benzodiazepines (e.g., triazolam, temazepam, flurazepam) and
nonbenzodiazepines (e.g., zolpidem, zaleplon, eszopiclone)—that had a common
mechanism: sleep enhancement via positive allosteric modulation of GABAA
receptors (Krystal 2009; Krystal et al. 2013b). Systematic data on clinical effects
were essentially available only for these agents for which the
pharmacokinetics/dose model is largely correct. Their peak effect occurs at the
time of peak blood level, the speed of onset of clinical effects is proportional to
rate of absorption, and the duration of effects is proportional to the elimination
half-life. However, medications are available for the treatment of insomnia that
have a fundamentally different mechanism and specifically block a single wake-
promoting system (Krystal et al. 2013b). These agents with targeted, less global
effects have the promise of an improved risk–benefit ratio when used in patients
who have the type of sleep problem that is effectively treated with a particular
agent. Studies characterizing the clinical effects of these medications have only
relatively recently been carried out, and these studies verify the improved risk–
benefit ratio and indicate that the model in which dose and pharmacokinetics are
the prime drivers of clinical effects such that the mechanism of action is
irrelevant to clinical effects is incorrect (Herring et al. 2016; Krystal et al. 2010,
2011; Michelson et al. 2014).
One agent that illustrates this point is doxepin 3–6 mg, a highly selective
histamine H1 receptor antagonist that enhances sleep by specifically blocking the
wake-promoting effects of histamine (Krystal et al. 2010, 2011, 2013b). The
peak therapeutic effect does not occur at peak blood level, which is
approximately 3–4 hours after ingestion, but instead occurs at the end of the
night about 4 hours later (Krystal et al. 2010, 2011, 2013b). According to the
model in which pharmacokinetics and dose dominate clinical effects, this would
not be possible and a drug with peak effect at the end of the night would be
useless because it would cause prohibitive morning sedation or impairment
(Krystal et al. 2013b). Because clinical effects should be proportional to blood
level, and blood level only decreases incrementally over time, a drug with its
biggest effect in hour 8 of an 8-hour night should have effects that are nearly as
large in hour 9, the first hour of the day, at which time sleep-enhancing effects
are problematic (Krystal et al. 2013b). Yet doxepin 3–6 mg has its greatest
effects in hour 8 without clinically significant effects during waking 1 hour later
(Krystal et al. 2010, 2011). This profile of effects is incompatible with a model
in which therapeutic effects are dominated by pharmacokinetic factors and
indicates that factors other than pharmacokinetics play an important role in
determining clinical effects (Krystal et al. 2013b). These factors include the
specific properties of the pharmacological system(s) modulated by a given drug
and the activity in other systems that can affect sleep–wake function, which are
determined by factors such as time of day and the behavior of the individual
taking the medication and the psychosocial context (e.g., stress, novel
environment, excitement) (Krystal et al. 2013b). The relevance of other systems
was not apparent during the era when GABAA-positive allosteric modulators
dominated insomnia pharmacotherapy, because those agents broadly inhibit
brain function, nonspecifically shutting down all of the wake-promoting
systems. Agents that specifically inhibit a single wake-promoting system have
brought to light how activity in systems that are not inhibited can contribute to
clinical effects.
When using doxepin 3–6 mg as an example, the clinical effects of specifically
blocking the histamine system reflect both the characteristics of the histamine
system and the activity in parallel wake-promoting systems. Histamine is under
control of the circadian clock, and its release varies systematically over the 24-
hour cycle (Krystal et al. 2013b). When its release is minimal, the clinical effects
of blocking histamine H1 receptors should be minimal, whereas at times of
significant release of histamine, a therapeutic effect can be expected. However,
the activity of other sleep–wake–modulating systems that are not inhibited by
doxepin 3–6 mg also plays a role. Whether blockade of histamine H1 receptors
manifests in a clinical sleep-enhancing effect will depend on the activity in other
wake-promoting systems. If this activity is high, those systems will themselves
sustain wakefulness even with significant blockade of H1 receptors (Krystal et
al. 2013b).
The activity in these parallel wake-promoting systems can be dependent on
psychosocial context; for example, in an individual who is stressed or excited,
noradrenergic neuronal activity is likely to be high and could maintain
wakefulness despite histamine H1 receptor antagonism (Krystal et al. 2013b).
Another example of effects of time of day is that after an individual awakens for
the day during the usual waking period, activity in the neuropeptide
hypocretin/orexin system is increased and can maintain wakefulness even if H1
receptors are blocked (Krystal et al. 2013b). This explains why doxepin 3–6 mg
might have its largest effects in hour 8 of an 8-hour night and not have impairing
effects after waking: at the end of the night, histamine release is high, and the
parallel wake-promoting activity is normally relatively minimal, yet after
waking, activity in parallel wake-promoting systems increases and can maintain
wakefulness despite blockade of H1 receptors (Krystal et al. 2013b). Thus, to
determine the likely clinical effects of a medication, it is necessary to know not
only dose and pharmacokinetic parameters but also mechanism of action in
terms of which pharmacological system(s) it modulates, whether that system is
modulated by the circadian rhythm and state (e.g., activity, stress, novelty), and
what the circadian and state dependence are of the parallel pharmacological
systems that could oppose or enhance clinical effects.
Accordingly, the model that is the basis for the current chapter is that
“mechanism matters” and that three primary factors determine the clinical
effects of medications used to treat insomnia: 1) mechanism of action, 2) drug
pharmacokinetics, and 3) dosage. I review the characteristics of the various
medications available for the treatment of insomnia organized by
pharmacological mechanism of action. This includes reviews of the important
sleep-promoting system–enhancing drugs, which consist of the benzodiazepines,
nonbenzodiazepines, and melatonin receptor agonists, and the important wake-
promoting system antagonists, which consist of the selective antihistamines,
selective hypocretin/orexin receptor antagonists, selective adrenergic receptor
antagonists, and nonselective wake-promoting system antagonists. It must be
understood that in this chapter, the clinical effects of the agents with highly
specific pharmacological effects can only be partially characterized because the
activity in parallel systems that are not inhibited can vary greatly based on
factors such as behavior and psychosocial context, as described earlier, making
clinical effects more variable within and between individuals. As a result, rather
than trying to characterize the full range of possible clinical effects as influenced
by these factors for each agent, I indicate for each agent what the clinical effects
are likely to be, assuming no contributions from behavioral or psychosocial
context factors, and then also indicate whether behavioral and psychosocial
context factors could contribute to clinical effects.
Optimal target patient population. Benzodiazepines are best suited for use
in those who can benefit from the effects these agents may have on systems
other than sleep–wake systems, including those with anxiety or pain problems.
These agents also have beneficial effects for sleep-onset problems that are
stronger than other available options (Krystal 2009). However, the adverse
effects of these medications outweigh the beneficial effects for most patients; for
some with sleep-onset problems and comorbid conditions, these may have the
best risk–benefit ratio of the available agents.
Optimal target patient population. The limited available data do not make a
strong case for the utility of the nonselective antihistamines. However, to the
extent that they have therapeutic effects, they appear to be limited to
improvements in sleep maintenance and not sleep onset (Glass et al. 2008;
Morin et al. 2005). Thus, use should be limited to those without sleep-onset
difficulty who have problems with sleep maintenance. The H1 and cholinergic
receptor antagonism of the agents suggests that they would be best suited for use
in individuals experiencing sleep problems related to allergies or those with
nasal congestion due to other causes such as upper respiratory infection.
Antidepressants
The group of agents developed for the treatment of depression are referred to as
antidepressants. They have broad pharmacological effects, being antagonists at
several receptors, including at least one wake-promoting system, which leads
these medications to have sleep-promoting effects (Krystal 2010). These
medications are used off label for the treatment of insomnia, often at dosages
lower than the antidepressant dosage. With a few exceptions, the risk–benefit
profile of these medications for the treatment of insomnia has not been evaluated
in placebo-controlled trials. This is a significant limitation to including them in
an evidence-based approach to insomnia therapy. However, it can be assumed
that their nonspecific pharmacology leads them to have therapeutic effects on
conditions other than insomnia, some of which are common comorbid conditions
such as depression, anxiety, and pain, but at the same time associates these
medications with a relatively high side-effect burden (Krystal et al. 2013b).
Benzodiazepines
Triazolam GABA — Insomnia 0.125–
0.8
Nonbenzodiazepines
Zolpidem GABA — Insomnia: 5–10
sleep onset
Antipsychotics
The antipsychotics share similarities to the antidepressants in being medications
with broad pharmacological effects that were developed for an indication other
than insomnia disorder but are used off label in treating insomnia at lower-than-
usual dosages. In this case, they were developed for treatment of psychosis,
although some have more recently received FDA indications for bipolar mania
and depression as well. Like the antidepressants, the antipsychotics are
antagonists at several receptors, at least one of which includes a wake-promoting
system, which is the basis for their sleep-promoting effects (Krystal 2010;
Krystal et al. 2008b). Very limited data are available on the risk–benefit profile
of these medications for the treatment of insomnia. In fact, even fewer placebo-
controlled trials have been carried out with antipsychotics than with
antidepressants, which is a significant limitation to including the antipsychotics
in an evidence-based approach to insomnia therapy. However, it can be assumed
that their nonspecific pharmacology leads them to have therapeutic effects on
conditions other than insomnia, some of which are common comorbid conditions
such as schizophrenia, mania, delirium, depression, anxiety, and pain, but at the
same time associates these medications with a relatively high side-effect burden
(Krystal 2010; Krystal et al. 2008b, 2013b).
Conclusion
An increasing set of medications is becoming available to help patients with
insomnia. For many years, investigators believed that the mechanism of action
of insomnia medications was without clinical implications. Clinical effects were
assumed to be determined primarily by dose and drug pharmacokinetic
properties. It is now clear that this is not the case. Mechanism of action matters.
Clinical effects reflect not only dose and pharmacokinetics but also the specific
properties of the pharmacological system(s) being modulated by a given drug
and the nature and state of other parallel pharmacological systems that continue
to function during the period of action of that drug. As a result, factors such as
time of day, the behavior of the patient, and the patient’s psychosocial context
(e.g., stress, novelty, excitement) can play a role in determining the clinical
effects of medications used to treat insomnia. This has become apparent only
through experience with the relatively more recently available agents, including
selective antagonists of a single wake-promoting system. These agents promise
improved risk–benefit ratio over older, broadly acting agents for specific
subgroups of patients who have the specific type of sleep problem targeted by a
given selective wake-promoting system antagonist. To take advantage of this
promise requires knowledge of the specific clinical effects of each agent and the
type of sleep difficulty that they best treat. It is also important to appreciate the
instances when it is best to use a nonselective, more broadly acting agent.
Knowledge of the properties of each agent and the best target patient
subpopulation can then serve as a basis for optimally matching patients to
therapies in clinical practice. I hope this chapter provided the scientific basis and
practical information needed to work toward achieving this type of
personalization of insomnia therapies and ultimately to achieving better clinical
outcomes in insomnia patients.
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17557470
CHAPTER 54
Psychiatric Comorbidity
Pain is even more prevalent in patients with psychiatric comorbidity, particularly
mood disorders. The overlap between pain and depression ranges from 30% to
60% (Ang et al. 2006; Bair et al. 2003; Magni et al. 1993). Pain is a strong
predictor of both the onset and the persistence of depression (Ohayon and
Schatzberg 2003), and depression is likewise a powerful predictor of pain,
particularly persistent pain (Bair et al. 2003; Gureje et al. 1998). Concurrent pain
and depression have a much greater impact than either disorder alone on
multiple domains of functional status as well as health care utilization (Bair et al.
2003). Comorbid depression worsens disability and decreases active coping in
patients suffering from pain (Arnow et al. 2006; Demyttenaere et al. 2006).
Comorbidity decreases the likelihood of a favorable response of either condition
to treatment and also diminishes patient satisfaction with treatment (Bair et al.
2004; DeVeaugh-Geiss et al. 2010; Karp et al. 2005; Kroenke et al. 2008;
Mavandadi et al. 2007; Thielke et al. 2007). Thus, reliable methods for assessing
the presence and severity of pain in patients with depression (particularly those
not responding to initial treatment) and strategies for effectively and efficiently
integrating evidence-based depression care into the management of patients with
chronic pain are sorely needed (Kroenke 2003a).
Although not as extensively studied, the comorbidity of pain with anxiety
appears to be nearly as strong as its comorbidity with depression (Bair et al.
2008, 2013; Kroenke 2003b; Kroenke and Price 1993; Kroenke et al. 1994,
1997; McWilliams et al. 2003). Indeed, a global study conducted by the World
Health Organization in 17 countries and involving more than 85,000 community-
dwelling adults showed that pain is associated with mood and anxiety disorders,
but not with alcohol use disorders (Gureje et al. 2008). The prevalence of
specific mood and anxiety disorders was lowest among persons with no pain,
intermediate among those with one pain site, and highest among those with
multiple pain sites. Relative to persons not reporting pain, the age–sex adjusted
odds ratios were 1.8 (95% confidence interval [CI]=1.7–2.0) for mood disorders
and 1.9 (95% CI=1.8–2.1) for anxiety disorders for persons with single-site pain,
and 3.7 (95% CI=3.3–4.1) for mood disorders and 3.6 (95% CI=3.3–4.0) for
anxiety disorders among those with multisite pain.
Treatment of Pain
Overview
The focus of this chapter is twofold. First, we discuss major classes of
medications as they relate to pain management. Because a number of drugs are
effective across multiple types of pain disorders, it is useful to consider them in a
cross-cutting as well as a disease-specific fashion. Nonpharmacological
treatments are also reviewed. In the following main section (“Selected Pain
Disorders”), we briefly address several specific categories of disorders chosen
because they 1) account for the most common types of chronic pain, 2) are
conditions for which pain management is the principal focus, and 3) have been
studied in numerous clinical trials. In short, prevalence, pain management as a
priority rather than disease modification, and evidence-based therapy are the
three selection criteria for the discussion of specific disorders. Even within these
two broad foci (disorders and treatments), there will perforce be some
intermingling. For example, certain drug classes have been heavily studied
within certain pain disorders, and conversely, certain pain disorders have been a
common target of several classes of medications or other treatments.
The prototypical diseases discussed are musculoskeletal disorders (principally
fibromyalgia, low back pain, and osteoarthritis), headaches, and neuropathic
pain. Musculoskeletal disorders account for more than two-thirds of pain-related
outpatient visits, and headaches follow as the next most prevalent pain disorder.
Neuropathic pain not only is prevalent but also is a popular target for clinical
trials in pain management, and therefore is a common reason pain. Acute pain
(e.g., injuries, postoperative pain), cancer pain, and visceral pain are not
addressed. Although a moderate amount of thefor seeking U.S. Food and Drug
Administration (FDA) approval of pain as a drug indication. Although
pharmacotherapy receives the greatest attention in this chapter, we briefly review
nonpharmacological treatments due to their important role in the management of
chronic information presented in this chapter is relevant to the treatment of pain
in these and other conditions (especially the discussion of specific analgesics), a
detailed discussion of these specialized topics is beyond the scope of this
chapter.
Strength of Evidence
The majority of the information in this chapter was derived from meta-analyses
and systematic reviews. Individual randomized controlled trials (RCTs) are not
presented unless they reported on a promising treatment for which multiple trials
had not yet been performed. Certainly, evidence is strongest for those treatments
that have shown efficacy in multiple trials rather than just a single RCT,
particularly because individual trials sometimes yield contradictory findings.
Uncontrolled or open-label studies provide still weaker evidence and are cited in
only a few instances.
In meta-analyses and systematic reviews, the magnitude of a treatment’s effect
on particular domains such as pain and physical function is often reported as an
effect size. The effect size is a standard way to determine the degree of
improvement (or change) related to a particular therapy compared with a placebo
or other type of control group. The effect size is calculated as the mean change
in the treatment group minus the mean change in the control group, divided by
the pooled standard deviation. By convention, an effect size of less than 0.2 is
considered trivial; 0.2–0.5, small; 0.5–0.8, moderate; 0.8–1.2, important; and 1.2
or greater, very important (Cohen 1998).
Effect size can be useful when comparing continuous variables such as mean
differences (e.g., in pain scores). When comparing response rates on a
categorical variable (e.g., “improved” or “≥50% reduction in pain”), the number
needed to treat (NNT) is another common metric. The NNT is calculated as the
reciprocal of the absolute difference between treatment groups. For example, if a
clinical trial demonstrates that 60% of subjects improve while taking a new
analgesic versus 35% of subjects receiving a placebo, that is an absolute
difference of 25%. The NNT is the reciprocal of that: 1÷0.25=4. This means that
for every four patients who receive the analgesic, one additional patient would
achieve a therapeutic response over and above placebo (i.e., the other three
patients may have done just as well taking the placebo). Actually, an NNT of ≤5
typically represents a reasonably good analgesic.
When studying the same pain condition, the NNT may also be useful in
comparing different drugs. For example, in one study of acute pain after certain
operative procedures, 10 mg of morphine, 30 mg of ketorolac, and 100 mg of
meperidine (all administered by intramuscular injection) and 1,000 mg of
acetaminophen (administered orally) all had NNTs between 3 and 4;
furthermore, their 95% confidence intervals overlapped, implying no significant
difference in the analgesic efficacy between intramuscular opioids, intramuscular
nonsteroidal anti-inflammatory drugs (NSAIDs), and oral acetaminophen
(Barden et al. 2004). However, analgesic effect may depend on the type of pain
condition being treated or clinical context as well. For example, one study found
that the NNT for acetaminophen after dental extraction was 3.8, compared with
1.9 after orthopedic surgery (Barden et al. 2004). Also, small sample sizes may
affect the precision of NNT estimates; some feel that NNT calculations based on
trial data involving fewer than 500 subjects should be interpreted cautiously.
Second, it is more problematic to compare the NNTs of different drugs estimated
from separate studies than to compare the NNTs estimated for different drugs
tested in the same clinical trial. Third, NNTs derived from studying analgesics in
acute pain conditions may not be readily generalizable to their efficacy in the
treatment of chronic pain.
Pharmacotherapy
Nonopioid Analgesics
The anti-inflammatory properties of the extract of willow bark have been known
for centuries. Salicylic acid was discovered as the extract’s active ingredient in
the nineteenth century and was subsequently acetylated to improve its
gastrointestinal tolerability; acetylsalicylic acid became the prototypical
analgesic aspirin. Aspirin and other related compounds constitute a class of
drugs known as NSAIDs. All NSAIDs have three desirable pharmacological
effects—anti-inflammatory, analgesic, and antipyretic. NSAIDs and
acetaminophen are among the most commonly prescribed medications for acute
and chronic pain and can also be obtained without a prescription.
Acetaminophen has analgesic and antipyretic effects similar to those of the
NSAIDs but lacks a specific anti-inflammatory effect. Despite the widespread
use of acetaminophen, its analgesic mechanism is poorly understood.
Acetaminophen is a slightly weaker analgesic than NSAIDs (<10 point
difference on a 100-point visual analog pain scale) (Lee et al. 2004; Towheed et
al. 2006; Wegman et al. 2004) but is a reasonable first-line option because of its
more favorable safety profile and low cost. A recent trial found acetaminophen
to be no more effective than placebo in acute back pain (Williams et al. 2014),
whereas a much earlier trial found acetaminophen to be equivalent to low- or
high-dose ibuprofen in treating knee osteoarthritis (Bradley et al. 1991). It is
possible that analgesic effectiveness may vary with type of pain condition,
duration (acute vs. chronic), comparison group, and other factors.
Acetaminophen is associated with asymptomatic elevations of aminotransferase
levels at dosages of 4 g/day even in healthy adults, although the clinical
significance of these findings is uncertain (Watkins et al. 2006). Thus, known
liver disease is a reason either to use analgesics other than acetaminophen or to
lower the acetaminophen maximum daily dosage to 2,000 mg or less.
NSAIDs block the enzymatic activity of cyclo-oxygenase (COX), which uses
arachidonic acid to generate prostanoids. Prostanoids influence immune,
cardiovascular, gastrointestinal, renovascular, pulmonary, central nervous
system, and reproductive function. Although gastrointestinal adverse effects
have traditionally been considered the most common and worrisome
complication, cardiovascular risk has gained increasing attention (Antman et al.
2007). Aspirin was the first and at one time the most commonly used NSAID.
There are two major COX isoenzymes: COX-1 is expressed constantly in
most tissues, whereas COX-2 is induced by inflammation. NSAIDs vary in their
chemical structure and relative ability to block the COX-1 versus the COX-2
isoenzymes. Several prostaglandins are both hyperalgesic and gastroprotective.
Thus, nonselective COX inhibition with NSAIDs like aspirin, ibuprofen,
indomethacin, and naproxen, which inhibit both COX-1 and COX-2 enzymes,
provides effective pain relief for inflammatory conditions but carries a risk for
erosive gastritis and gastrointestinal bleeding. Selective COX-2 inhibitors
(valdecoxib, rofecoxib, celecoxib) have less gastrointestinal toxicity because of
the relative paucity of COX-2 expression in the gastrointestinal tract compared
with inflammatory tissue. However, data from meta-analyses and registries have
shown an increased risk of cardiovascular events and mortality from COX-2 use,
particularly in patients with known cardiovascular disease who receive
prolonged treatment. Rofecoxib (Vioxx) has been withdrawn from the market,
and all COX-2 inhibitors should be used cautiously, if at all, in patients with
cardiovascular disease or risk factors for cardiovascular disease. All NSAIDs,
including nonselective COX inhibitors and COX-2 agents, appear equally
effective in the treatment of pain disorders (Chou et al. 2006). The NSAID that
appears to be the safest in terms of cardiovascular risk is naproxen.
In July 2015, the FDA decided to strengthen its existing label warning that
NSAIDs increase the chance of a heart attack or stroke. Although there is some
risk even with short-term use or in patients without a history of cardiovascular
(CV) disease or risk factors, both longer duration of use and presence of CV
disease or risk factors substantially increase CV risk in patients receiving
NSAIDs. However, the actual increased risk in a specific patient is still low, and
given the prevalence of and disability associated with chronic pain and the
limitations of other treatment options, NSAIDs are likely to remain a staple of
pain management. Concerns about chronic use are particularly focused on
special populations including those at greater risk of cardiovascular (e.g., known
CV disease or >2 CV risk factors), gastrointestinal, or renal complications
(Marks et al. 2012).
Opioid Analgesics
The analgesic effects of opium have been known to mankind for more than
5,000 years. However, their inherent abuse risk soon became evident. Ever since,
society has attempted to find a balance between licit and illicit use, therapeutic
versus adverse effects, and medical needs and legal issues. Despite all the legal,
administrative, and social interference, no other class of drugs has remained in
use for as long as the opioids (Schug 2005).
Opioids have a leading place in the treatment of acute pain and advanced
cancer pain of moderate to severe intensity, because in both instances treatment
is expected to be of short to medium duration. In contrast, opioid treatment for
chronic noncancer pain is frequently delayed until first- or second-line
treatments have failed because of less clarity about the benefits of chronic use
and greater concerns about addiction, long-term effects (e.g., immunological,
reproductive), opioid-induced hyperalgesia, and regulatory difficulties.
The Controlled Substances Act of 1970 divided substances to be regulated
into five schedules, as determined by the U.S. Drug Enforcement
Administration. These schedules govern the legal distribution and use of most
substances with a significant abuse liability. Schedule I drugs have the highest
abuse potential; they are available for research only and have no approved
medical uses. Schedule II–IV substances have decreasing abuse liabilities (II is
the highest) and approved medical uses. Physicians are licensed to prescribe
these compounds, and pharmacies can dispense them, although pharmacies do
not stock all of these substances. Schedule II compounds have more stringent
record-keeping and storage requirements than do Schedule III and Schedule IV
substances. Schedule V substances have a recognized abuse liability (and
approved medical uses) but are generally not as highly regulated vis-à-vis record
keeping. Most opioids prescribed for pain are now Schedule II substances, and
refills are not authorized; instead, each dispensation requires a new prescription.
Exceptions are combination analgesics (e.g., those containing acetaminophen)
that contain less than 90 mg of codeine per unit dose, which are Schedule III
substances; and tramadol, which is a Schedule IV substance.
Opioids were initially reserved for the short-term treatment of pain following
surgery, trauma, and other acute conditions as well as palliative therapy for
cancer and other terminal diseases. In the 1990s, however, there was advocacy
for improved treatment of chronic pain, which led to a more liberal use of
opioids (Franklin 2014; Nuckols et al. 2014; Rauenzahn and Del Fabbro 2014;
Reuben et al. 2015). In the first decade of the twenty-first century, the number of
opioid prescriptions increased by more than 60%. Opioids are now the leading
cause of overdose deaths (about 16,000 deaths in the United States annually) and
are also associated with diversion to nonmedical uses. Because the long-term
benefits of opioid therapy for chronic pain have not been well established, there
are increasing state and federal regulations that are making the prescribing of
opioids more onerous for both clinicians and patients. Nonetheless, many experts
still believe that opioids have a role in that subset of patients whose chronic pain
has been refractory to other treatments, as long as there is appropriate
monitoring of response, attention to adverse effects, and minimization of
diversion and abuse.
Antidepressants
Anticonvulsants
Anticonvulsant drugs have been used in the management of pain since the
1960s. The clinical impression is that they are useful for chronic neuropathic
pain, especially when the pain is lancinating or burning. Three of the most
extensively studied anticonvulsants are gabapentin, pregabalin, and
carbamazepine. Gabapentin and pregabalin have the strongest evidence for the
treatment of pain. These two gabapentinoids act as neuromodulators by
selectively binding to the α2δ-subunit protein of calcium channels in various
regions of the brain and the superficial dorsal horn of the spinal cord. This
results in inhibition of the release of excitatory neurotransmitters that are
important in the production of pain. Gabapentin and pregabalin are analogs of γ-
aminobutyric acid (GABA), but they have no activity at GABA receptors and do
not alter GABA uptake or degradation.
Nonpharmacological Treatments
Nonpharmacological treatments will not be discussed in detail but need to be
mentioned because of their important role in the management of chronic pain.
Medications are typically targeted to the symptoms, but dysfunctional beliefs,
attitudes, coping styles, and behaviors frequently develop in patients with
chronic pain and contribute to its perpetuation and their disability. Moreover, just
as in other chronic medical disorders, pharmacotherapy is necessary but not
sufficient for optimizing outcomes. For example, the patient with diabetes not
only needs insulin or other hypoglycemic drugs but also requires dietary
changes, exercise, and other lifestyle modifications to achieve target blood
glucose levels. Cognitive-behavioral therapy, pain self-management, and
exercise are among the most evidence-based approaches and are discussed
below, along with several other behavioral interventions. Table 54–3 summarizes
the level of evidence for a variety of nonpharmacological interventions in the
treatment of chronic pain.
Strength of
evidencea Therapy References
Strong
Cognitive-behavioral therapy Dixon et al. 2007;
Institute of
Medicine 2011;
Jackson et al.
2006; Morley et
al. 2013
Pain self-management Du et al. 2011;
Institute of
Medicine 2011;
McBeth et al.
2012; Warsi et al.
2003
Exercise Fricton et al. 2009;
Häuser et al.
2010; Institute of
Medicine 2011;
Kelley et al.
2011; McBeth et
al. 2012; Naugle
et al. 2012; van
Middelkoop et al.
2011
Moderate
Acupuncture Dhanani et al. 2011;
Ernst et al. 2011;
Furlan et al.
2012; Institute of
Medicine 2011;
Manheimer et al.
2005; Manheimer
et al. 2007;
Rubinstein et al.
2010; Tan et al.
2007; A. White
et al. 2007
Yoga Crawford et al.
2014; Posadzki et
al. 2011; Sharma
and Haider 2013;
Tan et al. 2007;
Wren et al. 2011
Mindfulness/meditation/acceptance- Crawford et al.
based 2014; Reiner et
al. 2013; Tan et
al. 2007; Veehof
et al. 2011
Chiropractic (spinal manipulation) Furlan et al. 2012;
Institute of
Medicine 2011;
Rubinstein et al.
2010; Tan et al.
2007
Massage Dhanani et al. 2011;
Furlan et al.
2012; Institute of
Medicine 2011;
Tan et al. 2007
Tai chi Crawford et al.
2014; Dhanani et
al. 2011
Music therapy Crawford et al.
2014
Mixed (inconclusive)
Biofeedback Crawford et al.
2014; Dhanani et
al. 2011; Tan et
al. 2007
Hypnosis Crawford et al.
2014; Dhanani et
al. 2011; Jensen
and Patterson
2014; Tan et al.
2007
Herbal therapyb Dhanani et al. 2011;
Rubinstein et al.
2010
Guided imagery Crawford et al.
2014; Posadzki
and Ernst 2011a;
Posadzki et al.
2012
Qigong Crawford et al.
2014
Epidural corticosteroids Chou et al. 2015b;
Institute of
Medicine 2011;
Manchikanti et
al. 2015
Injection therapy/denervation Henschke et al.
procedures 2010; Institute of
Medicine 2011
Osteopathic manipulation Posadzki and Ernst
2011b
Internet-based psychological therapies Bender et al. 2011;
Eccleston et al.
2014
Minimal to low
Transcutaneous electrical nerve Bennett et al. 2011;
stimulation Crawford et al.
2014; Nnoaham
and Kumbang
2008; van
Middelkoop et al.
2011; Zeng et al.
2015
Magnets (static or pulsed Eccles 2005;
electromagnets) Institute of
Medicine 2011;
McCarthy et al.
2006; Pittler et
al. 2007; Tan et
al. 2007
Noninvasive brain stimulation O’Connell et al.
2014
a
Evidence based on number and sample size of trials, methodological quality of
trials, and outcomes, including effect sizes.
b
The most frequently studied herbals for pain include feverfew, devil’s claw, and
white willow bark.
Exercise
Exercise has been extensively studied in chronic pain patients and has been
demonstrated to be an effective adjunctive treatment for several types of chronic
pain disorders. Evidence regarding its effectiveness is discussed in more detail in
the “Fibromyalgia” and “Osteoarthritis” sections. Six general issues relevant to
initiating and maintaining an exercise program for chronic pain are summarized
in Table 54–4.
Principle Comments
Type of exercise Aerobic exercise is particularly
important for some types of
chronic pain (e.g., fibromyalgia),
whereas strengthening and
flexibility exercises may be helpful
in others (back pain,
osteoarthritis).
Catastrophizing as a barrier Fear that movement or activity will
worsen pain is common.
Emphasizing that gradual activity
will not cause further harm but
instead can be beneficial is
essential to activation and
rehabilitation.
Stage of change For patients in precontemplation
phase, motivating them to initiate
exercise is the challenge. For many
others who begin an exercise
program, getting them to maintain
regular exercise for more than a
few months is the critical issue.
This is analogous to weight loss,
smoking cessation, and other
lifestyle or behavioral changes.
Graduated program Patients should not try to do too
much initially. Instead, they should
begin slowly and increase the
amount of exercise gradually over
a matter of weeks to months.
Structured vs. home based The benefits of structured exercise
programs demonstrated in some
research studies may have a
“voltage drop” when patients are
instructed to begin an exercise
program on their own. Exercise
conducted in clinical settings (e.g.,
physical therapy, rehabilitation
programs) or community settings
(e.g., YMCA, fitness centers) may
be reinforced by motivation, group
participation, expert leadership,
guidance, and/or an externally
imposed regular schedule.
Monotherapy vs. bundled Many studies of exercise have
included other components, such
as education about the particular
pain disorder, self-management
techniques, relaxation, and other
cognitive-behavioral strategies.
Certainly, exercise coupled with
one or more of these is ideal.
Combination Therapy
Over time, the treatment of chronic pain often includes stepwise addition to a
patient’s regimen (and deletion if a therapy shows no benefit) of medications
from several classes (Black and Sang 2005; Gallagher 2005). In addition to
medications given to produce analgesia, pain management may include
medications to treat the side effects of the analgesics, such as laxatives or stool
softeners for patients receiving opioids, gastroprotective medications for those
receiving NSAIDs, and psychostimulants to combat excessive somnolence.
Very few studies have tested combinations of treatments to determine their
additive value, if any, compared with monotherapy. Only limited data suggest
that the combination of acetaminophen with NSAIDs has additive pain-relieving
effects (Schug 2005). The largest trial (892 community-derived subjects) found
greater pain relief with the combination of acetaminophen and ibuprofen than
with either drug alone (Doherty et al. 2011). More data show a beneficial effect
in combining acetaminophen with opioids, including codeine, tramadol, and
morphine. Indeed, one of the more common fixed combinations in a single pill
has been the coupling of an opioid, such as codeine, tramadol, oxycodone, or
hydrocodone, with a nonopioid analgesic such as acetaminophen or aspirin. One
important consideration in using fixed-dose combinations is that the maximum
daily dosage of one component may restrict flexibility in optimizing the dosage
of the other component. For example, when oxycodone 5 mg is combined with
acetaminophen 500 mg, the maximum number of tablets that can be
administered is eight in a 24-hour period (i.e., 4,000 mg of acetaminophen). If
this is insufficient to manage the patient’s pain, the opioid and nonopioid should
be given as separate medications to allow further upward titration of the opioid.
Head-to-head clinical trials comparing different analgesics for chronic pain,
separately or in combination, are rare. In addition to the acetaminophen–
ibuprofen trial (Doherty et al. 2011), a second example is a small (57 subjects
enrolled; 41 trial completers) randomized, double-blind crossover trial in
patients with neuropathic pain, which showed that gabapentin and morphine
combined achieved better analgesia at lower doses of each drug than either as a
single agent (Gilron et al. 2005). On the other hand, the gabapentin–morphine
combination resulted in a higher frequency of constipation than gabapentin alone
and a higher frequency of dry mouth than morphine alone. A third small
crossover trial (56 subjects enrolled; 45 trial completers) found the combination
of gabapentin and nortriptyline to be superior to either drug alone for
neuropathic pain (Gilron et al. 2009).
The common decision in clinical practice when optimal pain relief has not
been achieved is whether to switch to a new treatment or to add it to what is
currently being provided. Given the paucity of combination drug trials, this
decision is currently guided by practical considerations. Switching to another
monotherapy is often less costly than combining two or more treatments and
often is done when a patient has had only a minimal response to and/or poor
tolerance of the initial treatment. On the other hand, adding a second treatment
may be favored when there has been at least a partial response to the first
therapy or when the second treatment has a different mechanism of action that
may complement the original treatment. Factors influencing combination
therapy decisions include not only added efficacy but also costs, side effects,
adherence, and patient preferences. Sometimes, the secondary effects of a drug
may influence the decision to use it in a particular patient. For example, the side
effect of sedation that occurs with certain medications (e.g., gabapentin or
pregabalin) may be troublesome in one patient, whereas in another it may be
useful to treat comorbid insomnia, particularly if taken at bedtime. Likewise, the
antidepressant effects of a particular adjunctive pain medication (e.g., an SNRI
such as duloxetine) may reduce both pain and mood disturbances in the patient
with diabetic neuropathic pain and comorbid major depression. TCAs could
serve the same purpose, although higher dosages of TCAs are typically required
for antidepressant action than for analgesic action, in which case the side effects
of higher-dose TCAs, especially their cardiovascular effects, must be considered
as well.
Neuropathic pain (NP) is often classified by etiology or by the presumed site of neurologic
involvement (central or peripheral). More complex classification systems based on symptoms,
signs, anatomical distribution, or hypotheses regarding etiologies have been proposed, but it is not
clear if such classifications are accurate or reproducible. NP is characterized by continuous or
intermittent spontaneous pain, typically characterized by patients as burning, aching, or shooting.
Up to 3% of the general population reports NP at some time. NP is most commonly associated
with painful diabetic neuropathy, postherpetic neuralgia (PHN), or lumbar nerve root
compression. Diabetic neuropathy occurs in approximately 10% of persons with diabetes. The
most common form of diabetic peripheral neuropathy is a distal symmetric polyneuropathy,
typically manifested by symptoms beginning in the feet. PHN is defined as pain persisting or
recurring at the site of acute herpes zoster 3 or more months after the acute episode. It occurs in
up to 25% of patients following an episode of shingles. Symptomatic spinal stenosis and lumbar
disc herniation with nerve root compression occur in approximately 3% and 4% of patients with
low back pain, respectively. Other causes of NP include cancer-related pain, spinal cord injury,
poststroke pain, HIV-associated neuropathy, and phantom limb pain. Uncommon but potentially
debilitating NP conditions include trigeminal neuralgia (incidence 4/100,000 population). In the
U.S., health care and disability-related costs associated with NP are estimated at almost $40
billion annually. (Chou et al. 2007a, p. 6)
Fibromyalgia
Mechanisms and Evaluation
Fibromyalgia is one of the most common musculoskeletal disorders seen in
rheumatology practice as well as primary care. It is often classified among the
functional somatic syndromes (FSSs), which include irritable bowel syndrome,
chronic fatigue syndrome, temporomandibular joint disorder, interstitial cystitis,
and other symptom-based conditions manifested by a cluster of symptoms for
which the pathophysiological mechanism is not well understood (Aaron and
Buchwald 2001). Patients with one FSS often have one or more other FSSs as
well as psychological comorbidity, including depression and anxiety, and a
history of abuse during childhood or as adults. However, it does not appear that
FSSs are entirely explained by psychological factors (Henningsen et al. 2003),
and emerging research also shows biological factors that may be causative or
contributory.
The American College of Rheumatology core diagnostic criteria for
fibromyalgia depend entirely on clinical history and exam and do not require any
laboratory or radiological testing (Wolfe et al. 2010). Although tender points on
physical examination were originally required, the revised diagnostic criteria
now require only the following:
1. Generalized pain that is both widespread (i.e., on both the right and left sides
of the body, upper and lower halves, and axial as well as proximal arms and
legs) and chronic (lasting ≥3 months)
2. Somatic symptoms of which 3 cardinal symptoms are fatigue, unrefreshing
sleep, and cognitive symptoms (sometimes called “fibro fog”) but can also
include high numbers of other somatic symptoms
The other diagnostically useful finding is that unlike patients with arthritic
conditions (e.g., osteoarthritis, rheumatoid arthritis, systemic lupus), who mainly
suffer from arthralgias (pain and tenderness over the joints or periarticular
regions), patients with fibromyalgia experience myalgias (pain and tender points
in nonarticular regions). In fact, research shows that fibromyalgia patients feel
tenderness wherever pressure is applied, including areas previously considered
to be “control points” (Clauw 2007). The tenderness simply reflects the
fibromyalgia patient’s tendency toward allodynia (experiencing pain from
stimuli that would normally be nonpainful) or hyperalgesia (experiencing more
severe pain from stimuli that would normally be only mildly painful). Given that
the symptoms seem to arise from disturbances in the central processing of pain
and that tender points are a relatively nonspecific finding, some have advocated
calling the condition chronic widespread pain (Lee et al. 2014).
The primary problem in fibromyalgia appears to be not that there is too much
input coming from the pressure nociceptors peripherally but rather that there is
inadequate filtering of that activity, perhaps because of decreased activity of
descending anti-nociceptive pathways. In fact, multiple mechanisms seem to be
operative in fibromyalgia (Abeles et al. 2007). Two key mechanisms are as
follows:
Pharmacotherapy
A comparison of fibromyalgia guidelines from three different countries (Table
54–5) reveals that the most evidence-based medications are TCAs, SNRIs
(duloxetine, milnacipran), α2δ-ligand anticonvulsants (pregabalin, gabapentin),
and tramadol (Ablin et al. 2013). The strongest evidence is for the three drugs
that have received FDA approval for fibromyalgia: pregabalin, duloxetine, and
milnacipran. Although several trials (Bennett et al. 2003; Biasi et al. 1998;
Russell et al. 2000) have shown the effectiveness of tramadol in fibromyalgia,
the few studies of stronger opioids have not established their efficacy, and
adverse effects appear to outweigh benefits (Goldenberg et al. 2016). Also, the
few studies of NSAIDs in fibromyalgia have also had negative results,
suggesting that a class of drugs considered first-line treatment for arthritis and
other musculoskeletal disorders may not be effective in treating fibromyalgia.
Nonpharmacological Treatment
More than with most other pain disorders, nonpharmacological treatment for
fibromyalgia is especially important, and few patients should be treated with
medication only. Several systematic reviews have shown that the three
treatments with the most evidence of efficacy are exercise (particularly aerobic
exercise), education about fibromyalgia (either individually or in groups), and
CBT (Goldenberg et al. 2004; Henningsen et al. 2007; Sim and Adams 2002;
van Koulil et al. 2007). Similarly, guidelines emphasize CBT and exercise
(Ablin et al. 2013). A systematic review of 34 RCTs (involving 2,276 subjects)
evaluated exercise in fibromyalgia and found that aerobic-only exercise had
moderate positive effects on global well-being (effect size, 0.49), physical
function (effect size, 0.66), and pain (effect size, 0.65) (Busch et al. 2007).
Strength and flexibility exercises were underevaluated. A review of eight RCTs
of balneotherapy (pool exercise) also showed beneficial results in fibromyalgia
(Gowans and deHueck 2007), and this may be an alternative as an initial form of
exercise for individuals with arthritis, to reduce weight bearing on arthritic
joints, or for patients who fear exercise will exacerbate their pain. Seven RCTs
of CBT (two of which also included exercise) involving a total of 595 patients
showed benefits for CBT in five of the seven trials (van Koulil et al. 2007).
Education about fibromyalgia has been studied in numerous trials, both
individually and coupled with one or more other interventions, and appears to
have a positive effect (Goldenberg et al. 2004; Sim and Adams 2002). Education
coupled with exercise seems a particularly valuable bundled intervention
(Burckhardt 2006; Karjalainen et al. 2000; Rooks et al. 2007). Educational and
self-management resources are readily available online from organizations like
the National Fibromyalgia Association, the American College of Rheumatology,
and the Arthritis Foundation. Finally, data are inconclusive regarding
acupuncture, chiropractic therapy, massage therapy, yoga, trigger point
injections, and other nonpharmacological or CAM treatments for fibromyalgia
(Ablin et al. 2013; Goldenberg et al. 2004; Henningsen et al. 2007; Mayhew and
Ernst 2007; Sim and Adams 2002; Tan et al. 2007).
Low back pain is the fifth most common reason for all physician office visits in the U.S. and the
second most common symptomatic reason. Approximately one quarter of U.S. adults reported
having low back pain lasting at least one whole day in the past 3 months, and 7.6% reported at
least one episode of severe acute low back pain within a 1-year period. Low back pain is also very
costly: Total incremental direct health care costs attributable to low back pain in the U.S. were
estimated at $26.3 billion in 1998. In addition, indirect costs related to days lost from work are
substantial, with approximately 2% of the U.S. work force compensated for back injuries each
year. (Chou et al. 2007b, p. 478)
The authors go on to describe several other key points relevant to the clinical
epidemiology of low back pain. Most low back pain (85%) is nonspecific—that
is, it cannot be attributed to a specific disease or spinal abnormality.
Classification schemes frequently conflict with one another, and there is little
evidence that labeling patients by using specific anatomical diagnoses improves
outcomes. In a primary care setting, low back pain is only occasionally caused
by a specific serious disorder, such as cancer (0.7% of cases), compression
fracture (4%), or spinal infection (0.01%). The estimated prevalence of
ankylosing spondylitis in primary care patients ranges from 0.3% to 5%. Spinal
stenosis and symptomatic herniated disc are present in about 3% and 4% of
patients, respectively. The cauda equina syndrome, due to massive midline disc
herniation, is very rare (occurring in 0.04% of patients with low back pain).
Urinary retention is 90% sensitive, and the probability of the cauda equina
syndrome in back pain patients without urinary retention is approximately 1 in
10,000. The probability of cancer in patients presenting with back pain increases
from approximately 0.7% to 9% in patients with a history of cancer (not
including nonmelanoma skin cancer). In patients with any one of three other risk
factors (unexplained weight loss, failure to improve after 1 month, and age
greater than 50 years), the likelihood of cancer only increases to approximately
1.2%.
Table 54–6 outlines some key recommendations with respect to the evaluation
and management of low back pain. In the absence of red flags, a conservative
approach for at least 4 weeks is usually warranted, even if sciatica is present.
Magnetic resonance imaging is the preferred imaging procedure but can be
reserved for the minority of patients with red flags or persistent symptoms,
especially neurological findings. The two most common indications for surgery
are herniated disc with persistent symptoms (especially radiculopathy) and
spinal stenosis, which together account for less than 10% of cases of chronic
back pain. Trial data suggest that surgery may be only marginally beneficial for
pain due to a herniated disc but more helpful for spinal stenosis (Weinstein et al.
2006, 2008). Psychological factors are stronger predictors of low back pain
treatment outcomes than either physical examination findings or the severity or
duration of pain. Psychosocial factors that may predict poorer low back pain
outcomes include presence of depression, passive coping strategies, job
dissatisfaction, higher disability levels, disputed compensation claims, and
somatization.
Most back pain (>70%–80%) improves in the first 2–6 weeks. Thus, a 4-week
wait (i.e., a conservative approach) is warranted (even with sciatica) in the
absence of red flags.
Red flags that may prompt earlier diagnostic testing or referral include the
following:
• Cancer: history of cancer (strong predictor) or unexplained weight loss,
failure to improve after 4 weeks, and age greater than 50 years (all weaker
predictors)
• Infection (vertebral): fever, intravenous drug use, recent infection (none
well studied)
• Compression fracture: older age, osteoporosis, steroid use
• Cauda equina syndrome rare (0.04%); urinary retention 90% sensitive.
Physical examination focuses on a few cardinal neurological parts of the
lower-body exam:
• Straight-leg raising (SLR) in which the hip is flexed while the knee
remains extended. Ipsilateral-positive SLR is 91% sensitive but only 26%
specific for radiculopathy, whereas a crossed-positive SLR (i.e., sciatica
in the other leg) is only 29% sensitive but 88% specific.
• Lower-extremity motor and sensory exam:
– Knee strength and reflexes (L4 nerve root); screen with squat and rise
– Great toe and foot dorsiflexion strength (L5 nerve root); screen with
heel walking
– Foot plantar-flexion and ankle reflexes (S1 nerve root); screen with
walking on toes
Diagnostic tests are needed in only a minority of cases (with red flags or
persistent neurological signs).
• MRI is the preferred imaging study (less radiation and better visualization
of soft tissue, vertebral marrow, and the spinal canal).
• With some weaker red flags (e.g., age >50 years), plain films and ESR
may be obtained first and MRI obtained only if these tests are abnormal
or symptoms persist.
Psychological factors are a stronger predictor of chronicity and functional
outcomes such as disability than physical exam findings or the severity or
duration of pain.
Treatment: No treatment for back pain has good-quality (grade A) evidence of
substantial benefit. The following have fair-quality (grade B) evidence of
moderate benefit or small benefit but no significant harm, costs, or burdens:
• Pharmacotherapy: acetaminophen, NSAIDs, TCAs, tramadol/opiates,
benzodiazepines
• Nonpharmacological: chiropractic, acupuncture, massage, yoga, exercise,
progressive relaxation, cognitive-behavioral therapy, intensive
interdisciplinary rehabilitation
Note. ESR=erythrocyte sedimentation rate; MRI=magnetic resonance imaging;
NSAIDs=nonsteroidal anti-inflammatory drugs; TCAs=tricyclic antidepressants.
NSAIDs=nonsteroidal anti-inflammatory drugs; TCAs=tricyclic antidepressants.
Medications are the most frequently recommended intervention for low back
pain. The most commonly prescribed medications for low back pain are
NSAIDs, skeletal muscle relaxants, and opioid analgesics (Chou and Huffman
2007a). Benzodiazepines, systemic corticosteroids, antidepressant medications,
and antiepileptic drugs are also prescribed. Frequently used over-the-counter
medications include acetaminophen, aspirin, and certain NSAIDs. No treatments
for back pain have grade A evidence supporting their use—that is, good-quality
evidence of substantial benefits. Table 54–6 summarizes treatments with grade B
evidence. For pharmacotherapy, this includes acetaminophen, NSAIDs,
tramadol, and TCAs. For all medications, the evidence of beneficial effects on
functional outcomes is limited. Skeletal muscle relaxants, which may be
beneficial for acute back pain, do not have established efficacy for chronic pain.
Although systematic reviews of opioids for various chronic pain conditions have
shown moderate benefits, the evidence for opioids specifically for low back pain
is sparse and inconclusive (Martell et al. 2007). A prospective study found that
early prescription of opioids for acute occupational low back injury was
associated with an increased risk of work disability at 1 year, even after
adjustment for severity of pain, function, and initial injury (Franklin et al. 2008).
A systematic review of 25 trials involving 2,206 patients found no benefits for
either continuous or intermittent traction in the treatment of low back pain
(Clarke et al. 2007). There is also good evidence that systemic corticosteroids
are ineffective for low back pain with or without sciatica. One systematic review
identified only 7 trials evaluating medications for sciatica (Vroomen et al. 2000).
Two small trials suggest that gabapentin may be useful in the subset of patients
with radiculopathy.
Ten trials were included in two systematic reviews of antidepressants (Salerno
et al. 2002; Staiger et al. 2003). In all of the trials, the duration of therapy ranged
from 4 to 8 weeks. Antidepressants were consistently superior to placebo for
pain relief, whereas the benefits in terms of functional outcomes were uncertain.
The pooled effect size for pain relief was moderate (0.41). Indirect comparisons
suggested modest benefits with TCAs but not with paroxetine or trazodone. A
recent review of six trials of duloxetine in patients with back pain showed an
analgesic benefit (Pergolizzi et al. 2013).
Osteoarthritis
Osteoarthritis is one of the most common musculoskeletal pain disorders (along
with low back pain and fibromyalgia) in both primary care and specialty
settings. It typically increases with age (particularly after age 50 years), with the
majority of individuals older than 65 years having at least one joint affected by
osteoarthritis. Common joints involve the distal and proximal interphalangeal
(but not metacarpal) joints of the fingers, the base of the thumb, the knees, the
hips, and the cervical and lumbar regions of the spine. The shoulder and elbow
are rarely involved. The most common finding on physical examination is an
increase in joint size secondary to osteophyte formation. Plain radiographs are
typically the only diagnostic test required to confirm the diagnosis of
osteoarthritis, which is manifested by loss of joint space and/or osteophyte
formation.
In contrast to the case in rheumatoid arthritis and other inflammatory types of
arthritis, the structural changes in osteoarthritis are not amenable to specific
disease-modifying treatments. Thus, the focus of treatment in osteoarthritis is
reduction of pain and preservation of function. Acetaminophen and NSAIDs,
which are inexpensive and available without a prescription, are the mainstays of
pharmacotherapy. A systematic review of 13 trials in patients with osteoarthritis
of the knee found that both aerobic exercise and home-based quadriceps-
strengthening exercise reduced pain (effect sizes, 0.52 and 0.39, respectively)
and disability (effect sizes, 0.46 and 0.32) (Roddy et al. 2005). Benefits of
aerobic and strengthening exercises in osteoarthritis patients were confirmed in a
second systematic review (Brosseau et al. 2003). For advanced disease with
progressive pain and functional impairment, total hip arthroplasty and knee
arthroplasty are effective. In contrast, a systematic review of 23 studies found
inconclusive evidence for the benefits of arthroscopic lavage and/or debridement
in knee osteoarthritis (Samson et al. 2007). The lack of efficacy for lavage, with
or without intra-articular corticosteroids, was confirmed in a meta-analysis of six
trials involving 855 patients (Avouac et al. 2010). Glucosamine, chondroitin, and
intra-articular hyaluronic acid have been the most popular CAM treatments for
osteoarthritis, but multiple meta-analyses and systematic reviews (Table 54–7)
found insufficient evidence to support the efficacy of either glucosamine or
chondroitin. In contrast, hyaluronic acid seems to be effective in knee
osteoarthritis, although it does require intra-articular administration. It also
seems to be similar in efficacy to continuous NSAID therapy (Bannuru et al.
2014) and intra-articular corticosteroids (Bannuru et al. 2009).
Strength
of
Treatment Study Condition Review type Benefits evidence
Glucosamine Vlad et al. Knee or Meta- Not Moderate
2007 hip analysis known
OA (15 trials,
2,825
patients)
Headache
Although there are less common and/or more serious causes of headache, most
individuals with chronic headache have either migraine headache or tension-type
headache (TTH). Up to one-third of the general population report TTH, and 10%
experience migraine headaches (Robbins and Lipton 2010). However, more
patients with migraine headache present to physicians for care. Contrary to
public perceptions, sinus disease, hypertension, and eye strain are not common
causes of headache.
Migraine is easier to diagnose in the presence of aura, which most commonly
include a visual prodrome such as blind spots (scotomas), zigzag patterns
(fortification spectra), or flashing lights (scintilla). However, aura occur in less
than 20% of patients with migraine attacks.
Diagnostic criteria can differentiate migraine headache from TTH (Toward
Optimized Practice 2012). Migraine without aura is diagnosed if at least two of
the following are present: 1) nausea during the attack, 2) light sensitivity during
the attack; and 3) some of the attacks interfere with the patient’s activities. TTH
is diagnosed if headaches are not associated with nausea and at least two of the
following are present: 1) bilateral headache, 2) nonpulsating pain, 3) mild to
moderate intensity, and 4) headache is not worsened by activity.
Some individuals with migraine or TTH develop chronic daily headache
(CDH), defined as a headache frequency of ≥15 days a month for longer than 3
months. A common reversible cause of CDH is medication overuse headache
(MOH), which can develop when analgesics are taken for headaches more than
2–3 days per week. Whereas all analgesics have the potential for MOH, the risk
appears to be the highest with opioids or combination analgesics containing
butalbital or caffeine, intermediate with triptans, and lowest with NSAIDS.
MOH often manifests as a headache that is present upon awakening and that
responds to analgesics with only transient relief. This is turn can lead to a
vicious circle of increased analgesic use.
Neuroimaging has a low yield in the evaluation of headaches. Even among
selected patients with headache seen in tertiary referral centers, less than 1%–2%
have abnormal imaging findings that influence treatment (Clarke et al. 2010;
Dumas et al. 1994). Factors that may justify an imaging study are focal
neurological signs or symptoms, onset of headache after age 40 years, and severe
or worsening headaches that do not respond to appropriate therapy.
An initial stepped-care approach to pharmacotherapy for migraine and TTH is
summarized in Table 54–8. Because migraine headache is both more disabling
and more prevalent among patients who seek care, the amount of clinical trial
evidence available, as well as the number of medications that have been well
studied, is greater than for TTH. Treatment of less common types of headache
(e.g., cluster headache) or chronic refractory headache probably warrants referral
to a neurologist or other clinician specializing in headache management.
Morphine 15 mg bid ±
sustained
release; try
to keep ≤60
mg bid
A Migraine-specific agentsb,d
Triptansb
Sumatriptan 50–100 mg
oral or 5–
20 mg
nasal spray
Zolmitriptan 2.5–5.0 mg
oral or
nasal spray
Beta-blockersb
Propranolol 20–80 mg bid
Metoprolol 25–100 mg
bid
Topiramate Start at 25 mg
hs to bid;
titrate to 50
mg bid (or
100 mg hs)
Divalproex Start at 250
mg bid;
titrate to
500 mg bid
B Topical analgesics
Capsaicin Apply +
0.025%–
0.075%
cream 2–4
times/day
over
painful area
Other Issues
Placebo Effect
As with other symptom-based conditions (e.g., depression, anxiety, somatoform
disorders), pain has a placebo response in the 30%–40% range or higher. This
can make it challenging to separate the specific effects of a pain treatment—
medication or nonpharmacological—from placebo or other nonspecific effects.
A network meta-analysis of 149 trials in adults with osteoarthritis showed that
the effect size for intra-articular or topical placebo was greater than that for oral
placebo (Bannuru et al. 2015). In the model accounting for differential effects,
intra-articular and topical therapies were superior to oral treatments in reducing
pain. When these differential effects were ignored, oral NSAIDs were superior.
At the same time, the role of placebo effects on pain outcomes can be useful in
clinical practice, including patient expectancy for an analgesic outcome and the
clinical benefits of a positive therapeutic relationship. Pain is the most frequent
reason for seeking CAM care (Astin 1998). Although evidence for several CAM
treatments may still be lacking, their placebo effects coupled with frustration
among many allopathic physicians and patients in the context of chronic pain
may account for the popularity of CAM treatments for pain.
Experimental work has also revealed some interesting physiological effects of
placebo. A meta-analysis of 12 studies (1,183 participants) was conducted to
examine the effects of placebo and an opioid antagonist, naloxone, on pain
(Sauro and Greenberg 2005). Placebo administration was associated with a
decrease in self-reported pain, and a hidden or blind injection of naloxone
reversed placebo-induced analgesia. An experimental study in 20 healthy
subjects found that the placebo and nocebo effects (i.e., the therapeutic and
adverse effects, respectively, of inert substances or sham procedures) are
associated with opposite responses of dopaminergic and endogenous opioid
neurotransmission in a distributed network of regions throughout the brain (Scott
et al. 2008). The results support other literature showing that the belief in and
expectation of analgesia induce discrete physiological changes, leading to relief
from pain, and this response may be mediated by endogenous opioids.
Clinical ways to take advantage of the placebo effects of an analgesic are
summarized by Klinger et al. (2014):
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CHAPTER 55
Diagnostic Accuracy
The diagnosis should be reassessed. Often there is symptomatic overlap among
disorders that may lead to misdiagnosis. For example, symptoms of excessive
energy and distractibility are common features of both attention-
deficit/hyperactivity disorder (ADHD) and bipolar disorder.
Comorbid Disorders
Unrecognized comorbid disorders may adversely affect treatment outcome. As
an example, comorbid ADHD may lower response rates in the treatment of
bipolar disorder (Pavuluri et al. 2006).
Psychosocial Factors
Child abuse, domestic violence, family conflict, parental psychopathology, and
bullying by peers may lead to symptoms that mimic or exacerbate a preexisting
psychiatric disorder.
Medication Compliance
Some children and adolescents are reluctant to take medication because of such
reasons as denial of illness, perceived stigma, and side effects. For increased
medication compliance, the child or adolescent, as well as the parents, must
understand the youth’s disorder, course of illness, and goals of treatment. It is
important for parents to participate in monitoring their child’s medication
compliance.
Nonpharmacological Treatment
Psychotherapy may be beneficial, either alone or in conjunction with medication.
Specific psychotherapies have been found to be effective in the treatment of
some childhood disorders. For example, cognitive-behavioral therapy (CBT) and
interpersonal therapy have demonstrated efficacy in the treatment of adolescents
with depression (Zhou et al. 2015). Similarly, CBT is commonly used for the
treatment of childhood anxiety disorders (Roblek and Piacentini 2005). Behavior
therapy has led to improvement in symptoms of ADHD for children (Pelham et
al. 1998). Adjunctive psychoeducation with medication treatment has shown
benefit in the treatment of children with bipolar disorder (Fristad et al. 2003).
Social skills training can be a useful component of treatment in autism spectrum
disorder (Krasny et al. 2003).
Informed Consent
Informed consent is necessary prior to prescribing psychotropic medication to
any patient, but it is particularly important in pediatric psychopharmacology
because few medications have been approved by the U.S. Food and Drug
Administration (FDA) for young populations. There are five recommended
components of informed consent for prescribing psychotropic medications to
children and adolescents (Popper 1987). The child’s parent(s) and the child or
adolescent should be provided with the following information:
Evidence Base
It is important for clinicians to be aware of the evidence base for medication
treatment of each childhood psychiatric disorder. Clinical treatment guidelines
generally rely on the strength of the available data in determining first-line
agents. In most cases, clinicians should select a medication within the group of
first-line agents when initiating medication treatment with a child. Additional
factors that will dictate medication choice are prior medication history, medical
history, side-effect profile of the drug, and adolescent and parent preferences.
Fluoxetine
There have been three positive controlled medication trials of fluoxetine in the
treatment of major depression in children and adolescents. In the first study, 96
child and adolescent outpatients (ages 8–17 years) with major depression were
randomly assigned to fluoxetine 20 mg/day or placebo for an 8-week trial
(Emslie et al. 1997). The fluoxetine group, with 27 youths (56%) much or very
much improved, showed statistically significantly greater improvement in
Clinical Global Impression (CGI) Scale scores than the placebo group, with 16
youths (33%) much or very much improved. Medication side effects leading to
discontinuation in the study were manic symptoms in three patients and severe
rash in one patient.
In a double-blind, placebo-controlled multicenter study of fluoxetine, 219
child and adolescent outpatients (ages 8–17 years) with major depression were
randomly assigned to fluoxetine 20 mg/day or placebo for an 8-week trial
(Emslie et al. 2002). Improvement in depression was statistically significantly
greater for the fluoxetine group, as assessed by means of the Children’s
Depression Rating Scale—Revised (CDRS-R), than for the placebo group. Fifty-
two percent of patients treated with fluoxetine were rated as much or very much
improved, compared with 37% of patients treated with placebo. Headache was
the only side effect that was reported more frequently in the group treated with
fluoxetine than in the group treated with placebo.
In a multicenter trial of 439 adolescent outpatients with a diagnosis of major
depression (March et al. 2004), patients were randomly assigned to 12 weeks of
fluoxetine (10–40 mg/day), fluoxetine (10–40 mg/day) with CBT, CBT alone, or
placebo. Compared with placebo, the combination of fluoxetine with CBT was
significantly superior, according to changes in CDRS-R scores. Combination
treatment with fluoxetine and CBT was significantly superior to treatment with
fluoxetine alone or CBT alone. Fluoxetine monotherapy was superior to CBT.
Response rates (defined as CGI ratings of much or very much improved), were
71% for fluoxetine–CBT combination therapy, 61% for fluoxetine, 43% for
CBT, and 35% for placebo.
Escitalopram
There have been two controlled trials of escitalopram in the treatment of youth
with depression, one positive and one negative. The efficacy of escitalopram in
adolescents was demonstrated in a double-blind, placebo-controlled multicenter
trial of 157 adolescents with major depression (Emslie et al. 2009). Patients were
randomly assigned to escitalopram (dosage range=10–20 mg/day) or placebo for
an 8-week trial. The group treated with escitalopram showed statistically
significantly greater improvement in depression (CDRS-R scores) than the
placebo group. Sixty-four percent of escitalopram-treated patients were much or
very much improved, compared with 53% of placebo-treated patients. In a study
that included 264 children and adolescents with major depression (Wagner et al.
2006a), there was no significant improvement on CDRS-R scores at endpoint
between escitalopram and placebo. The most common adverse events with
escitalopram were headache, abdominal pain, nausea, insomnia, and menstrual
cramps.
Citalopram
There have been two controlled trials of citalopram in the treatment of
depression in youth, one with positive and one with negative results. The
efficacy of citalopram was demonstrated in a double-blind, placebo-controlled
multicenter trial of 174 outpatient children and adolescents (ages 7–17 years)
with major depression (Wagner et al. 2004b). Patients were randomly assigned to
receive citalopram (dosage range=20–40 mg/day; mean daily dosage=23 mg for
children, 24 mg for adolescents) or placebo for an 8-week trial. Compared with
the placebo group, the citalopram group showed statistically significantly greater
improvement in depression (CDRS-R scores). The most frequent adverse events
were headache, nausea, rhinitis, abdominal pain, and influenza-like symptoms. A
European double-blind, placebo-controlled multicenter study (von Knorring et
al. 2006) of citalopram in 224 adolescents with major depression failed to show
superiority of citalopram to placebo on the primary efficacy measures, the
Schedule for Affective Disorders and Schizophrenia for School-Aged Children
—Present Episode Version (Kiddie-SADS-P) and the Montgomery-Åsberg
Depression Rating Scale (MADRS). The most commonly reported adverse
events were headache, nausea, and vomiting.
Sertraline
The efficacy of sertraline was assessed in two identical double-blind, placebo-
controlled multicenter studies of 376 outpatient children and adolescents with
major depression (Wagner et al. 2003a). Patients were randomly assigned to
sertraline (dosage range=50–200 mg/day; mean daily dosage=131 mg) or
placebo for a 10-week trial. Compared with the placebo group, the group
receiving sertraline showed a statistically significantly greater improvement in
depression (CDRS-R scores). Response rates (decrease ≥40% in baseline CDRS-
R scores) were 69% in the group treated with sertraline and 59% in the group
treated with placebo. The most common side effects in the group treated with
sertraline were headache, nausea, insomnia, upper respiratory tract infection,
abdominal pain, and diarrhea.
Sertraline, CBT, and combined CBT plus sertraline were compared in the
treatment of 73 adolescents with depressive disorders (Melvin et al. 2006). All
treatments resulted in statistically significant improvement on all outcome
measures; there were no significant advantages of combined treatment.
In the Adolescent Depression and Psychotherapy Trial (ADAPT; Goodyer et
al. 2008), 208 adolescents with major depression were randomly assigned to
receive an SSRI alone or an SSRI plus CBT for 12 weeks. No significant
differences were found between the groups; 44% of the SSRI-alone group and
42% of the SSRI-plus-CBT group were much or very much improved on the
CGI Improvement subscale (CGI-I).
Paroxetine
There have been three double-blind, placebo-controlled trials of paroxetine for
treatment of depression in children and adolescents, all of which had negative
findings on the primary outcome measure. In a study of 275 adolescent
outpatients (ages 12–18 years) with major depression, patients were randomly
assigned to paroxetine (dosage range=20–40 mg/day; mean daily dosage=28
mg), imipramine (dosage range=200–300 mg/day; mean daily dosage=205 mg),
or placebo for an 8-week trial (Keller et al. 2001). There was no statistically
significant difference among the treatment groups on the primary efficacy
measure of reduction in total score on the Hamilton Rating Scale for Depression
(Ham-D). The most common side effects reported for paroxetine were headache,
nausea, dizziness, dry mouth, and somnolence.
Two hundred six children and adolescents (ages 7–17 years) with major
depression were included in an 8-week double-blind, placebo-controlled,
randomized multicenter study of paroxetine treatment (Emslie et al. 2006). There
was no statistically significant difference between patients treated with
paroxetine and patients given placebo on change from baseline in CDRS-R total
score at endpoint. Adverse events reported for paroxetine with an incidence of
>5% and at least twice that of placebo were dizziness, cough, dyspepsia, and
vomiting.
A 12-week international placebo-controlled multicenter trial of paroxetine in
286 adolescents with major depression failed to show superiority for paroxetine
compared with placebo on change from baseline in MADRS or Schedule for
Affective Disorders and Schizophrenia for School-Aged Children—Lifetime
Version (Kiddie-SADS-L) total score (Berard et al. 2006).
Other Antidepressants
Venlafaxine
Two double-blind, placebo-controlled multicenter studies have evaluated the
efficacy of venlafaxine extended release (XR) in the treatment of major
depression in 165 and 169 child and adolescent outpatients, respectively (Emslie
et al. 2007). Patients were randomly assigned to venlafaxine XR (37.5–225
mg/day; flexible dosage based on body weight) for 8-week trials. Both studies
were negative on the primary outcome measure of change from baseline to
endpoint in the CDRS-R scores. The most common adverse events were
anorexia and abdominal pain (Emslie et al. 2007).
Nefazodone
There have been two double-blind, placebo-controlled multicenter trials of
nefazodone in the treatment of major depression in youth (Rynn et al. 2002; U.S.
Food and Drug Administration 2004b). These studies failed to find statistically
significant improvement in baseline-to-endpoint CDRS-R scores between the
nefazodone-treated group and the placebo-treated group. The most common
adverse events with nefazodone were headache, abdominal pain, nausea,
vomiting, somnolence, and dizziness.
Bupropion
There are no controlled trials of bupropion for the treatment of pediatric
depression.
In an 8-week study of bupropion sustained release (dosage range=100–400
mg/day; mean daily dosage=362 mg) for treating 11 adolescents with major
depression, 8 adolescents (79%) showed a 50% reduction in depression scores
from baseline (Glod et al. 2000). Bupropion sustained release was assessed in an
8-week open study for the treatment of comorbid depression and ADHD in 24
adolescents (Daviss et al. 2001). Global improvement was reported in 14
subjects (58%) for both depression and ADHD and in 7 subjects (29%) for
depression only. Common side effects were headache, nausea, rash, and
irritability.
Mirtazapine
There have been two double-blind, placebo-controlled multicenter trials of
mirtazapine in the treatment of child and adolescent outpatients with major
depression. In these studies, mirtazapine was not superior to placebo on the
primary efficacy measure of change from baseline to endpoint in CDRS-R scores
(U.S. Food and Drug Administration 2004b).
Duloxetine
There have been two failed 10-week trials of duloxetine in the treatment of
children and adolescents with major depression (Atkinson et al. 2014; Emslie et
al. 2014). Duloxetine and fluoxetine were not superior to placebo on the primary
efficacy measure of change from baseline to endpoint in CDRS-R scores. The
most common adverse events were nausea, vomiting, nasopharyngitis, upper
abdominal pain, headache, and somnolence.
Treatment-Resistant Depression
In the National Institute of Mental Health (NIMH)–funded multisite Treatment
of SSRI-Resistant Depression in Adolescents (TORDIA) trial (Brent et al. 2008),
334 adolescents with SSRI-resistant depression were randomly assigned to one
of four treatments for 12 weeks: 1) switch to an alternate SSRI (paroxetine,
citalopram, or fluoxetine), 2) switch to an alternate SSRI plus CBT, 3) switch to
venlafaxine, or 4) switch to venlafaxine plus CBT. CBT plus a medication switch
(to venlafaxine or to an alternate SSRI) produced the highest rate of response
(54.8%). Response rates (CGI-I score ≤2 and CDRS-R ≥50% reduction) were
similar for switching to an alternate SSRI and switching to venlafaxine (47% and
48.2%, respectively). Skin problems and increases in diastolic blood pressure
and pulse were more frequently experienced during venlafaxine treatment than
during SSRI treatment.
Clinical Recommendations for Major
Depressive Disorder
An evidence-based consensus medication algorithm for the treatment of
childhood major depression is available (Texas Children’s Medication Algorithm
Project [TMAP]; Hughes et al. 2007). Based on research evidence and panel
discussion, four stages of medication treatment are identified:
Stage 1: SSRI
Stage 2: Alternate SSRI
Stage 2A (if partial response to SSRI): SSRI+lithium, bupropion, or
mirtazapine
Stage 3: Different class of antidepressant medication (venlafaxine, bupropion,
mirtazapine, duloxetine)
Stage 4: Reassessment, treatment guidance
Bipolar Disorder
The prevalence of bipolar disorder in a community sample of adolescents was
found to be 1% (Merikangas et al. 2010). Although DSM-5 criteria are used to
diagnose bipolar disorder in youth, the clinical features in children may differ
from those in adolescents and adults. Children with bipolar disorder frequently
exhibit mixed mania and rapid cycling (B. Geller et al. 2000). One-year recovery
rates of 87% and relapse rates of 64% have been reported in children with
bipolar disorder (B. Geller et al. 2004).
Six medications have FDA approval for the acute treatment of bipolar I
disorder, mixed or manic episode, in youth: lithium (≥12 years old), aripiprazole
(≥10 years old), asenapine (≥10 years old), olanzapine (≥13 years old),
risperidone (≥10 years old), and quetiapine (≥10 years old). Ziprasidone has
been studied for the treatment of bipolar disorder in youth, but it does not have
FDA approval for that indication.
Lithium
The efficacy of lithium for the treatment of bipolar I disorder, manic or mixed
episode, was assessed in an 8-week double-blind, placebo-controlled trial
involving 81 youths (ages 7–17 years) (Findling et al. 2015b). The mean lithium
serum level at endpoint was 0.98 mEq/L. Lithium was superior to placebo on the
primary outcome measure of change in Young Mania Rating Scale (YMRS)
score from baseline to endpoint. On CGI-I scores, 47% of lithium-treated and
21% of placebo-treated patients were much or very much improved. The most
common adverse events with lithium were vomiting, nausea, and headache.
There was a statistically significant increase in thyrotropin concentration with
lithium.
In an NIMH-funded study, 153 children and adolescents with bipolar I
disorder, mixed or manic episode, were randomly assigned to treatment with
lithium, divalproex, or placebo in an 8-week trial (Kowatch et al. 2007). Target
lithium serum levels were 0.8–1.2 mEq/L. Lithium was not significantly superior
to placebo.
There is one small double-blind, placebo-controlled study of lithium treatment
for adolescent bipolar disorder and DSM-III-R (American Psychiatric
Association 1984)–defined substance dependence (B. Geller et al. 1998).
Twenty-five adolescent outpatients were randomly assigned to either lithium
(mean serum level=0.97 mEq/L) or placebo for a 6-week trial. There was
significantly greater improvement in global functioning with lithium than with
placebo. Side effects in the group treated with lithium were polyuria, thirst,
nausea, vomiting, and dizziness.
Atypical Antipsychotics
Aripiprazole
The efficacy of aripiprazole was assessed in a 4-week double-blind, placebo-
controlled trial that included 296 youths with bipolar I disorder, mixed or manic
episode (Findling et al. 2009). Both low-dosage aripiprazole (10 mg/day) and
high-dosage aripiprazole (30 mg/day) were significantly superior to placebo in
reduction of YMRS scores. The response rate (≥50% reduction in YMRS score)
was 44.8% for low-dosage aripiprazole, 63.6% for high-dosage aripiprazole, and
26.1% for placebo. The most common adverse events with aripiprazole were
somnolence, extrapyramidal side effects (EPS), and tremor, which were more
frequent in the high-dosage aripiprazole group.
Asenapine
The efficacy of asenapine was evaluated in a 3-week, double-blind, placebo-
controlled trial of 403 youths (ages 10–17 years) with bipolar I disorder, mixed
or manic episode (Actavis 2017). Dosages ranged from 2.5 to 10 mg twice daily.
Asenapine was significantly superior to placebo on outcome measures of change
in YMRS and CGI Bipolar (CGI-BP) Severity of Illness scores from baseline to
endpoint. The most comment adverse events were somnolence, dizziness, oral
hypoesthesia, headache, fatigue, and increased appetite.
Olanzapine
There is one reported double-blind, placebo-controlled multicenter study of
olanzapine (2.5–20 mg/day) in the treatment of adolescent outpatients with
bipolar I disorder, mixed or manic episode (Tohen et al. 2007). Adolescents were
randomly assigned to receive olanzapine (n=107) or placebo (n=54) for 3 weeks.
Response rates (defined as ≥50% decrease in YMRS score) were significantly
greater for the olanzapine group (44.8%) than for the placebo group (18.5%).
Remission rates (defined as YMRS score <12) were significantly greater for the
olanzapine group (35.2%) than for the placebo group (11.1%). Adverse effects in
the olanzapine group were hyperprolactinemia, weight gain (mean=3.7 kg),
somnolence, and sedation.
Risperidone
In a 3-week double-blind, placebo-controlled trial, the efficacy of risperidone
was assessed in 169 children and adolescents with bipolar I disorder, manic or
mixed episode (Haas et al. 2009). Both low-dosage risperidone (0.5–2.5 mg/day)
and high-dosage risperidone (3–6 mg/day) were significantly superior to placebo
in reduction of YMRS scores. The response rate (≥50% reduction in baseline
YMRS score) was 59% for low-dosage risperidone and 63% for high-dosage
risperidone, compared with a placebo response rate of 26%. The most common
adverse events with risperidone were somnolence, headache, and fatigue. EPS
were more frequent in the high-dosage risperidone group than in the low-dosage
group.
Quetiapine
In a 3-week double-blind, placebo-controlled trial, the efficacy of quetiapine was
assessed in 277 youths with bipolar I disorder, manic or mixed episode
(DelBello et al. 2007). Both low-dosage quetiapine (400 mg/day) and high-
dosage quetiapine (600 mg/day) were significantly superior to placebo in
reduction of YMRS scores. The response rate (≥50% reduction in baseline
YMRS score) was 64% for low-dosage quetiapine, 58% for high-dosage
quetiapine, and 37% for placebo. The most common adverse events with
quetiapine were somnolence, sedation, dizziness, and headache.
Ziprasidone
The efficacy of ziprasidone was assessed in a 4-week double-blind, placebo-
controlled trial that included 150 youths with bipolar I disorder, manic or mixed
episode (DelBello et al. 2008). Ziprasidone dosages ranged from 80 to 160
mg/day. Ziprasidone was significantly superior to placebo in reduction of YMRS
scores. The response rate (≥50% reduction in YMRS score) was 62% for
ziprasidone and 35% for placebo. The most common side effects with
ziprasidone were sedation, somnolence, nausea, fatigue, and dizziness.
Anticonvulsants
Divalproex
A 4-week double-blind, placebo-controlled multicenter trial of 150 youths (ages
10–17 years) with bipolar I disorder, mixed or manic episode, did not show a
significant difference in YMRS scores from baseline to endpoint for those
patients given divalproex extended release (ER) and those given placebo
(Wagner et al. 2009). The mean modal dose of divalproex ER was 1,286 mg.
There were no statistically significant differences in adverse-event incidents
between the divalproex ER and placebo groups. Gastrointestinal symptoms were
more commonly reported in divalproex ER than in placebo groups.
Carbamazepine
In an open-label study of carbamazepine ER for 137 youths (ages 10–17 years)
with bipolar I disorder, mixed or manic episode, there was a statistically
significant reduction in scores on the YMRS from baseline to endpoint (Findling
and Ginsberg 2014). At endpoint, the most prevalent dosage of carbamazepine
ER was 1,200 mg/day. The most common adverse events were rash, decreased
white blood cell count, nausea, and vomiting.
Oxcarbazepine
The only double-blind, placebo-controlled multicenter trial of oxcarbazepine for
the treatment of children and adolescents with bipolar I disorder, current episode
mixed or manic, failed to show superiority of oxcarbazepine over placebo. The
researchers randomly assigned 116 youths (ages 7–18 years) to receive
oxcarbazepine (mean dosage=1,515 mg/day) or placebo for a 7-week trial
(Wagner et al. 2006b). There was no significant difference in YMRS scores at
endpoint between the oxcarbazepine and placebo groups. The most common side
effects in the oxcarbazepine-treated patients were dizziness, nausea, somnolence,
diplopia, fatigue, and rash.
Topiramate
A double-blind, randomized, placebo-controlled multicenter study assessing the
efficacy of topiramate treatment in children and adolescents with acute mania
was designed as a 200-patient study but was terminated after randomization of
56 patients (ages 6–17 years) when adult mania trials failed to show efficacy
(DelBello et al. 2005). Dosages were titrated to 400 mg/day (mean dosage=278
mg/day). Over a 4-week period, no significant difference was found between the
topiramate and placebo groups. The most common adverse events in the
topiramate group included decreased appetite, nausea, diarrhea, paresthesias, and
somnolence.
Lamotrigine
In a 12-week open-label trial, the efficacy of lamotrigine was assessed in 30
children and adolescents with bipolar spectrum disorders (Biederman et al.
2010). The mean lamotrigine dosage at endpoint was 160.7 mg/day. Significant
improvement in mean YMRS scores was reported; however, only about half the
participants completed the trial, and seven participants discontinued lamotrigine
because of rash.
Comparator Studies
The Treatment of Early Age Mania (TEAM) study compared the effectiveness of
risperidone, lithium, and divalproex in the treatment of 279 youths (ages 6–15
years) with bipolar I disorder, manic or mixed episode (B. Geller et al. 2012).
Response was defined as a CGI-BP-Improvement Mania score of 2 or lower.
The mean lithium level was 1.09 mEq/L, the mean divalproex level was 113.6
μg/mL, and the mean risperidone dosage was 2.57 mg/day. The risperidone
response rate (68.5%) was significantly higher than response rates for lithium
(35.6%) and divalproex (24%). There was no significant difference between
lithium and divalproex response rates. Increased weight gain, body mass index
(BMI), and prolactin levels occurred significantly more frequently with
risperidone than with lithium or divalproex.
Similarly, a comparator analysis of the efficacy of antipsychotics and mood
stabilizers for the treatment of pediatric bipolar disorder showed significantly
greater improvement in YMRS scores for patients given antipsychotics than for
those given mood stabilizers (Correll et al. 2010). Effect sizes were 0.65 for
antipsychotics and 0.24 for mood stabilizers.
The comparative efficacy of lithium, divalproex, and carbamazepine was
assessed in a 6-week randomized open-label trial involving 42 children and
adolescents with bipolar disorder (Kowatch et al. 2000b). There were no
significant differences in response rates (≥50% reduction in YMRS score)
among the groups given lithium (38%), divalproex (53%), and carbamazepine
(38%).
The comparative efficacy of risperidone and divalproex was assessed in an 8-
week double-blind, randomized trial in 66 children and adolescents with bipolar
disorder (Pavuluri et al. 2010). Significantly higher response rates (≥50%
reduction in YMRS) were found for risperidone (78.1%) than for divalproex
(45.5%), and improvement was more rapid in risperidone-treated patients than in
divalproex-treated patients.
The comparative efficacy of quetiapine and divalproex was assessed in a 4-
week double-blind, placebo-controlled trial involving 50 adolescents with
bipolar I disorder, manic or mixed episode (DelBello et al. 2006). No significant
group differences were found in YMRS scores during the trial.
In an 8-week open-label trial, the efficacies of olanzapine and risperidone
were compared in preschool-age children with bipolar disorder (Biederman et al.
2005). There were no significant differences in response rates between
risperidone (69%) and olanzapine (53%).
In a 6-week placebo-controlled trial of valproic acid versus risperidone for
children (ages 3–7 years) with bipolar disorder, manic, mixed or hypomanic
episode, risperidone was superior to placebo on reduction in YMRS scores from
baseline to endpoint. There was no significant difference found between valproic
acid and placebo (Kowatch et al. 2015).
Combination Treatment
Some children with bipolar disorder may not respond to initial monotherapy
treatment or may need combination treatment over the course of the illness. For
example, in a study by Kowatch et al. (2000a), following acute 6-week treatment
with one mood stabilizer, 20 of 35 youths (58%) required additional
psychotropic medication over the next 16 weeks. The response rate to
combination treatment with two mood stabilizers was high (80%) for those
youths who did not respond to monotherapy.
The FDA has approved the use of quetiapine or aripiprazole as an adjunct to
lithium or valproate treatment in children ages 10 years and older with bipolar I
disorder, mixed or manic episode.
The effectiveness of combination treatment with lithium and divalproex was
assessed in an open trial (Findling et al. 2003). Ninety youths (ages 5–17 years)
with bipolar I or II disorder were treated for up to 20 weeks with divalproex
(mean blood level=79.8 μg/mL) and lithium (mean blood level=0.9 mmol/L).
The clinical remission rate (defined as contiguous weekly ratings of YMRS
scores ≤12.5, CDRS-R scores ≤40, Children’s Global Assessment Scale [CGAS]
scores ≥51, clinical stability, and no mood cycling) was 42%.
The efficacy of risperidone in combination with lithium or divalproex was
assessed in a 6-month open-label trial (Pavuluri et al. 2004). Thirty-seven youths
(ages 5–18 years) with bipolar I disorder, manic or mixed episode, received
either risperidone (mean dosage=0.75 mg/day) plus divalproex (mean serum
level=106 μg/mL) or risperidone (mean dosage=0.70 mg/day) plus lithium
(mean serum level=0.9 mEq/L). Response rates (≥50% reduction in baseline
YMRS scores) were similar for both combinations: 80% for divalproex plus
risperidone, and 82.4% for lithium plus risperidone. There were no significant
differences between the groups in safety and tolerability.
Risperidone augmentation for lithium nonresponders was assessed in a 1-year
open-label study (Pavuluri et al. 2006). Twenty-one of 38 youths (ages 4–17
years) who failed to respond to lithium monotherapy or relapsed after initial
response were given risperidone (mean dosage=0.99 mg/day) for 11 months.
Response rates in the lithium plus risperidone group were 85.7%.
In a double-blind, placebo-controlled study of quetiapine, 30 adolescents with
bipolar disorder received divalproex (20 mg/kg) and were randomly assigned to
adjunctive quetiapine (mean daily dosage=432 mg) or placebo for 6 weeks
(DelBello et al. 2002). Response rates (≥50% reduction in baseline YMRS
score) were significantly higher in the group receiving divalproex and quetiapine
(87%) than in the group receiving divalproex and placebo (53%).
Maintenance Treatment
Sixty youths who had responded to a combination of lithium and divalproex in a
20-week trial were randomly assigned in a double-blind trial to either lithium or
divalproex for 18 months (Findling et al. 2005). There was no significant
difference in the time to relapse between the groups (median days: divalproex
112, lithium 114).
If a child fails to respond to treatment in one stage, the clinician should move to
the next stage of treatment. For treatment of bipolar I disorder, manic or mixed
episode with psychosis, the recommendation for initial treatment is a mood
stabilizer plus an atypical antipsychotic. A minimum of 4–6 weeks at therapeutic
blood levels and/or adequate dosages for each medication is recommended.
Following sustained remission of at least 12–24 months, medication taper should
be considered.
Anxiety Disorders
DSM-5 anxiety disorders include generalized anxiety disorder, social anxiety
disorder, panic disorder, selective mutism, agoraphobia, specific phobia, and
separation anxiety disorder. Obsessive-compulsive disorder and posttraumatic
stress disorder are now in separate DSM-5 categories (Obsessive-Compulsive
and Related Disorders and Trauma- and Stressor-Related Disorders, respectively.
Duloxetine
Duloxetine has been approved by the FDA for the treatment of GAD in youths
ages 7–17 years.
The efficacy of duloxetine was assessed in a 10-week double-blind, placebo-
controlled trial for 272 youths (ages 7–17 years) with GAD (Strawn et al. 2015).
Duloxetine was flexibly dosed from 30 to 120 mg/day. The primary efficacy
measure was the Pediatric Anxiety Rating Scale (PARS). Duloxetine was
significantly superior to placebo on improvement in PARS scores from baseline
to endpoint. Response (defined as 50% improvement on PARS severity for
GAD) and remission (defined as a PARS severity for GAD ≤8) were
significantly greater for the duloxetine group (59% and 50%, respectively) than
the placebo group (42% and 34%, respectively). Adverse events reported with
significantly greater frequency for the duloxetine group than for the placebo
group were nausea, vomiting, decreased appetite, oropharyngeal pain, dizziness,
cough, and palpitations.
Venlafaxine
The efficacy of venlafaxine XR in children and adolescents with GAD (N=320)
was evaluated in two double-blind, placebo-controlled trials (Rynn et al. 2007).
Venlafaxine was given at dosages up to 225 mg/day. In one study, venlafaxine
XR was superior to placebo on primary and secondary measures; however, in the
other study, the results were negative.
Sertraline
Twenty-two children and adolescents (ages 5–17 years) with GAD were
randomly assigned to sertraline or placebo in a 9-week double-blind trial (Rynn
et al. 2001). The maximum dosage of sertraline was 50 mg/day. Significant
differences in favor of sertraline over placebo were observed on the Hamilton
Anxiety Scale (Ham-A) scores and on CGI Severity of Illness (CGI-S) and CGI-
I ratings. Side effects found to be more common (but not statistically
significantly so) with sertraline than with placebo were dry mouth, drowsiness,
leg spasm, and restlessness.
Buspirone
The efficacy of buspirone was evaluated for 559 youths (ages 6–17 years) with
GAD who participated in a 6-week randomized placebo-controlled trial (Bristol-
Myers Squibb 2010). Buspirone dosages ranged from 15 to 60 mg/day. There
was no statistically significant difference in outcome between buspirone and
placebo.
Venlafaxine
In a 16-week double-blind, placebo-controlled trial, 293 children and
adolescents with social anxiety disorder were randomly assigned to venlafaxine
XR (dosage range=37.5–225 mg) or placebo (March et al. 2007). Venlafaxine
XR was significantly superior to placebo in reducing ratings of social anxiety.
Response rates (CGI-I score ≤2) were 56% for the venlafaxine XR group and
37% for the placebo group.
Panic Disorder
The prevalence of panic disorder in children and adolescents ranges from 0.6%
to 5.0% in the community and from 0.2% to 9.6% in clinical settings (Masi et al.
2001). The DSM-5 diagnostic criteria for panic disorder in children and
adolescents are the same as those for adults. Panic disorder in youth is a chronic
condition, and there is continuity between pediatric and adult panic disorder
(Biederman et al. 1997).
Citalopram. Three youths (ages 9, 13, and 16 years) with panic disorder and
school phobia were treated with citalopram (up to 20 mg/day) over an 8- to 15-
month period. All patients experienced resolution of panic attacks during the
course of citalopram treatment (Lepola et al. 1996).
Benzodiazepines
In a 2-week open trial, four adolescents with panic disorder were treated with
clonazepam (0.5 mg twice daily). A significant reduction in panic attacks (from
3 attacks per week to 0.25 per week) was reported (Kutcher and MacKenzie
1988).
Obsessive-Compulsive Disorder
OCD has a prevalence rate of 2%–4% in youth (Douglass et al. 1995; Zohar
1999). The DSM-5 criteria for OCD are the same in children and adults. The
course of OCD in youth is chronic.
Sertraline
In a double-blind, placebo-controlled multicenter study, 187 children and
adolescents (ages 6–17 years) with OCD were randomly assigned to sertraline or
placebo (March et al. 1998). Sertraline dosages were titrated to a maximum of
200 mg/day during the first 4 weeks of the trial, and these dosages were
maintained for an additional 8 weeks. The mean dosage of sertraline was 167
mg/day at endpoint. Compared with patients receiving placebo, patients
receiving sertraline showed significantly greater improvement on the CY-BOCS,
the NIMH Global Obsessive Compulsive Rating Scale (NIMH GOCS), and the
CGI-S and CGI-I subscales. Forty-two percent of patients in the sertraline group
and 26% of patients in the placebo group were rated as very much or much
improved. Side effects of insomnia, nausea, agitation, and tremor occurred
significantly more often in the group receiving sertraline than in the group
receiving placebo.
In an assessment of the long-term safety and effectiveness of sertraline for
pediatric OCD, 137 patients who completed the 12-week double-blind, placebo-
controlled sertraline study (March et al. 1998) were given open-label sertraline
(mean dosage=120 mg/day) in a 52-week extension study. Significant
improvement was found on CY-BOCS, NIMH GOCS, and CGI scores. Rates of
response (defined as >25% decrease in CY-BOCS and a CGI-I score of 1 or 2)
were 72% for children and 61% for adolescents (Cook et al. 2001). Full
remission (defined as a CY-BOCS score <8) was achieved in 47% of patients,
and an additional 25% achieved partial remission (CY-BOCS score >8 but <15)
(Wagner et al. 2003b). The most common side effects were headache, nausea,
diarrhea, somnolence, abdominal pain, hyperkinesias, nervousness, dyspepsia,
and vomiting.
The relative and combined efficacy of sertraline and CBT was assessed in a
12-week trial for 112 children and adolescents (ages 7–17 years) with OCD
(Pediatric OCD Treatment Study [POTS] Team 2004). Patients were randomly
assigned to sertraline, CBT, combined sertraline and CBT, or placebo. Combined
treatment was significantly superior to CBT alone and sertraline alone, which
did not differ from each other.
The efficacy of sequential sertraline and CBT compared with CBT and
placebo was assessed in an 18-week trial for 47 youths (ages 7–17 years) with
OCD (Storch et al. 2013). No significant difference was found between the
groups on improvement in OCD symptoms.
Fluoxetine
The safety and efficacy of fluoxetine were assessed in a 13-week double-blind,
placebo-controlled multicenter trial (D.A. Geller et al. 2001). One hundred three
children and adolescents (ages 7–17 years) with OCD were randomly assigned
in a 2:1 ratio to either fluoxetine (dosage range=10–60 mg/day; mean daily
dosage=24.6 mg) or placebo. The group treated with fluoxetine showed a
statistically significant reduction in OCD severity compared with the group
treated with placebo, as determined by changes in CY-BOCS scores. Rates of
response (defined as >40% reduction in CY-BOCS score) were 49% in the
fluoxetine group and 25% in the placebo group. There were no significant
differences in treatment-emergent adverse events between the fluoxetine and
placebo groups.
Fluoxetine was compared with placebo in a controlled trial in 43 children and
adolescents with OCD (Liebowitz et al. 2002). After 16 (but not 8) weeks of
treatment, the fluoxetine group had significantly lower CY-BOCS scores than
the placebo group.
Fluvoxamine
The safety and efficacy of fluvoxamine were evaluated in a double-blind,
placebo-controlled multicenter study (Riddle et al. 2001). One hundred twenty
outpatient children and adolescents (ages 8–17 years) with OCD were randomly
assigned to receive fluvoxamine (dosage range=50–200 mg/day; mean daily
dosage=165 mg) or placebo for a 10-week trial. Patients who did not respond
after 6 weeks could discontinue the double-blind phase and enter an open-label
trial of fluvoxamine. Mean scores on the Children’s Yale-Brown Obsessive
Compulsive Scale (CY-BOCS) were significantly different for the fluvoxamine
and the placebo groups at weeks 1, 2, 3, 4, 6, and 10. Response rates (>25%
reduction in CY-BOCS scores) were 42% in the group being treated with
placebo. Adverse events occurring at a placebo-adjusted frequency of greater
than 10% were insomnia and asthenia.
In an assessment of the safety and effectiveness of fluvoxamine in the long-
term treatment of pediatric OCD, 99 patients who completed the acute double-
blind, placebo-controlled fluvoxamine study by Riddle et al. (2001) participated
in a 1-year open-label extension study (Walkup et al. 1998). Fluvoxamine
dosages were titrated to 200 mg/day over the first 4 weeks. Patients experienced
a 42% reduction in CY-BOCS scores by the end of long-term treatment. Clinical
improvement plateaued at about 6 months of treatment. The most common side
effects of fluvoxamine were insomnia, asthenia, nausea, hyperkinesias, and
nervousness.
Clomipramine
Clomipramine has been shown to be efficacious in the treatment of pediatric
OCD in two double-blind, placebo-controlled trials. In the first study (Flament et
al. 1985), 19 children (ages 10–18 years) with OCD were randomly assigned to
clomipramine (dosage range=100–200 mg/day; mean daily dosage=141 mg) or
placebo for 5 weeks. Significant improvement in observed and self-reported
obsessions and compulsions was found for patients who received clomipramine.
The most common side effects with clomipramine were tremor, dry mouth,
dizziness, and constipation. One patient had a grand mal seizure.
In an 8-week double-blind, placebo-controlled multicenter study of 60
children and adolescents (ages 10–17 years) with OCD, it was found that
patients who received clomipramine (up to 200 mg/day) had significantly greater
reductions in scores on the CY-BOCS than the placebo group (37% and 8%,
respectively). Forty-seven patients continued in a 1-year open-label extension
trial, and effectiveness was maintained with long-term treatment. The most
frequent side effects with clomipramine were dry mouth, somnolence, dizziness,
fatigue, tremor, headache, constipation, and anorexia (DeVeaugh-Geiss et al.
1992).
Citalopram
Twenty-three child and adolescent outpatients (ages 9–18 years) with OCD were
administered open-label citalopram (dosage range=10–40 mg/day; mean daily
dosage=37 mg) in a 10-week trial (Thomsen 1997). There was a statistically
significant improvement in CY-BOCS scores from baseline to endpoint. Adverse
effects were minimal and transient.
In an 8-week open-label citalopram study of 15 youths (ages 6–17 years) with
OCD, 14 patients showed significant improvement in CY-BOCS scores from
baseline to endpoint (Mukaddes and Abali 2003).
In a long-term open study of 30 adolescents with OCD, citalopram (dosage
range=20–70 mg/day; mean daily dosage=46.5 mg) was administered for 1–2
years (Thomsen et al. 2001). There was a significant reduction in CY-BOCS
scores from baseline to assessment at 2 years. No serious adverse events were
reported, and the most common side effects were sedation, sexual dysfunction,
and weight gain.
Paroxetine
The efficacy and safety of paroxetine were assessed in a double-blind, placebo-
controlled multicenter study of 203 outpatient children and adolescents (ages 7–
17 years) with OCD (D.A. Geller et al. 2004). Patients were randomly assigned
to paroxetine (dosage range=10–50 mg/day; mean daily dosage=23 mg) or
placebo for a 10-week trial. There was a statistically significant greater reduction
in CY-BOCS scores from baseline to endpoint in patients treated with paroxetine
than in patients treated with placebo. Response rates (>25% reduction in CY-
BOCS scores) were 64.9% in the paroxetine-treated patients and 41.2% in the
placebo-treated patients. The most common adverse effects in the paroxetine
group were headache, abdominal pain, nausea, respiratory disorder, somnolence,
hyperkinesias, and trauma.
The efficacy of paroxetine in 335 outpatients (ages 7–17 years) with OCD was
assessed in a 16-week open-label multicenter study of paroxetine (10–60
mg/day), followed by double-blind randomization of responders to paroxetine or
placebo for an additional 16 weeks (Emslie et al. 2000). No significant
differences in response rates were found between the group receiving paroxetine
and the group receiving placebo in the randomization phase.
Riluzole
Sixty children and adolescents with treatment-resistant OCD participated in a
12-week double-blind, placebo-controlled trial of add-on riluzole or placebo
with current treatment (Grant et al. 2014). The riluzole final dosage was 100
mg/day. All participants significantly improved on CY-BOCS ratings, and there
was no significant difference between riluzole and placebo on any outcome
measures. Adverse events reported for patients given riluzole included one case
of pancreatitis and five instances of slight increase with transaminases.
N-Acetylcysteine
The authors of a case report (Yazici and Percinel 2014) and a case series (Yazici
and Percinel 2015) describe the use of N-acetylcysteine (NAC) augmentation for
treatment-resistant OCD in children and adolescents. NAC dosages were
initiated at 600 mg/day and increased up to 2,400–3,000 mg/day. Improvement
in OCD symptoms was found in some cases.
Sertraline
The efficacy of sertraline was evaluated in a 10-week double-blind, placebo-
controlled trial in 131 children and adolescents with PTSD (Robb et al. 2010).
Sertraline dosages ranged from 50 to 200 mg/day. There was no difference
between sertraline-treated patients and placebo-treated patients in scores on the
primary outcome measure, the University of California, Los Angeles Post-
Traumatic Stress Disorder Index for DSM-IV (UCLA PTSD-I).
The benefit of adding sertraline versus placebo to trauma-focused CBT was
assessed in a controlled 12-week trial (Cohen et al. 2007). Although both groups
showed significant improvement in symptoms of PTSD, there was no significant
advantage from adding sertraline rather than placebo to CBT.
Citalopram
Eight adolescents with PTSD received citalopram in a fixed daily dosage of 20
mg in a 12-week open-label study (Seedat et al. 2001). Core PTSD symptoms of
reexperiencing, avoidance, and hyperarousal showed statistically significant
improvement at week 12, with a 38% reduction in total score on the Clinician-
Administered PTSD Scale—Child and Adolescent Version (CAPS-CA).
Citalopram was well tolerated, and the most common side effects were increased
sweating, nausea, headache, and tiredness.
In a larger 8-week open trial, Seedat et al. (2002) treated 24 children and
adolescents with citalopram (dosage range=20–40 mg/day; mean daily
dosage=20 mg). Both the children and the adolescents had a significant
reduction in CAPS-CA scores at endpoint. Common side effects of citalopram
were drowsiness, headache, nausea, and increased sweating.
Guanfacine
The effectiveness of guanfacine extended release (GXR) was assessed in an 8-
week open-label trial for 19 youths (ages 6–18 years) with current traumatic
stress symptoms (Connor et al. 2013). GXR dosages ranged from 1 to 4 mg/day.
On parent report, symptom clusters of reexperiencing, avoidance, and
overarousal significantly improved.
Clonidine
Seven preschool children (ages 3–6 years) with a diagnosis of PTSD received
open treatment with clonidine at a dosage range of 0.05–0.15 mg/day (Harmon
and Riggs 1996). To decrease sedation, oral clonidine was subsequently
converted to a clonidine patch. The majority of children showed at least
moderate improvements in hyperarousal, hypervigilance, insomnia, nightmares,
and mood lability.
Carbamazepine
Twenty-eight children and adolescents (ages 8–17 years) with a diagnosis of
PTSD received carbamazepine (dosage range=300–1,200 mg/day) for an
average of 35 days. Twenty-two patients (78%) became asymptomatic, and the
remaining six patients were significantly improved during the course of
treatment (Looff et al. 1995).
Propranolol
The efficacy of propranolol initiated within 12 hours after emergency department
admission in preventing PTSD in 29 injured youths was assessed in a 10-day
double-blind, placebo-controlled trial (Nugent et al. 2010). There was no
significant difference between the propranolol and placebo groups on PTSD
symptoms at 6 weeks.
Eleven children (ages 6–12 years) with a diagnosis of PTSD participated in an
off-on-off medication design of 4 weeks of propranolol treatment (Famularo et
al. 1988). Propranolol was initiated at 0.8 mg/kg/day and titrated to a maximum
of 2.5 mg/kg/day. A significant improvement in PTSD symptoms was found
during the treatment period. Side effects included sedation and mildly lowered
blood pressure and pulse.
Prazosin
In case studies (Oluwabusi et al. 2012; Strawn and Keeshin 2011; Strawn et al.
2009), prazosin 1–3 mg/day was reported to decrease symptoms of PTSD in
children and adolescents.
D-Cycloserine
In a controlled trial, 57 youths (ages 7–18 years) with PTSD were randomly
assigned to receive D-cycloserine and CBT or placebo and CBT (Scheeringa and
Weems 2014). Although both groups had significant reductions in PTSD
symptoms, there was no significant difference between the groups.
Risperidone
In case reports and a small open-label trial, risperidone has shown some benefit
in reducing symptoms of PTSD in children and adolescents (Horrigan and
Barnhill 1997; Keeshin and Strawn 2009; Meighen et al. 2007).
Quetiapine
In a case series, six adolescents with PTSD reported improvement in symptoms
after 6 weeks of low-dosage (50–200 mg/day) quetiapine (Stathis et al. 2005).
Attention-Deficit/Hyperactivity Disorder
The prevalence of ADHD in children and adolescents is estimated to range from
5% to 12%, whereas about 4% of adults in the general population meet criteria
for ADHD (Kessler et al. 2006). In addition to demonstrating the core behavioral
features of inattention, hyperactivity, and impulsivity, children with ADHD often
have significant impairment in social and academic functioning (Barkley 2005).
Of all of the childhood psychiatric disorders, ADHD has the greatest number of
pharmacological treatment studies.
Psychostimulants
The classes of psychostimulants include methylphenidate, dexmethylphenidate,
dextroamphetamine, mixed amphetamine salts, and L-lysine-D-amphetamine
(lisdexamfetamine). By the 1980s, there were already hundreds of randomized
controlled trials showing the efficacy of stimulants in the treatment of ADHD in
school-age children (Greenhill et al. 1999). Arnold (2000) reviewed studies in
which subjects underwent a trial of both amphetamine and methylphenidate.
This review suggested that approximately 41% of subjects with ADHD
responded equally to methylphenidate and amphetamine, whereas 44%
responded preferentially to one of the classes of stimulants. This finding
suggests that the initial response rate to stimulants may be as high as 85% if both
stimulants are tried (in contrast to the finding of 65%–75% response when only
one stimulant is tried). In contrast, placebo response rates in stimulant trials are
rarely above 20%–30%, making the effect size of the stimulants (0.8–1.0) one of
the largest among all the psychotropics. At present, however, no method is
available to predict which stimulant will produce the best response in a given
patient. The past decade has seen the emergence of the long-acting stimulants;
studies of these agents have been the focus of major reviews (Biederman and
Spencer 2008; Pliszka and AACAP Work Group on Quality Issues 2007).
Initial research with stimulants was carried out in school-age children, but
more recent controlled trials of stimulants have focused on adolescents (Spencer
et al. 2006b; Wilens et al. 2006a) and adults (Biederman et al. 2006a; Weisler et
al. 2006). These studies show that older individuals’ rates of response to
stimulants are similar to those of children, with adequate response for most
subjects being obtained with 70–100 mg/day of methylphenidate or 40–60
mg/day of amphetamine.
Preschoolers with ADHD have also been the focus of investigation. In the
NIMH Preschool ADHD Treatment Study (PATS), 183 children (ages 3–5 years)
underwent an open-label trial of methylphenidate, with 165 of these subjects
subsequently randomly assigned to a double-blind, placebo-controlled crossover
trial of methylphenidate lasting 6 weeks (Greenhill et al. 2006; Wigal et al.
2006). The mean optimal dosage of methylphenidate was found to be 0.7 ±0.4
mg/kg/day, which is lower than the mean of 1.0 mg/kg/day found to be optimal
in school-age children. Eleven percent of subjects discontinued methylphenidate
because of adverse events. Compared with school-age children, the preschool
group showed a higher rate of emotional adverse events, including crabbiness,
irritability, and proneness to crying. The conclusion was that the dosage of
methylphenidate (or any stimulant) should be titrated more conservatively in
preschoolers than in school-age patients, and lower mean dosages may be
effective.
The appendix at the end of this chapter shows the recommended dosage
ranges for these agents. The appendix also discusses adverse events, particularly
growth suppression, that occur with psychostimulants.
Atomoxetine
Atomoxetine is a noradrenergic reuptake inhibitor that has indirect effects on
dopamine reuptake in the cortex but not in the striatum (Bymaster et al. 2002).
Numerous double-blind, placebo-controlled trials have demonstrated the
medication’s efficacy in the treatment of ADHD in children, adolescents, and
adults (Michelson et al. 2001, 2002, 2003). Given its pharmacokinetic half-life
of 5 hours, it is generally dosed twice a day. Although open trials comparing
methylphenidate with atomoxetine showed the two agents to have similar
efficacy (Kratochvil et al. 2002), double-blind, placebo-controlled trials
comparing atomoxetine with amphetamine (Biederman et al. 2006b; Wigal et al.
2005) and methylphenidate (Newcorn et al. 2008) have shown the stimulants to
be more efficacious.
Atomoxetine is effective in treating ADHD in patients with comorbid tics and
may also reduce tics (Allen et al. 2005). It is also useful in children with ADHD
who have comorbid anxiety, showing effectiveness in treating anxiety and
inattention (Sumner et al. 2005). Atomoxetine is well tolerated in long-term use.
In a global multicenter study, 416 children and adolescents who responded to an
initial 12-week open-label period of treatment with atomoxetine were randomly
assigned to continued atomoxetine treatment or placebo for 9 months under
double-blind conditions. Relapse (defined as a return to 90% of baseline
symptom severity) occurred significantly less often with atomoxetine (22.3%)
than with placebo (37.9%) (Michelson et al. 2001). Data from 13 (6 double-
blind, 7 open-label) atomoxetine studies were pooled for youths (ages 12–18
years) with ADHD (Wilens et al. 2006b). Of the 601 atomoxetine-treated
subjects in this meta-analysis, 537 (89.4%) completed 3 months of acute
treatment. At the time of the article’s publication, 259 subjects (48.4%) were
continuing atomoxetine treatment; 219 of these subjects had completed at least 2
years of treatment. Symptoms remained improved for up to 24 months without
dosage escalation. During the 2-year treatment period, 99 subjects (16.5%)
discontinued treatment due to lack of effectiveness, and 31 subjects (5.2%)
discontinued treatment due to adverse events. No clinically significant
abnormalities in height, weight, blood pressure, pulse, mean laboratory values,
or electrocardiography parameters were found.
Clonidine
A review of the literature from 1980 to 1999 found 39 studies regarding the use
of clonidine for symptoms of childhood ADHD, and 11 of these studies had
sufficient data to be included in a meta-analysis (Connor et al. 1999). Of the 150
subjects in these studies, 42 received clonidine for ADHD, and the others
received clonidine for ADHD comorbid with tic disorders (n=67),
developmental disorders (n=15), or conduct disorders (n=26). The mean daily
dosage of clonidine was 0.18 mg, and the average length of treatment was 10.9
weeks. Clonidine showed a moderate effect size of 0.58 on symptoms of ADHD,
which is smaller than the effect size (0.82) reported for stimulant treatment of
ADHD (Swanson et al. 1995b).
An extended-release (ER) form of clonidine was more recently developed,
and this formulation was evaluated in an 8-week double-blind, placebo-
controlled trial (Jain et al. 2011) in which patients (N=236) were randomly
assigned to receive clonidine ER 0.2 mg/day, clonidine ER 0.4 mg/day, or
placebo. Improvement in ADHD symptoms was significantly greater in the
clonidine groups relative to the placebo group, with this difference apparent at
week 2 and greatest at week 5. Somnolence was the most common side effect,
and the rate of withdrawal due to adverse events was higher in the clonidine ER
0.4-mg/day group than in the other groups. There were no serious adverse
events, and bradycardia was the most common cardiovascular side effect.
Clonidine ER has been added to stimulant medication in an effort to improve
the initial stimulant response in the treatment of ADHD (Kollins et al. 2011).
Children and adolescents with ADHD who had an inadequate response to their
initial stimulant regimen (n=198) were randomized to receive placebo or
clonidine extended release added to their stable stimulant dosage for 8 weeks.
Clonidine ER was flexibly dosed. At weeks 4 and 5, of the patients within the
group receiving clonidine ER plus stimulant, 3%, 15%, 68%, and 14% received
clonidine ER 0.1 mg/day, 0.2 mg/day, 0.3 mg/day, and 0.4 mg/day, respectively.
Reduction in ADHD Rating Scale IV (ADHD-RS-IV) scores was greater for the
group receiving clonidine ER than for the group receiving placebo in weeks 2–7
but not at week 8. Oddly, although addition of clonidine ER to amphetamine led
to significantly greater improvement, addition to methylphenidate did not. No
serious adverse events were reported.
Guanfacine
In a study by Hunt et al. (1995), 13 children and adolescents with ADHD
received guanfacine (mean daily dosage=3.2 mg) for 1 month. Significant
improvements in hyperactivity and inattention were found. In an 8-week double-
blind, placebo-controlled trial, 34 children and adolescents (ages 7–14 years)
with ADHD and tic disorder were randomly assigned to receive guanfacine
(dosage range=1.5–3.0 mg/day) or placebo (Scahill et al. 2001). A 37%
improvement in ADHD symptoms was reported for children treated with
guanfacine, compared with an 8% improvement for children who received
placebo. The most common side effects of guanfacine were sedation and dry
mouth. There were no significant changes in pulse or blood pressure with
guanfacine treatment.
An extended-release formulation of guanfacine (GXR) is also used for the
treatment of ADHD (Biederman et al. 2008; Sallee et al. 2009). In a double-
blind, placebo-controlled Phase III multicenter trial (Melmed et al. 2006),
children and adolescents ages 6–17 years were randomly assigned to placebo or
2 mg, 3 mg, or 4 mg/day of GXR. All three dosages of GXR were superior to
placebo in reducing symptoms of ADHD. The most commonly reported side
effects of GXR were headache, somnolence, and fatigue. No serious adverse
events were reported. In healthy young adults (ages 19–24 years), abrupt
discontinuation of 4 mg/day of GXR did not lead to increases in blood pressure
or electrocardiogram (ECG) abnormalities (Kisicki et al. 2006).
GXR has also been assessed as add-on therapy when children with ADHD
have only a partial response to stimulants (Wilens et al. 2012). In a 9-week
double-blind, placebo-controlled dosage optimization study, patients (N=461)
continued their stable dosage of psychostimulant given in the morning and were
randomized to receive GXR in the morning (GXR AM), GXR in the evening
(GXR PM), or placebo. At endpoint, compared with the group receiving placebo
plus psychostimulant, each guanfacine treatment group showed significantly
greater improvement from baseline on ADHD-RS-IV total scores. Results did
not differ between the GXR AM and GXR PM groups in either efficacy or
adverse events. There were no serious or unexpected adverse events.
Atomoxetine
Children and adolescents (ages 8–18 years) with ADHD were treated for
approximately 8 weeks with placebo or atomoxetine under randomized, double-
blind conditions. Of the 293 subjects, 39% were diagnosed with comorbid ODD
and 61% were not (Newcorn et al. 2005). Treatment group differences and
differences between patients with and without comorbid ODD were examined
post hoc for changes on numerous clinical measures. Treatment response was
similar in youth with and without ODD, although the comorbid group may
require higher dosages to achieve response than those with ADHD alone.
In general, a child with ODD or CD should be treated with a stimulant or
atomoxetine before proceeding to the use of other psychotropic agents. The use
of more potent agents (mood stabilizers, antipsychotics) is generally reserved for
those with severe aggression, and then only after a behavioral treatment has
failed.
Aggression
Psychostimulants
In a meta-analysis of the literature from 1970 to 2001 that examined 28 studies
to determine the effect size for stimulants on overt and covert aggression-related
behaviors in children with ADHD, it was found that the mean effect size for
aggressive behaviors was similar to that for core behaviors of ADHD (Connor et
al. 2002).
Risperidone
A significant body of research has accumulated showing the effectiveness of
risperidone in the treatment of aggression, although most of these studies involve
patients with subaverage intelligence (Snyder et al. 2002); 80% of subjects had
comorbid ADHD. Risperidone dosages ranged from 0.02 to 0.06 mg/kg/day. The
risperidone-treated subjects showed a significant (P<0.001) reduction (47.3%) in
conduct problems compared with placebo-treated subjects (20.9%). The effect of
risperidone was unaffected by diagnosis, presence versus absence of ADHD,
psychostimulant use, and IQ status. Risperidone produced no changes in the
cognitive variables, and the most common side effects were somnolence,
headache, appetite increase, and dyspepsia. Somnolence did not predict response
of aggressive symptoms. Side effects related to EPS were reported in 7 (13.2%)
and 3 (5.3%) of the subjects in the risperidone and placebo groups, respectively
(P=0.245).
Other double-blind, placebo-controlled trials of risperidone in children and
adolescents with disruptive behavior disorders (and subaverage IQ) have yielded
similar results, with no negative trials reported (Aman et al. 2002; Buitelaar et al.
2001; LeBlanc et al. 2005). Weight gain was a significant side effect in these
studies, but there has not been evidence of adverse neuropsychological effects
(Günther et al. 2006). Addition of risperidone to a stimulant does not appear to
increase rates of side effects and enhances treatment of hyperactivity (Aman et
al. 2004). Indeed, adding risperidone to a stimulant to control aggression has
become a common practice, although a controlled study showed that aggression
was equally reduced when either placebo or risperidone was added to
psychostimulant medication (Armenteros et al. 2007). The sample in this study
was small (N=25), but the study should caution clinicians that aggression can
respond to psychosocial events, such as the expectations of a study.
Pandina et al. (2006) wrote a full review of all studies of risperidone in the
treatment of childhood aggression. This review pooled adverse-event data from
these studies, showing the most common side effects of risperidone to be
somnolence (33%), weight gain (20%), hyperprolactinemia (10.2%), and fatigue
(10%). In the pooled studies, there was an excess mean weight gain (over normal
growth) of 6.0±7 kg after 35–43 weeks of treatment. Of the 688 patients, 651
were free of dyskinetic movements at baseline, and only 1 patient developed
new dyskinetic movements during the follow-up period (these symptoms
resolved even though risperidone was continued). There was no worsening of
dyskinetic movements in those patients with such preexisting symptoms. Rates
of EPS were low throughout the long-term follow-up period. It should be noted
that the dosages of risperidone used in these studies were quite low (1–2
mg/day); thus, these results may not apply to dosages in the 6-mg/day range.
Aman et al. (2014) tested the efficacy of adding risperidone to concurrent
psychostimulant treatment and parent training (PT) in behavior management in
children with ADHD and severe comorbid aggression. Children ages 6–12 years
(mean age 8.89 years) with severe physical aggression were randomly assigned
to a 9-week trial of PT, stimulant, and placebo (basic treatment; n=84) or of PT,
stimulant, and risperidone (augmented treatment; n=84). Children received a
psychostimulant for 3 weeks, titrated for optimal effect, while parents received
PT. If there was room for improvement at the end of week 3, placebo or
risperidone was added for an additional 3 weeks. Both groups showed
substantial reductions in aggressive behavior during the first 3 weeks of
stimulant plus PT treatment. In the second phase, the risperidone group showed
significantly greater reduction in rating scale measures of aggressive behavior,
but CGI-I scores did not discriminate the groups. Adverse events were as
expected, with the risperidone group experiencing greater weight gain and
increases in serum lipid and prolactin levels than the placebo group. The study
clearly showed the need to adequately treat ADHD in the aggressive child before
prescribing second-generation antipsychotics.
Lithium
The efficacy of lithium in the treatment of CD in youth has been demonstrated in
three double-blind, placebo-controlled studies. Haloperidol, lithium, and placebo
were compared in a double-blind, randomized trial in 61 hospitalized children
(ages 5–12 years) with aggression and CD (Campbell et al. 1984). The optimal
dosages of haloperidol ranged from 1 to 6 mg/day; the optimal dosages of
lithium ranged from 500 to 2,000 mg/day. Both haloperidol and lithium were
found to be significantly superior to placebo in reducing aggression. However,
there were more adverse effects associated with haloperidol than with lithium,
including excessive sedation, acute dystonic reaction, and drooling.
Stomachache, headache, and tremor were more common with lithium than with
haloperidol.
In a subsequent study, Campbell et al. (1995) conducted a 6-week double-
blind, placebo-controlled trial of lithium treatment for 50 hospitalized children
(ages 5–12 years) with aggression and CD. The mean optimal daily dosage of
lithium was 1,248 mg, and the mean serum level was 1.12 mEq/L. Lithium was
significantly superior to placebo in reducing aggression. The most common
lithium side effects were stomachache, nausea, vomiting, headache, tremor, and
urinary frequency.
Eighty-six inpatients (ages 10–17 years) with CD were randomly assigned to
treatment with lithium (mean daily dosage=1,425 mg; mean serum level=1.07
mmol/L) or placebo in a 4-week double-blind trial. Aggression ratings decreased
significantly for the group treated with lithium, compared with the group treated
with placebo. More than 50% of patients in the lithium group experienced
nausea, vomiting, and urinary frequency (Malone et al. 2000).
In contrast, Rifkin et al. (1997) found no significant differences between
lithium and placebo in aggression ratings in a 2-week double-blind study of 33
inpatients with CD. The short duration of treatment may have accounted for the
lack of efficacy, suggesting that a 4- to 6-week trial is necessary to show
response.
Severe mood dysregulation, referred to in DSM-5 as disruptive mood
dysregulation disorder, is often characterized by severe aggressive outbursts.
Dickstein et al. (2009) studied the effect of lithium in youths (ages 7–17 years)
with severe mood dysregulation who were tapered off their medications. Those
who continued to have significant mood dysregulation after a 2-week single-
blind placebo run-in were randomized to a 6-week double-blind trial of either
lithium (n=14) or placebo (n=11). Interestingly, 20 of 45 youths (45%) with
severe mood dysregulation were not randomized due to significant clinical
improvement during the placebo run-in. Among randomized patients, there were
no significant between-group differences in any clinical measures. The placebo
group showed no improvement at all (a true negative trial), with no evidence that
an increase in sample size would have changed the results.
Divalproex
Twenty outpatient children and adolescents (ages 10–18 years) with CD or ODD
were randomly assigned to divalproex (dosage range=750–1,500 mg/day; mean
blood level=82 μg/mL) or placebo in a 6-week double-blind, placebo-controlled
crossover study. Of the 15 patients who completed both phases, 12 (80%) had a
statistically significant superior response to divalproex. Increased appetite was
the only significant side effect (Donovan et al. 2000). Steiner et al. (2003)
randomly assigned 71 adolescents with CD in a residential facility for juvenile
offenders to two groups, which received either a therapeutic dosage or a low
dosage of divalproex for 7 weeks; both subjects and outcome raters were blind to
treatment status. Reduction in aggression severity (P=0.02), improvement in
impulse control (P<0.05), and global improvement (P=0.0008) were greater in
the group with therapeutic divalproex levels than in the low-dosage condition.
As reported in another article from the same study, serum level and “immature
defenses” (as assessed by the Weinberger Adjustment Inventory) predicted
response to divalproex, but psychiatric comorbidity did not (Saxena et al. 2005).
Blader et al. (2009) treated 74 children with ADHD and aggression with open
stimulant treatment during a lead-in phase that averaged 5 weeks. Children
whose aggressive behavior persisted at the conclusion of the lead-in phase
(n=30) were randomly assigned to receive double-blind, flexibly dosed
divalproex or a placebo adjunctive to stimulant for 8 weeks. Families received
weekly behavioral therapy throughout the trial. A significantly higher proportion
of the children randomly assigned to divalproex met remission criteria (8 of 14;
57%) than of those randomly assigned to placebo (2 of 13; 15%).
Clonidine
Clonidine has often been combined with stimulants to treat comorbid aggression
in children with ADHD. In a 2-month randomized comparison of clonidine,
methylphenidate, and clonidine combined with methylphenidate in the treatment
of 24 children and adolescents (ages 6–16 years) with ADHD and CD or ODD,
it was found that all three treatment groups showed significant improvement in
oppositional and CD symptoms (Connor et al. 2000). No significant ECG
changes were noted.
Children (ages 6–14 years) with ADHD currently taking methylphenidate
were randomly assigned to receive clonidine syrup 0.10–0.20 mg/day (n=37) or
placebo (n=29) for 6 weeks (Hazell and Stuart 2003). Analysis showed that
significantly more clonidine-treated children than control subjects were
responders on the Conduct subscale (21 of 37 vs. 6 of 29; P<0.01) of the parent-
report Conners Behavior Checklist, but not on the Hyperactive Index subscale
(13 of 37 vs. 5 of 29). Compared with placebo, clonidine was associated with a
greater reduction in systolic blood pressure measured standing and with transient
sedation and dizziness. Clonidine-treated individuals had a greater reduction in a
number of unwanted effects associated with psychostimulant treatment
compared with placebo. The findings supported the use of clonidine in
combination with psychostimulant medication to reduce conduct symptoms
associated with ADHD.
Tourette Syndrome
The prevalence of Tourette syndrome is estimated to be 0.7% in children
(Comings et al. 1990). Tourette syndrome is characterized by multiple motor tics
and by one or more vocal tics that occur frequently for longer than 1 year. More
commonly children suffer from chronic motor or vocal tics, but treatment is the
same as for Tourette syndrome. A meta-analysis has been performed examining
the effects of α2-adrenergic receptor agonists and antipsychotics in the
pharmacological treatment of tics (Weisman et al. 2013).
Antipsychotics
Weisman et al. (2013) reviewed five placebo-controlled studies of haloperidol
and pimozide (Sallee et al. 1997; Shapiro et al. 1989), ziprasidone (Sallee et al.
2000), and risperidone (Dion et al. 2002; Scahill et al. 2003). Two studies
directly compared haloperidol and risperidone without a placebo control
(Bruggeman et al. 2001; Gilbert et al. 2004), one study compared risperidone
and clonidine (Gaffney et al. 2002), and one study compared haloperidol and the
clonidine patch (Kang et al. 2009). However, the Kang et al. (2009) study, unlike
the others, was not blinded. In the meta-analysis, all antipsychotics were superior
to placebo, with a standardized mean difference of 0.61 (95% CI, 0.36–0.86).
There was no difference between the various antipsychotic agents with regard to
their efficacy for reducing tics. Gaffney et al. (2002) found clonidine and
risperidone to be equivalent in efficacy. Studies of aripiprazole were not
included in the Weisman et al. (2013) meta-analysis.
Murphy et al. (2005) reported six cases of children and adolescents (age
range= 8–19 years; mean age=12.1 years) who had comorbid tic disorder and
OCD and were treated with aripiprazole (mean dosage=11.7 mg/day; range=5–
20 mg/day) for 12 weeks. The subjects experienced a mean reduction of 56% in
the severity of their tics as assessed by the Yale Global Tic Severity Scale
(YGTSS). Similarly, Yoo et al. (2006) treated 15 children and adolescents who
had tic disorder with aripiprazole (mean dosage=10.89 mg/day; range=12.5–15
mg/day) and reported a mean reduction of 40% in YGTSS scores; side effects
were minimal. Two subjects experienced nausea, one experienced weight gain,
and one experienced sedation. The sedation responded to dosage reduction.
In a case series, 11 consecutive patients with Tourette syndrome (mean age=7
years; age range=7–50 years) were treated with aripiprazole; the symptoms of
the majority of these patients had been refractory to previous treatments with
other antipsychotics (Davies et al. 2006). Ten of the 11 patients who were treated
with aripiprazole improved, although to variable degrees. In the majority of
patients, response was sustained with aripiprazole dosages ranging from 10 to 20
mg/day. Side effects were mild and transient.
Zheng et al. (2016) reviewed six studies of the treatment of tics with
aripiprazole. This study included two randomized controlled trials, but in these
studies aripiprazole was compared only with tiapride, an antipsychotic not
available in the United States. The other four were open trials. The review found
aripiprazole to be well tolerated and effective in reducing tics relative to baseline
levels.
Clinical Recommendations for Tourette
Syndrome
If a tic is not severe or socially impairing, observation may be in order because
tics typically wax and wane; in general, tics improve over time (Leckman 2002).
Often, psychosocial treatment such as habit reversal training is highly effective
at reducing tics (Piacentini and Chang 2006). If conservative treatment fails, use
of an α2 agonist would be desirable, due to the risk of weight gain and
dyslipidemia with atypical antipsychotics. The atypical antipsychotics are
preferred to typical antipsychotics because the latter have lower efficacy and a
higher risk of tardive dyskinesia. Haloperidol and pimozide should be used only
as a last resort when several atypical agents have failed.
In children with comorbid ADHD, a stimulant can be used, but a nonstimulant
is indicated if the stimulant exacerbates tics (Pliszka et al. 2006a). Stimulants
often must be combined with α2 agonists or antipsychotics to control both the
ADHD and the tics (Pliszka et al. 2006a; Tourette’s Syndrome Study Group
2002).
Schizophrenia
Cases of schizophrenia in children younger than age 13 years are very rare;
however, the prevalence rises in adolescence, with peak onset between ages 15
and 30 years (McClellan and Werry 2001). The clinical features of the disorder
are similar in youth and adults, and the same DSM-5 criteria are used to
establish a diagnosis. The outcome of childhood-onset schizophrenia is reported
to be poor (Eggers and Bunk 1997).
Atypical Antipsychotics
Five atypical antipsychotics have FDA approval for the treatment of
schizophrenia in adolescents: olanzapine (for ages ≥13 years), risperidone (≥13
years), aripiprazole (≥13 years), quetiapine (≥13 years), and paliperidone ER
(≥12 years). Ziprasidone, asenapine, and clozapine have been studied for
treatment of schizophrenia in youth but do not have FDA approval.
Olanzapine
In a double-blind, placebo-controlled multicenter study of olanzapine (mean
dosage=11.1 mg/day) for the treatment of adolescents with schizophrenia
(Kryzhanovskaya et al. 2009), 107 adolescents were randomly assigned to
receive olanzapine (n=72) or placebo (n=35) for a 6-week trial. Olanzapine-
treated adolescents had significant improvements on the Brief Psychiatric Rating
Scale for Children (BPRS-C) and on CGI-S scores compared with the placebo
group. There was no significant difference in response rate (defined as a ≥30%
decrease in BPRS-C and a CGI-S score ≤3) between the olanzapine (37.5%) and
placebo (25.7%) groups. Significantly more olanzapine-treated adolescents had
high aspartate aminotransferase/serum glutamic oxaloacetic transaminase
(AST/SGOT), alanine aminotransferase/serum glutamic pyruvic transaminase
(ALT/SGPT), and prolactin levels, as well as low bilirubin levels and hematocrit
values, during treatment. There was a significant increase in fasting triglycerides
at endpoint in the olanzapine-treated adolescents. Early response at 2 and 3
weeks has been shown to predict ultimate response and remission at week 6
(Stentebjerg-Olesen et al. 2015).
Risperidone
Positive findings were reported in a double-blind, placebo-controlled multicenter
trial of risperidone in the treatment of adolescents with schizophrenia (Haas et
al. 2007). One hundred sixty adolescents were randomly assigned to risperidone
1–3 mg/day (n=55), risperidone 4–6 mg/day (n=51), or placebo (n=54) for a 6-
week trial. Both dosage ranges of risperidone were significantly superior to
placebo on the primary efficacy measure, the Positive and Negative Syndrome
Scale (PANSS) total change score at endpoint. The most common adverse events
in the risperidone 1- to 3-mg/day group were somnolence (24%), agitation
(15%), and headache (13%). EPS (16%), dizziness (14%), and hypertonia (14%)
were the most common adverse events in the risperidone 4- to 6-mg/day group.
The investigators concluded that the overall risk–benefit ratio favored the lower
dosage range of risperidone.
Aripiprazole
In a large double-blind, placebo-controlled multicenter trial of aripiprazole for
the treatment of schizophrenia in adolescents (Findling et al. 2008), 302
adolescents were randomly assigned to receive aripiprazole 10 mg/day,
aripiprazole 30 mg/day (after 5- or 11-day titration), or placebo over a 6-week
period. Both dosages of aripiprazole showed statistically significant differences
from placebo on the PANSS total score at week 6. The most common adverse
events associated with aripiprazole were EPS, somnolence, and tremor. Early
response to aripiprazole at weeks 2 and 3 has been shown to predict later
response and remission (Correll et al. 2013).
Quetiapine
The efficacy of quetiapine in the treatment of schizophrenia in adolescents was
evaluated in a 6-week double-blind, placebo-controlled trial in which subjects
(N=222) were randomly assigned to quetiapine 400 mg/day, quetiapine 800
mg/day, or placebo (Findling et al. 2012). Both quetiapine dosages were
significantly superior to placebo in reduction of total PANSS scores. The most
common adverse events with quetiapine were somnolence, headache, and
dizziness. Mean changes in body weight, total cholesterol, and total triglycerides
were greater in the quetiapine group than the placebo group.
Ziprasidone
The efficacy of ziprasidone was evaluated in a 6-week double-blind, placebo-
controlled trial for 283 adolescents ages 13–17 years with schizophrenia
(Findling et al. 2013). Ziprasidone was flexibly dosed (40–160 mg/day). There
was no significant difference between ziprasidone and placebo on change from
baseline to endpoint on the BPRS-Anchored. The most common adverse events
in the ziprasidone group were somnolence and EPS. During the 26-week open-
label follow-up, there were no clinically significant changes in metabolic indices
and laboratory measures.
Asenapine
The efficacy of asenapine was assessed in an 8-week double-blind, placebo-
controlled trial for adolescents ages 12–17 years with schizophrenia (Findling et
al. 2015a). Asenapine dosing was 2.5 mg bid or 5 mg bid. Asenapine was not
significantly superior to placebo on the primary efficacy measure of change from
baseline to endpoint on the PANSS total score. Weight gain ≥7%, somnolence,
sedation, and hypersomnia were more common in the asenapine group than the
placebo group. Adverse events of akathisia, fasting glucose elevation, and EPS
were more common in the asenapine 5 mg bid group than the placebo group.
Those youth who showed improvement during the acute phase maintained
improvement in the 26-week open-label extension.
Clozapine
A 6-week double-blind, placebo-controlled comparison of clozapine and
haloperidol was conducted in 21 children and adolescents (ages 6–18 years) with
schizophrenia (Kumra et al. 1996). Clozapine (mean dosage=176 mg/day;
range=25–525 mg/day) was significantly superior to haloperidol (mean
dosage=16 mg/day; range=7–27 mg/day) in reducing positive and negative
symptoms of schizophrenia. Clozapine improved interpersonal functioning and
enabled patients to live in a less restrictive setting. Side effects, however, were
significant with clozapine. One patient had a seizure, and three patients were
given anticonvulsants after they became more irritable and aggressive and
experienced epileptiform changes on electroencephalogram (EEG). Mild to
moderate neutropenia, weight gain, and sinus tachycardia were the other major
side effects.
Typical Antipsychotics
Haloperidol
Haloperidol has been compared with placebo and other typical antipsychotics in
controlled trials in youth. In a 10-week double-blind, placebo-controlled
crossover study, the safety and efficacy of haloperidol were assessed in 12
hospitalized children (ages 5–12 years) with schizophrenia. Haloperidol (optimal
dosage range=0.5–3.5 mg/day) was significantly superior to placebo in
improving overall clinical functioning and reducing ideas of reference,
delusions, and hallucinations. Common side effects were acute dystonic reaction,
drowsiness, and dizziness (Spencer et al. 1992).
Haloperidol and loxapine were compared in a 4-week double-blind, placebo-
controlled study of 75 adolescent inpatients with schizophrenia. Both haloperidol
and loxapine were significantly superior to placebo, and there was no significant
difference in efficacy between the two medications. Response rates (based on
CGI-I scores) were 87.5% for loxapine, 70% for haloperidol, and 36.4% for
placebo. Common side effects were sedation, EPS, and somnolence (Pool et al.
1976).
Thiothixene
Thiothixene was compared with thioridazine in a 6-week single-blind study in
21 adolescent inpatients with schizophrenia. Thiothixene (optimal mean
dosage=16.2 mg/day) and thioridazine (optimal mean dosage=178 mg/day) were
equally effective in controlling symptoms, although most of the adolescents
continued to be quite impaired. Thiothixene was less sedating than thioridazine
(Realmuto et al. 1984). Thiothixene was also compared with trifluoperazine in
an 8-week double-blind study of 16 children (ages 8–15 years) with
schizophrenia (Wolpert et al. 1967). The effects of both medications were similar
in terms of decreasing avoidance behavior, reducing stereotypic behavior, and
increasing peer socialization.
Atypical Antipsychotics
For the treatment of irritability associated with autism spectrum disorder, the
FDA has approved risperidone (for patients ≥5 years old) and aripiprazole (≥6
years old). Olanzapine, quetiapine, and ziprasidone have been studied for autism
spectrum disorders but do not have FDA approval for use in youth.
Risperidone
One hundred one children (ages 5–17 years) with DSM-IV–defined autistic
disorder participated in an 8-week double-blind, placebo-controlled trial of
risperidone (dosage range=0.5–3.5 mg/day; mean dosage=1.8 mg/day)
(McCracken et al. 2002). A significantly greater positive response (defined as a
25% decrease on the irritability subscale of the Aberrant Behavior Checklist
[ABC] and a rating of much or very much improved on the CGI-I) was found for
the risperidone group (69%) than the placebo group (12%). Adverse events of
increased appetite, fatigue, drowsiness, dizziness, and drooling were more
common in the risperidone group than in the placebo group. Mean weight gain
was 2.7 kg in the risperidone group and 0.8 kg in the placebo group. An 18-
month follow-up showed that the majority of subjects who responded to
risperidone during intermediate-length treatment continued to show
improvement (McDougle et al. 2005).
In a 24-month follow-up of 84 of these youths, there was continued
improvement in maladaptive behavior from baseline (Aman et al. 2015). Social
skills improved and irritability decreased for those youths who were taking
risperidone at follow-up. Risperidone treatment was associated with enuresis,
excessive appetite, and weight gain.
In an 8-week double-blind, placebo-controlled trial, 79 children (ages 5–12
years) with a DSM-IV diagnosis of autistic or other pervasive developmental
disorder were randomly assigned to receive either placebo or risperidone (mean
dosage=1.5 mg/day). Risperidone-treated patients exhibited a 64% improvement
over baseline irritability, compared with a 30.7% improvement in subjects
receiving placebo (Shea et al. 2004).
In a 6-month placebo-controlled study of 40 children (ages 2–9 years) with
autism, risperidone (1 mg/day) decreased aggressiveness, hyperactivity, and
irritability and improved social responsiveness and nonverbal communication.
Appetite increase, weight gain, sedation, and transient dyskinesias were reported
in the risperidone-treated children (Nagaraj et al. 2006).
The long-term effects of risperidone were assessed in youths (ages 5–17
years) with autism spectrum disorder (Troost et al. 2005). Twenty-four youths
received risperidone for 6 months, followed by a double-blind discontinuation to
placebo or continued risperidone. Risperidone was superior to placebo in
preventing relapse, with relapse rates of 25% and 75%, respectively.
In a double-blind, placebo-controlled risperidone dosing study for 96 youths
(ages 5–17 years), high-dosage risperidone (1.25 mg/day for youths weighing 20
to <45 kg; 1.75 mg/day for youths weighing ≥45 kg) was significantly superior
to placebo in baseline-to-endpoint change in score on the ABC Irritability
subscale (Kent et al. 2013b). There was no significant difference, however,
between scores of patients given low-dosage risperidone (0.125 mg/day for
youths weighing 20 to <45 kg; 0.175 mg/day for youths weighing ≥45 kg) and
scores of patients given placebo. In an open-label extension study with flexibly
dosed risperidone, all groups showed additional improvement in efficacy scores
(Kent et al. 2013a).
The comparative efficacy of risperidone and haloperidol was assessed in an 8-
week double-blind trial that included 30 children and adolescents with DSM-IV
autistic disorder (Miral et al. 2008). Risperidone produced significantly greater
reductions in scores on the ABC as well as on other scales used to assess
symptoms of autism. An open-label continuation study (Gencer et al. 2008) of
this controlled trial showed that risperidone-treated patients had greater
improvement than haloperidol-treated patients on CGI ratings and on the ABC.
In a 24-week randomized trial, combined treatment of risperidone and PT was
compared with risperidone alone for the treatment of severe behavioral problems
in 124 children with autism spectrum disorder (Scahill et al. 2012). Combined
treatment was superior to medication alone in reduction of noncompliant
behavior as assessed by the Home Situation Questionnaire (HSQ). In a 1-year
follow-up, there was no significant difference between treatment groups on
noncompliant behavior (Arnold et al. 2012).
Aripiprazole
The efficacy of aripiprazole in the treatment of irritability was evaluated in 218
children and adolescents with DSM-IV autistic disorder in an 8-week double-
blind, placebo-controlled trial (Marcus et al. 2009). Aripiprazole dosages were 5,
10, or 15 mg/day. Compared with placebo, all aripiprazole dosages produced
significantly greater improvement on mean scores on the ABC Irritability
subscale. The most common adverse events were sedation, tremor, and
somnolence. The efficacy of aripiprazole was assessed in another 8-week
double-blind, placebo-controlled trial that included 98 children and adolescents
with DSM-IV autistic disorder (Owen et al. 2009). Aripiprazole dosages were 5,
10, or 15 mg/day. Significantly greater improvements in mean scores on the
ABC Irritability subscale were seen with aripiprazole versus placebo. Rates of
EPS-related adverse events were 14.9% with aripiprazole and 8% with placebo.
Long-term maintenance treatment with aripiprazole was examined in a
double-blind, placebo-controlled relapse-prevention trial for 86 youths with
autism spectrum disorder (Findling et al. 2014). There was no statistically
significant difference in time to relapse between aripiprazole and placebo.
Relapse rates at week 16 were 35% for the aripiprazole group and 52% for the
placebo group.
The efficacy of aripiprazole and risperidone were compared in a 2-month
randomized, double-blind trial that included 59 children and adolescents with
autism spectrum disorder (Ghanizadeh et al. 2014). Both aripiprazole and
risperidone groups had lower scores on the ABC; there was no statistically
significant difference between these medications.
Olanzapine
The efficacy of olanzapine was evaluated in an 8-week double-blind, placebo-
controlled trial that included 11 children and adolescents with pervasive
developmental disorders (Hollander et al. 2006). Rates of response (CGI-I score
≤2) were 50% for olanzapine-treated patients and 20% for placebo-treated
patients. Olanzapine-treated patients experienced significantly greater weight
gain (mean 7.5 lbs for olanzapine vs. 1.5 lbs for placebo-treated patients).
In a 12-week open-label study of olanzapine (mean dosage=7.8 mg/day) in
eight patients (ages 5–42 years) with DSM-IV autistic disorder or pervasive
developmental disorder not otherwise specified, the six patients who completed
the trial showed much or very much global improvement (Potenza et al. 1999).
Significant improvements were found in hyperactivity, social relatedness,
affectual responses, sensory responses, language usage, self-injurious behavior,
aggression, irritability, anxiety, and depression. The most significant adverse
effects were increased appetite and weight gain in six patients and sedation in
three patients.
In a 3-month open study of olanzapine (dosage range=1.25–20 mg/day) in 25
subjects (ages 6–16 years) with pervasive developmental disorder, significant
global improvement was reported. The most common side effect was weight
gain (mean=4.8 kg) (Kemner et al. 2002).
Olanzapine was compared with haloperidol in a 6-week open trial in 12
children (ages 4–11 years) with DSM-IV autistic disorder (Malone et al. 2001).
Both the olanzapine treatment (mean dosage=7.9 mg/day) and the haloperidol
treatment (mean dosage=1.4 mg/day) reduced symptoms of social withdrawal
and stereotypies and improved speech and object relations.
Quetiapine
The effectiveness of quetiapine (dosage range=100–350 mg/day) was assessed in
a 16-week open-label trial in six children with DSM-IV autistic disorder (Martin
et al. 1999). No significant behavioral improvements were found from baseline
to endpoint.
In a 12-week open-label study of quetiapine in nine adolescents (mean
age=14.6 years) with DSM-IV autistic disorder, only two patients were much or
very much improved at study endpoint (Findling et al. 2004).
Ziprasidone
The efficacy of ziprasidone was evaluated in a 6-week open-label study in 12
adolescents with autism (Malone et al. 2007). Ziprasidone dosages ranged from
20 mg/day to 160 mg/day (mean dosage=98.3 mg/day). Of the 12 patients, 9
(75%) were considered treatment responders (based on CGI-I scores ≤2). The
mean change in QTc from baseline to endpoint was 14.7, which was a
statistically significant increase. There was no significant weight change.
The efficacy and safety of ziprasidone in children, adolescents, and young
adults with autism were evaluated in an open-label study in which 12 patients
(ages 8–20 years) were treated with ziprasidone (mean daily dosage=59.23 mg)
for at least 6 weeks (McDougle et al. 2002). Fifty percent of patients were
responders based on a CGI rating of much improved or very much improved.
Transient sedation was the most common side effect.
Typical Antipsychotics
Haloperidol
Haloperidol has been the most widely studied typical antipsychotic for the
treatment of autism in children and adolescents. In double-blind, placebo-
controlled studies, haloperidol has been shown to be significantly superior to
placebo in reducing maladaptive behaviors and facilitating learning on
discrimination tasks (Campbell et al. 1982); in increasing retention of
discrimination learning and decreasing maladaptive behaviors in the classroom
(Anderson et al. 1984); in decreasing occurrence of stereotypies and increasing
orienting reactions of children (Cohen et al. 1980); and in decreasing
hyperactivity, temper tantrums, withdrawal, and stereotypies and increasing
relatedness (Anderson et al. 1989). Optimal dosages of haloperidol in these
studies ranged from 0.25 to 4 mg/day. The most common side effects were
sedation, increased irritability, and acute dystonic reactions. Weight gain was
modest (0.2 kg) in autistic children who received haloperidol 0.25–3.5 mg/day
for a 6-month period (Silva et al. 1993).
The long-term efficacy of haloperidol was assessed in 48 children (ages 2–8
years) with autism who received haloperidol for 6 months (Perry et al. 1989).
Haloperidol remained effective throughout the 6-month treatment period, and it
was equally effective whether it was given continuously or on a discontinuous
schedule consisting of 5 days on haloperidol and 2 days on placebo. Children
who had symptoms of irritability, angry and labile affect, and uncooperativeness
were the best responders to haloperidol.
Fluvoxamine
A double-blind, placebo-controlled study of fluvoxamine treatment (mean
dosage=106.9 mg/day) in 34 children and adolescents with DSM-IV autistic
disorder did not find significant clinical improvement with fluvoxamine
(McDougle et al. 2000).
Sertraline
Open-label sertraline (dosage range=25–50 mg/day) was administered to nine
children with DSM-IV autistic disorder (Steingard et al. 1997). Eight of the nine
patients showed clinically significant improvement in ability to tolerate changes
in their routine or environment without displaying symptoms of anxiety,
irritability, or agitation.
Citalopram
The efficacy of citalopram was evaluated for treatment of repetitive behavior in
children with autism spectrum disorder (King et al. 2009). One hundred forty-
nine children and adolescents with autism spectrum disorder were randomly
assigned to receive citalopram or placebo in a 12-week controlled trial. The
mean dosage of citalopram at endpoint was 16.5 mg/day. There was no
significant difference in rates of response (CGI-I score ≤2) between citalopram-
treated patients (39.2%) and placebo-treated patients (34.2%). No difference was
found in reduction in CY-BOCS scores between the citalopram group and the
placebo group. Adverse events that were significantly more common in the
citalopram group were increased energy level, impulsiveness, hyperactivity,
stereotypy, decreased concentration, diarrhea, insomnia, and dry skin or pruritus.
Escitalopram
In a 10-week open-label study, 28 children and adolescents (ages 6–17 years)
with pervasive developmental disorder received escitalopram. There was
significant improvement in irritability and clinical global functioning. Twenty-
five percent of youths responded at escitalopram daily dosages less than 10 mg,
and 36% of youths responded at dosages greater than or equal to 10 mg (Owley
et al. 2005).
Other Antidepressants
Clomipramine
Controlled trials with clomipramine in the treatment of autism spectrum disorder
have yielded mixed results. Clomipramine and haloperidol were compared in a
placebo-controlled crossover study for 7 weeks with active treatment
(Remington et al. 2001). Thirty-six patients (ages 10–36 years) with DSM-IV
autistic disorder were randomly assigned to clomipramine (mean dosage=128.4
mg/day; range=100–150 mg/day), haloperidol (mean dosage=1.3 mg/day;
range=1–1.5 mg/day), or placebo. A significant advantage for haloperidol was
found on global measures of autism symptom severity and on specific measures
of irritability and hyperactivity. Clomipramine was comparable to haloperidol
only among patients who were able to complete a full therapeutic trial. However,
significantly fewer patients receiving clomipramine versus haloperidol were able
to complete the trial (37.5% vs. 69.7%, respectively) for reasons related to
inefficacy, side effects, or behavioral problems.
Mirtazapine
In an open-label study of mirtazapine (dosage range=7.5–45 mg/day; mean=30.3
mg/day) in 26 patients (ages 3–23 years) with pervasive developmental
disorders, 9 patients (34.6%) were judged much or very much improved in
symptoms of aggression, self-injury, irritability, hyperactivity, anxiety,
depression, and insomnia (Posey et al. 2001). Mirtazapine did not improve
symptoms of social or communication impairment. Common side effects
included increased appetite, irritability, and transient sedation.
Venlafaxine
The effectiveness of venlafaxine was assessed in an open retrospective study of
10 patients (ages 3–21 years) with pervasive developmental disorders (Hollander
et al. 2000). Six of 10 patients who received venlafaxine (mean dosage=24.4
mg/day; range=6.25–50 mg/day) over an average of 5 months were much or
very much improved. Improvements were observed in repetitive behaviors,
restricted interests, social deficits, communication and language function,
inattention, and hyperactivity. Side effects of venlafaxine included behavioral
activation, nausea, inattention, and polyuria.
Reboxetine
Eleven adolescents with autism spectrum disorder with depressive and ADHD
symptoms were treated with reboxetine (maximum dosage 4 mg/day) in a 12-
week open-label trial (Golubchik et al. 2013). Significant, but modest, decreases
in depressive and ADHD symptoms were found with reboxetine treatment.
Irritability and insomnia were adverse events.
Anticonvulsants
Lamotrigine
Twenty-eight children (ages 3–11 years) with DSM-IV autistic disorder
participated in a double-blind, placebo-controlled study of lamotrigine (mean
main-tenance dosage=5 mg/kg/day) for a 12-week study period (Belsito et al.
2001). There were no significant differences between the lamotrigine and
placebo groups on severity of behavioral symptoms. Insomnia and hyperactivity
were the most frequently reported side effects. No children in the study were
withdrawn because of rash.
Valproate
Three double-blind, placebo-controlled trials have been conducted to assess the
efficacy of valproate in the treatment of autism spectrum disorder. In one 8-week
trial with 13 children, divalproex was superior to placebo in improvement in
repetitive behaviors (Hollander et al. 2006). In another 8-week trial that included
27 youths with autism spectrum disorder, divalproex significantly reduced
symptoms of irritability compared with placebo (Hollander et al. 2010).
However, valproate was not superior to placebo in reduction of aggression and
irritability for 30 youths with pervasive developmental disorders who
participated in an 8-week trial (Hellings et al. 2005).
Oxcarbazepine
In a retrospective case series of 30 youths (ages 5–21 years) with autism
spectrum disorder, 14 patients (47%) who were treated with oxcarbazepine
(mean final dosage=1,360 mg/day) had CGI-I scores of 2 or lower on ratings of
irritability/agitation symptoms (Douglas et al. 2013).
Levetiracetam
A 10-week double-blind, placebo-controlled trial was conducted to assess the
efficacy of levetiracetam in the treatment of 20 children with autism (Wasserman
et al. 2006). The mean maximum dosage of levetiracetam was 862.50 mg/day.
There were no significant differences between levetiracetam and placebo on
measures of global improvement of autism, aggression and affective instability,
and impulsivity and hyperactivity.
Other Agents
Lithium
In a retrospective chart review of 30 children with autism spectrum disorder who
were treated with lithium (mean blood level 0.70 mEq/L), 13 youths (43%) were
rated as improved on the CGI-I (Siegel et al. 2014). Vomiting, tremor, fatigue,
irritability, and enuresis were the most common adverse effects.
Clonidine
A double-blind, placebo-controlled crossover study of transdermal clonidine
(0.005 mg/kg/day or placebo by a weekly transdermal patch) in nine patients
(ages 5–33 years) with autistic disorder was conducted for a total active period
of 8 weeks (Fankhauser et al. 1992). Significant improvement with clonidine,
compared with placebo, was found on measures of social relationship, affectual
responses, and sensory responses. In a double-blind, placebo-controlled
crossover trial of clonidine in eight children with autistic disorder, clonidine was
found to be modestly effective in reducing irritability and hyperactivity
(Jaselskis et al. 1992).
Methylphenidate
A meta-analysis of four methylphenidate trials for treatment of ADHD
symptoms in children with pervasive developmental disorders showed an effect
size of 0.67 (Reichow et al. 2013). The most likely adverse events were
decreased appetite, insomnia, depressive symptoms, irritability, and social
withdrawal. Us of an extended-release methylphenidate formulation has also
been shown to reduce hyperactive and impulsive behavior in children with
autism spectrum disorder and ADHD symptoms (Pearson et al. 2013).
Atomoxetine
Atomoxetine as a treatment for symptoms of ADHD in children and adolescents
with autism spectrum disorder was examined in a double-blind, placebo-
controlled 8-week trial that included 97 youths (Harfterkamp et al. 2012). The
atomoxetine dosage was 1.2 mg/kg/day. There was a statistically significant
difference between atomoxetine and placebo on change from baseline to
endpoint ADHD-RS-IV scores. Adverse effects of nausea, decrease in appetite,
fatigue, and early morning awakening were more common in the atomoxetine
group than in the placebo group. In a subsequent analysis, atomoxetine did not
improve social functioning, but there was some improvement on stereotyped
behaviors, inappropriate speech, and fear of change (Harfterkamp et al. 2014).
In a placebo-controlled crossover trial that included 16 youths with autism
spectrum disorder and ADHD symptoms, atomoxetine was superior to placebo
in reduction of hyperactivity and impulsivity symptoms as measured on the ABC
(Arnold et al. 2006).
Long-term efficacy and tolerability of atomoxetine were assessed in a 20-
week follow-up of an 8-week controlled trial for 88 youths with autism spectrum
disorder and autism (Harfterkamp et al. 2013). Continued treatment with
atomoxetine resulted in further improvement of ADHD symptoms. Adverse
events, particularly nausea and fatigue, diminished over time with continued
treatment.
N-Acetylcysteine
The efficacy of NAC in the treatment of behavioral disturbance was assessed in
33 children with autism in a 12-week double-blind, placebo-controlled trial
(Hardan et al. 2012). The NAC dosage was titrated up to 900 mg three times
daily. Compared with placebo, NAC resulted in significant improvement on
scores on the ABC Irritability subscale. The most common adverse effects were
constipation, nausea and vomiting, and diarrhea. One participant treated with
NAC had worsening agitation and irritability and was removed from the study.
Bumetanide
The efficacy of bumetanide for the treatment of 60 children with autism
spectrum disorder was evaluated in a 3-month double-blind, placebo-controlled
trial (Lemonnier et al. 2012). The bumetanide dosage was 1 mg/day. Bumetanide
was significantly superior to placebo in reduction of symptoms on the primary
outcome measure, the Childhood Autism Rating Scale (CARS). Occasional mild
hypokalemia was an adverse event.
Intranasal Oxytocin
Intranasal oxytocin has been examined as a treatment for autism spectrum
disorder in controlled trials and a long-term open-label study. Oxytocin nasal
spray (18 or 24 international units [IU]) or placebo was administered to 16
youths were autism spectrum disorder in a double-blind, placebo-controlled
crossover design (Guastella et al. 2010). Compared with placebo, oxytocin
significantly improved emotion recognition.
In a double-blind, placebo-controlled trial, 36 male youths with autism
spectrum disorder received 24 or 12 IU of oxytocin or placebo over a 4-day
period (Dadds et al. 2014). There were no significant differences between
intranasal oxytocin and placebo on measures of social interaction skills,
repetitive behaviors, and emotion recognition.
In a 7-month open-label study, intranasal oxytocin was administered (8- to 24-
IU dose every 2 months) to eight male youths with autism spectrum disorder
(Tachibana et al. 2013). Six of eight youths showed improvement in
communication and social interaction on the Autism Diagnostic Observation
Schedule—Generic (ADOS-G).
Arbaclofen
The efficacy of arbaclofen was assessed in a 12-week double-blind, placebo-
controlled trial that included 150 children, adolescents, and young adults
(Delahunty et al. 2013). Arbaclofen was titrated to a maximum of 10 mg three
times daily for youths ages 5–11 years and 15 mg three times daily for youths
ages 12–21 years. There was no significant difference between arbaclofen and
placebo in improving lethargy or social withdrawal.
Adjunctive Treatments
Memantine
Memantine as adjunctive treatment to risperidone for autism spectrum disorder
was assessed in a 10-week double-blind, placebo-controlled trial for 40 children
(Ghaleiha et al. 2013a). The dosage of memantine was titrated to 20 mg/day, and
the risperidone dosage was titrated to 3 mg/day. Compared with the placebo
group, the group that received adjunctive memantine had a significantly greater
reduction in the Irritability score on the ABC—Community version. There was
no significant difference in adverse effects between the groups.
Amantadine
Amantadine as adjunctive treatment to risperidone for treatment of 40 children
with autism spectrum disorder was evaluated in a 10-week double-blind,
placebo-controlled trial (Mohammadi et al. 2013). Amantadine was titrated to
100–150 mg/day, and risperidone was titrated to 1–2 mg/day. Compared with the
placebo group, the adjunctive amantadine group had a significantly greater
reduction in Hyperactivity and Irritability scores on the ABC—Community
version. There were no significant adverse effects among the groups.
Riluzole
The efficacy of riluzole as adjunctive treatment to risperidone was assessed in a
10-week double-blind, placebo-controlled trial for 40 children with autism
spectrum disorder (Ghaleiha et al. 2013b). Riluzole was titrated to 50–100
mg/day, and risperidone was titrated to 2–3 mg/day. Significantly greater
improvement in irritability, as assessed by the ABC—Community version, was
found for the adjunctive riluzole group than the placebo group. Increased
appetite and weight gain were more common in the riluzole group than the
placebo group.
Buspirone
Buspirone as adjunctive treatment to risperidone was evaluated in an 8-week
double-blind, placebo-controlled trial for 40 youths with autism (Ghanizadeh
and Ayoobzadehshirazi 2015). The mean dosage of buspirone was 6.7 mg/day.
Compared with the placebo group, the adjunctive buspirone group showed a
significantly greater reduction in the Irritability subscale score of the ABC—
Community version. The most common adverse events in the buspirone group
were increased appetite, drowsiness, and fatigue.
Celecoxib
Adjunctive treatment with celecoxib to risperidone was evaluated in a 10-week
double-blind, placebo-controlled trial that included 40 children with autism
(Asadabadi et al. 2013). Celecoxib was titrated to 300 mg/day and risperidone to
3 mg/day. Adjunctive celecoxib was superior to placebo in reducing irritability,
social withdrawal, and stereotypy as measured on the ABC—Community
version.
Pentoxifylline
The efficacy of adjunctive pentoxifylline to risperidone was assessed in a 10-
week double-blind, placebo-controlled trial that included 40 children with a
DSM-IV-TR (American Psychiatric Association 2000) diagnosis of autistic
disorder (Akhondzadeh et al. 2010). Pentoxifylline was titrated to 600 mg/day,
and risperidone was titrated to 3 mg/day. Adjunctive pentoxifylline was superior
to placebo in reducing scores on the ABC—Community version subscales for
irritability, lethargy/social withdrawal, stereotypic behavior,
hyperactivity/noncompliance, and inappropriate speech. There was no
significant difference between the groups in adverse events.
N-Acetylcysteine
NAC as adjunctive treatment to risperidone for treatment of irritability in autism
spectrum disorder has been evaluated in two double-blind, placebo-controlled
studies. In a 10-week study that included 40 children with autism spectrum
disorder, the NAC dosage was 600–900 mg/day (Nikoo et al. 2015). In an 8-
week study that included 40 children with autism spectrum disorder, the NAC
dosage was 1,200 mg/day (Ghanizadeh and Moghimi-Sarani 2013). Adjunctive
NAC was superior to placebo in the reduction of irritability as assessed by the
ABC in both studies.