Schizophrenia
Schizophrenia
Schizophrenia
METHODOLOGY
Earlier versions of this parameter were published
in 1994 and 2001. The most recent literature search
covered a 5-year period (January 2004 through
August 2010) using PubMed, PsycInfo (Ovid),
CINAHL (EBSCO), and Web of Science databases.
The initial searches were inclusive and sensitive for
PubMed using a combination of MeSH headings
and key words. The search was adjusted for
CINAHL and PsycInfo by translating, where
necessary, from the MeSH thesaurus to the
CINAHL and PsycInfo thesauri, and using the
same key words. The Web of Science search also
was adjusted because this database responds only
to key-word searching.
JOURNAL
976
www.jaacap.org
OF THE
adjusted to work in the PubMed database): akathisia OR neuroleptic OR neuroleptics OR neuroleptic* OR parkinsonian* OR psychoses OR
psychotic OR psychosis OR schizoaffective OR
schizophren* OR tardive OR childhood onset
schizophrenia OR early onset schizophrenia OR
((chronic OR paranoid) AND schizophren*) OR
Akathisia, Drug-Induced [MeSH] OR Dyskinesia, Drug-Induced [MeSH] OR Psychoses,
Substance-Induced [MeSH] OR (Antipsychotic
Agents [MeSH] OR Catatonia [MeSH]) OR
Neuroleptic Malignant Syndrome [MeSH] OR
Parkinsonian Disorders [MeSH] OR Schizophrenia and Disorders with Psychotic Features
[MeSH] OR Schizophrenia, Childhood[MeSH].
DEFINITIONS
EOS is dened as onset before 18 years of age.
Onset before 13 years of age is often described as
childhood-onset schizophrenia (COS). The diagnosis of schizophrenia in children and adolescents is made using the same criteria as in adults,
following the criteria outlined by the DSM-52 or
International Classication of Diseases, 10th Revision.3 The DSM-5 requires that two or more
characteristic symptoms, i.e., hallucinations,
delusions, disorganized speech, disorganized or
catatonic behavior, and/or negative symptoms,
must be present for at least 1 month (or shorter if
successfully treated). During this active phase,
hallucinations, delusions, or disorganized speech
must be present. Evidence of the disorder must be
present for at least 6 months and must be associated with a signicant decline in social or
occupational functioning. In children and
adolescents, decline in function may include the
failure to achieve age-appropriate levels of interpersonal or academic development. The International Classication of Diseases, 10th Revision
diagnostic criteria are similar to the DSM-5
criteria except that the total duration of illness
required is at least 1 month.
Schizophrenia as dened by the DSM-5 differs
from the DSM-IV-TR4 by the following: delusions,
hallucinations, or disorganized speech are required
for diagnosis and commenting and conversing
hallucinations and bizarre delusions are no
longer accorded special diagnostic status.
BRIEF HISTORY
Descriptions of madness and insanity date to
antiquity. In the early 20th century, Kraeplin
characterized two forms of insanity, manic-
depressive illness and dementia praecox.5 Bleuler substituted the term schizophrenia (splitting of
the mind) for dementia praecox,6 given the observation that the illness was not associated with
dementia, but rather with the loss of association
of thought processes and the disruption of
thought, emotions, and behavior.7
The original descriptions of the disorder
recognized a typical pattern of onset during
adolescence and young adulthood, with reports
of rare cases in children. However, beginning
with the works of Bender, Kanner, and others,8
the concept of childhood schizophrenia was
broadened to include syndromes dened by developmental lags in the maturation of language,
perception, and motility (which also included
infantile autism).9 Hallucinations and delusions
were not required criteria. This nosology was
adopted by the DSM-II. As a result, the childhood
schizophrenia literature from this period overlaps
with that of autism and other pervasive developmental disorders.
Seminal work by Kolvin10 and Rutter11 established the distinctiveness of the various childhood psychoses and the similarity between child
and adult schizophrenia. Therefore, beginning
with the DSM-III, the diagnosis of schizophrenia
in youth has been made using the same criteria as
for adults, regardless of age of onset. Subsequent
research has generally validated this decision.
EPIDEMIOLOGY
The worldwide prevalence of schizophrenia is
generally held to be approximately 1%, with
some variation noted across studies and populations. The male-to-female ratio is approximately 1.4 to 1.12
The prevalence of EOS has not been
adequately studied. Onset before 13 years of age
appears to be quite rare. The rate of onset then
increases during adolescence, with the peak ages
of onset for the disorder ranging from 15 to 30
years. EOS tends to occur more often in male
individuals. As age increases, this ratio tends to
even out. The diagnostic validity of schizophrenia
in young children, e.g., younger than 6 years, has
not been established.
CLINICAL PRESENTATION
Psychosis is dened as the severe disruption of
thought and behavior resulting in the loss of
reality testing. The diagnosis of psychosis is
based on overt changes in a persons behavior
www.jaacap.org
977
Symptomatology
Schizophrenia is characterized by positive and
negative symptoms. Positive symptoms refer to
hallucinations, delusions, and thought disorder.
Negative symptoms are those of decits, i.e., at
affect, anergy, and paucity of speech or thought.
Disorganized behavior may represent an independent third domain, including disorganized
speech (e.g., incoherence, looseness of associations), bizarre behavior, and poor attention.4
Hallucinations, thought disorder, and attened
affect have been consistently found in EOS,
whereas systematic delusions and catatonic
symptoms occur less frequently.25 Developmental
variation in language and cognition may affect the
range and quality of symptom presentation.
Cognitive Delays
Cognitive delays are common with EOS.26 Decits in memory, executive functioning, attention,
and global impairments are generally noted.
Children who later develop schizophrenia often
have premorbid problems with verbal reasoning,
Premorbid Functioning
Premorbid abnormalities are evident in most
youth who develop schizophrenia, especially
those with COS.29 Common premorbid difculties include social withdrawal and isolation,
disruptive behavior disorders, academic difculties, speech and language problems, and cognitive delays. Because schizophrenia in youth often
has an insidious onset, the gradual development
of psychotic symptoms in a child with premorbid
language delays and social withdrawal can be
difcult to recognize.
Predicting which youth with premorbid characteristics of schizophrenia will eventually develop the disorder remains a challenge. Factors in
high-risk youth that predict progression into the
illness include familial risk for schizophrenia plus
a recent deterioration in functioning; unusual,
suspicious, or paranoid thought content; greater
social impairment; and/or a history of substance
abuse.30
ETIOLOGY
Genetic Factors
Family, twin, and adoption studies support
a strong genetic component for schizophrenia.
The lifetime risk of developing the illness is 5 to
20 times higher in rst-degree relatives of affected
probands compared with the general population.
The rate of concordance between monozygotic
twins is approximately 40% to 60%. Concordance
rates in dizygotic twins and other siblings are
5% to 15%.34 Genomewide association studies,
using large collaborative international cohorts,
have published ndings implicating different
JOURNAL
978
www.jaacap.org
OF THE
www.jaacap.org
979
DIFFERENTIAL DIAGNOSIS
The effective treatment of schizophrenia relies on
an accurate diagnosis and a thorough assessment
to identify any other contributing medical or
psychiatric conditions and/or psychosocial
stressors. The proper assessment of psychosis in
youth requires the gauging of potential symptom
reports in the context of normal development.
The mere fact that a child responds afrmatively
to questions regarding hallucinations or delusions does not ipso facto mean the child is
psychotic. Psychotic symptoms occur in the
context of an illness, and psychotic illnesses are
JOURNAL
980
www.jaacap.org
OF THE
www.jaacap.org
981
RECOMMENDATIONS
Recommendation 1. Psychiatric assessments for
children and adolescents should include
screening questions for psychosis. [CS]
In the psychiatric assessment, general inquiries
should be made regarding changes in behavior or
any evidence of problems with thinking or
perceptions. Questions such as Does your mind
ever play tricks on you?, Do you hear voices
talking to you when no one is there?, and Does
your mind ever feel confused help elicit possible
symptoms. Youth with EOS can generally describe
relevant aspects of their psychotic symptoms,
although some will be too disorganized, confused,
and/or paranoid to provide accurate details or
relevant history. Parents, family members,
teachers, and treatment providers are important
sources of information for documenting overt
changes in behavior and thinking.
It is important to gauge suspected psychosis in
a developmental context. When evaluating youth,
especially children younger than 12 years, the
clinician must ensure that the child understands
the question and that developmental considerations are taken into account. True psychotic
symptoms are generally confusing to the individual and experienced as distressing external
phenomena beyond the individuals control.
Highly descriptive, detailed, organized, and/or
situation-specic reports are less likely to represent true psychosis. Schizophrenia and other
psychotic illnesses are associated with disorganized thinking and behavior and deterioration in
functioning. Overt signs of the illness should be
evident on the mental status examination and in
descriptions of the childs behavior. Without
overt evidence of psychosis, the validity of
symptom reports suggestive of schizophrenia in
children needs to be carefully scrutinized.
Recommendation 2. The diagnosis of
schizophrenia in children and adolescents
should follow DSM-5 criteria, using the same
criteria as for adults. [CS]
JOURNAL
982
www.jaacap.org
OF THE
www.jaacap.org
983
JOURNAL
984
www.jaacap.org
OF THE
schizophrenia, further research is needed to establish their efcacy.107 Medication trials need to be
conducted systematically to avoid unnecessary
polypharmacy. Although youth with schizoaffective disorder are often assumed to need
concurrent antidepressants or mood stabilizers,
these practices have not been systematically
studied. In the TEOSS, there were no signicant
differences in treatment response between patients
with schizophrenia and those with schizoaffective
disorder.104
The u-3 fatty acids have been suggested to be
potentially useful as an adjunctive treatment for
schizophrenia or as preventive therapy.108 One
randomized controlled trial found that u-3 fatty
acids helped delay the onset of psychosis in highrisk patients.109[rct] As of yet, this study has not
been replicated, and at this time there are no
interventions with conclusive evidence for treating prodromal psychosis.110
Recommendation 7. A trial of clozapine
should be considered for youth with treatment
resistant schizophrenia spectrum disorders. [CS]
Clozapine is the only antipsychotic agent for
which there is established superiority over other
agents. For treatment-refractory EOS, clozapine
was more benecial than haloperidol (n 21) or
high-dose olanzapine (n 39) for positive and
negative symptoms (n 21)111[rct],112[rct] and
superior to olanzapine for negative symptoms
(n 25).113[rct] A naturalistic follow-up study of
EOS found clozapine more effective than haloperidol, risperidone, or olanzapine (n 47).114[cs]
However, owing to potential side effects, clozapine is reserved for treatment refractory cases,
i.e., patients with two or more failed trials of
a rst-line antipsychotic agent.
Before using clozapine, it is important to
review the childs clinical status and treatment
history to ensure that the presentation accurately
reects treatment refractory schizophrenia. For
complicated cases or the apparent diagnosis of
schizophrenia in a younger child (e.g., <12 years),
a diagnostic second opinion may be warranted.
When using clozapine, systematic monitoring
of side effects, including following established
protocols for blood count monitoring, is
required. White blood cell and absolute neutrophil counts are obtained at baseline and weekly
for the rst 6 months to monitor the risk for
agranulocytosis. These protocols require a coordinated effort among the pharmacy, laboratory,
and physician to ensure that the blood count
www.jaacap.org
985
JOURNAL
986
www.jaacap.org
OF THE
PARAMETER LIMITATIONS
The AACAP Practice Parameters are developed to
assist clinicians in psychiatric decision making.
These parameters are not intended to dene the
sole standard of care. As such, the parameters
should not be deemed inclusive of all proper
methods of care or exclusive of other methods of
care directed at obtaining the desired results. The
ultimate judgment regarding the care of a particular patient must be made by the clinician in light
of all the circumstances presented by the patient
and his or her family, the diagnostic and treatment
options available, and other available resources. &
This Practice Parameter was developed by Jon McClellan, M.D.,
Saundra Stock, M.D., and the American Academy of Child and
Adolescent Psychiatry (AACAP) Committee on Quality Issues (CQI):
Heather J. Walter, M.D., M.P.H., and Oscar G. Bukstein, M.D,
M.P.H., Co-Chairs; and Christopher Bellonci, M.D., R. Scott Benson,
M.D., Allan Chrisman, M.D., Tiffany R. Farchione, M.D., John Hamilton, M.D., Helene Keable, M.D., Joan Kinlan, M.D., Nicole Quiterio,
M.D., Ulrich Schoettle, M.D., Matthew Siegel, M.D., and Saundra
Stock, M.D.
AACAP Practice Parameters are developed by the AACAP CQI in
accordance with American Medical Association policy. Parameter
development is an iterative process among the primary author(s), the
CQI, topic experts, and representatives from multiple constituent
groups, including AACAP membership, relevant AACAP committees,
the AACAP Assembly of Regional Organizations, and the AACAP
REFERENCES
*References marked with an asterisk are particularly recommended.
www.jaacap.org
987
32. Vyas NS, Patel NH, Puri BK. Neurobiology and phenotypic
expression in early onset schizophrenia. Early Interv Psychiatry.
2011;5:3-14.
33. Rapoport JL, Gogtay N. Childhood onset schizophrenia: support
for a progressive neurodevelopmental disorder. Int J Dev Neurosci. 2011;29:251-258.
34. Cardno AG, Gottesman II. Twin studies of schizophrenia: from
bow-and-arrow concordances to star wars Mx and functional
genomics. Am J Med Genet. 2000;97:12-17.
35. Psychiatric GWAS Consortium Coordinating Committee.
Genomewide association studies: history, rationale, and prospects for psychiatric disorders. Am J Psychiatry. 2009;166:
540-556.
36. Schizophrenia Psychiatric Genome-Wide Association Study
(GWAS) Consortium. Genome-wide association study identies
ve new schizophrenia loci. Nat Genet. 2011;43:969-976.
37. Addington AM, Rapoport JL. The genetics of childhood-onset
schizophrenia: when madness strikes the prepubescent. Curr
Psychiatry Rep. 2009;11:156-161.
38. International Schizophrenia Consortium. Rare chromosomal
deletions and duplications increase risk of schizophrenia. Nature.
2008;455:237-241.
39. Stefansson H, Rujescu D, Cichon S, et al. Large recurrent microdeletions associated with schizophrenia. Nature. 2008;455:
232-236.
40. Walsh T, McClellan JM, McCarthy SE, et al. Rare structural
variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science. 2008;320:539-543.
41. Xu B, Roos JL, Levy S, et al. Strong association of de novo copy
number mutations with sporadic schizophrenia. Nat Genet. 2008;
40:880-885.
42. Vacic V, McCarthy S, Malhotra D, et al. Duplications of the
neuropeptide receptor gene VIPR2 confer signicant risk for
schizophrenia. Nature. 2011;471:499-503.
43. Sporn A, Addington A, Reiss AL, et al. 22q11 deletion syndrome
in childhood onset schizophrenia: an update. Mol Psychiatry.
2004;9:225-226.
44. *McClellan J, King MC. Genetic heterogeneity in human disease.
Cell. 2010;141:210-217.
45. Harrison PJ, Weinberger DR. Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence.
Mol Psychiatry. 2005;10:40-68.
46. McClellan JM, Susser E, King MC. Maternal famine, de novo
mutations, and schizophrenia. JAMA. 2006;296:582-584.
47. McGrath JJ, Susser ES. New directions in the epidemiology of
schizophrenia. Med J Aust. 2009;190(suppl):S7-S9.
48. Gur RE, Keshavan MS, Lawrie SM. Deconstructing psychosis
with human brain imaging. Schizophr Bull. 2007;33:921-931.
49. Frazier JA, Giedd JN, Hamburger SD, et al. Brain anatomic
magnetic resonance imaging in childhood-onset schizophrenia.
Arch Gen Psychiatry. 1996;53:617-624.
50. Lim KO, Harris D, Beal M, et al. Gray matter decits in young
onset schizophrenia are independent of age of onset. Biol
Psychiatry. 1996;40:4-13.
51. White T, Cullen K, Rohrer LM, et al. Limbic structures and
networks in children and adolescents with schizophrenia.
Schizophr Bull. 2008;34:18-29.
52. Janssen J, Reig S, Parellada M, et al. Regional gray matter volume
decits in adolescents with rst-episode psychosis. J Am Acad
Child Adolesc Psychiatry. 2008;47:1311-1320.
53. *Thompson PM, Vidal C, Giedd JN, et al. Mapping adolescent
brain change reveals dynamic wave of accelerated gray matter
loss in very early-onset schizophrenia. Proc Natl Acad Sci U S A.
2001;98:11650-11655.
54. Penttila J, Paillere-Martinot ML, Martinot JL, et al. Global and
temporal cortical folding in patients with early-onset schizophrenia. J Am Acad Child Adolesc Psychiatry. 2008;47:1125-1132.
55. Gogtay N. Cortical brain development in schizophrenia: insights
from neuroimaging studies in childhood-onset schizophrenia.
Schizophr Bull. 2008;34:30-36.
56. Greenstein D, Lerch J, Shaw P, et al. Childhood onset schizophrenia: cortical brain abnormalities as young adults. J Child
Psychol Psychiatry. 2006;47:1003-1012.
57. Sporn AL, Greenstein DK, Gogtay N, et al. Progressive brain
volume loss during adolescence in childhood-onset schizophrenia. Am J Psychiatry. 2003;160:2181-2189.
JOURNAL
988
www.jaacap.org
OF THE
58. Rapoport JL, Gogtay N. Brain neuroplasticity in healthy, hyperactive and psychotic children: insights from neuroimaging.
Neuropsychopharmacology. 2008;33:181-197.
59. Gogtay N, Greenstein D, Lenane M, et al. Cortical brain development in nonpsychotic siblings of patients with childhood-onset
schizophrenia. Arch Gen Psychiatry. 2007;64:772-780.
60. Mattai AA, Weisinger B, Greenstein D, et al. Normalization of
cortical gray matter decits in nonpsychotic siblings of patients
with childhood-onset schizophrenia. J Am Acad Child Adolesc
Psychiatry. 2011;50:697-704.
61. van Winkel R, Stefanis NC, Myin-Germeys I. Psychosocial stress
and psychosis. A review of the neurobiological mechanisms and
the evidence for gene-stress interaction. Schizophr Bull. 2008;34:
1095-1105.
62. Tienari P, Wynne LC, Sorri A, et al. Genotype-environment
interaction in schizophrenia-spectrum disorder. Long-term
follow-up study of Finnish adoptees. Br J Psychiatry. 2004;184:
216-222.
63. Vyas NS, Hadjulis M, Vourdas A, Byrne P, Frangou S. The
Maudsley early onset schizophrenia study: predictors of
psychosocial outcome at 4-year follow-up. Eur Child Adolesc
Psychiatry. 2007;16:465-470.
64. Werry JS, McClellan J. Predicting outcome in child and adolescent (early onset) schizophrenia and bipolar disorder. J Am Acad
Child Adolesc Psychiatry. 1992;31:147-150.
65. R
opcke B, Eggers C. Early-onset schizophrenia: a 15-year followup. Eur Child Adolesc Psychiatry. 2005;14:341-350.
66. Maziade M, Bouchard S, Gingras N, et al. Long-term stability
of diagnosis and symptom dimensions in a systematic sample
of patients with onset of schizophrenia in childhood and
early adolescence. II: Postnegative distinction and childhood
predictors of adult outcome. Br J Psychiatry. 1996;169:
371-378.
67. Jarbin H, Ott Y, Von Knorring AL. Adult outcome of social
function in adolescent-onset schizophrenia and affective
psychosis. J Am Acad Child Adolesc Psychiatry. 2003;42:
176-183.
68. Hollis C. Adult outcomes of child- and adolescent-onset schizophrenia: diagnostic stability and predictive validity. Am J
Psychiatry. 2000;157:1652-1659.
69. Barrett EA, Sundet K, Faerden A, et al. Suicidality in rst episode
psychosis is associated with insight and negative beliefs about
psychosis. Schizophr Res. 2010;123:257-262.
70. *Eggers C. Course and prognosis in childhood schizophrenia.
J Autism Child Schizophr. 1978;8:21-36.
71. Goff DC, Sullivan LM, McEvoy JP, et al. A comparison of ten-year
cardiac risk estimates in schizophrenia patients from the CATIE
study and matched controls. SchizophrRes. 2005;80:45-53.
72. Hsiao R, McClellan JM. Substance abuse in early onset psychotic
disorders. J Dual Diagn. 2007;4:87-99.
73. Moore TH, Zammit S, Lingford-Hughes A, et al. Cannabis use
and risk of psychotic or affective mental health outcomes:
a systematic review. Lancet. 2007;370:319-328.
74. Frazier JA, McClellan J, Findling RL, et al. Treatment of EarlyOnset Schizophrenia Spectrum Disorders (TEOSS): demographic and clinical characteristics. J Am Acad Child Adolesc
Psychiatry. 2007;46:979-988.
75. McClellan J, Kowatch R, Findling RL; Work Group on Quality
Issues. Practice parameter for the assessment and treatment of
children and adolescents with bipolar disorder. J Am Acad Child
Adolesc Psychiatry. 2007;46:107-125.
76. Birmaher B, Brent D; AACAP Work Group on Quality Issues.
Practice parameter for the assessment and treatment of children
and adolescents with depressive disorders. J Am Acad Child
Adolesc Psychiatry. 2007;46:1503-1526.
77. Scott J, Martin G, Bor W, Sawyer M, Clark J, McGrath J. The
prevalence and correlates of hallucinations in Australian
adolescents: results from a national survey. Schizophr Res. 2009;
107:179-185.
78. Breslau N. Inquiring about the bizarre: false positives in Diagnostic Interview Schedule for Children (DISC) ascertainment of
obsessions, compulsions, and psychotic symptoms. J Am Acad
Child Adolesc Psychiatry. 1987;26:639-644.
79. Hornstein JL, Putnam FW. Clinical phenomenology of child and
adolescent dissociative disorders. J Am Child Adolesc Psychiatry.
1992;31:1077-1085.
www.jaacap.org
989
102.
103.
104.
105.
106.
107.
108.
109.
110.
111.
112.
113.
114.
115.
116.
117.
118.
119.
120.
121.
122.
123.
124.
125.
126.
127.
128.
129.
130.
JOURNAL
990
www.jaacap.org
OF THE