Bande Low 2016

The World Journal of Biological Psychiatry
ISSN: 1562-2975 (Print) 1814-1412 (Online) Journal homepage: http://www.tandfonline.com/loi/iwbp20
Biological markers for anxiety disorders,

OCD and PTSD: A consensus statement. Part
II: Neurochemistry, neurophysiology and
neurocognition
Borwin Bandelow, David Baldwin, Marianna Abelli, Blanca Bolea-Alamanac,

Michel Bourin, Samuel R. Chamberlain, Eduardo Cinosi, Simon Davies,
Katharina Domschke, Naomi Fineberg, Edna Grünblatt, Marek Jarema,
Yong-Ku Kim, Eduard Maron, Vasileios Masdrakis, Olya Mikova, David Nutt,
Stefano Pallanti, Stefano Pini, Andreas Ströhle, Florence Thibaut, Matilde
M. Vaghi, Eunsoo Won, Dirk Wedekind, Adam Wichniak, Jade Woolley, Peter
Zwanzger & Peter Riederer
To cite this article: Borwin Bandelow, David Baldwin, Marianna Abelli, Blanca Bolea-Alamanac,
Michel Bourin, Samuel R. Chamberlain, Eduardo Cinosi, Simon Davies, Katharina Domschke,
Naomi Fineberg, Edna Grünblatt, Marek Jarema, Yong-Ku Kim, Eduard Maron, Vasileios
Masdrakis, Olya Mikova, David Nutt, Stefano Pallanti, Stefano Pini, Andreas Ströhle, Florence
Thibaut, Matilde M. Vaghi, Eunsoo Won, Dirk Wedekind, Adam Wichniak, Jade Woolley, Peter
Zwanzger & Peter Riederer (2016): Biological markers for anxiety disorders, OCD and PTSD:
A consensus statement. Part II: Neurochemistry, neurophysiology and neurocognition, The
World Journal of Biological Psychiatry, DOI: 10.1080/15622975.2016.1190867
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THE WORLD JOURNAL OF BIOLOGICAL PSYCHIATRY, 2016
http://dx.doi.org/10.1080/15622975.2016.1190867
WFSBP CONSENSUS PAPER
Biological markers for anxiety disorders, OCD and PTSD: A consensus

statement. Part II: Neurochemistry, neurophysiology and neurocognition
Borwin Bandelowa , David Baldwinb, Marianna Abellic , Blanca Bolea-Alamanaci, Michel Bourine ,
Samuel R. Chamberlainf,g , Eduardo Cinosih , Simon Daviesd,i, Katharina Domschkej, Naomi Finebergf ,
Edna Gru€nblattj,k,l,m , Marek Jareman , Yong-Ku Kimo , Eduard Maronp,q,t, Vasileios Masdrakisr ,
Olya Mikovas, David Nuttt , Stefano Pallantiu , Stefano Pinic , Andreas Stro €hlev, Florence Thibautw ,
x o
Matilde M. Vaghi , Eunsoo Won , Dirk Wedekind , Adam Wichniak , Jade Woolleyb, Peter Zwanzgery,z
a n
j
and Peter Riederer
a
Department of Psychiatry and Psychotherapy, University of G€ottingen, Germany; bFaculty of Medicine, University of Southampton,
Southampton, UK; cDepartment of Clinical and Experimental Medicine, Section of Psychiatry, University of Pisa, Pisa, Italy; dCentre for
Addiction and Mental Health, Geriatric Psychiatry Division, University of Toronto, Toronto, Canada; eNeurobiology of Anxiety and Mood
Downloaded by [University of California, San Diego] at 11:16 16 July 2016
Disorders, University of Nantes, Nantes, France; fHertfordshire Partnership University NHS Foundation Trust and University of
Hertfordshire, Parkway, UK; gDepartment of Psychiatry, University of Cambridge, Cambridge, UK; hDepartment of Neuroscience Imaging
and Clinical Sciences, Gabriele D’Annunzio University, Chieti, Italy; iSchool of Social and Community Medicine, Academic Unit of
Psychiatry, University of Bristol, Bristol, UK; jDepartment of Psychiatry Psychosomatics and Psychotherapy, University of Wuerzburg,
Wuerzburg, Germany; kDepartment of Child and Adolescent Psychiatry and Psychotherapy, Psychiatric Hospital, University of Zurich,
Zurich, Switzerland; lNeuroscience Center Zurich, University of Zurich and the ETH Zurich, Zurich, Switzerland; mZurich Center for
Integrative Human Physiology, University of Zurich, Zurich, Switzerland; nThird Department of Psychiatry, Institute of Psychiatry and
Neurology, Warszawa, Poland; oDepartment of Psychiatry College of Medicine, Korea University, Seoul, Republic of Korea; pDepartment
of Psychiatry, North Estonia Medical Centre, Tallinn, Estonia; qDepartment of Psychiatry, University of Tartu, Estonia; rAthens University
Medical School, First Department of Psychiatry, Eginition Hospital, Athens, Greece; sFoundation Biological Psychiatry, Sofia, Bulgaria;
t
Faculty of Medicine Department of Medicine, Centre for Neuropsychopharmacology, Division of Brain Sciences, Imperial College
London, UK; uUC Davis Department of Psychiatry and Behavioural Sciences, Sacramento, CA, USA; vDepartment of Psychiatry and
Psychotherapy, Campus Charite Mitte, Charite – University Medica Center Berlin, Berlin, Germany; wFaculty of Medicine Paris Descartes,
University Hospital Cochin, Paris, France; xDepartment of Psychology and Behavioural and Clinical Neuroscience Institute, University of
Cambridge, UK; ykbo-Inn-Salzach-Klinikum Wasserburg am Inn, Germany; zDepartment of Psychiatry and Psychotherapy, Ludwig-
Maximilian-University Munich, Munich, Germany
ABSTRACT ARTICLE HISTORY

Objective: Biomarkers are defined as anatomical, biochemical or physiological traits that are spe- Received 2 May 2016
cific to certain disorders or syndromes. The objective of this paper is to summarise the current Accepted 3 May 2016
knowledge of biomarkers for anxiety disorders, obsessive-compulsive disorder (OCD) and post-
traumatic stress disorder (PTSD).
KEYWORDS
Methods: Findings in biomarker research were reviewed by a task force of international experts Anxiety disorders;
in the field, consisting of members of the World Federation of Societies for Biological Psychiatry neuroimaging; genetic;
Task Force on Biological Markers and of the European College of Neuropsychopharmacology neurochemistry;
Anxiety Disorders Research Network. neurobiology; review
Results: The present article (Part II) summarises findings on potential biomarkers in neurochem-
istry (neurotransmitters such as serotonin, norepinephrine, dopamine or GABA, neuropeptides
such as cholecystokinin, neurokinins, atrial natriuretic peptide, or oxytocin, the HPA axis, neuro-
trophic factors such as NGF and BDNF, immunology and CO2 hypersensitivity), neurophysiology
(EEG, heart rate variability) and neurocognition. The accompanying paper (Part I) focuses on neu-
roimaging and genetics.
Conclusions: Although at present, none of the putative biomarkers is sufficient and specific as a
diagnostic tool, an abundance of high quality research has accumulated that should improve our
understanding of the neurobiological causes of anxiety disorders, OCD and PTSD.
Abbreviations: 5-HIAA: 5-Hydroxyindoleacetic acid; 5-HT: Serotonin; 5-HTP: Hydroxytryptophan; 5-

HTT: Serotonin transporter; 5-HTTLPR: Serotonin-transporter-linked polymorphic region; A-SepAD:
Adult Separation Anxiety Disorder; ACC: Anterior cingulate cortex; ACTH: Adrenocorticotropic hor-
mone or corticotropin; ADRN: Anxiety Disorders Research Network; ANP: Atrial natriuretic peptide;
ASLO: Anti-streptolysin O; BDD: Body Dysmorphic Disorder; BDNF: Brain-derived neurotrophic fac-
tor; C-SepAD: Childhood Separation Anxiety Disorder; CBT: Cognitive-behavioural therapy; CCK:
Cholecystokinin; CNS: Central nervous system; COMT: Catechol-O-methyltransferase; CRH:
CONTACT Prof. Dr. Borwin Bandelow Sekretariat.Bandelow@med.uni-goettingen.de von-Siebold-Str. 5, Department of Psychiatry and Psychotherapy,
University of G€ottingen D-37075 G€ottingen, Germany
ß 2016 Informa UK Limited, trading as Taylor & Francis Group
2 B. BANDELOW ET AL.
Corticotropin-releasing hormone; CRP: C-reactive protein; CSF: Cerebro-spinal fluid; DHEAS:

Dehydroepiandrosterone sulphate; DAT: Dopamine transporter; DSM: Diagnostic and Statistical
Manual of Mental Disorders; DST: Dexamethasone suppression test; ECNP: European College of
Neuropsychopharmacology; EEG: Electroencephalography; ELISA: Enzyme-linked immunosorbent
assay; ERN: Error-related negativity; ERP: Event-related potential; fMRI: Functional magnetic reson-
ance imaging; GABA: c-Aminobutyric acid; GABHS: Group A beta haemolytic streptococci ; GAD:
Generalized Anxiety Disorder; GWAS: Genome-wide association study; HF: High frequency (high
frequency oscillation is a frequency-domain heart rate variability measure); HPA axis:
Hypothalamic-pituitary-adrenal axis; HPLC: High-performance liquid chromatography; HRV: Heart
rate variability; IL: Interleukin; LF: Low frequency (low frequency oscillation is a frequency-domain
heart rate variability measure); MAO: Monoamine oxidase; MDD: Major Depressive Disorder;
mPFC: Medial prefrontal cortex; mRNA: Messenger ribonucleic acid; NE: Norepinephrine (noradre-
nalin); NET: Norepinephrine transporter; NGF: Nerve growth factor; NK: Neurokinin; OCD:
Obsessive-Compulsive Disorder; OC-RD: Obsessive-Compulsive-Related Disorders; OFC:
Orbitofrontal cortex; PANDAS: Pediatric autoimmune neuropsychiatric disorder associated with
streptococcal infections; PANS: Pediatric acute-onset neuropsychiatric syndrome; PDA: Panic dis-
order with or without Agoraphobia; PFC: Prefrontal cortex; POMC: Proopiomelanocortin; PSG:
Polysomnography; PTSD: Posttraumatic Stress Disorder; RMSSD: Root mean square of successive
differences; SAD: Social Anxiety Disorder; SDNN: Standard deviation of normal sinus intervals;
SNRI: Serotonin norepinephrine reuptake inhibitor; SSRI: Selective serotonin reuptake inhibitor;
SSRT: Stop signal reaction task; TNF: Tumor necrosis factor ; TSPO: Translocator protein; WFSBP:
World Federation of Societies for Biological Psychiatry
Introduction between CNS and periphery. In the following sections,

some of these findings are listed and described.
This consensus statement on biological markers of anx-
iety disorders was organised by members of the World
Federation of Societies for Biological Psychiatry Task
Neurotransmitters
Force on Biological Markers and of the Anxiety Disorders
Research Network (ADRN) within the European College Monoaminergic systems have long been suggested to
of Neuropsychopharmacology Network Initiative (ECNP- play a major role in depression and anxiety disorders.
NI; Baldwin et al. 2010), an initiative intended to meet While the ‘‘reward system’’ is modulated by endogen-
the goal of extending current understanding of the ous dopamine and opioids (Barbano & Cador 2007;
causes of central nervous system (CNS) disorders, Berridge & Aldridge 2008; Le Merrer et al. 2009;
thereby contributing to improvements in clinical out- Bandelow & Wedekind 2015), the ‘‘punishment system’’
comes and reducing the associated societal burden. is mainly driven by serotonin (5-HT; Stein 1971; Daw
The present article (Part II) summarises the findings et al. 2002). Goal-directed behaviours are stimulated by
on potential biomarkers in neurochemistry, neurophysi- dopamine (DA), and dopamine neurons have been sug-
gested to be a substrate for intracranial self-stimulation
ology, and neurocognition. Part I (Bandelow et al.
(Wise & Bozarth 1982; Mason & Angel 1984; Aboitiz
2016) focuses on neuroimaging and genetics.
2009). Norepinephrine (noradrenaline; NE) has been
connected to ‘‘emotional memory’’ and the consolida-
Neurochemistry tion and retrieval of the emotional arousal induced by
Plasma appears to be a rational source for proteomic particular behaviours (van Praag et al. 1990; Goddard
and metabolomic measurements in psychiatric condi- et al. 2010). NE neurons regulate vulnerability to social
tions because it is easily accessible, and several mole- defeat through inhibitory control of ventral tegmental
cules from the brain are transported across the area DA neurones (Isingrini et al. 2016).
blood–brain barrier and reach the peripheral circula-
tion. However, it is difficult to draw inferences from Serotonergic system
the neurochemical composition of plasma on the situ- Findings on brain imaging and genetics of the sero-
ation in brain cells. Lumbar puncture is an invasive tonin system are summarised in Part I (Bandelow et al.
method, and the composition of cerebrospinal fluid 2016).
(CSF) does not reflect exactly the neurochemistry in 5-HT is a monoamine, found in the CNS, in blood pla-
brain cells. Nevertheless, as a biomarker measure, such telets, and the gastrointestinal tract. The principal
recourses are highly valuable, and several examples of source of serotonin release in the brain are the raphe
evidence in the literature points to possible links nuclei in the brainstem. They are hypothesised to have
THE WORLD JOURNAL OF BIOLOGICAL PSYCHIATRY 3
a dual role in aversive contingencies (Deakin & Graeff although symptom improvements were observed
1991; Deakin 2013). 5-HT can inhibit periaqueductal (Shutov & Bystrova 2008).
grey matter-medicated fight/flight responses from Platelet 5-HT reuptake site binding was found to be
threats, while it can also facilitate amygdala-mediated decreased in PDA patients in two studies (Iny et al.
anxiety responses. The latter mechanism has been dem- 1994; Lewis et al. 1985), while most studies reported no
onstrated both in animals (Deakin & Graeff 1991; Deakin difference comparing to controls (Innis et al. 1987; Nutt
2013) and humans (Blanchard et al. 2001; Mobbs et al. & Fraser 1987; Pecknold et al. 1987; Schneider et al.
2007; Feinstein et al. 2013). Such differences may 1987a; Uhde et al. 1987; Norman et al. 1989a, 1989b;
explain partly the different types of emotions (Mobbs Butler et al. 1992;). Moreover, platelet 5-HT concentra-
et al. 2007) and anxiety disorders seen in humans tion was reported also not to change in PDA patients
(Deakin & Graeff 1991). Therefore, reaction to threat, (Balon et al. 1987; McIntyre et al. 1989), except in one
mediating periaquaeductal-grey-mediated threats, report, where decreased 5-HT concentrations were
related to the emotion named ‘‘fear’’, may be more observed (Evans et al. 1985). Two studies have reported
closely related with phobic, escape-dominant behav- increased platelet 5-HT uptake in PDA patients (Norman
ioural syndromes, such as specific phobias, social anx- et al. 1986; Norman et al. 1989b), while two studies
iety disorder (SAD) and panic disorder with or without reported decreased platelet 5-HT uptake in a PDA
agoraphobia (PDA; Gray & McNaughton 2000; group, compared with controls (Pecknold et al. 1988;
McNaughton & Corr 2004), while amygdala-mediated Butler et al. 1992). Moreover, platelet aggregation in
threats seem to be linked to the emotion named ‘‘anx- response to 5-HT was significantly lower in panic
iety’’ such as general anxiety disorder (GAD) and obses- patients compared with controls (Butler et al. 1992).
sive-compulsive disorder (OCD; Gray & McNaughton CSF levels of the 5-HT metabolite 5-hydroxyindole-
2000; McNaughton & Corr 2004). Recently, a functional acetic acid (5-HIAA) were not different between PDA
difference in 5-HT between fear and anxiety disorders patients and healthy controls; nevertheless, in a small
was demonstrated using an acute tryptophan depletion study with PDA patients responding to clomipramine
technique that transiently lowers brain 5-HT (Corchs or imipramine for at least 2 months, CSF 5-HIAA levels
et al. 2015). In this study, decreasing the function of the decreased significantly compared with baseline levels
5-HT system, using tryptophan depletion in patients in (Eriksson et al. 1991). Nevertheless, in female patients
clinical remission lead to psychological and physio- with major depressive disorder (MDD) comorbid with
logical exacerbation in response to stressors in PDA, PDA, CSF 5-HIAA levels were significantly higher than
SAD and posttraumatic stress disorder (PTSD), but not in MDD patients without PDA and in healthy volun-
in GAD or OCD. This difference might be due to long- teers (Sullivan et al. 2006). Higher CSF 5-HIAA in
lasting neuronal changes, needed in anxiety disorders women with comorbid MDD and lifetime panic dis-
after serotonin-mediated therapeutics, in which acute 5- order was indicative of greater 5-HT release, increased
HT depletion does not cause such effects (Graeff & 5-HT metabolism, and/or decreased 5-HIAA clearance
Zangrossi 2010). Animal data and genetic and neuroi- in this group. Esler et al. (2004) measured brain 5-HT
maging studies in humans point to a role of the 5HT1A turnover via measurement of 5-HIAA levels in plasma
receptor in the neural processing of anxiety (Akimova from internal jugular veins that has a direct overflow
et al. 2009). Recently, a review of the 5HT2C receptor from brain neurons and not from the cerebrovascular
suggested that this receptor may play a crucial role in sympathetic nerves (Lambert et al. 1995). A significant
anxiety (Chagraoui et al. 2016). increase in brain 5-HT turnover, estimated from the
In the following paragraphs, the 5-HT involvement jugular venous overflow of 5-HIAA, was observed in
in various disorders is discussed in more details. non-medicated PDA patients compared with healthy
subjects (Esler et al. 2004).
PDA. 5-HT plasma levels measured by high-perform- Another approach measuring 5-HT disruption is via
ance liquid chromatography were found to be signifi- measurement of antibodies directed at the 5-HT sys-
cantly lower in PDA patients compared with control tem, such as anti-serotonin and 5-HT anti-idiotypic
volunteers (Schneider et al. 1987b). Furthermore, in a antibodies (directed at the serotonin receptors).
study of males with PDA, serum 5-HT concentrations Using this approach, Coplan et al. (1999) showed sig-
were measured via enzyme-linked immunosorbent nificantly elevated levels of plasma anti-serotonin and
assay. The authors reported lower serum 5-HT in serotonin anti-idiotypic antibodies in panic disorder
patients compared with control group at baseline, patients compared with controls. These findings sug-
which was further decreased after treatment with the gest an autoimmune mechanism interrupting the 5-HT
selective serotonin reuptake inhibitor (SSRI) paroxetine, system in PDA.
GAD. Platelet 5-HT reuptake site binding was found to 1,4,5-triphosphate content, is the oldest classical
be decreased in GAD patients (Iny et al. 1994). 5-HT approach, which has identified some predictors of clin-
binding in lymphocytes did not differ in GAD patients ical outcome of the treatment in OCD patients medi-
compared with controls (Hernandez et al. 2002). cated with SSRIs.
Moreover, both 5-HT and 5-HIAA in platelet-rich and - In an early study, Thoren et al. (1980) showed ini-
poor plasma as well as in lymphocytes did not differ tially elevated 5-HIAA levels in the CSF and a decrease
between GAD patients and controls (Hernandez et al. during treatment were associated with better clinical
2002). outcome in patients treated with clomipramine
(Flament et al. 1985).
SAD. The therapeutic efficacy of SSRIs and serotonin There was no difference in blood 5-HT content
norepinephrine reuptake inhibitors (SNRIs) strongly between children and adolescents with severe OCD and
suggests that 5-HT plays a crucial role in SAD. Patients the normal controls. However, OCD patients with a fam-
with SAD show an exaggerated cortisol response to ily history of OCD had significantly higher blood 5-HT
the serotonin-releasing compound fenfluramine, indi- levels than did either the OCD patients without family
cating supersensitivity of the post-synaptic serotonin history or the healthy controls (Hanna et al. 1991).
receptors (Tancer 1993). In a similar study, SAD Blood 5-HT levels were decreased after treatment with
patients underwent challenges for serotonergic (fen- SSRIs (Kremer et al. 1990; Humble & Wistedt 1992;
fluramine), dopaminergic (levodopa), and noradrener- Humble et al. 2001), and higher 5-HT concentrations
gic (clonidine) systems in a double-blind study. They were associated with better outcome after treatment of
had an increased cortisol response to fenfluramine OCD (Aymard et al. 1994; Delorme et al. 2004).
administration, compared with healthy volunteers. Serotonin reuptake binding capacity on platelets
Neither the prolactin response to fenfluramine, the was found to be reduced in children and adolescents
growth hormone or norepinephrine response to cloni- with OCD, but not in Tourette syndrome (Sallee et al.
dine, nor prolactin or eye-blink responses to levodopa, 1996). The binding capacity of the 5-HTT for SSRIs and
differed between patients with SAD and healthy volun- the tricyclic antidepressant (TCA) imipramine decreased
teers (Tancer et al. 1994b). in untreated OCD patients (Marazziti et al. 1996; Sallee
Platelet 5-HT2 receptor density did not differentiate et al. 1996). After treatment with the TCA clomipr-
between the SAD patients and controls, but was asso- amine, binding was decreased (Black et al. 1990),
ciated with severity (Chatterjee et al. 1997). whereas another study has found increased binding
Patients with SAD, healthy control subjects, and after treatment with the SSRI with fluvoxamine and or
OCD control subjects were challenged with single clomipramine (Marazziti et al. 1992).
doses of the partial serotonin agonist oral meta-chloro-
phenylpiperazine (mCPP) and placebo. SAD patients PTSD. In an early review of trauma-related studies
did not significantly differ from normal or OCD control involving epinephrine, norepinephrine, and serotonin,
subjects in prolactin response to mCPP. Female evidence of serotonergic dysregulation in PTSD was
patients with SAD had more robust cortisol responses reported, including frequent symptoms of aggression,
to mCPP challenge (Hollander et al. 1998). impulsivity, depression and suicidality, decreased plate-
SAD patients, who had been successfully treated let paroxetine binding, blunted prolactin response to
with an SSRI, underwent a tryptophan depletion chal- fenfluramine, exaggerated reactivity to m-chlorophenyl-
lenge combined with a public speaking task. Salivary piperazine (mCPP), and clinical efficacy of SSRIs
a-amylase, a marker of autonomic nervous system (Southwick et al. 1999).
response, and hypothalamic-pituitary-adrenal (HPA) No change in 5-HT1A receptor binding was found in
axis response, as measured with salivary cortisol, were a study by Bonne et al. (2005). A lower number of plate-
assessed. The tryptophan depletion group showed a let [3H]paroxetine binding sites and a lower dissociation
significant larger salivary a-amylase response to the constant for [3H]paroxetine binding in combat veterans
public speaking task as compared with the placebo with PTSD compared with normal control subjects was
group, whereas no differences were seen in cortisol reported (Fichtner et al. 1995). Platelet 5-HT concentra-
responses (van Veen et al. 2009). tion was significantly lower in suicidal PTSD and non-
PTSD patients compared with non-suicidal patients or
OCD. Measurement of peripheral serotonergic parame- healthy controls (Kovacic et al. 2008). Compared with
ters, like whole-blood 5-HT concentration, CSF concen- the control subjects, the PTSD patients showed signifi-
tration, platelet 5-HT transporter (5-HTT), 5-HT2A cantly lower platelet-poor plasma 5-HT levels, elevated
receptor binding characteristics and platelet inositol platelet-poor plasma norepinephrine levels, and
significantly higher mean 24-hour urinary excretion of and functions of norepinephrine have been studied
all three catecholamines (norepinephrine, dopamine extensively in depression and anxiety disorders.
and homovanillic acid; HVA) (Spivak et al. 1999). Hypofunction is postulated for the former, and hyper-
During presentation of a trauma-related video, CSF function for the latter. Findings on brain imaging and
concentrations of 5-HIAA diminished, but there was genetics of the noradrenergic system are summarised
only a trend for statistical significance for this finding in Part I (Bandelow et al. 2016).
(Geracioti et al. 2013).
PDA. Stimulation of noradrenergic systems produces
Dopaminergic system abnormal changes in measures of anxiety, somatic
Dopamine is involved in reward-motivated behaviour symptoms, blood pressure and plasma NE metabolite
and motor control. Findings on brain imaging and gen- and cortisol levels in patients with PDA but not in
etics of the dopamine system are summarised in Part I patients with GAD, OCD, depression or schizophrenia,
(Bandelow et al. 2016). Similarly as for the serotonergic indicating specificity of abnormality in the regulation
system, current findings related to the dopaminergic of the NE system in patients with PDA (Boulenger &
system are described in the following paragraph. Uhde 1982; Heninger & Charney 1988).
There is a body of evidence for NE involvement in

PDA. Eriksson et al. (1991) reported no significant anxiety in humans; e.g., anxiety can be induced using
change in CSF levels of HVA, the major metabolite of NE neuronal activators such as piperoxane and yohim-
dopamine in patients with PDA compared with healthy bine (Redmond & Huang 1979). In patients with PDA,
controls. Nevertheless, in another study in both PDA peripheral markers, including platelet aggregation to NE
and SAD, low CSF HVA levels were observed (Johnson and to 5-HT, platelet A2-receptor density, lymphocyte b-
et al. 1994). receptor density, [3H]ketanserin binding to platelet 5-
HT2 receptors and [3H]5-HTT uptake into platelets,
SAD. In a study evaluating eye-blink response to admin- largely remained abnormal during 6 months treatment
istered levodopa, no dysfunction of the dopaminergic with either clomipramine or lofepramine, despite clin-
system was reported (Tancer et al. 1994a). Another ical improvement (Butler et al. 1992). Therefore, these
approach is to challenge with dopamine agents such as peripheral markers have been suggested to be potential
the antagonist sulpiride and the agonist pramipexole. trait markers in patients with PDA. Adrenergic receptor
Hood et al. (2010) found that patients with SAD res- function has been measured in several clinical studies.
ponded with increased anxiety to both drugs but that Platelet a2-adrenoceptors have been studied in PDA
the effect of treatment with SSRIs was to attenuate the patients using clonidine and yohimbine binding assays
impact of pramipexole, suggesting a degree of dopa- and correlated to symptom ratings and measurement
mine D3 receptor desensitisation after SSRI treatment. of lying and standing plasma adrenaline and NE levels
(Cameron et al. 1996; Nutt & Fraser 1987). Tritiated clo-
OCD. Acute deep brain stimulation targeted at the nidine binding was decreased and resting heart rate
nucleus accumbens of 15 OCD patients induced a was increased in PDA patients before treatment (fluox-
decrease in binding potential to the dopamine D2/D3 etine, tricyclics or alprazolam). The magnitude of
receptor (measured via SPECT [123I]IBZM binding), and decrease in receptor binding was correlated with symp-
chronic stimulation induced an increase in HVA plasma tom severity and standing plasma NE (Cameron et al.
levels, implying that deep brain stimulation induces 1996). In a similar approach, Gurguis et al. (1999)
striatal dopamine release in OCD patients (Figee et al. showed that patients with PDA had high a2-adrenocep-
2014). tor density in both conformational states.
Stimulation of the locus coeruleus, an area contain-
PTSD. In the aforementioned study by Geracioti et al. ing most of the noradrenergic cell bodies of the brain,
(2013), CSF HVA concentrations diminished significantly has been shown to induce anxiety and to raise the
after a traumatic video. Compared with control subjects, concentration of the main central NE metabolite,
PTSD subjects showed significantly higher mean 24-h 3-methoxy-4-hydroxyphenyl glycol (MHPG) in patients
urinary excretion of dopamine (Spivak et al. 1999). with panic attacks. The decrease in plasma MHPG con-
centrations was found to parallel the response of
Noradrenergic system
patients with PDA to treatment (Charney et al. 1983).
NE is a catecholamine produced mainly in the locus However, this could not be confirmed in a study of the
coeruleus in the pons. It is an important neurotransmit- effects of imipramine in PDA by Nutt & Glue (1991).
ter in the autonomic nervous system. The metabolism Similarly, CSF levels of MHPG were not changed
significantly in patients with PDA (Eriksson et al. 1991). central inhibitory mechanisms. With regard to neuro-
On the other hand, Lista (1989) reported short time transmission, the c-aminobutyric acid (GABA) system
urine sampling to measure NE excretion as a marker serves as the most important inhibitory neurotransmit-
for monitoring sympathetic activity. NE excretion was ter system (Domschke & Zwanzger 2008). According to
highest in major depression, followed by ‘‘minor’’ both preclinical and clinical studies, this system has
depression, anxiety disorders and healthy controls. been suggested to be strongly involved in the patho-
Although plasma catecholamines (NE and epinephrine), physiology of anxiety and anxiety disorders. For
blood pressure and heart rate were only partially corre- example, benzodiazepines, which act at the GABA sys-
lated with salivary A-amylases, Kang (2010) proposed tem, are used to treat anxiety. GABA is synthesised by
a-amylase as a measure of stress sensitivity causing an a specific enzyme – glutamate acid decarboxylase –
increase in anxiety scores. Recently, it was shown that from glutamate. Released in the synaptic cleft, it either
epinephrine (24-h urine collection) was positively corre- binds on GABA receptors or is removed by the main
lated with anxiety but not with depression, whereas degradative enzyme GABA-transaminase (GABA-T) (for
24-h urinary NE excretion was neither correlated with a review, see Olson 2002).
anxiety nor depression (Paine et al. 2015). So far, three major subtypes of GABA receptors
A low pre-treatment b-adrenoceptor affinity was have been identified: GABAA, GABAB and GABAC
found to predict the treatment response to paroxetine receptors. GABAA and GABAC receptors belong to the
in patients with PDA and was suggested as a bio- class of ligand-gated ion channels, GABAB receptors
serve as transmembrane receptors, coupled with G-
marker of pharmacological outcome in PDA (Lee et al.
proteins and activate second messenger systems
2008).
(Chebib & Johnston 1999). However, the fast inhibi-
tory action of the neurotransmitter GABA is mediated
PTSD. Compared with control subjects, PTSD patients
through GABAA receptors. A large variety of GABAA
showed significantly elevated platelet-poor plasma NE
receptor subtypes has been characterised so far: a 1-
levels, and significantly higher mean 24-h urinary
6, b 1-3, c 1-3, d, e 1-3, h, p (Jacob et al. 2008); see
excretion of all three catecholamines (NE, dopamine
Figure 1.
and HVA) (Spivak et al. 1999).
GABAA receptors consist of two a subunits, two b
subunits and one c or d subunit (Jacob et al. 2008).
c-Aminobutyric acid
Moreover, there are two distinct binding sites on the
There is ample evidence that the pathogenesis of anx- GABAA receptor: whereas GABA itself binds on the
iety disorders is in part linked to a dysfunction of GABA binding site, which is located at the interface
Figure 1. GABA-A receptor and subunit structure; GABA and benzodiazepine (BZD) binding site (Domschke & Zwanzger 2008).
between the a and c subunit, anxiolytic agents such as et al. 2002). The TSPO ligand XBD173 enhanced GABA-
benzodiazepines bind at the benzodiazepine binding mediated neurotransmission and exerted antipanic
site at the interface between the a and the c subunit. activity in humans. In contrast to benzodiazepines, the
According to several preclinical studies, anxiolytic drug did not cause withdrawal symptoms or sedation.
effects of benzodiazepines have been shown to be Thus, TSPO ligands are promising candidates for novel
mostly mediated by the a2-subunit of the GABAA anxiolytic drugs (Rupprecht et al. 2009), though a poly-
receptor (Low et al. 2000). morphism of the binding site exists in humans that
Therefore, a specific role of distinct GABAA receptor means around 10% have a low affinity variant (Owen
subunits can be hypothesised with regard to the et al. 2011).
pathogenesis of anxiety. Research on specific subunit Neuroimaging studies have found a reduction of
selective psychopharmacological compounds targeting GABA concentrations and benzodiazepine binding in
the a2-subunit of the GABAA receptor and lacking patients with PDA (see chapter Neuroimaging, Part I;
sedative or other associated side effects of benzodiaze- Bandelow et al. 2016). A few genetic studies have
pines is ongoing. attempted to elucidate the role of GABA in anxiety disor-
ders (see chapter Genetics, Part I (Bandelow et al. 2016).
PDA. Neurochemistry. An interesting approach investi- Pharmacological modulation of the GABA system.
gating the role of GABAA receptors on the pathogen- From a clinical point of view, the significance of the
esis of panic attacks stems from Nutt et al. (1990) who GABA system in the pathophysiology of panic and anx-
suggested alterations in benzodiazepine receptor sensi- iety has also been derived from observing beneficial
tivity in patients with PDA. After intravenous challenge, effects on symptoms following selective GABAergic
subjects with panic disorder exhibited panic attacks
treatment. In addition to the rapid and strong anxio-
after flumazenil injection, a phenomenon which has
lytic properties of benzodiazepines, targeting the
been interpreted as a possible shift of the ‘‘receptor
benzodiazepine binding site of the GABAA receptor,
setpoint’’ (Nutt et al. 1990). However, these results
modulation of GABA metabolism has also been shown
have not been replicated (Strohle et al. 1999).
to reduce anxiety and the occurrence of panic attacks.
There is also evidence for a dysfunction of GABAA
Among anticonvulsants, tiagabine and vigabatrin both
receptor modulatory neuroactive steroid regulation in
increase GABA availability via a reduction of GABA
panic disorder patients (Rupprecht 2003). It has been
degradation by inhibition of the GABA transaminase
demonstrated that panic disorder patients show
(vigabatrin) or inhibition of GABA reuptake via block-
increased concentrations of GABA agonistic 3a-reduced
ade of the GABA transporter GAT-I (tiagabine). For
neuroactive steroids (Strohle et al. 2002), which has
both compounds, anxiolytic action has been suggested
been interpreted as a counter-regulatory mechanism
against the occurrence of spontaneous panic attacks. through clinical studies and studies using pharmaco-
In contrast, during experimentally induced panic induc- logical panic induction with CCK-4 (for a review, see
tion with lactate or cholecystokinin-tetrapeptide Zwanzger & Rupprecht, 2005).
(CCK-4) panic disorder patients show a significant Other drugs that enhance GABAergic tone (e.g., bar-
decrease of GABA agonistic 3a-reduced neurosteroids biturates, ethanol, valproate) have anxiolytic effects,
along with an increase of the antagonistic 3a-reduced whereas negative modulators produce anxiogenic-like
isomer, when compared with healthy controls (Strohle effects (Zwanzger et al. 2001; Kalueff & Nutt 2007;
et al. 2003). Zwanzger et al. 2009).
Translocator protein (TSPO) is an 18-kDa protein in
the mitochondrial membrane which was first thought SepAD and benzodiazepines. Several studies favour
to be a peripheral binding site for benzodiazepines the role of TSPO as a useful biological marker of adult
(Papadopoulos et al. 2006). However, recent research separation anxiety disorder (A-SepAD). The TSPO is
has found that it is not only expressed in the body but involved in the secretion of neurosteroids, whose levels
also in the brain. Ligands of this protein may promote are reported to be changed in several diseases and to
the synthesis of endogenous neurosteroids. Some be implicated in the pathogenic mechanisms of anx-
metabolites of progesterone are potent, positive allo- iety and mood disorders in humans. A reduction of
steric modulators of GABAA receptors. Their concentra- platelet expression of TSPO density was found to relate
tions are reduced during panic attacks in patients with specifically to the presence of A-SepAD in samples of
PDA (Strohle et al. 2003). Unexpectedly, patients with patients with PDA (Pini et al. 2005) or major depression
PDA had significantly greater concentrations of the (Chelli et al. 2008) or bipolar depression (Abelli et al.
agonistic 3a-reduced neuroactive steroids (Strohle 2010). Furthermore, Costa et al. (2012) found Ala147Thr
substitution in TSPO to be associated with A-SepAD in to CCK-4, emphasising the importance of neurobio-
patients with depression. logical factors (Eser et al. 2008). It was proposed that
benzodiazepine-mediated antagonism of CCK-induced
excitation might be an important mechanism by
Neuropeptides
which benzodiazepines exert their clinically relevant
CCK actions.
Moreover, in PDA patients, decreased concentrations
CCK is one of the most abundant neurotransmitter
of CCK-8 in the CSF have been reported compared with
peptides in the brain and has been shown to induce
control subjects (Lydiard et al. 1992). Concentrations of
excitation of central neurons as well as inhibitory post-
CCK-8 in lymphocytes were also significantly reduced in
synaptic effects (Bourin & Dailly 2004). CCK-1 and -2
patients with PDA compared with healthy controls
receptors (G protein-coupled receptors) (recently
(Brambilla et al. 1993). Finally, CCK-B receptor expres-
reclassified as A and B) are widely distributed through-
sion and binding are increased in animal models of anx-
out the CNS. A large body of evidence suggests that
iety. These findings are in favour of abnormalities in the
the neuropeptide CCK might be an important modula-
CCK system in PDA patients.
tor of the neuronal networks that are involved in anx-
The key regions of the fear network, such as baso-

iety, in particular in PDA.
lateral amygdala (Del Boca et al. 2012), hypothalamus,
periaqueductal grey, or cortical regions such as the
PDA. In humans, CCK-induced anxiety may be medi-
anterior cingulate cortex (ACC), seem to be connected
ated via CCK-B receptors (vs. CCK-B and -A in mice) (Li
by CCK-ergic pathways (Dieler et al. 2008). Moreover,
et al. 2013). Intravenous administration of exogenous these effects seem to be modulated by molecular
CCK-4, -8 or the CCK agonist pentagastrin produced mechanisms, since neurochemical alterations were
panic-like attacks in healthy volunteers within one dependent on neuropeptide S genotype (Ruland et al.
minute, and these effects were attenuated by pre- 2015). In humans, amygdala activation may be
treatment with benzodiazepines (de Montigny 1989; involved in the subjective perception of CCK-4-induced
Bradwejn et al. 1991b). The most common clinical fear (Eser et al. 2009). In the amygdala, CCK may act in
effects observed after administration of intravenous concordance with the endogenous cannabinoid system
CCK-4 were dyspnoea, palpitations/tachycardia, chest in the modulation of fear inhibition and extinction. In
pain/discomfort, faintness, dizziness, paresthaesia, hot addition, CCK-4-induced panic is accompanied by a
flushes/cold chills, nausea/abdominal distress, anxiety/ significant glutamate increase in the bilateral ACC (for
fear/apprehension and fear of losing control – a cluster a review, see Bowers et al., 2012). In contrast to pla-
of symptoms similar to those observed in spontaneous cebo, alprazolam abolished the activation of the rostral
panic attacks in PDA. ACC after challenge with CCK-4 and increased func-
In addition, the dose-response to intravenous CCK-4 tional connectivity between the rostral ACC and other
reliably differentiates PDA patients from healthy con- anxiety-related brain regions such as the amygdala
trols with no personal or family history of panic attacks and the prefrontal cortex (PFC). Moreover, the reduc-
(Bradwejn et al. 1992). Furthermore, a relationship tion in the CCK-4 induced activation of the rostral ACC
between dose and effect was found in healthy volun- correlated with the anxiolytic effect of alprazolam
teers (Bradwejn et al. 1991a). While the panic rate after (Leicht et al. 2013). Finally, social stress-induced behav-
injection of 25 lg of CCK-4 was 91% for patients as ioural deficits are mediated partly by CCK-B receptors
compared with only 17% for controls, and 50 lg as a molecular target of DFosB in the medial prefrontal
induced a full-blown panic attack in 100% of patients cortex (mPFC) and by molecular adaptations in the
vs. 47% of controls. mPFC involving DFosB and CCK through cortical pro-
In contrast to the findings in patients with PDA, jections to distinct subcortical targets. In fact, CCK in
in CCK-4-sensitive healthy volunteers, treatment with mPFC-basolateral amygdala projections mediates anx-
an antipanic SSRI did not cause a reduction of CCK- iety symptoms (Vialou et al. 2014).
4-induced panic attacks beyond the effect of placebo CCK also interacts with several anxiety-relevant
(Toru et al. 2013). However, a significant reduction in neurotransmitters such as the serotonergic,
CCK-induced anxiety was observed after administra- GABAergic and noradrenergic systems, as well as
tion of the benzodiazepine alprazolam and the with endocannabinoids, neuropeptides Y and S (for a
GABAergic anticonvulsant vigabatrin (Zwanzger et al. review, see Zwanzger et al., 2012). For a review of
2001; Zwanzger et al. 2003). Baseline anxiety is a not CCK genes in anxiety disorders, see Part I (Bandelow
a major determinant of the subjective panic response et al. 2016).
In conclusion, experimental panic induction with increase also contributes to the paradoxical blunting of
CCK-4 has been established as a model to study the ACTH and cortisol secretion during lactate-induced and
pathophysiology of PDA and might serve as a tool to possibly spontaneous panic attacks. As physical activity
assess the anti-panic potential of novel anxiolytic com- increases ANP concentrations, the anxiolytic activity of
pounds if the challenge procedure is carried out exercise might be associated with increased ANP con-
according to strictly comparable conditions (Eser et al. centrations. And indeed, the anxiolytic activity of a sin-
2007). gle exercise bout was correlated with the increased
ANP concentrations (Strohle et al. 2006).
Neurokinins (tachykinins) Although there have been major efforts to develop
small-molecule, non-peptide receptor ligands acting as
Central neurokinins (tachykinins) have been shown to
CRH1 antagonists, NK-antagonists or ANP agonists, we
play a role in the modulation of stress-related behav-
still lack convincing clinical proof-of-concept studies
iours and anxiety. Different forms exist, termed neuro-
with peptidergic treatment approaches in patients with
kinins 1, 2 and 3. Substance P, a ligand of the
anxiety disorders.
neurokinin 1 (NK1) receptor, is released in response to
stress, anxiety, and pain (Saria 1999; Carrasco & Van de
Oxytocin
Kar 2003; Ebner & Singewald 2006).
SAD. In humans, modulation of anxiety by oxytocin
has been demonstrated by showing reduced amygdala
PDA. In a positron emission tomography (PET) study, responses to aversive stimuli. Moreover, intranasal oxy-
decreased NK1 receptor binding was found in patients tocin promotes trust, and reduces the level of anxiety,
with PDA (Fujimura et al. 2009); see Part I (Bandelow possibly at the level of the amygdala (Kirsch et al.
et al. 2016). Attempts have been made to develop 2005; Kosfeld et al. 2005; Zak et al. 2005; Heinrichs
neurokinin antagonists for the treatment of anxiety dis- et al. 2009). The dysregulation of oxytocin as a putative
orders. The NK1 receptor antagonist vestipitant showed mechanism underlying social attachment has been
anxiolytic effects in a preliminary study (Poma et al. examined widely in animal studies (e.g., Williams et al.
2014). However, vofopitant, a NK1 antagonist, and ona- 1994), and recently has become of interest in human
setant, a NK3-receptor antagonist, were not effective studies.
(Kronenberg et al. 2005; Poma et al. 2014). In a study examining oxytocin as add-on to expos-
ure therapy in patients with SAD, participants adminis-
Specific phobia. In a PET study in women with specific tered with oxytocin showed improved positive
phobias, uptake of the labelled NK1 receptor antagon- evaluations of appearance and speech performance,
ist [11C]GR205171 was significantly reduced in the right but these effects did not generalise to improve overall
amygdala during phobic stimulation (Michelgard et al. treatment outcome from exposure therapy (Guastella
2007). et al. 2009).
The role of oxytocin in SAD has also been shown in
Atrial natriuretic peptide neuroimaging studies (chapter Neuroimaging, Part I;
PDA. Atrial natriuretic peptide (ANP) is not only syn- Bandelow et al. 2016).
thesised by atrial myocytes and released in the circula-
tion (de Bold 1985), but is also found in various brain SepAD. Genetic studies have shown a possible role of
areas where specific receptors have been identified. oxytocin in SePAD (chapter Genetics, Part I; Bandelow
ANP has been shown to inhibit the corticotropin-releas- et al. 2016).
ing hormone (CRH)-stimulated release of adrenocortico-
tropic hormone (ACTH; Kellner et al. 1992) and cortisol PTSD. In Vietnam veterans with PTSD, no beneficial
(Strohle et al. 1998a). Also, peripheral and central effects of intranasal oxytocin on physiological
administration of ANP has an anxiolytic activity in differ- responses to combat imagery were observed (Pitman
ent animal models of anxiety (Strohle et al. 1997). In et al. 1993).
patients with PDA, ANP reduced CCK-4-induced panic
attacks (Strohle et al. 2001) and an activation of the HPA axis
HPA system (Wiedemann et al. 2001). Furthermore, a
PDA
significantly accelerated ANP release has been
described in patients with lactate-induced panic attacks A growing number of studies has aimed to delineate
(Kellner et al. 1995), and it has been suggested that this the possible role of HPA axis function in the
pathophysiology of the anxiety disorders, mainly study by Liebowitz et al. (1985), only patients who rap-
through the use of plasma, urine, or saliva cortisol lev- idly developed panic attacks after lactate infusion had
els in basal conditions or after pharmacological or psy- marginally higher cortisol levels than controls. By con-
chological challenge test as a potential biological trast, Hollander et al. (1998) found that cortisol levels
marker (Elnazer & Baldwin 2014). fell significantly during lactate-induced panic in
patients and controls. Interestingly, patients who pan-
Basal levels. Baseline plasma levels of cortisol in PDA icked after lactate had higher plasma cortisol levels
patients were reported to be elevated during the day before the infusion than controls (Coplan et al. 1998).
(Nesse et al. 1984; Roy-Byrne et al. 1986; Goetz et al. Inhalation of carbon dioxide (CO2) did not induce a
1989) or during the night (Abelson et al. 1996) by significant increase in plasma or salivary cortisol in
some authors, but to be normal by others (Brambilla panickers (Gorman et al. 1989; van Duinen et al. 2004).
et al. 1995; Cameron et al. 1987; Stein & Uhde 1988). However, subsequent studies suggested that 35% CO2
Urinary free cortisol in PDA patients was found to be significantly increases plasma levels of ACTH and corti-
normal (Uhde et al. 1988), elevated (Bandelow et al. sol in PDA patients (van Duinen et al. 2007) and of cor-
1997) or elevated only in patients with complicated tisol in healthy subjects (Argyropoulos et al. 2002).
PDA (Lopez et al. 1990) when compared with healthy Nevertheless, in PDA patients, no specific association
controls. emerged between the 35% CO2-induced panic attacks
Baseline ACTH concentration in plasma was and HPA axis activation observed after this challenge
increased in patients compared with controls (van Duinen et al. 2007).
(Brambilla et al. 1992). HPA axis stimulation tests Patients reporting yohimbine-induced panic attacks
showed significantly lower ACTH responses to CRH in had significantly larger increases in plasma cortisol
patients compared with normal control subjects in than healthy subjects (Charney et al. 1987). mCPP or
three studies (Roy-Byrne et al. 1986; Holsboer et al. oral caffeine increased plasma cortisol in both patients
1987; Brambilla et al. 1992) and normal responses in and controls (Charney et al. 1985; Klein et al. 1991).
one (Rapaport et al. 1989). Cortisol release after CRH However, a placebo-controlled study suggested that
was found to be lower in two (Roy-Byrne et al. 1986; the significant increases in plasma cortisol, ACTH and
Brambilla et al. 1992) and normal in two other studies dehydroepiandrosterone sulphate (DHEAS) observed
(Holsboer et al. 1987; Rapaport et al. 1989). after oral caffeine (400 mg) administration in PDA
patients are not associated with the occurrence or
HPA axis response during panic attacks. Cameron non-occurrence of a panic attack at post-challenge
et al. (1987) measured cortisol during spontaneously (Masdrakis et al. 2015). Pentagastrin (CCK-4) induced
occurring panic attacks while patients stayed at bed- panic attacks were associated with a pronounced rise
rest with an indwelling venous catheter for sampling of plasma cortisol levels (Abelson et al. 2007).
of blood. They found non-significantly elevated plasma
cortisol levels during attacks. HPA axis response to treatment. Some studies inves-
During naturally occurring panic attacks, a signifi- tigated the effect of treatment on the HPA axis in
cantly increased salivary cortisol secretion could be patients with PDA. Nocturnal urinary cortisol excre-
shown in PDA patients compared with values of the tion did not change during treatment with paroxe-
same individuals obtained at comparable daytime on tine vs. placebo combined with relaxation training or
panic-free days (Bandelow et al. 2000). The salivary aerobic exercise (Wedekind et al. 2008). On the con-
method used in this study proved to be a useful non- trary, exercise training was associated with lowered
invasive method to measure HPA function in anxiety salivary cortisol levels in PDA patients (Plag et al.
disorders, and has often been used in subsequent 2014).
research.
During exposure to feared situations, PDA patients HPA axis suppression tests. Findings with the dexa-
did not show increased levels of concentrations of cor- methasone suppression test (DST) were summarised by
tisol and ACTH (Siegmund et al. 2011). In order to Ising et al. (2012). Most studies found a normal reac-
investigate cortisol levels during panic attacks, panic tion in the DST in PDA patients, e.g., Cameron & Nesse
provocation tests have been performed. In most stud- (1988), while cortisol non-suppression after dexametha-
ies, patients who panicked during lactate infusion did sone was found in at least some patients in some
not show elevations in ACTH or cortisol (Carr et al. other investigations (Avery et al. 1985; Erhardt et al.
1986; Levin et al. 1987; Den Boer et al. 1989; Gorman 2006; Petrowski et al. 2013). Results of studies employ-
et al. 1989; Targum 1992; Strohle et al. 1998b). In a ing the CRH stimulation test in PDA have been mixed.
While two studies suggest an abnormal CRH response showed similar cortisol and DHEAS plasma levels and
pattern in terms of a blunted ACTH response and a cortisol/DHEAS ratio (Phillips et al. 2011).
reduced ACTH/cortisol ratio, three studies were nega- Corresponding to younger subjects, baseline cortisol
tive or showed inconsistent findings (Ising et al. 2012). levels of 201 elderly subjects with at least one anxiety
Also, combined dexamethasone suppression/CRH tests disorder (including GAD and phobias) were compar-
supported the assumption of an impaired HPA axis able with those of normal controls. However, under
regulation in PDA (Ising et al. 2012). Demiralay et al. stress, males showed a slower decline rate of post-
(2012) found a blunted response of ACTH release fol- stress cortisol increases compared with controls, while
lowing CCK-4 injection only after hydrocortisone preclinical severity was associated with larger post-stress
treatment. cortisol increases and lower recovery capacity in
females (Chaudieu et al. 2008). Administration of 7.5%
HPA axis and neurotrophic factors. Early stressful life CO2 did not significantly change salivary cortisol levels
events may provoke alterations of the stress in medication-free GAD patients (Seddon et al. 2011).
response and the HPA axis, which can endure until Finally, 7–11-year-old children with GAD did not differ
adulthood (Faravelli et al. 2012). Glucocorticoids sup- from controls concerning pre-sleep salivary cortisol,
press brain-derived neurotrophic factors (BDNF) at despite the presence of sleep disturbances (Alfano
messenger ribonucleic acid and protein level. et al. 2013).
Activated glucocorticoid and mineralocorticoid recep- On the contrary, other studies report abnormal –
tors repress the transcription activity of the BDNF either increased or decreased – HPA axis activity in
promoter site. Neurogenesis in the human brain is GAD. Thus, in elderly GAD patients, compared with
most prominent in the dentate gyrus of the hippo- non-anxious controls, cortisol levels were overall signifi-
campus. Hypercortisolism caused by prolonged stress cantly more elevated, were higher during morning
can suppress this neuroplasticity process. Acute hours and were positively associated with GAD symp-
stress, however, activates BDNF, stimulates neuroplas- toms (Mantella et al. 2008). Moreover, not only
ticity and hence improves learning and memory. untreated but also SNRI-treated GAD patients demon-
Therefore, under chronic stress conditions such as in strated significantly higher cortisol levels compared
PDA, an increasing loss of neural plasticity may with normal controls (Hood et al. 2011).
emerge and consequently the ability to appropriate A recent development is the analysis of hair cortisol
coping (Bandelow & Wedekind 2006). The role of concentrations, which reflect the long-term cortisol lev-
neurotrophic factors is reviewed in the next chapter els independently of the acute HPA axis responses in
(Neurotrophic factors, page 33). the laboratory context. GAD patients demonstrate up
to 50–60% lower hair cortisol concentrations compared
GAD with healthy controls (Staufenbiel et al. 2013;
Steudte et al. 2011). These results accord with the
Basal levels and HPA axis response to stressors. It notion that chronic anxiety – an essential clinical fea-
remains uncertain whether untreated GAD is associ- ture of GAD – may result in down-regulation of HPA
ated with abnormally increased cortisol levels. Thus, axis activity. Thus, older adults (65 years old) suffer-
some studies suggest that GAD patients and controls ing from long-lasting anxiety disorders demonstrated a
demonstrate similar baseline cortisol levels and corti- lower cortisol awakening response than normal con-
sol responses to challenge tests. More precisely, base- trols. This association was most prominent in GAD
line urinary free cortisol levels between patients with patients, however, irrespectively of the duration of ill-
‘‘chronic moderate-to-severe anxiety’’ and normal con- ness (Hek et al. 2013). Likewise, chronic anxiety may
trols did not differ significantly (Rosenbaum et al. finally exhaust the capacity for increase in 5-HTT activ-
1983). Twenty GAD male adolescents and normal con- ity due to the chronically elevated plasma cortisol lev-
trols displayed similar cortisol plasma levels after a els, e.g., GAD patients could not increase serotonin
stressful test, but anxious subjects had demonstrated uptake in their lymphocytes after cortisol administra-
greater pre-stress ACTH concentrations (Gerra et al. tion (Tafet et al. 2001).
2000). In an extensive study with 1427 anxious
patients and normal controls, GAD patients demon- HPA axis suppression tests. Non-suppression in the
strated significantly greater cortisol awakening DST in GAD patients (up to 27%) is comparable to that
response than controls, only when also suffering MDD of MDD outpatients, but seems to have little value in
(Vreeburg et al. 2010). Among 4256 Vietnam-era veter- distinguishing between GAD and other disorders,
ans, those suffering from GAD and normal controls including PDA, MDD and agoraphobia (Avery et al.
1985; Schweizer et al. 1986; Tiller et al. 1988; Okasha SAD

et al. 1994; Schittecatte et al. 1995).
The HPA axis is an important stress system concerning
social interaction. Primates with higher baseline HPA
HPA axis response to treatment. Some studies report
axis activity and greater reactivity to stressful stimuli
that successful psychological or pharmacological treat-
demonstrate increased social avoidances (Sapolsky &
ment of GAD is associated with post-treatment corti-
Plotsky 1990; Kalin et al. 1998). Consequently, research
sol level reductions. Thus, after successful cognitive-
concerning the pathophysiology of SAD has focussed
behavioural therapy (CBT) treatment for GAD, signifi-
on the potential role of cortisol in regulating cognitive
cant decreases in both anxiety symptoms and (the lat-
processes and behavioural responses (e.g., avoidances)
ter already elevated at baseline) plasma cortisol levels
to social stressors (Sapolsky 1990; de Kloet et al. 1999;
were observed (Tafet et al. 2005). GAD patients over
60 years of age displayed greater reductions in both Roelofs et al. 2009; van Peer et al. 2010; Elnazer &
peak and total salivary cortisol after escitalopram Baldwin 2014).
treatment, compared with placebo-treated patients
(Lenze et al. 2011). Furthermore, cortisol reductions Basal levels and HPA axis response to stressors.
Some studies suggest that baseline cortisol levels or
were positively associated with improvements in anx-

iety, although this was limited to subjects with ele- cortisol responses after pharmacological or psycho-
vated (above the median) baseline cortisol levels. Of logical challenges are similar between SAD patients
note, genetic variability at the 5-HTT promoter pre- and controls. Thus, no evidence of HPA axis hyperactiv-
dicted these cortisol changes. Furthermore, in the ity in SAD patients compared with healthy controls
escitalopram (but not in the placebo) treatment was observed, as this is reflected in urinary free cortisol
group, salivary cortisol changes were significantly levels or in the free cortisol/creatinine ratio (Potts et al.
associated with changes in immediate and delayed 1991), as well as in the 24-h excretion of urinary free
memory tasks, suggesting that targeting HPA axis dys- cortisol and in post-dexamethasone cortisol levels
function may improve memory in older GAD patients (Uhde et al. 1994). In addition, diurnal saliva cortisol
(Lenze 2008). Tiller et al. (1988) reported that all GAD levels and cortisol increases observed both before
patients who were DST non-suppressors at pre-treat- attending school and before the Trier Social Stress Test
ment were suppressors after successful behavioural were similar between 27 adolescent girls with SAD and
treatment. Finally, refocusing GAD patients’ attention healthy controls (Martel et al. 1999). Moreover, SAD
(and thus distracting them from their anxious patients, compared with controls, demonstrated signifi-
thoughts) seems to reduce cortisol levels (Rosnick cantly greater ACTH and cortisol responses to stress
et al. 2013). (Young et al. 2004) and a significantly greater cortisol
However, other studies report no association awakening response (Vreeburg et al. 2010), only when
between a positive treatment outcome and suffering major depression as well. Intravenous admin-
post-treatment changes in cortisol levels, or no change istration of CCK-4 in SAD or OCD patients, or normal
of cortisol levels at all. Thus, effective treatment of controls did not reveal any significant between-groups
GAD either with buspirone (Cohn et al. 1986) or with differences concerning post-challenge ACTH, cortisol,
alprazolam (Klein et al. 1995) did not significantly alter growth hormone and prolactin responses (Katzman
cortisol levels. Intravenous administration of diazepam et al. 2004). Intravenous administration of citalopram in
in eight GAD patients was associated with post-chal- SAD patients and healthy controls resulted in signifi-
lenge reductions in cortisol (dose dependently) and cantly greater increases in cortisol and prolactin
ACTH (dose independently) (Roy-Byrne et al. 1991). plasma levels compared with placebo administration,
There was no interaction with diagnosis for any of but the changes were similar in patients and controls
these endocrine measures, indicating no differential (Shlik et al. 2002). Although a rapid intravenous mCPP
effects of diazepam on ACTH or cortisol in the GAD challenge resulted in significantly greater rate of panic
and control groups. Subsequently, in a larger study in attacks in PDA patients (85%) compared with general-
GAD patients and healthy controls, diazepam reduced ised SAD patients (14%) and healthy controls (0%),
plasma cortisol levels both when acutely administered post-challenge changes in cortisol levels were still com-
at baseline and during chronic treatment and this parable between these groups (Van Veen et al. 2007).
effect was most apparent in the elderly (60–79 years) In SAD patients evaluated at baseline and after dexa-
compared with the young adults (19–35 years) methasone, no differences were found concerning corti-
(Pomara et al. 2005). However, this effect was not asso- sol awakening response, post-dexamethasone and
ciated with the presence of GAD. other cortisol measurements, in contrast to the
observed elevations in diurnal and post-dexamethasone suggested to be a potential neurobiological marker for
levels of salivary a-amylase, a marker of autonomic ner- pre-pubertal SAD children (van West et al. 2008).
vous system function (van Veen et al. 2008). Moreover, an elevated afternoon salivary cortisol level
Subsequently, SAD patients successfully treated with a at the age of 4.5 years was one of four risk factors (the
SSRI underwent either a tryptophan depletion challenge others being female gender, early exposure to mater-
or a placebo-test, combined with a public speaking- nal stress and early manifestation of behavioural inhib-
challenge. The tryptophan depletion group showed a ition) mediating the association between chronic high
significant larger salivary a-amylase response compared inhibition in school age and SAD occurrence during
with the placebo group, but the two groups demon- adolescence (Essex et al. 2010). In addition, in adoles-
strated similar salivary cortisol responses (van Veen cents, a higher baseline cortisol awakening response
et al. 2009). Accordingly, SAD patients who underwent significantly predicted increased first onsets mainly of
an electrical stimulation test demonstrated significantly SAD (among other anxiety disorders) over a 6-year fol-
greater baseline and post-challenge salivary a-amylase low-up (Adam et al. 2014). Finally, recent data suggest
levels compared with controls. Concerning salivary cor- that 8–12-year-old children with an anxiety disorder
tisol levels, neither within-subject nor group differences (including SAD, GAD, specific phobia and SePAD) dem-
were observed (Tamura et al. 2013). These findings led onstrate psychophysiological characteristics resembling
some researchers to suggest that pathological vulner- those of chronic stress, i.e., a baseline pattern compris-
ability of the autonomic nervous system – and not of ing reduced HPA axis functioning and elevated sympa-
the HPA axis – may underlie SAD psychopathology (van thetic and lowered parasympathetic activity compared
Veen et al. 2008, 2009; Tamura et al. 2013). However, with controls (Dieleman et al. 2015).
both salivary cortisol and a-amylase levels were similar Increased cortisol stress-responsiveness may be
between SAD children (aged 8–12 years) and healthy linked to increased social avoidance behaviours in SAD
controls after undergoing the Trier Social Stress Test for patients. Indeed, SAD patients showed larger cortisol
Children, although the former demonstrated signifi- responses to a social stressor, compared with healthy
cantly higher reactivity compared with the latter controls. Most crucially, cortisol responses were corre-
(Kramer et al. 2012). lated positively to avoidance behaviours displayed dur-
On the contrary, other studies suggest that SAD ing the social stressor and, furthermore, predicted
patients differ significantly from controls concerning them irrespective of blood pressure and anxiety
baseline cortisol levels and/or cortisol responses to (Roelofs et al. 2009). The authors speculate that some
pharmacological or psychological challenges. Thus, in studies failed to find an increased HPA axis response
SAD patients, administration of fenfluramine (Tancer to social stressors in SAD patients due to protocol vio-
et al. 1994b) or mCPP (Hollander et al. 1998) resulted lations – e.g., manipulations that reduce a patient’s
in significantly greater cortisol responses compared experimentally induced stress in order to avoid drop-
with controls. Furlan et al (2001) reported different out of the patient – which might critically reduce their
dichotomies in magnitude and in distribution of corti- cortisol responses.
sol responses to a speech-stressor between SAD The potential role of cortisol in threat processing in
patients and normal controls. Thus, seven patients and SAD remains unclear. Event-related potential (ERP) ana-
14 controls demonstrated post-challenge cortisol lysis indicated that in SAD patients, cortisol administra-
increases (90 and 50%, respectively), while in the tion prior to a social stress-related reaction time task
remaining 11 patients and three controls, cortisol increases the early processing of social stimuli (particu-
decreased. Of note, both patient groups were signifi- larly angry faces) during avoidance (van Peer et al.
cantly more anxious at post-challenge compared with 2009). A subsequent ERP study suggested a highly spe-
controls. On the contrary, SAD patients and controls cific effect of cortisol on early motivated attention to
showed similar cortisol responses to a physical exercise social threat in SAD (van Peer et al. 2010).
challenge, suggesting that distinct biological processes
underlie responses to different stressors in SAD (Furlan HPA axis response to treatment. Clinical improvement
et al. 2001). Patients with SAD, compared with healthy after fluvoxamine treatment in SAD patients was not
controls, had a significantly larger cortisol response associated with baseline and post-treatment plasma
when performing an arithmetic/working memory task cortisol responses to a speech-test (DeVane et al.
in front of an audience (Condren et al. 2002). Baseline 1999).
ACTH and cortisol, as well as post-challenge ACTH
responses were all similar between the two groups. Glucocorticoids in the treatment of SAD. Elevated
Exaggerated cortisol response to a speech-stressor was glucocorticoid levels might inhibit the retrieval of fear-
related memories and, thereby, reduce phobic fear. regarding HPA axis function when exposed to phobic
Thus, in SAD patients, cortisone administered orally 1 h stimuli and that this should be taken into consideration
before a social stressor significantly reduced social fear when tailoring individualised psychotherapeutic inter-
(but not general anxiety) during the anticipation, ventions. Hence, only two-thirds of women with spider
exposure and recovery phase of the stressor. Moreover, phobia showed increased cortisol responses when
the stress-induced release of cortisol in placebo-treated exposed to spider photographs, while the rest, defined
subjects correlated negatively with fear ratings, sug- as ‘‘low-responsive’’, showed lower cortisol responses
gesting that endogenously released cortisol in a pho- compared with ‘‘medium-to-high responsive’’ non-
bic context buffers fear symptoms (Soravia et al. 2006). phobic individuals (Knopf & Possel 2009).
Specific Phobia Glucocorticoids in the treatment of specific phobia.

Basal levels and HPA axis response to stressors. Glucocorticoid treatment seems to reduce symptoms
Most studies suggest that specific phobia is character- of specific phobia acutely and might have a prolonged
ised by exaggerated cortisol increases during exposure effect concerning fear extinction, especially in combin-
to phobic stimuli. Thus, in patients with specific pho- ation with exposure therapy (de Quervain & Margraf
bia, exposure to phobic slides elicited larger cortisol 2008; Soravia et al. 2006). Thus, in subjects with spider
excretion (as well as greater distress and skin-conduct- phobia, repeated oral administration of cortisone
ance responses), compared to neutral exposures (25 mg) 1 h before exposure to spider photographs
(Fredrikson et al. 1985). Likewise, in women with ani- reduced phobic (but not general) anxiety significantly
mal phobias, cortisol levels (as well as levels of epi- more than placebo, and this effect was maintained for
nephrine, norepinephrine, growth hormone and 2 days (Soravia et al. 2006). In addition, patients fearing
insulin) significantly rose during in vivo exposure ses- heights who underwent a three-session virtual-reality
sions, together with increases in anxiety, blood pres- exposure therapy after receiving cortisol (20 mg) 1 h
sure and heart rate (Nesse et al. 1985). Moreover, in before each session, demonstrated significant fear
two patients who underwent exposure therapy for reduction, as well as reductions in acute anxiety and in
height phobia, increased cortisol responses remained skin conductance during exposures to phobic stimuli
over the course of treatment despite behavioural and (de Quervain et al. 2011).
subjective improvements (‘‘desynchrony’’) (Abelson &
Curtis 1989). Subjects with driving phobia, compared OCD
to healthy controls, had significantly greater cortisol
Basal levels and HPA axis response to stressors.
increases during driving and its anticipation one hour
Some studies found no difference in plasma and saliv-
before driving. Cortisol levels were similar between the
ary levels of cortisol or circadian plasma cortisol varia-
two groups on a non-driving day and on morning
tions (Brambilla et al. 1997a; Brambilla et al. 2000;
awakening (Alpers et al. 2003). Pregnant women with
blood-injection phobia, when compared with healthy Kawano et al. 2013; Millet et al. 1998), while one study
pregnant women, had a higher output of cortisol, found increased diurnal secretion of ACTH and cortisol
although both groups demonstrated similar diurnal in patients (Kluge et al. 2007).
cortisol rhythms (Lilliecreutz et al. 2011). After apomorphine infusion but also after saline
Of note, van Duinen et al. (2010) reported that – infusion, OCD patients showed a higher rise in cortisol
although during exposure to phobic stimuli spider pho- levels than healthy controls (Brambilla et al. 2000).
bic patients demonstrated significantly stronger fear Cortisol responses to administration of saline and of
reaction compared with controls –cortisol levels were clonidine were the same in patients and controls
however similar between both groups, thereby suggest- (Brambilla et al. 1997a).
ing a ‘‘desynchrony’’ in patients’ response systems. In a study with youth with OCD, higher early-morn-
ing cortisol values were found when compared with
HPA axis response to treatment. In army recruits with healthy controls. Cortisol levels in the OCD group
protective mask phobia, exaggerated salivary cortisol diminished in response to a psychological stressor
secretion was observed at both baseline and post-treat- (exposure to a feared stimulus or a fire alarm), while
ment, as well as in the morning. After successful 2-day an increase was found in healthy controls (Gustafsson
intensive CBT, significant reductions in cortisol levels et al. 2008). In a similar study, exposure with response
were observed (Brand et al. 2011). It has been sug- prevention, was used as a stressor. Despite consider-
gested that phobic patients may not respond uniformly able psychological stress, no difference in increase of
salivary cortisol was observed when compared with Indeed, individuals who received a high dose of hydro-
controls (Kellner et al. 2012). cortisone within 6 h of a traumatic event had a reduced
In a study using deep brain stimulation for OCD, an risk for the development of PTSD, compared with indi-
increase in obsessive–compulsive and depressive viduals who received placebo (Zohar et al. 2011).
symptoms correlated strongly with an increase in urin- In summary, although the clinical picture of anxiety
ary free cortisol levels after the DBS device was disorders suggests the potential for a prominent role
switched off (de Koning et al. 2013). for disturbed stress response regulation, there are
more inconsistencies than consistencies in the relevant
PTSD research findings.
In PDA, findings are inconsistent regarding baseline
Some studies have found lower cortisol excretion in
cortisol and ACTH levels, response to spontananeously
PTSD patients. According to a review by Yehuda
occurring panic attacks, response to exposure to feared
(2005), most studies demonstrate alterations consistent
situations, chemically provoked panic attacks or response
with an enhanced negative feedback inhibition of cor-
to the dexamethasone suppression or CRH challenge.
tisol on the pituitary, an overall hyper-reactivity of
In GAD, findings are inconsistent regarding whether
other target tissues (adrenal gland, hypothalamus), or
baseline cortisol levels are normal or pathologically ele-

both in PTSD. However, findings of low cortisol and vated, while findings from hair cortisol analysis – a
increased reactivity of the pituitary in PTSD are also recently developed technique, which reflects the long-
consistent with reduced adrenal output. The possible term cortisol levels – suggest significantly lower hair
clinical applications of HPA biomarkers have been cortisol concentrations. Although dexamethasone non-
reviewed by Lehrner & Yehuda (2014). suppression in GAD patients is comparable to that of
MDD outpatients, it seems to be of little value in the
Basal levels. Low urinary cortisol excretion was found differential diagnosis of GAD from other mental disor-
in combat veterans with PTSD as compared with con- ders. Most, but not all, related studies suggest that suc-
trols (Yehuda et al. 1990). Holocaust survivors with PTSD cessful psychotherapy or pharmacotherapy of GAD is
showed significantly lower mean urinary cortisol excre- associated with post-treatment reductions in cortisol
tion than subjects without PTSD (Yehuda et al. 1995). In concentrations.
a small study, patients with PTSD were compared with With regard to patients with SAD, some, but not all,
patients with PDA and healthy controls. PTSD patients studies suggest that they differ significantly from
had lower cortisol and marginally reduced cortisol vola- healthy controls concerning baseline cortisol levels,
tility compared with patients with panic disorder and/or demonstrate exaggerated cortisol stress-respon-
(Marshall et al. 2002). Low cortisol levels in the immedi- siveness possibly linked to increased social avoidances.
ate aftermath of trauma were found to predict the Regarding specific phobia, most studies suggest
development of PTSD (Delahanty et al. 2005; Delahanty inflated cortisol responses during exposure to phobic
et al. 2000; Yehuda et al. 1998). A meta-analysis of 47 stimuli, which are however amenable to behaviour
studies revealed that daily cortisol output was lower for therapy.
PTSD patients relative to healthy controls without Overall, it seems that various pathological findings
trauma; subjects who were exposed to trauma but did are found in HPA axis function across the anxiety disor-
not develop PTSD did not differ from healthy controls ders. Nevertheless, it is not clear, as yet, whether this
without trauma (Morris et al. 2012). reflects reality, or is due to methodological weaknesses
However, in a recent study assessing hair cortisol of current research. In order to more vigorously evalu-
(which reflects long-term cortisol changes), PTSD ate the potential role that HPA axis function plays in
patients and traumatised control subjects without the pathophysiology of anxiety disorders, a number of
PTSD exhibited lower hair cortisol concentrations than strategies have previously been proposed, such as
non-traumatised control subjects suggesting that achieving greater consensus on study objectives and
trauma exposure per se, either in the absence or pres- on clinical features of patient groups and designing
ence of PTSD is a correlate of long-term lower basal meticulous methodological protocols (Baldwin et al.
cortisol levels (Steudte et al. 2013). 2010; Elnazer & Baldwin 2014).
Glucocorticoids in the treatment of PTSD. Based on

Neurotrophic factors
the above-mentioned findings of decreased cortisol
concentrations in PTSD, it has been hypothesised that Neurotrophins are proteins involved in neurogenesis.
glucocorticoid administration might benefit patients. Although most of the neurons in the brain are formed
prenatally, some parts of the adult brain have the abil- aerobic exercise in subjects with panic but not in
ity to form new neurons from neural stem cells, a pro- healthy controls (Strohle et al. 2010).
cess named neurogenesis. Neurotrophins include nerve
growth factor (NGF), BDNF, neurotrophin-3, neurotro- GAD. In a treatment study with GAD patients, no sig-
phin-4, and artemin. nificant association was found between baseline
plasma BDNF levels and GAD severity. Patients who
Nerve Growth Factor (NGF) received the SNRI duloxetine had a significantly greater
mean increase in plasma BDNF level, when compared
NGF is a neuropeptide involved in the regulation of
with patients who had received placebo (Ball et al.
neuron growth. It may be involved in the alert mech-
2013). In a sample of 393 patients with panic disorder,
anism associated with homeostatic adaptations (Cirulli
agoraphobia, GAD or SAD, no differences in BDNF lev-
& Alleva 2009), and might modulate sympathetic neu-
els were found when compared with 382 healthy con-
rons, and therefore occupies a key position in control-
trols (Molendijk et al. 2012).
ling the responsiveness of immune-competent cells A small study comparing patients with GAD or MDD
(Levi-Montalcini et al. 1995). Furthermore, NGF, via the to healthy subjects showed doubled levels of BDNF
hypothalamus (Scaccianoce et al. 1993), can activate and artemin, a glial cell-line derived neurotrophic fac-
the HPA axis (Otten et al. 1979) and plays a role in tor family member, in GAD patients compared with
adaptive responses. More importantly, there is evi- normal controls, while depressed patients showed a
dence that NGF might be an autocrine/paracrine factor reduction (Pallanti et al. 2014).
for the development and regulation of immune cells In summary, neurotrophic factors seem to play a dif-
(Levi-Montalcini et al. 1995). NGF is produced by T and ferent role in mood disorders compared with anxiety
B lymphocytes (Lambiase et al. 1997), which display disorders. While brain atrophy and growth factor
functional NGF receptors (Franklin et al. 1995). reduction have been observed in mood disorders the
Furthermore, NGF promotes the proliferation and dif- opposite has been demonstrated in anxiety disorders.
ferentiation of T and B lymphocytes (Brodie & Gelfand One hypothesis could be that the increase of neuro-
1992), and acts as a survival factor for memory B lym- trophic factors and inflammatory factors observed in
phocytes (Torcia et al. 1996). anxiety disorders are related to brain volume increase
An association between trait anxiety and a genetic observed in brain areas such as the dorsal midbrain by
variation of NGF was found in healthy volunteers (Lang some studies on anxiety disorders (Fujiwara et al. 2011;
et al. 2008). In soldiers making their first parachute Uchida et al. 2008) (see also Chapter neuroimaging,
jump, NGF was increased during and after the jump Part I (Bandelow et al. 2016)).
(Aloe et al. 1994).
While a reduction of NGF in depression has been
Immunological markers
consistently reported (Wiener et al. 2015), NGF has not
been studied widely in patients with anxiety disorders. Neurobiological research on anxiety disorders has
In one GAD study, NGF was increased after successful shown the possible relevance of neuroplasticity and
CBT (Jockers-Scherubl et al. 2007). inflammation processes in the pathophysiology of
these disorders. The high rate of comorbidity between
anxiety disorders and several inflammatory medical
BDNF
conditions has been interpreted as the result of spe-
BDNF is a protein that acts on neurons in the brain cific inflammatory pathways. Anxiety has been linked
and the peripheral nervous system, involved in to cardiovascular risk factors and diseases such as ath-
neurogenesis and in the forming of new synapses. It erosclerosis (Seldenrijk et al. 2010), metabolic syn-
has been assumed that BDNF is implicated in the drome (Carroll et al. 2009), and coronary heart disease
aetiologies of depression and anxiety, but data (Roest et al. 2010), which are also associated with low-
on brain BDNF levels in anxiety disorders are grade systemic inflammation (Libby 2002). While
inconsistent. depressive disorders, which are highly comorbid with
anxiety disorders, have repeatedly been associated
PDA. Serum BDNF levels of PDA patients with poor with the immune system (Kim et al. 2007; Myint & Kim
response to CBT were significantly lower than those of 2014), only few studies have investigated the relation-
patients with good response (Kobayashi et al. 2005). ship between anxiety disorders and inflammation
Moreover, BDNF serum levels increased after 30 min of (Vogelzangs et al. 2013). These have suggested that
certain inflammatory markers are elevated in anxiety acetylcholine can decrease, due to continuous sympa-
disorders (Weik et al. 2008). thetic activation and the lack of parasympathetic coun-
teractivation. Therefore, pro-inflammatory cytokines
The immune system such as TNF, IL1, and IL6 can increase in prolonged
stressful situations, such as anxiety disorders.
The immune system is divided into the innate and the
acquired immune system. The latter again is divided
The autonomic nervous system and the immune sys-
into the cellular and the humoral immune system. The
tem. Although stress initially activates both the sympa-
humoral system is based on antibodies, while the cel-
thetic nervous system and the HPA axis, the role of the
lular immune system involves the phagocytes, cyto-
autonomic nervous system and its interactions with
toxic T-lymphocytes, and cytokines. Lymphocytes are
stress and the immune system has received much less
white blood cells in the lymph that include thymus
attention than the HPA axis (Elenkov et al. 2000).
cells (T cells), which can produce enzymes that destroy
Stress-induced interactions between nervous, endo-
pathogenic cells, bone marrow cells (B cells), which
crine and immune systems are depicted in Figure 2.
produce antibodies for the humoral immune system to
Mental arithmetic and public speaking tasks applied
fight bacteria and viruses, and natural killer cells, which
as brief laboratory stressors induce increases in natural

defend the host from tumour cells and virus infections.
killer cell activity (Breznitz et al. 1998). These increases
Inflammatory responses are characterised by a complex
were potentiated in individuals who had greater car-
interaction between pro- and anti-inflammatory cyto-
diovascular reactivity to stress (Cacioppo et al. 1995).
kines (Pavlov & Tracey 2005). Cytokines are small pro-
In other words, individuals who showed the greatest
teins, including the interleukins (ILs) such IL1, -2, -6, -10,
sympathetic nervous system and endocrine response
-18 and others, tumour necrosis factors (TNFs) and inter-
to brief psychological stressors, also showed increased
ferons (IFNs) such as IFNa, b and c. Interferons are
immune system alterations. Thus, the effect of stress
released by cells that have been infected by a virus,
on the neuroendocrine system and the mechanism by
and are used as drugs (e.g., a-interferon for the treat-
which that effect influences the immune system has
ment of hepatitis C or cancer, b-interferon for multiple
become a subject of interest in recent years (Larson
sclerosis or interleukin 2 for cancer). Interferons also
et al. 2001).
activate natural killer cells.
Epinephrine and norepinephrine modulate the
Cellular Immunity
release of cytokines and inflammation through a- and
b-adrenoceptors on immune cells (Hasko & Szabo PDA. In PDA patients, peripheral lymphocyte subsets
1998). Results of in vitro and in vivo studies have sug- did not differ initially from control subjects. However,
gested that norepinephrine enhances TNF production after three months of treatment with the SSRI paroxe-
(Bertini et al. 1993; Spengler et al. 1994). TNF is an tine, the percentages of some lymphocyte subsets
early cytokine mediator of local inflammatory response were significantly increased, while others were
that causes inflammation and secondary tissue damage decreased (Kim et al. 2004). This finding suggests that
when released in excess (Tracey 2002). Both catechol- pharmacological treatment may affect immune func-
amines have been reported to stimulate IL-6 release by tion in panic disorder patients. In a study by Schleifer
immune cells and other peripheral cells (Chrousos et al. (2002), drug-free patients with PDA showed
2000). NE augments macrophage phagocytosis and decreased percentages and total circulating CD19 þ
tumouricidal activity (Koff & Dunegan 1985). In con- B lymphocytes, but no differences in other lymphocyte
trast, acetylcholine dose-dependently inhibit the measures. Natural killer cell activity did not differ
release of TNF and other pro-inflammatory cytokines between PDA patients and healthy control subjects in
such as IL1, IL6, and IL18, from endotoxin-activated pri- this study.
mary human macrophages (Borovikova et al. 2000).
However, the production of IL10, which is an anti- GAD. In a study by Wingo & Gibson (2015), anxiety as
inflammatory cytokine, was unaffected by acetylcho- a symptom of GAD was associated with blood gene
line. Inhibition of acetyl-cholinesterase activity, which expression profiles in 336 community participants (157
increases acetylcholine levels in the CNS, resulted in anxious subjects and 179 controls). Findings did not
the suppression of the immune response, indicating show a significant differential expression in females,
that acetylcholine has an immunoinhibitory role in the but 631 genes were differentially expressed between
brain (Pavlov et al. 2009). When stressful situations are anxious male and healthy controls. Gene set-enrich-
prolonged, adrenergic agents can increase and ment analysis revealed that genes with altered
Figure 2. Stress-induced interactions between nervous, endocrine and immune systems. The hypothalamus secretes CRH in response
to stress, and from the paraventricular nucleus of the hypothalamus. CRH-containing neurons have projections to the locus coeru-
leus. The locus coeruleus sends direct projections to the sympathetic and parasympathetic preganglionic neurons, increasing sympa-
thetic activity and decreasing parasympathetic activity through the activation of adrenoceptors. In turn, the activation of the
sympathetic nervous system stimulates the release of CRH. The products of sympathetic and parasympathetic nervous system activ-
ity are NE and E, and ACh, respectively. When stress is prolonged, as in anxiety disorders, the sympathetic nervous system continues
to be activated with a lack of parasympathetic counteractivity. As a result, NE and E levels are increased and ACh levels are
decreased, which leads to an increased release of pro-inflammatory cytokines from immune cells. Pro-inflammatory cytokines such
as TNF, IL1 and IL6 then trigger the activation of the sympathetic nervous system. CRH, corticotropin-releasing hormone; NE, nor-
epinephrine; E, epinephrine; ACh, acetylcholine, TNF, tumour necrosis factor; IL1, interleukin-1; IL6, interleukin-6; þ, stimulation; ,
inhibition.
expression levels in anxious men were involved in illness, or a lack of true remission (Ravindran et al.
response of various immune cells (B-cells, myeloid den- 1999). Another study found that patients with child-
dritic cells and monocytes) to vaccination and to acute hood onset of OCD had significantly more natural killer
viral and bacterial infection (peripheral blood mono- cells than patients with late onset OCD (Denys et al.
nuclear cells). In addition, this analysis also identified a 2004). A subsequent study reported that the percent-
network affecting traits of metabolic syndrome. These age and absolute numbers of natural killer cells meas-
results suggest potential molecular pathways that can ured as CD56 lymphocyte subpopulations, were
explain the negative effects of GAD on physical health unchanged (Marazziti et al. 1999). Patients with first-
that are observed in epidemiological studies. degree relatives with OCD also had significant lower
Remarkably, even mild anxiety, which most of the natural killer cell activity compared with patients who
study participants had, was associated with observable had no relative with OCD (Denys et al. 2004). In a
changes in immune-related gene expression levels. study by Marazziti et al. (1999), OCD patients had
increased CD8 þ T cells, both in terms of percent val-
OCD. Studies in OCD have shown that circulating nat- ues and absolute number, and decreased CD4 þ T cells.
ural killer cells were either increased, decreased or not The CD3þ, CD19þ and CD56 þ lymphocyte subpopula-
changed compared with controls. In one study, circu- tions were unchanged.
lating natural killer cells were elevated predominantly
in males which persisted after 12 weeks of SSRI treat- Cytokines. PDA. Patients with PDA had reduced cell-
ment, possibly reflecting either characteristic of the mediated functions compared with healthy controls
before pharmacological treatment, but after treatment, neuroendocrine systems, but does not affect cortisol
no significant differences were seen (Koh & Lee 2004). levels.
One study showed increased levels of 18 cytokines in In OCD, several studies have demonstrated dimin-
subjects with PDA and PTSD, leading the authors to ished production of TNF-a (Brambilla et al. 1997b;
suggest that a generalised inflammatory state may be Denys et al. 2004; Fluitman et al. 2010). One of the first
present in these diseases (Hoge et al. 2009). However, studies in the field (Brambilla et al. 1997b) showed
small studies on cytokines in PDA showed non-signifi- lower plasma concentrations of IL1b and TNF-a in OCD
cant elevations of TNF-a, IL1-a, IL2 and IL3 but a sig- patients compared with controls, which has been
nificant increase of IL1 b (Brambilla et al. 1994; related to hyperactivity of the noradrenergic system
Rapaport & Stein 1994; Weizman et al. 1999). In a study and of the HPA axis. In a study by Denys et al. (2004),
conducted on PDA patients and healthy controls, the ex vivo production of TNF-a in whole blood cul-
plasma concentrations of TNF-a, IFN-c, IL1b, IL2, IL6 tures was significantly decreased in medication-free
and IL12 were measured. Decreased levels of IFN-c patients with OCD compared with controls. The same
and IL12 were observed, which suggested a correlation study showed reduced natural killer cells activity. The
between levels of IFN-c and anxiety-like behaviour, as reduction in both TNF-a and natural killer cells activity
seen in animal models (Tukel et al. 2012). suggests a potential role of altered immune function in
GAD. C-reactive protein (CRP) was found to be the pathophysiology of OCD. Other studies have
increased in some studies (Bankier et al. 2008; revealed normal cytokine production in OCD patients
Copeland et al. 2012). A pilot study measured periph- (Weizman et al. 1996). On the other hand, the possible
involvement of the immune system in certain subtypes
eral levels of relevant cytokines (a-MSH, IL2 and IL10)
of OCD is supported by the relationship between the
in small cohorts of GAD and MDD patients and com-
severity of the disorder and the IL6/IL6 receptor levels
pared them to healthy controls. They found increases
(Maes et al. 1994). However, childhood OCD appears to
in plasma concentrations of IL10 and a-MSH, but no
differ from that occurring at other ages, as increased
significant variations in IL2 (Tofani et al. 2015). One
CSF levels of cell-mediated cytokines have been
study in patients with GAD and PDA measured cell-
reported in children with OCD, when compared with
mediated immune functions through the lymphocyte
children with schizophrenia or attention deficit hyper-
proliferative response to phytohemagglutinin, IL2 pro-
activity disorder (Mittleman et al. 1997). Hounie et al.
duction and natural killer cell activity. This study sug-
(2008) reported a genetic association between the -
gested a reduction in this function when compared
308 G/A and -238 G/A TNF-a polymorphisms and OCD
with healthy controls (Koh & Lee 1998).
in a Brazilian sample.
PTSD. Cytokine levels appear to be constantly elevated
SAD. Among individuals with an anxiety disorder, in PTSD. Some studies have reported higher plasma
those with SAD, females in particular, had lower levels
IL6 and TNF (von Kanel et al. 2007; Gill et al. 2008),
of CRP and IL6. The highest CRP levels were found in and CSF IL6 levels (Baker et al. 2001) among PTSD.
those with an older age at anxiety disorder onset Higher levels of IL6 are linked to PTSD vulnerability fol-
(Vogelzangs et al. 2013). CRP is an acute-phase protein lowing trauma (Sutherland et al. 2003; Pervanidou
produced in the liver that increases stimulated by IL6, et al. 2007; Gill et al. 2009). Higher levels of stimulated
which is in turn secreted by macrophages and T cells. TNF and IL6 were reported in PTSD patients. In a study
OCD Different methodologies, including ex vivo pro- by Rohleder et al. (2004), LPS-stimulated production of
duction and peripheral blood or CSF measurements via IL6, but not TNF-a, was markedly increased in patients.
a variety of techniques, make comparisons difficult. Spivak et al. (1997) showed that serum ILlb levels (but
Several studies (Mittleman et al. 1997; Fluitman et al. not slL-2R) were significantly higher in PTSD patients
2010) have shown that cytokine levels may depend on than in controls. As these levels correlated significantly
factors such as age, and the content of obsessions. For with the duration of PTSD symptoms, it was proposed
example, a study by Fluitman et al. (2010) showed that that desensitisation of the HPA axis in chronic PTSD
norepinephrine levels increased while lipopolysacchar- patients counteracted the stimulatory effect of ILlb on
ide-stimulated TNF-a and IL6 production by peripheral cortisoI secretion. Another study showed that levels of
leucocytes decreased during exposure to disgust- TNF-a and of IL1b were higher in patients than in con-
related objects in OCD patients, but not in healthy trols, while CRP, IL4 and IL10 were not significantly dif-
controls. These data suggest that symptom provoca- ferent (von Kanel et al. 2007). One study found higher
tion in OCD patients with contamination fear is accom- IL1 b and lower IL2R levels in PTSD patients than in
panied by alterations in the immune and controls (Tucker et al. 2004). In all participants, TNF-a
was correlated with PTSD severity. IL4 correlated with and grandparents of Sydenham’s chorea patients and
total hyperarousal symptoms, and PTSD total symptom 6.7% of the parents and grandparents of PANDAS
score, after controlling for systolic blood pressure and patients had a history of rheumatic fever compared
smoking status. PTSD patients showed a low-grade sys- with 1.4% of parents and grandparents of controls.
temic proinflammatory state that was related to dis- This suggests a common liability between rheumatic
ease severity, suggesting one mechanism by which fever and OCD triggered by streptococcus infections
PTSD could contribute to atherosclerotic disease. A (Swedo 2002). The presence of autoantibodies due to
study by Miller et al. (2001) reported a positive rela- molecular mimicry mechanisms is one potential
tionship between posttraumatic psychological distur- explanation for the association between OCD and
bances and serum levels of receptors to interleukin 6 rheumatic fever, following the autoimmune model for
(sIL6r) and CRP, which provides the basis for further Sydenham’s chorea.
research on the effects of psychological disturbance on Infections with GABHS might result in PANDAS, and
physical recovery after injury. viral infections might trigger the autoimmune process
that leads to OCD (Allen et al. 1995; Khanna et al.
Humoral Immunity 1997). Furthermore, patients with rheumatic fever
show a high level of antineural antibodies against the

PDA. Mannan-binding lectin (MBL) and MBL-associated caudate (Husby et al. 1976). They also have high levels
serineprotease-2 (MASP-2) represent important arms of of a monoclonal antibody called D8/D17, which reacts
the innate immune system, and different deficiencies with a particular antigen in B lymphocytes (Zabriskie
may result in infections or autoimmune diseases. 1986). The search for the trait marker for susceptibility
Although PDA was associated with increased inflamma- (Singer & Loiselle 2003) showed that this antigen is
tory response, infections and high comorbidity, the also present in patients with childhood OCD, Tourette
basis for these findings is not clear. A study by syndrome, and chronic tic disorder (Murphy et al.
Foldager et al. (2014) investigated associations with 1997). This D8/D17 antibody has expanded expression
MBL, MASP-2 or the gene MBL2 (which codes for MBL) in individuals with Sydenham’s chorea (89%) compared
with PDA. A large proportion (30%) of MBL deficient with healthy children (17%). Preliminary studies of the
individuals was observed along with significantly lower D8/17 antibody in individuals with PANDAS also found
levels of MBL and MASP-2 plus association with the that 85% of children with PANDAS compared with
MBL2 YA two-marker haplotype. Since MBL deficiency 17% of healthy children have this antibody (Swedo
is highly heterogeneous and associated with both et al. 1997). The exact significance of these finding and
infectious and autoimmune states, more research is how this marker is related to the disease process is
needed to identify which complement pathway com- remain unclear, especially since it has been reported in
ponents could be associated with PDA. patients with other neuropsychiatric disorders of child-
hood onset, including autism (Hollander et al. 1999;
Antibodies. PANDAS (PANS/CANS). OCD is a clinically Murphy et al. 1997).
heterogeneous disorder with several possible subtypes. An autoimmune hypothesis has been suggested for
It has been hypothesised that one of these subtypes is early onset OCD and Tourette syndrome. Antineural
associated with autoimmune disorders triggered by antibodies have been studied and found in the sera of
streptococcal infections (e.g., rheumatic fever and some patients with these disorders, and they are
Sydenham’s chorea) (Miguel et al. 2005). Children who thought to cross-react with streptococcal and basal
develop acute OCD after a group A b-haemolytic strep- ganglia antigens (Morer et al. 2008). Positive anti-basal
tococci (GABHS) infection were first described by ganglia antibodies were found in 64% of PANDAS
Swedo (2002), who coined the acronym PANDAS patients but in only 9% of controls with a documented
(Paediatric Autoimmune Neuropsychiatric Disorders streptococcal infection but no neuropsychiatric symp-
Associated with Streptococci). However, as the aeti- toms (Pavone et al. 2004). Immunoblotting has identi-
ology of the syndrome remains controversial, new fied multiple bands against the caudate supernatant
descriptions have been proposed, including paediatric fraction in PANDAS with primary tics that are different
acute-onset neuropsychiatric syndrome (PANS) and from the control group (Church et al. 2004). The pres-
idiopathic childhood acute neuropsychiatric syndrome ence of antibrain antibodies was reported in 42% of a
(CANS; APA 2013). group of children with OCD compared with rates
Children with PANDAS showed OCD symptoms and between 2% and 10% in three different paediatric con-
tics, but did not have rheumatic fever or Sydenham’s trol (autoimmune, neurological and streptococcal)
chorea. It has also been reported that 4% of parents groups (Church et al. 2004). In addition, antibodies
from a Sydenham’s chorea patient reacted against (Kirvan et al. 2003; Dale et al. 2006). However, these
lysoganglioside and N-acetyl-beta-D-glucosamine, a antibodies might not be pathogenic, but may instead
neuronal antigen also found on the GABHS surface result from local damage.
(Kirvan et al. 2003). In a second study of the same However, some studies do not support an auto-
group (Kirvan et al. 2006), antibodies in PANDAS immune hypothesis. If proved true, this hypothesis
reacted with the neuronal cell surface and the cauda- gives rise to new therapeutic approaches. In fact, some
te–putamen and induced calcium–calmodulin-depend- studies suggest that immuno-modulating strategies are
ent protein (CaM) kinase II activity in neuronal cells. effective in children with PANDAS (Garvey et al. 1999;
Depletion of serum IgG abrogated CaM kinase II cell Perlmutter et al. 1999; Murphy & Pichichero 2002;
signalling and reactivity of CSF was blocked by strepto- Snider et al. 2005). A study by Perlmutter et al. (1999)
coccal antigen N-acetyl-beta-D-glucosamine (GlcNAc). has demonstrated an improvement of obsessive–com-
Antibodies against GlcNAc in PANDAS sera were inhib- pulsive symptoms after plasmapheresis or intravenous
ited by lysoganglioside GM1. Results suggest that anti- immunoglobulin treatment. Twenty-nine children with
bodies from an infection may signal neuronal cells in PANDAS recruited from a nationwide search were
some behavioural and movement disorders. randomised in a partially double-blind fashion (no
Dale et al. (2006) have identified antibodies against sham apheresis) to an immunoglobulin, ‘‘immuno-
neuronal glycolytic enzymes (NGE) autoantigens (pyru- globulin placebo’’ (saline), and plasmapheresis group.
vate kinase M1, aldolase C, neuronal-specific and non- One month after treatment, the severity of obsessive-
neuronal enolase) in 20 unselected post-streptococcal compulsive symptoms improved by 58 and 45% in the
patients with central nervous diseases compared with plasmapheresis and immunoglobulin groups, respect-
20 controls. These enzymes are multifunctional pro- ively, compared with only 3% in the saline control
teins that are expressed both intracellularly and on the group. In contrast, tic scores significantly improved
neuronal cell surface. On the neuronal plasma mem- only after plasmapheresis treatment, but not in the
brane, NGEs are involved in energy metabolism, cell immunoglobulin and the control group. Improvements
signalling and synaptic neurotransmission. GABHS also in both tics and obsessive-compulsive behaviours were
expresses glycolytic enzymes on cell surfaces that have sustained for 1 year.
0–49% identity with human NGE. This suggests Even though PANDAS is by definition a paediatric
molecular mimicry and autoimmune cross-reactivity disorder, patients with adult onset (after the age of 27)
may be the pathogenic mechanism in post-streptococ- OCD or tic disorders related to streptococcal infections
cal CNS disease. Kansy et al. (2006) identified the M1 have also been described. These cases support the
isoform of the glycolytic enzyme pyruvate kinase (PK) hypothesis that streptococcal disease may result in
as an autoimmune target in Tourette syndrome and adult-onset OCD in some patients. It is possible that
associated disorders. Antibodies to PK reacted strongly GABHS infection just serves as a trigger in childhood,
with surface antigens of infectious strains of strepto- and that autoimmune antibodies directed against neur-
coccus, and antibodies to streptococcal M proteins onal structures later maintain obsessive–compulsive
reacted with PK. Moreover, immunoreactivity to PK in symptoms without new infections. In such cases, adult
patients with exacerbated symptoms who had recently OCD with childhood onset may show anti-brain anti-
acquired a streptococcal infection was 7-fold higher bodies without elevated anti-streptolysin O (ASLO)
compared with patients with exacerbated symptoms titres or other signs of recent streptococcal infections.
and no evidence of a streptococcal infection. These For a small proportion of OCD patients, autoimmune
data suggest that PK can also function as an auto- reactions towards neuronal structures are present, but
immune target and that this immunoreactivity may be further investigations are needed to demonstrate their
associated with Tourette syndrome, OCD, and associ- aetiopathogenetic relevance (Maina et al. 2009). The
ated disorders. vast majority of OCD patients are diagnosed and
Further support for an autoimmune hypothesis treated for the first time while they are already adults;
comes from evidence of induced stereotypic move- the mean time from initial symptom manifestation to
ments in rats after infusion of IgG of sera from seeking professional care is approximately 10 years
patients with PANDAS (Taylor et al. 2002). The patho- (Maina et al. 2009).
genic role of these antibodies remains unclear. Immunological alterations appear to be different in
Specific binding with molecules from the GABHS sur- paediatric and adult patients and probably reflect dif-
face, such as lysoganglioside or glucosamine, and ferent pathophysiological mechanisms, such as primary
more NGE as piruvate kinase, aldolase or enolase processes in the first case, and perhaps, secondary
support the notion of an autoimmune brain disease alterations in adulthood (Marazziti et al. 1999).
A study by Maina et al. (2009) showed that the pro- could prolong the inflammatory state. The effects of
portion of subjects with tic comorbidity or positive these cytokines are synergistic when produced in com-
ASLO titre (>200 IU/ml) was significantly greater in bination (Chrousos 2000). In accordance with our cur-
OCD than in MDD patients. No other differences in rent understanding of how anxiety disorders represent
antibody parameters were found. Four of 74 OCD a state of inflammation, previous studies have
patients (5.4%) and none of the controls were positive attempted to investigate whether anti-inflammatory
for anti-brain antibodies. The majority of adult OCD drugs have treatment effects on anxiety disorders or
patients do not seem to have autoimmunity disturban- other psychiatric disorders deeply related to stress and
ces. However, a greater percentage of subjects with anxiety. Several human and animal studies have sug-
OCD have positive ASLO titres. For a small gested that certain anti-inflammatory drugs might play
proportion of OCD patients, autoimmune reactions an important adjunctive role in the treatment of major
towards neuronal structures are present although fur- depression, bipolar disorder and OCD (Najjar et al.
ther investigations are needed to demonstrate their 2013). Although only few studies have reported posi-
etiopathogenetic relevance. tive results for the efficacy of anti-inflammatory drug
Two studies evaluated antineuronal antibodies or treatment on anxiety disorders (Rodriguez et al. 2010;
other markers of autoimmunity in samples of adult Sayyah et al. 2011), such results do illustrate the pro-
OCD patients; Black et al. (1998) found no humoral evi- inflammatory nature of anxiety disorders. As such,
dence of autoimmunity, but the study has certain limi- inflammatory conditions are considered to be triggered
tations. The sample was small and heterogeneous, the by an over-driven sympathetic nervous system
severity of symptoms was not assessed at the time together with an under-driven parasympathetic ner-
that blood was drawn, and an age- and gender- vous system, treatments that increase parasympathetic
matched control group was not utilised. In a second tone and hence strengthen the cholinergic anti-inflam-
study, child onset OCD was associated with higher matory pathway (Pavlov 2008) could be useful in treat-
mean ASLO titres and higher frequencies of tic disor- ing anxiety related disorders. This may explain why
ders and tonsillitis in childhood, while no differences methods that increase parasympathetic tone, such as
were found in D8/17 antibody titres or in other auto- vagus nerve stimulation, may be effective in treating
immune parameters (Morer et al. 2006). This study sug- anxiety disorders (George et al. 2008).
gested that OCD in adults is a heterogeneous disorder
and that only childhood-onset OCD is related to an
CO2 hypersensitivity
autoimmune aetiology. This topic needs further investi-
gation, as the possible autoimmune aetiopathogenesis Inhalation of air ‘‘enriched’’ with an increased propor-
in some OCD patients could lead to new therapeutic tion of CO2 can be used to induce anxiety in non-clini-
scenarios for adults similar to those already suggested cal (healthy volunteers) and clinical (patients) groups,
for the children. In fact, as a significant proportion of and represents a human translational model aiding
adult OCD patients do not respond to conventional development of potential new treatments for anxiety
treatment strategies, the search for alternative and disorders. CO2 inhalation has become one of the most
hypothesis-driven treatments is critical. frequently used experimental approaches to investigat-
Early detection of these conditions through serum ing panic, although studies employ variable challenge
search of antibodies against human brain enolase, procedures, altering the CO2 concentration, the dur-
neural tissue and Streptococcus can provide valuable ation of inhalation, the population sample, and the
information regarding etiopathogenesis and suitable range of outcome measures.
therapies (Nicolini et al. 2015). While prophylactic anti- Anxiety induction via CO2 challenge was first per-
biotic therapy is marginally helpful in preventing symp- formed in a small sample of patients with PDA under-
tom exacerbation, intravenous immunoglobulin going 5% CO2 inhalation, and was found to induce
therapy, plasmapheresis and immunosuppressive doses panic attacks (Gorman et al. 1984). This finding was
of prednisone may be effective treatments in select confirmed in a larger sample of PDA patients, who
individuals (Allen et al. 1995; Swedo et al. 2001; experienced a greater incidence of panic attacks dur-
Nicolini et al. 2015). ing challenge than did healthy controls or patients
In conclusion, elevated levels of pro-inflammatory with other anxiety disorders (Gorman et al. 1988). Brief
cytokines such as TNF, IL1 and IL6 could serve as bio- inhalation of air with high concentrations of CO2 (such
logical markers of anxiety disorders. TNF, IL1 and IL6 as single vital capacity inhalations of 35% CO2) is asso-
trigger the activation of both the HPA axis and the ciated with the experience of acute severe anxiety,
sympathetic nervous system (Chrousos 1995), which which often includes panic attacks. A single vital
capacity breath of air enriched with 35% CO2 was neurones originating in the locus coeruleus, and affer-
found to induce panic and so was suggested as an ent locus coeruleus neurones project to components
approach for conducting exposure therapy in patients of the limbic system that are known to be overactive
with PDA (Van den Hout & Griez 1984): the same in anxiety disorders (Martin et al. 2010). Changes in
group reported that patients with panic disorder were CO2 saturation may act upon pH or CO2-dependent
more sensitive to CO2 challenge than were healthy chemoreceptors within the locus coeruleus and
controls (Griez et al. 1987). Findings from subsequent thereby increase the release of NE, as 5% CO2
studies in a range of diagnostic groups indicated that increases locus coeruleus neuronal firing rate in rat
panic disorder patients were more sensitive to the brain slices (Martin et al. 2010). This CO2-induced
panicogenic effects of CO2 challenge than were release of NE may mediate autonomic and subjective
patients with other diagnoses (Leibold et al. 2015; features of anxiety through afferent projections to
Vollmer et al. 2015). brain centres involved in cardiovascular control and
The mechanisms underlying the provocation of anx- the limbic system; and endocrine responses may be
iety by CO2 challenge are not fully established, mediated by altered noradrenergic input into the para-
although findings from animal models and human ventricular nucleus, thereby causing release of cortico-
pharmacological intervention studies provide many trophin releasing factor (CRF) and anti-diuretic
insights (Leibold et al. 2015; Vollmer et al. 2015). Twin hormone, and triggering subsequent cortisol secretion.
studies suggest an association between genetic factors There are limitations in an explanation of the anxio-
and CO2 hypersensitivity (Battaglia et al. 2007, 2008). genic effects of CO2 challenge which is based solely on
Inhalation of air enriched with a high proportion (35%) altered NE function. For example, autonomic arousal is
of CO2 may be associated with increased cortisol secre- not consistently observed, and the effect of 7.0–7.5%
tion (Argyropoulos et al. 2002; Kaye et al. 2004), CO2 on plasma cortisol is inconsistent. The attenuating
although it is unclear how specific the cortisol effect of benzodiazepines and certain SSRIs on self-
response is to CO2 challenge, rather than to other report anxiety but not on physiological markers sug-
aspects of the experimental procedure (Leibold et al. gest alterations in autonomic function may lie
2015): most studies employing lower CO2 concentra- upstream of psychological anxious responding (Bailey
tions find no increase in cortisol levels, when com- et al. 2011a). Drugs which affect noradrenergic func-
pared with baseline (Woods et al. 1988; Coplan et al. tion have shown little effect on subjective responses to
2002; Kaye et al. 2004). The potential role of disturban- CO2 (Pinkney et al. 2014). Overall, it appears that while
ces in respiratory physiology in panic attack induction norepinephrine may be important in mediating anxiety
through CO2 inhalation is not fully clarified, but experi- provoked by 35% CO2 challenge, there is persisting
mentally induced panic attacks are associated with low uncertainty about the exact mechanism underlying
end-tidal CO2 and high ventilation variance at baseline 7.5% CO2-induced anxiety in humans.
(Papp et al. 1997). In a functional magnetic resonance Chemosensors within the amygdala are known to
imaging (fMRI) study, a greater activation in the brain- be directly linked to CO2 reactivity in mice (Ziemann
stem during CO2 inhalation was found in patients with et al. 2009). The most well-characterised chemosensor
PDA compared with normal controls. Interestingly, the is the acid-sensing ion channel 1 (ASIC1a), which is a
authors also showed that experienced divers showed voltage-insensitive Hþ-gated cation channel, highly
the opposite, i.e., they were less sensitive than normals expressed in the amygdala, dentate gyrus, cortex, stri-
to increased CO2 (Goossens et al. 2014). atum and nucleus accumbens (Wemmie 2011).
Serotonergic mechanisms may influence the panic Inhalation of 2–20% CO2 elicits normal mouse fear
response to CO2 challenge. Although tryptophan behaviour in the presence of fully functioning acid-
depletion does not have panicogenic effects (Goddard sensing ion channels (ASIC1a), which are expressed in
et al. 1994), depletion can enhance the panic response the amygdala, but pharmacological blockade or elimin-
to CO2 inhalation (Schruers et al. 2000), and adminis- ation of ASIC1a in knockout mice impairs fear
tration of the 5-HT precursor L-5-hydroxytryptophan responses to CO2, whereas subsequent amygdala-local-
can reduce the panic response (Schruers et al. 2002). ised re-expression restores fear behaviour.
Correlations between increases in subjective anxiety, Other potentially relevant chemosensitive structures
heart rate and blood pressure in healthy volunteers fol- include orexin neurones in the hypothalamus, seroto-
lowing 35% CO2 challenge suggest a common and nergic neurones in the medullary raphe (Wang et al.
presumably noradrenergic-mediated mechanism 1998), T cell death-associated gene-8 receptors in the
underlying CO2 sensitivity (Bailey et al. 2003). Most nor- subfornical organ, and hypoxia-sensitive chemosensory
epinephrine (NE) in the brain is synthesised by neurones in the periaqueductal grey (Vollmer et al.
2015). Perturbations in the activities of chemosensors attention network function in a manner consistent
may not fully explain the physiological effects of with that seen in GAD (Garner et al. 2012).
changes accompanying CO2 challenge and may not Inhalation challenges with less than 15% CO2 pro-
translate to humans, but suggest potential additional voke significantly more panic attacks in patients with
mechanisms, which operate alongside CO2-provoked PDA than in healthy controls (Bailey et al. 2011a), but
alterations in noradrenergic activity. it is uncertain whether altered sensitivity to ‘‘low dose’’
CO2 inhalation is also seen in patients with GAD. A sin-
Low dose (less than 15%) CO2 inhalation in healthy gle-blind, randomised, cross-over design study in medi-
volunteers and patients cation-free GAD patients which employed a repeated
7.5%, 20-min inhalation paradigm found CO2 inhalation
More prolonged (typically 15–20 min) inhalation of CO2
increased subjective anxiety and systolic blood pres-
at lower concentration (between 5.0 and 7.5%) does sure, when compared with air: a qualitative assessment
not frequently result in panic, but reliably induces an indicated participants’ experiences resembled their
experience which resembles the symptoms of GAD, usual symptoms, more closely for physiological rather
with increased subjective and physiological features of than cognitive symptoms (Seddon et al. 2011). The
anxiety, but no accompanying changes in cortisol
findings should be viewed cautiously given the small

secretion. Studies in healthy volunteers support the sample (n ¼ 12) and discontinuation of three partici-
use of 20-min, 7.0–7.5% CO2 challenge to induce sub- pants due to panic responses.
jective and autonomic responses and neurocognitive
changes which resemble the features of generalised Attenuation of CO2-induced anxiety by
anxiety. Increases in heart rate and systolic blood pres- pharmacological interventions
sure are consistently seen, but an increase in diastolic
The effectiveness of psychotropic medication (benzo-
blood pressure is less frequently observed.
diazepines, antidepressants, novel compounds) in
Low dose (7.5%) but prolonged (20 min) CO2
attenuating CO2-evoked anxiety, has been assessed in
inhalation was first found to induce anxiety in a dou-
a number of studies, with variable findings. In general
ble-blind, placebo-controlled trial involving healthy vol-
terms, acute benzodiazepine administration reduces
unteers: when compared with normal (placebo) air
subjective CO2-provoked anxiety but has little impact
inhalation, CO2 inhalation was associated with
on the physiological response. Administration of select-
increased heart rate and blood pressure and height-
ive SSRIs, the SNRI venlafaxine, tricyclic antidepressants
ened subjective anxiety (Bailey et al. 2005). A single-
and the monoamine oxidase inhibitor toloxatone can
blind, placebo-controlled healthy volunteer study
all attenuate the panic response to CO2 challenge
found that when compared with air, 7% CO2 inhalation
(Leibold et al. 2015). Administration of 2 mg of loraze-
increased respiratory rate, minute volume and end-
pam was found to attenuate subjective anxiety (with
tidal CO2, skin conductance and subjective feelings of no accompanying change in autonomic measures)
anxiety: a subgroup of participants who experienced when compared with placebo in healthy participants
marked anxiety underwent a subsequent identical undergoing 20-min 7.5% CO2 inhalation (Bailey et al.
inhalation with good test-retest repeatability. However, 2007). These findings were replicated when lorazepam
the study findings highlight potential limitations of the was employed as a control in studies using the same
model, as 30% of participants were ‘‘non-responders’’, inhalation procedure to assess novel anxiolytic com-
and 10% of participants experienced significant anxiety pounds (Bailey et al. 2011b; de Oliveira et al. 2012).
during (placebo) air inhalation (Poma et al. 2005). Both alprazolam (1 mg) and the partial benzodiazepine
The effect of CO2 inhalation on attentional biases, receptor antagonist zolpidem (5 mg) attenuated sub-
which characterise anxiety states, has also been investi- jective anxiety in healthy volunteers after 20 min of
gated. For example, 20-min 7.5% CO2 challenge is 7.5% CO2 inhalation (Bailey et al. 2009). However, a
associated with performance deficits in an emotional subsequent double-blind, placebo-controlled cross-over
anti-saccade task, similar to those seen in individuals study which investigated dose-response relationships
with high levels of generalised trait anxiety (Garner with lorazepam and which used the same experimen-
et al. 2011). As 20 min of 7.5% CO2 inhalation has been tal paradigm and measures found no attenuation of
found to significantly modulate attention, with subjective or autonomic responses (Diaper et al. 2012).
increased alerting and orienting network function in Certain SSRIs and SNRIs are licenced for the treat-
the Attention Network Task, this suggests that CO2 ment of GAD and their effect in attenuating the anxio-
challenge facilitates hypervigilance to threat and alters genic effects of CO2 inhalation is a marker of the
predictive validity of the model. Investigations in small clonazepam treatment found that when compared
groups of patients with panic disorder found that treat- with placebo both acute and chronic clonazepam
ment with different SSRIs and SNRIs reduced subjective administration reduced objectively rated panic attacks
anxiety following 5 and 7% CO2 challenge, when com- after CO2 inhalation (Valenca et al. 2002).
pared with baseline, pre-treatment inhalation (Gorman Inhalation of air ‘‘enriched’’ with 7.5% CO2 is an
et al. 2004). However, a larger study involving 3 min of experimental tool for inducing anxiety without features
5% CO2 in individuals ‘‘at high risk of panic disorder’’ of panic in healthy volunteers, the anxious response
found that 2-week administration of the SSRI escitalo- being composed of replicable changes in autonomic
pram had no effect on self-report or autonomic indica- arousal (increased heart rate and systolic blood pres-
tors of anxiety (Coryell & Rickels 2009). Given that SSRIs sure), neurocognitive function (impaired performance
typically take 2–4 weeks to exert notable therapeutic in emotional antisaccade and attention control tasks)
effects in GAD, longer drug administration may be and subjective experience. The CO2 inhalation experi-
needed to generate valid results. mental model of anxiety disorders may therefore be
Studies involving SSRI or SNRI administration in useful for signalling the potential efficacy of novel
healthy volunteers using a 20-min 7.5% CO2 challenge therapeutic agents: and has been utilised in investiga-
have generated variable findings. Placebo-controlled tions of the CRF1 receptor antagonist R317573 (Bailey
administration of the SSRI paroxetine for 21 days et al. 2011a) which did attenuate subjective effects,
reduced subjective anxiety (Bailey et al. 2007). A pla- and the NK1 receptor antagonists vestipitant and
cebo-controlled investigation of 3-week administration vofopitant (Poma et al. 2014).
of the SNRI venlafaxine or the anxiolytic pregabalin The model may be suitable for testing putative anx-
found no significant effect on change from baseline to iolytics (Bailey et al. 2007), and compounds which are
post-treatment ratings of subjective anxiety or auto- found to attenuate CO2-induced anxiety have potential
nomic response in the venlafaxine group (Diaper et al. clinical relevance. Studies with compounds which tar-
2013). A 2-week randomised double-blind, placebo- get chemosensory mechanisms may be informative in
controlled study of the SNRI duloxetine in healthy sub- the development of anxiolytics with a novel mechan-
jects found it had little attenuating effect on subjective ism of action: for example with the ASIC ion channel
anxiety or autonomic arousal following a 20-min, 7.5% antagonist amiloride, which has been found to have
CO2 challenge, though duloxetine administration was neuroprotective effects (Arun et al. 2013); with orexin
associated with improved accuracy in the anti-saccade receptor antagonists, which can attenuate anxiety-like
task and reduction in negative thought intrusions responses to CO2 challenge in rats (Johnson et al.
(Pinkney et al. 2014). 2012); and with the carbonic anhydrase inhibitor aceta-
As with benzodiazepines, SSRI or SNRI administration zolamide, which blocks the conversion of CO2 to car-
has a limited effect on physiological responses to CO2 bonic acid and thence to hydrogen and bicarbonate
challenge, and drugs within the same class may act vari- ions (Vollmer et al. 2015).
ably on subjective anxiety, which raises questions about
the validity of the model. However, a study involving SepAD
the beta-blocker propranolol (40 mg) found it had no
CO2 hypersensitivity was investigated in adult SepAD
attenuating effect on self-report anxiety in healthy vol-
because children of adults with PDA experience ele-
unteers undergoing 20 min of 7.5% CO2 (Papadopoulos
vated rates of SePAD and because childhood separ-
et al. 2010), which accords with its lack of efficacy in
ation anxiety disorder (C-SepAD) was found to be
anxiety disorders (Gorman et al. 1988; Steenen et al.
associated with adult PDA (Bandelow et al. 2001).
2016). The same study also found the anti-histamine
Support for this hypothesis comes from a study in
hydroxyzine (25 mg) had only limited effects.
which 104 children (aged 9–17 years), of whom 57 had
an anxiety disorder, underwent 5% CO2 inhalation
From current knowledge to potential clinical
(Pine et al. 1998; Pine et al. 2000). In this study, CO2
applications
hypersensitivity was clearly present for SepAD, as indi-
The response to CO2 inhalation could also be useful in cated by: (1) enhanced respiratory rate response dur-
predicting the likelihood of response to treatment, but ing CO2 breathing; (2) elevated minute ventilation; and
this potential application has not been examined (3) lower end-tidal CO2 during room-air breathing.
extensively. Investigation of the effects of double 35% These correlates were also observed – albeit to a much
CO2 vital capacity inhalations in a small sample of lesser degree – in GAD, and were absent in SAD.
patients with PDA after 1 h, 2 weeks and 6 weeks of Similarly, in a study of 212 offspring from 135 families,
abnormal respiratory physiology in response to CO2 increased high frequency EEG power and an elevated
exposure was found in offspring with both SepAD and PI component (Clark et al. 2009).
parental PDA relative to offspring with either of these
features alone (Roberson-Nay et al. 2010). Given the Specific phobias
common physiological perturbations of PDA and
In a few studies, cortical hypervigilance was reported
SepAD (i.e., physiological abnormalities, respiratory dys-
in specific phobias, with indications of enhanced P3
regulation, and reaction to inhaled CO2), the specificity
and CNV components of ERP to phobic stimuli. One
of this biological correlate need further confirmatory
study has shown that the P3 amplitude can be normal-
research data.
ised following successful behavioural therapy (Clark
et al. 2009).
Neurophysiology
Electroencephalography (EEG) and ERP PTSD
Basal instability of the cortical arousal system was Frontal asymmetry is a frequently studied biomarker in
reported in quantitative EEG (qEEG) studies as a com- PTSD, and is calculated as the difference in mean alpha
mon feature of most patients with anxiety disorders band power between the left and right frontal cortex
(Clark et al. 2009). This manifests as changed spectral over a time span of several minutes. Relatively greater
power of specific EEG frequency bands in the theta left frontal activity is regarded as being related to
(4–8 Hz) and alpha (8–13 Hz) ranges throughout most appetitive motivation, and lower levels of depression
of the brain areas and beta range (above 13 Hz) espe- and anxiety in PTSD patients (Meyer et al. 2015).
cially in frontal and central brain regions. While none However, this biomarker is not specific for PTSD, as it
of the qEEG alterations are specific for anxiety disor- has also been reported in depression, premenstrual
ders, they are regarded as related to anxiety symptoms dysphoric disorder, and schizophrenia. Moreover, in
and are targeted, e.g., by neurofeedback training some studies, no deviance in alpha asymmetry from
(Simkin et al. 2014). Generally, sleep EEG (polysomnog- healthy control groups was found in PTSD and anxiety
raphy; PSG) findings in anxiety disorders are in line disorders (Gordon et al. 2010).
with findings from wake EEG showing altered EEG-vigi- Patients with PTSD, when compared with controls,
lance regulation in these patients. Patients with anxiety were found to have decreased resting-state EEG frontal
disorders typically have prolonged sleep latency, connectivity, which was significantly correlated with
reduced sleep efficiency and shortened total sleep
PTSD symptom severity, and with depressive and
time. However, in contrast to patients with major
increased arousal symptoms (Lee et al. 2014). In a
depression, rapid eye movement (REM) sleep latency is
review, significant associations have been described
usually not shortened in patients with anxiety disor-
with PTSD symptoms not only for alpha EEG rhythm
ders. Furthermore, a reduction of slow wave sleep is
but also for P200 and P300 ERP components (Lobo
not as common as in some mental disorders, e.g.,
et al. 2015). Moreover, alterations of ERP components
schizophrenia (Cox & Olatunji 2016).
(N200 and P300 amplitudes) while performing an
PDA inhibitory control task (Stop Task) were reported to
classify veterans with mild traumatic brain injury asso-
Studies in patients with PDA showed increased cortical ciated or not associated with the development of PTSD
arousal in waking EEG, during sensory gating, and
with high accuracy (Shu et al. 2014).
heightened cerebral processing of panic-relevant stim-
In PTSD, sleep disturbances shortly after trauma
uli. This is reflected as increased beta power in qEEG
exposure predict the development of PTSD at follow-
and elevated contingent negative variation (CNV) and
up assessment, however, the evidence is less clear
P3 components of ERP (Clark et al. 2009).
regarding objective polysomnographic indices (Babson
GAD & Feldner 2010).
Electrophysiological studies in GAD studies did not

report any ERP abnormalities (Clark et al. 2009). OCD
Over the past two decades, performance monitoring
SAD
has been extensively studied in patients with OCD,
In SAD, studies generally indicate tonic hyperarousal, using advanced methodologies, such as EEG source
as reflected in reduced low frequency (LF) and localisation, simultaneous EEG and MRI recording,
intracerebral EEG recording, magnetoencephalography, response monitoring in people with OCD (Ursu et al.
EEG-informed fMRI and valuable results were obtained. 2003; Maltby et al. 2005). Broadly, amplified error sig-
Research on ‘‘performance monitoring’’ and ‘‘error nals in OCD might reflect hyperactive cortico-striatal
processing’’ has been undertaken extensively in OCD circuitry during action monitoring (Agam et al. 2014;
patients, who appear to monitor their thoughts and Grutzmann et al. 2014). Convergent results suggest the
actions more carefully to avoid losing control or com- existence of a self-monitoring imbalance involving
mitting errors. Theoretically, error processing involves inhibitory deficits and executive dysfunctions in OCD
both recognising that an error has occurred and (Melloni et al. 2012). In this model, the imbalance
adjusting future responses. Deficits in either of these might be triggered by an excitatory role of the basal
abilities could contribute to rigid, repetitive behaviour. ganglia (associated with cognitive or motor actions
Enlarged error signals have been consistently found in without volitional control) and inhibitory activity of the
patients with OCD (Endrass & Ullsperger 2014). The orbitofrontal cortex (OFC) as well as excessive monitor-
introduction of specific task paradigms and emotional ing of the ACC to block excitatory impulses. This imbal-
challenge conditions in such research has been shown ance would simultaneously interact with the reduced
to enhance individual differences, which can be more activation of the parietal-dorsolateral prefrontal cortex
reliable than resting state measurements (Zambrano- network, leading to executive dysfunction (Melloni
Vazquez & Allen 2014). et al. 2012).
Error processing is thought to be associated with Further electrophysiological data suggest that the
activity in anterior/posterior medial frontal cortex, candidate network might be extended and include
anterior insula/operculum, ventrolateral prefrontal cor- specific additional regions in the medial frontal cortex
tex, dorsolateral prefrontal cortex and lateral parietal involved in performance monitoring, such as anterior
cortex (Grutzmann et al. 2014). The mid-cingulate cor- insula or the pre-supplementary motor area (Bonini
tex is specifically recognised to signal the need for et al. 2014; Grutzmann et al. 2014; Ullsperger et al.
adjustment of cognitive control to prevent subsequent 2014); posterior mid-cingulate regions (Agam et al.
errors (Ullsperger et al. 2014). In particular, the error- 2011); and sub-genual ACC regions, for which
related negativity (ERN), a response-locked ERP, is increased activity has been found in OCD (Agam et al.
defined as a negative voltage deflection that occurs 2014). Thus, patients with OCD might tend to evaluate
50–100 ms after an error or conflict response and is errors as being disproportionately salient. This would
thought to specifically reflect activity of the response- support the theory that inappropriate and exaggerated
monitoring system (Gehring et al. 1990). error signalling leads to a pervasive sense of incom-
Numerous EEG studies have found larger ERN ampli- pleteness and self-doubt and triggers compulsions to
tudes in patients with OCD, in adult (Gehring et al. repeat behaviours (Maltby et al. 2005). Other theories
2000; Endrass et al. 2008; Endrass et al. 2010; Stern hypothesise that the ERN is not only associated with
et al. 2010; Riesel et al. 2011; Xiao et al. 2011; Klawohn error detection, but may be modulated by the affective
et al. 2014; Riesel et al. 2014) and paediatric (Hajcak significance of an error (Hajcak et al. 2005). Hence,
et al. 2008; Hanna et al. 2012; Carrasco et al. 2013) other factors that can potentially characterise the over-
samples. Enhancement of the ERN in OCD seems to be active response monitoring observed in individuals
independent of pharmacological or psychological inter- with OCD, such as error significance, have been also
ventions (Endrass et al. 2010; Stern et al. 2010) and investigated. However, the results have been equivocal
occurs among all major symptom dimensions (Riesel with some studies showing no difference in ERN ampli-
et al. 2014). Moreover, the same results have been tude between conditions with punishment and no
obtained in individuals with subclinical OCD symptoms punishment after error in participants with OCD but a
(Santesso et al. 2006; O’Toole et al. 2012) and non- significant difference in controls (Endrass et al. 2010);
affected first-degree relatives of patients with OCD others have found that punishing errors leads to an
(Riesel et al. 2011; Carrasco et al. 2013). enhanced ERN and, moreover, that it has long-lasting
Globally, these findings have identified increased effect on the ERN (Riesel et al. 2012).
ERN amplitudes as a promising candidate vulnerability In the analysis of the activity of intracortical EEG
marker for OCD. However, to date, its sensitivity and sources in patients with OCD using low-resolution elec-
specificity is not clearly defined (Manoach & Agam tromagnetic tomography and independent component
2013). For example, some studies have also found an analysis, both methods provided evidence for medial
enhanced negativity on correct trials (sometimes frontal hyperactivation in OCD (Koprivova et al. 2011).
referred to as the correct-related negativity), suggest- Patients with OCD were also found to have frontal
ing the presence of an overall hyperactivity during alpha rhythm asymmetry, compared with healthy
controls, with frontal slow alpha power (8–10 Hz) being many of these reported neurophysiological findings
more dominant in the left hemisphere at rest and dur- are influenced by comorbid depressive symptoms and
ing presentation of neutral, aversive, and OCD-related co-existing pharmacological treatment.
pictures. These changes in hemispheric alpha band
topography were proposed as biomarker for increased
Heart rate variability
avoidance motivation in OCD patients (Ischebeck et al.
2014). Cardiologists have long held the view that a heart rate
In sleep studies, OCD patients were reported to which fluctuates over time, in contrast to a heart beat-
have significant disturbances of sleep continuity meas- ing to a strict metronomic rhythm, is a marker of good
ures but in most cases, no abnormalities of slow wave cardiovascular health. Heart rate variability (HRV), the
sleep or REM sleep were found. Many of the sleep dis- extent to which the interval between beats varies with
turbances were characteristic for depression or related time, is reduced in several cardiovascular disorders
to depressive symptoms. Severe OCD symptoms were such as after myocardial infarction (Bigger et al. 1992;
consistently associated with greater sleep disturbance Carney et al. 2001), in coronary artery disease
(Paterson et al. 2013). (Wennerblom et al. 2000) and in hypertension (Singh
et al. 1998) and is a predictor of mortality (Dekker

Other Obsessive-Compulsive-Related Disorders et al. 2000; La Rovere et al. 2003). As will be described
(OCRDs). Electrophysiological studies in other OCRDs in this section, heart rate variability is thought to be
are still scarce. One study has attempted to explore closely linked to the function of the autonomic ner-
the ERN as a measure of response monitoring capabil- vous system and its sympathetic and inhibitory para-
ities in trichotillomania (Roberts et al. 2014). Results sympathetic influences.
reported that individuals with hair pulling symptom-
atology might have significantly smaller ERNs than the Anxiety, cardiovascular disorders and autonomic
control group, supporting the idea that trichotillomania dysfunction
is distinct from OCD. Smaller ERNs are believed to
reflect deficits in error checking that contribute to diffi- Anxiety disorders are associated with cardiovascular
culty monitoring one’s own actions, and such disease (Roest et al. 2010; Davies & Allgulander 2013)
results might indicate that individuals with symptoms and may be a risk factor in sudden cardiac death
of trichotillomania have shortfalls in self-monitoring, (Kawachi et al. 1994). The leap from employing HRV as
perhaps related to more impulsive tendencies a marker in cardiovascular disorders to anxiety disor-
(Roberts et al. 2014). One other study has used meta- ders relies on the hypothesis that there may be shared
analysis to further characterise the ERN in OCD, and dysfunctions in the autonomic nervous system, which
pooled data across studies to examine the ERN in OCD underlie, or at least are measurable in, many disorders
with or without hoarding (Mathews et al. 2012). When in both fields.
stratified, OCD showed a significantly enhanced ERN
only in response conflict tasks. However, OCD with PDA. An association of panic attacks or PDA with
hoarding showed a marginally larger ERN than OCD hypertension has been reported both in clinical sam-
without hoarding, but only for probabilistic learning ples (Davies et al. 1999) and in population-based data
tasks. These results suggest that the abnormal ERN in (Davies et al. 2012), and the possibility that this associ-
OCD might also be task-dependent, and that OCD with ation is due to shared autonomic dysfunction has been
hoarding might show different ERN activity from OCD explored (Davies et al. 2007). Symptoms of autonomic
without hoarding, perhaps suggesting different patho- activation, such as racing heart, sweating and flushing
physiological mechanisms of error monitoring across are included in diagnostic criteria for PDA. Several
these clinical dimensions. authors have suggested that autonomic nervous sys-
In summary, as neurophysiological examinations are tem dysfunction may be an important aetiological fac-
among the most sensitive tests in psychiatry, many tor in PDA, for instance, Klein (1993) categorised panic
alterations in EEG, ERP or PSG were found in patients attacks into two distinct types; attacks caused by false
with anxiety disorders. While some of these alterations suffocation alarms and those attributable to autonomic
can be used as biomarkers for specific research ques- surges or HPA axis activation.
tions, especially in treatment studies looking at hyper- Esler’s group studied norepinephrine and adrenaline
arousal performance monitoring and information release (spill-over) from major organs in patients with
processing, they are not specific and cannot be used PDA using invasive methods requiring cannulation of
as diagnostic tests for anxiety disorders. Moreover, large vessels. Spill-over of adrenaline from the heart
was significantly greater in patients with PDA than in ratio was previously employed as a proxy measure of
controls at rest. During panic attacks, whole body sympatheto-vagal balance (Pagani et al. 1984), having
adrenaline spill-over was markedly increased with pro- the advantage of being influenced by change in both
portionally smaller increases in norepinephrine spill- sympathetic and parasympathetic nervous system car-
over (Wilkinson et al. 1998). This finding supports sev- diac input but the problem that simultaneous change in
eral studies which report evidence of sympathetic both parameters might be undetected.
over-reactivity in PDA such as enhanced noradrenergic Time-domain measures of HRV fall into two catego-
volatility during clonidine challenge (Coplan et al. ries. The first are derived from the differences between
1997) and excess blood pressure overshoot on stand- adjacent beat intervals, the most frequently used being
ing (Coupland et al. 1995). The latter effect was not root mean square of successive differences (RMSSD)
observed in patients with autonomic failure (Mathias and pNN50 (mean occasions per hour where change in
2002) suggesting that the autonomic nervous system consecutive normal sinus (NN) intervals exceeds 50 ms
is essential in mediating this response. (Ewing et al. 1984)). RMSSD and pNN50 are highly cor-
Others have examined central autonomic system related with frequency domain derived HF oscillation
function and reported catecholamine or adrenoceptor (Stein et al. 1994). A second category, derived from
function as being altered centrally in PDA (Nutt 1989; observing beat to beat intervals over time, includes
Tancer et al. 1993). Esler has demonstrated excess cat- standard deviation of normal sinus intervals (SDNN)
echolamine spill-over in hypertension (Esler et al. 2001) which represents the standard deviation of ‘‘NN’’ inter-
and autonomic dysfunction is now understood to be a vals (Sztajzel 2004). Since SDNN varies with the total
core aetiology of what was previously termed ‘‘essen- recording time, comparisons between values obtained
tial’’ hypertension. PDA and hypertension may share a over widely differing time periods are problematic.
failure of control of sympathetic activation, perhaps
through compromise of those centres which control HRV: association of frequency domain and time
the C1-adrenergic cell group in the rostral-ventrolateral domain measures with anxiety disorders
medulla, which include the raphe pallidum and ventro-
While the possibility of HRV being a biomarker in anx-
lateral periaqueductal grey, the latter under the influ-
iety disorders has been considered for more than a
ence of the pre-frontal cortex (Johnson et al. 2004;
decade (Gorman & Sloan 2000), a systematically organ-
Davies et al. 2007).
ised meta-analysis of the relation of HRV to the pres-
ence of anxiety disorders has only recently been
HRV measures
published. Chalmers et al. (2014) identified 36 studies
Heart rate variability allows an estimation of autonomic meeting criteria requiring a comparison in HRV out-
nervous system input to the heart to be ascertained comes between patients with anxiety disorders and
speedily and non-invasively. There are both parasym- controls. The studies had 2086 participants with anx-
pathetic (cholinergic) and sympathetic (noradrenergic) iety disorders and 2204 controls and employed a var-
influences on the heart. The sympathetic nervous sys- iety of methodologies. Recording periods ranged from
tem is linked to mobilisation behaviours, often in 2 min to 24 h and studies used frequency domain
response to stressors, which may induce the classic measures such as LF and HF, time domain measures or
‘‘flight or fight response’’ requiring cardiac activation, other approaches including detection of respiratory
whereas the parasympathetic system, mediated sinus arrhythmia. The authors chose not to extract
through the vagus nerve, is linked to immobilisation data on LF/HF ratio given its questionable utility and
and disengagement (Porges 2001). Frequency of heart gave RMSSD preference over other time domain
rate fluctuations are decreased when sympathetic tone measures.
is increased (Pagani et al. 1984) and with parasympa- Across all anxiety disorders, the frequency domain
thetic blockade (Akselrod et al. 1985). HF oscillation variable (reported in 34 studies), was
The most commonly utilised measures HRV measures strongly and significantly associated with having an
are ‘‘frequency-domain’’ and ‘‘time-domain’’ variables. anxiety disorder. The association of time domain meas-
Frequency-domain measures are based on power spec- ures, reported in 20 studies, was of borderline signifi-
tral analysis, which allows detection of LF and high fre- cance but became highly significant after exclusion of
quency (HF) oscillation. HF oscillation relates to the one outlying study. The LF oscillation variable, reported
activity of the parasympathetic system, mainly mediated in 22 studies, was a poor predictor of anxiety disorders.
through the vagus nerve, while LF oscillation is thought When specific anxiety disorders were considered, PDA
to be linked to variation in sympathetic tone. The LF/HF featured in the most studies with 24 of the 34 papers
having some participants with this disorder, in com- The therapeutic effect of modulating serotonin in
parison to 13 for PTSD, five for GAD, four for SAD, two anxiety disorders appears, in the majority of studies, to
for OCD and one for specific phobia. The meta-analysis ameliorate autonomic function as reflected in improv-
revealed that time domain measures were strong pre- ing heart rate variability. One exception is a study
dictors of PDA, PTSD and GAD and weaker but still sig- reporting that CBT alone increased HRV in PDA, but
nificant predictors of SAD and specific phobia. HF was that a CBT/SSRI combination did not (Garakani et al.
strongly associated with GAD and SAD and had weaker 2009). Nevertheless, the potential for serotonin to influ-
but significant relations with PDA and PTSD. Neither ence autonomic function (and thereby HRV) has a
measure was associated with OCD. LF was not associ- neurobiological basis (Davies et al. 2007), since animal
ated with any of the anxiety disorders. The strength of studies suggest that pH-dependent serotonergic neu-
association of both HF and time domain measures of rons projecting to the RVLM may tonically inhibit sym-
HRV in generalised anxiety disorder, is of interest for pathetic outflow (Richerson et al. 2001). Clinically, the
the conceptualisation of this disorder. Although both enhanced noradrenergic volatility in PDA described
analyses rely on only three studies, the results suggest during clonidine challenge was attenuated after suc-
that despite Diagnostic and Statistical Manual of cessful treatment with SSRI antidepressants (Coplan
Mental Disorders (DSM)-IV and DSM-5 excluding clinical et al. 1997).

features suggestive of autonomic dysfunction from the
list of symptoms contributing to the diagnosis, GAD Utility of HRV as a biomarker
may indeed be associated with autonomic dysfunction
Heart rate variability, whether ascertained using the
(Thayer et al. 1996).
frequency-domain measure of HF oscillation or by time
domain measures, has advantages over other potential
Response of HRV to treatment and experimental
biomarkers of being non-invasive and easy to adminis-
neurotransmitter manipulation
ter with valid data being obtainable in a matter of
Treatment of anxiety disorders may be associated with minutes. As such, it has potential use in case detection
a restoration in HRV, especially when the treatment and in large population-based cohorts. As it is amelio-
involves modulation of serotonin. Reduced HRV dem- rated by treatments that are effective in anxiety disor-
onstrated in PDA was reversed by a serotonin promot- ders and reduced by neurotransmitter manipulations
ing antidepressant (Yeragani et al. 1999) but not by known to provoke anxiety, it offers the possibility of
nortriptyline, which primarily promotes central norepin- identification of treatment response.
ephrine transmission (Tucker et al. 1997). However, The proliferation of differing outcome measures is
serotonin-modulating drugs are not essential for receding in importance as a disadvantage since the
improvement in HRV on treating anxiety CBT and SSRIs frequency domain HF measure, and time domain
were equally capable of increasing HRV. measures (RMSSD, pNN50 and SDNN) appear to be
In healthy individuals, HRV is reduced during panic preferable to LF or the LF/HF ratio. However, several
provoking challenges but SSRI treatment appears to common disorders beyond the realm of anxiety are
blunt this response (Agorastos et al. 2015). The involve- also associated with reduced HRV, including the car-
ment of the serotonin system in the neurobiology of diovascular disorders discussed earlier, depression,
anxiety disorders has also been examined using the Alzheimer’s disease, fibromyalgia and diabetes, and
technique of tryptophan depletion (Hood et al. 2005). indeed any disorder where autonomic nervous sys-
When this method is applied in subjects who have tem dysfunction is typically present. This reduces
recovered from anxiety disorders, depletion is associ- specificity for detection of anxiety disorders.
ated with a transient return of anxiety symptoms and Furthermore, HRV is known to decrease with age
exaggerated response to stress challenges (Davies (Liao et al. 1995), which may complicate its interpret-
et al. 2006). In one study in remitted patients with ation. Finally, standard HRV measurements cannot be
depression, HRV was measured before and during tryp- used in subjects who are not in sinus rhythm
tophan depletion (Booij et al. 2006). Tryptophan deple- (Sztajzel 2004).
tion was associated with a significant reduction in HRV In summary, HRV appears to offer a degree of sensi-
(ascertained using both time domain measures and tivity but limited specificity in anxiety disorders. Ease
the frequency domain HF measure) although this effect of ascertainment and the ability to detect treatment
was limited to subjects who had experienced suicidal related changes are clear strengths. We await popula-
ideation. Notably, these patients experienced increased tion-based longitudinal studies in larger sample sizes
anxiety during the tryptophan depletion period. where more invasive approaches may be impractical.
Neurocognition performance than controls, but this finding did not

withstand Bonferroni correction. In a subsequent study,
PDA
SAD (n ¼ 42 patients) performed worse than healthy
In a review of the literature investigating the neuro- controls (n ¼ 42) on processing speed, visuospatial con-
psychological disturbances PDA, limited support for struction, visuospatial memory, verbal learning and
impairment in short-term memory among individuals word fluence (O’Toole et al. 2015).
with PD was found in some but not all studies.
Moreover, the studies did find some evidence for OCD
impairment in other areas of cognitive functioning,
including executive function, long-term memory, visuo- Considerable evidence demonstrates that behavioural
spatial or perceptual abilities and working memory performance during cognitive tests, and related func-
(O’Sullivan & Newman 2014). The review included 14 tional activations, are abnormal when OCD patients are
studies (total 439 patients, 510 healthy controls), the probed on domains dependent upon the integrity of
majority of which had average to high methodological fronto-striatal circuitry.
quality. Studies with a sample size of less than 15 par-
Response inhibition
ticipants per group were excluded.

The ability of response inhibition can be measured by
GAD means of go/no-go tasks and stop signal reaction time
(SSRT) tasks. Both types of paradigm require the partic-
In a study including 112 patients with different anxiety ipants to make a motor response on some trials and to
disorders, no differences in neuropsychological func- withhold the response on some other trials, with the
tions were found in seven patients with GAD compared SSRT being more sophisticated in using stepwise track-
with healthy controls; of course, such a study would only ing to measure inhibitory control. Deficits in response
have been powered to detect group differences with inhibition have been suggested as a candidate cogni-
massive effect size (Airaksinen et al. 2005). Another tive endophenotype for OCD (Chamberlain et al.
study found that performance on executive and non- 2007b). Moreover, impaired response inhibition was
verbal memory tasks of GAD patients (n ¼ 40) was shown to be associated with reduced grey matter vol-
largely worse than in healthy controls (n ¼ 31). These ume in the OFC and right inferior frontal regions, as
cognitive deficits seemed to be more marked in patients well as increased grey matter volume in the cingulate,
taking antidepressants than in drug-na€ıve patients parietal and striatal regions in OCD patients and
(Tempesta et al. 2013). However, the study was not rand-
matched-relative groups, as compared with controls
omised with regard to medication intake; therefore, it is
(Menzies et al. 2008); and these combined behavioural-
problematic to assume a causal relationship between
structural MRI measures were significantly heritable.
antidepressants and cognitive functioning.
Inhibition difficulties were also pinpointed at the func-
tional level, whereby successful inhibition on an SSRT
SAD task was associated with greater activation in the sup-
Cognitive models of SAD assume that patients with plementary motor area in OCD patients (n ¼ 41) and
SAD have cognitive biases regarding their interpret- their siblings (n ¼ 17), versus controls (n ¼ 37) (de Wit
ation of ambiguous social situations. A systematic et al. 2012). Impaired performance on response inhib-
review of 30 studies of the neuropsychological ition tasks was found to have a moderate effect size
performance in SAD (698 patients) revealed that indi- (0.49) in a meta-analysis on adult OCD patients as com-
viduals with SAD consistently showed decreased per- pared with control participants (Abramovitch et al.
formance on tests of verbal memory functions. In 2013). This meta-analysis comprised 115 studies (total
particular, the studies showed decreased performance 3452 patients) overall, although only a subset of these
regarding visual scanning and visuoconstructional abil- related to response inhibition.
ity as well as some indication for verbal memory diffi-
Cognitive flexibility
culties (O’Toole & Pedersen 2011). Since this review
was published, a study compared 25 subjects with SAD The clinical manifestation of OCD is commonly repre-
and 25 healthy controls and reported no significant sented by repetitive compulsive acts that might be
between-group differences, based on a composite ana- linked to impaired cognitive flexibility (Chamberlain
lysis of variance test (Sutterby & Bedwell 2012). In post et al. 2005). The Intradimensional/Extradimensional set
hoc tests, patients had worse visual working memory shifting paradigm allows a fine-grained examination of
different cognitive processes germane to flexible ganglia (caudate, putamen) hypo-activation in OCD
responding including reversal learning, set formation patients, in a study conducted in medication-
and the ability to inhibit and shift attention between free patients and healthy controls (van den Heuvel
stimuli. By employing this multiple stage paradigm, it et al. 2005). Behavioural impairment – fewer correct
was shown that OCD patients were generally able to responses and increased response times – was also
form an attentional set but impaired in their ability to found in unaffected relatives of OCD patients com-
switch their focus to a new, previously irrelevant pared with normal participants (Delorme et al. 2007),
dimension (extradimensional stage; ED shift) (Veale suggesting that planning deficits constitute a vulner-
et al. 1996; Watkins et al. 2005; Chamberlain et al. ability measure for OCD.
2006). Considering that impaired performance was
unrelated to symptom severity and present irrespective Goal-directed system and habit learning
of treatment, ED deficits might represent a trait marker
Convergent evidence from the animal and human lit-
of the disorder (Chamberlain et al. 2006). More conclu-
erature suggests that fronto-striatal loop circuits medi-
sively, non-affected first-degree relatives (n ¼ 20) exhib-
ate the balance between purposeful, goal-directed
ited impairments as well, versus controls (n ¼ 20)
actions and habitual, automatic behaviours.
(Chamberlain et al. 2007b).

Considering the literature linking fronto-striatal loops
Across species, the ability to flexibly adjust behav-
to OCD symptomatology, it was proposed that OCD
ioural responses in face of negative feedback is sub-
could be characterised as a disorder of maladaptive
served by the OFC and can be assessed by reversal
habit learning (Rauch et al. 2002). The hypothesis has
learning tasks. As such reversal of responses is nor-
been formally tested in a series of experiments that
mally relatively easy for humans to manage, reversal
led to the conclusion that a defective ‘‘goal-directed
learning abnormalities are mainly identified using
system’’ may bias OCD patients to heavily rely on hab-
imaging rather than behavioural tests, due to ceiling
its (Gillan & Robbins 2014). More specifically, it was first
effects for the latter. Dampened OFC activation during
shown using an appetitive instrumental learning task
reversal learning was reported in one fMRI study of
that OCD patients (n ¼ 21) were not able to refrain
OCD patients (n ¼ 20), as compared with controls
from responding to outcomes no longer associated
(n ¼ 27) (Remijnse et al. 2006). Controlling for the
with reward, as compared with controls (n ¼ 30) (Gillan
potential confounding effect of comorbid depression,
et al. 2011). Similarly, in an aversive context, OCD
Chamberlain et al. (2008) showed that patients with
patients were trained to avoid mildly aversive electrical
OCD (n ¼ 14) and unaffected relatives (n ¼ 12) had
shocks by performing the correct response to a pre-
extensive clusters of hypo-activation in the lateral OFC,
dictive stimulus. Following a training period, partici-
lateral PFC and parietal cortices, versus controls
pants were instructed that the cable delivering the
(n ¼ 15). Task switching abilities, strongly relying on
shock had been disconnected from one of their wrists.
the cross-talk between basal ganglia and PFC (Cools
Patients (n ¼ 25) on average made significantly more
et al. 2004), have separately been assessed in OCD
responses to the stimuli no longer associated with any
patients. Significantly higher error rates in task-switch-
shock than did controls (n ¼ 25) (Gillan et al. 2014). An
ing trials and reduced activation of dorsolateral pre-
fMRI-compatible version of the task showed that exces-
frontal cortex lateral OFC, ACC and caudate body were
sive caudate activity was associated with increased
observed in 21 OCD patients versus 21 controls
performance of the avoidance habits in 37 OCD
(Gu et al. 2008).
patients, compared with 33 healthy controls (Gillan
et al. 2015). The finding that aberrant activation in the
Planning
caudate nucleus occurred more in patients showing a
Executive planning entails the ability of attaining a bias towards the premature development of habits
goal through intermediate steps, which do not neces- suggested that, in OCD, reliance on repetitive, habit-
sarily lead directly to that goal. It is tested by means of like behaviours might stem from dysfunction within
the Tower of London task and its variants, for which goal-directed behaviour loci within the dorsal striatum
MRI versions are also often available. Studies in OCD (Yin & Knowlton 2006).
patients revealed lengthened responses times (Veale Despite the existence of some discordant findings,
et al. 1996; Nielen & Den Boer 2003) and, on more dif- deficits related to behavioural inhibition, cognitive
ficult task versions, impaired performance flexibility and executive functioning seem to represent
(Chamberlain et al. 2007a). Planning deficits have been core traits of OCD, and hold face validity considering
linked with dorsolateral prefrontal cortex and basal the clinical manifestation of the disorder.
Neuropsychological and imaging studies demonstrate (n ¼ 24), and healthy controls (n ¼ 28) (Morein-Zamir
that non-affected first-degree relatives show, to some et al. 2014). Deficits in cognitive flexibility were com-
extent, similar abnormalities to patients. On the one mon to both clinical groups, arguing against hoard-
hand, these shared findings represent valuable tools ing disorder having a distinct neuropsychological
for investigating the effect of specific genetic variants profile from that of OCD-hoarding, and highlighting
on both cognitive and neural substrates and import- the importance of cognitive rigidity in relation to
antly for investigating the disorder across species, pos- these two disorders.
sibly leading to better treatment. On the other hand, There are very few cognitive studies of body dys-
the similarity between affected and non-affected rela- morphic disorder (BDD). One study found that sub-
tives demonstrates that our understanding of the steps jects with BDD exhibited deficits in cognitive
leading from an ‘‘at risk’’ or vulnerable state to the flexibility in comparison to controls (Jefferies et al.,
development of ‘‘state’’ OCD is limited; as is our under- submitted for publication). Consistent with this prop-
standing of protective or resilience-related biological osition, patients with comorbid skin-picking disorder
factors. Multi-modal investigation, providing conver- and BDD (n ¼ 16) had disproportionately impaired
gent evidence and guided by specific theoretical set-shifting compared with subjects with non-comor-
hypotheses, might help to address these issues. bid skin-picking disorder (n ¼ 39) (Grant et al. 2015).
Other research suggests that individuals with BDD
Other OCRDs may have abnormalities in visual processing (Feusner
et al. 2010). The sample size was 17 patients and 16
Trichotillomania has been associated with impaired controls. In sum, caution is warranted due to the
stop-signal inhibitory control in multiple studies com- small numbers of studies, but there is some evi-
pared with controls, while set-shifting has generally dence that the grooming disorders (trichotillomania,
been reported to be intact (Chamberlain et al. 2006; excoriation disorders) are commonly associated with
Odlaug et al. 2014). The sample sizes were 17 patients impaired response inhibition; while hoarding disorder
and 20 controls in the former study; and 12 patients and BDD appear more OCD-like in their neuro-
and 14 controls in the latter study. However, there psychological profiles.
appear to be some differences in subtypes: in people
with childhood onset trichotillomania (<11 years of PTSD
age, n ¼ 42), the neuropsychological profile appears to
be more like OCD; i.e., impaired set-shifting and lesser Research on the neuropsychology of PTSD has identi-
stop-signal impairments; compared with later onset tri- fied several neurocognitive deficits associated with the
chotillomania (n ¼ 56) (Odlaug et al. 2012). disorder (Everly & Horton 1989; Vasterling et al. 1998;
Patients with excoriation (skin-picking) disorder Sachinvala et al. 2000; Levy-Gigi et al. 2012). In one
(n ¼ 20) showed impaired stop-signal inhibition but study, subjects with PTSD (n ¼ 38), trauma-exposed
intact set-shifting versus controls (n ¼ 20) (Odlaug subjects without PTSD (n ¼ 108) and healthy control
et al. 2010). Impaired response inhibition on a stop- subjects (n ¼ 89) did not differ significantly on a num-
signal task was found in patients with trichotilloma- ber of neuropsychological tests; however, the study
nia (n ¼ 12) and their clinically asymptomatic first- was done in a non-clinical sample of undergraduate
degree relatives (n ¼ 10) versus controls (n ¼ 14) in a students (Twamley et al. 2004). In a double-blind study
more recent study, suggesting that it may represent with 18 PTSD patients, treatment with the SSRI paroxe-
a vulnerability or predisposing factor (Odlaug et al. tine resulted in a significant increase in verbal declara-
2014). In a head-to-head comparison of skin- tive memory function (Fani et al. 2009). It remains
picking disorder (n ¼ 31 patients) against trichotillo- unclear whether the memory deficits in PTSD can only
mania (n ¼ 39 patients), stop-signal impairments be attributed to stress-related alterations. As there is a
were more marked in the former group (Grant genetic vulnerability for developing PTSD, cognitive
et al. 2011). dysfunctions may have existed before the trauma and
As is the case for imaging, cognitive studies in may have been, at least in part, the reason why vulner-
relation to compulsive hoarding have mostly been able individuals develop PTSD after a trauma.
undertaken in the context of other disorders, rather Cognitive impairments in PTSD have also been attrib-
than in ‘‘hoarding disorder’’ as a discrete entity. One uted to comorbidity with substance abuse or other
exception to this is a recent study that compared psychiatric disorders. However, in a study reporting
cognition in people with hoarding disorder without memory function in rape victims with PTSD (n ¼ 15),
OCD (n ¼ 22), people with OCD plus hoarding compared with rape victims without PTSD (n ¼ 16),
deficits were mild and not attributable to comorbid accompanying article (see Part I; Bandelow et al. 2016)
depression, anxiety or substance abuse (Jenkins et al. in a simple way.
1998). First, a change in paradigms has been observed. In
One DSM-5 criterion for PTSD is the ‘‘inability to the 1980s and 1990s, ‘‘wet research’’ predominated,
remember an important aspect of the traumatic event meaning that blood or CSF samples were taken from
(typically due to dissociative amnesia)’’. One may patients and healthy controls, either in resting state or
speculate that dissociative amnesia is associated with after challenge tests with anxiety-provoking agents,
the memory impairments generally found in PTSD. e.g., lactate or carbon dioxide. Blood-based biomarkers
However, it is contentious whether the phenomenon of treatment response in psychiatric disorders remain
of dissociative amnesia exists at all (for a discussion, in early stages of development and none has demon-
see McNally, 2007). strated reliability for predicting pharmacological out-
come. Although research efforts in the past decades
have definitely increased our knowledge of the neuro-
Gender issues
biological underpinnings of pathological anxiety, we
In international epidemiological surveys, the female to still do not have the proof that a specific dysfunction
male ratio of the prevalence rates of anxiety disorders of a neurotransmitter system, e.g., the serotonergic sys-
varied between 1.5:1 and 2.1:1% (Bandelow & tem, is the main cause for anxiety disorders. Still, the
Michaelis 2015). Psychosocial contributors (e.g., child- most robust evidence for an involvement of serotonin
hood sexual abuse and chronic stressors), but also gen- derives from the fact that a large number of drugs
etic and neurobiological factors have been discussed that are effective in anxiety disorders, OCD and PTSD
as possible causes for the higher prevalence in women. have a common denominator, i.e., that they have an
Identification of the causes of gender-specific suscepti- impact on serotonergic neurotransmission.
bility for anxiety disorders may be useful for better Serotonin reuptake inhibition is the main mechan-
understanding the aetiology of anxiety disorders in ism of action of these antidepressants but there also
general. It is most likely that higher anxiety susceptibil- some drugs that have agonist or antagonist properties
ity in women is due to a delicate interplay between at serotonin receptors. Other medications that can
psychosocial and neurobiological factors. Hypotheses treat anxiety act at the GABA binding site. However, as
about the role of gender-specific stressors, and gender these binding sites are widespread in the brain and
differences in the expression of fears warrant further have non-specific inhibitory effects, the efficacy of ben-
investigation. Sex-specific variance has been identified zodiazepines in anxiety disorders cannot be taken as
in numerous neurotransmitter systems. The serotonin evidence that a dysfunction of the GABA binding site
system may be of particular importance, as most drugs is the cause of pathological anxiety.
used in the treatment of anxiety disorders enhance Since the end of the 1990s, there has been a strong
serotonin neurotransmission and alterations in the shift to neuroimaging and genetic studies – which are
serotonergic system have been found in anxiety summarised in Part I of this consensus paper
patients relative to healthy controls. It seems likely that (Bandelow et al. 2016), while the publication output in
female sex hormones are involved, as periods of fluctu- neurochemistry studies seems to have declined.
ating levels of oestrogen and progesterone have been Interpreting the abundant number of results of neu-
linked to increase or decrease of symptomatology in roimaging studies in anxiety disorders is a difficult task.
patients with PDA. Moreover, a plausible explanation The existing studies have found abnormalities in many
for the gender-specific risk is a genetic one. For different regions of the brain, and it is a challenge to
example, in PDA, the catechol-O-methyltransferase and synopsise the often contradictory findings in a uniform
monoamine oxidase (MAOA) genes have been associ- theory. A problem is the high number of statistical
ated with the higher risk of women to develop PDA comparisons that are possible, and if the results are
(Bandelow & Domschke 2015). not corrected for multiple testing, there is a high
chance for false-positive findings. The main methodo-
logical problem in most of the studies is the small
Discussion
sample size, making it difficult to reliably separate arte-
To our knowledge, there has been no comparable con- facts from substantiate findings.
sensus initiative that put together all major research Likewise, there is a plethora of genetic studies. In
lines in the field of biomarkers for anxiety, OCD and association studies, a large number of candidate genes
PTSD. It is a challenge to summarise the incredible have been investigated. The only clear result that we
amount of findings collected in this paper and the can derive from these studies is that anxiety disorders
are not based on a single gene but are multigenic, Pharmacists, British Association for Psychopharmacology,
while the contribution of single genes is only small. International College of Obsessive-Compulsive Spectrum
Genome-wide association studies may be a future pos- Disorders, International Society for Behavioural Addiction,
World Health Organisation, Royal College of Psychiatrists.
sibility to separate relevant findings from findings by
Dr. Jarema has been on the speakers’ and/or advisory
chance. Again, correction for multiplicity is crucial, and board for Angelini, Janssen, Lilly, Lundbeck, and Servier.
this again requires larger sample sizes that are often €hle: Research funding: German Federal Ministry of
Prof. Stro
used in genetic research. International cooperation is Education and Research (BMBF), German Research Foundation
needed to generate adequate sample sizes for this (DFG), European Commission (FP6), Lundbeck; speaker hono-
kind of research. Despite the manifold methodological raria: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb,
Lilly, Lundbeck, Pfizer, Wyeth, UCB. Consultant for Actelion.
shortcomings, the neuroimaging and genetics fields
Educational grants: Stifterverband f€ ur die Deutsche
are two of the most promising areas for neurobio-
Wissenschaft, Berlin Brandenburgische Akademie der
logical research. In the future, neurochemistry, neuro- Wissenschaften, Boehringer Ingelheim Fonds, Eli Lilly
physiology, neuropsychology, neuroimaging, genetics International Foundation, Janssen-Cilag, Pfizer, and Lilly.
and other fields will have to be integrated in order to Prof. Thibaut is Editor-in-Chief of Dialogues in Clinical
elucidate the neurobiological causes of anxiety. Neurosciences (grant by Servier).
Dr. Wichniak has been on the speakers’ and/or advisory
Increasing efforts are being made to find reliable bio-

board for Angelini, Janssen, Lundbeck, and Servier.
markers for diagnostic procedures or prediction of
Prof. Zwanzger was on the speakers’ and/or
treatment outcome in anxiety disorders, OCD and advisory board for Lundbeck, Pfizer, Servier, Aristo, Merz
PTSD. However, as with research in other mental disor- and Hexal
ders such as depression, there is still no biological or All other authors reported no conflicts of interest to
genetic predictor of sufficient clinical utility to inform declare.
the selection of a specific pharmacological compound
for an individual patient, because of low sensitivity and Funding information
specificity of the suggested biomarkers. Ideally, in the
None.
future, we will possibly be able to diagnose a mental
disorder simply by taking a blood test and to choose a
personalised medication or psychological treatment for ORCID
a specific patient (‘‘precision medicine’’). Borwin Bandelow http://orcid.org/0000-0003-2511-3768
Marianna Abelli http://orcid.org/0000-0002-3877-7048
Acknowledgements Michel Bourin http://orcid.org/0000-0002-7268-4590
Samuel R. Chamberlain http://orcid.org/0000-0001-7014-
The present work was supported by the ADRN within the
8121
ECNP-NI.
Katherina Domschke’s work was supported by the Eduardo Cinosi http://orcid.org/0000-0002-8903-181X
German Research Foundation (DFG), Collaborative Research Naomi Fineberg http://orcid.org/0000-0003-1158-6900
Centre ‘‘Fear, Anxiety, Anxiety Disorders’’ SFB-TRR-58, Edna Gr€ unblatt http://orcid.org/0000-0001-8505-7265
projects C02 and Z02. Marek Jarema http://orcid.org/0000-0001-5267-5315
Yong-Ku Kim http://orcid.org/0000-0001-5694-7840
Statement of interest Vasileios Masdrakis http://orcid.org/0000-0003-0197-9583
David Nutt http://orcid.org/0000-0002-1286-1401
Prof. Bandelow has received research funding from European Stefano Pallanti http://orcid.org/0000-0001-5828-4868
Commission (FP7) and was on the speakers’ and/or advisory
board for Actelion, Glaxo, Janssen, Lundbeck, Meiji-Seika,
Stefano Pini http://orcid.org/0000-0001-9092-9144
Otsuka, Pfizer, and Servier. Florence Thibaut http://orcid.org/0000-0002-0204-5435
Prof. Baldwin has attended advisory boards for Matilde M. Vaghi http://orcid.org/0000-0002-0999-9055
Grunenthal, Eli Lilly, Lundbeck, Pfizer, and Servier. His univer- Eunsoo Won http://orcid.org/0000-0001-6825-032X
sity has received grants from Lundbeck and Pfizer to support Peter Zwanzger http://orcid.org/0000-0002-5385-8188
research into anxiety disorders.
Dr. Chamberlain consults for Cambridge Cognition.
Dr. Fineberg has received financial support in various
forms from the following: Otsuka, Lundbeck, Glaxo- References
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The World Journal of Biological Psychiatry

ISSN: 1562-2975 (Print) 1814-1412 (Online) Journal homepage: http://www.tandfonline.com/loi/iwbp20

Biological markers for anxiety disorders,

Borwin Bandelow, David Baldwin, Marianna Abelli, Blanca Bolea-Alamanac,

To link to this article: http://dx.doi.org/10.1080/15622975.2016.1190867

Published online: 15 Jul 2016. Submit your article to this journal

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WFSBP CONSENSUS PAPER

Biological markers for anxiety disorders, OCD and PTSD: A consensus

ABSTRACT ARTICLE HISTORY

Abbreviations: 5-HIAA: 5-Hydroxyindoleacetic acid; 5-HT: Serotonin; 5-HTP: Hydroxytryptophan; 5-

Corticotropin-releasing hormone; CRP: C-reactive protein; CSF: Cerebro-spinal fluid; DHEAS:

Introduction between CNS and periphery. In the following sections,

There is a body of evidence for NE involvement in

The key regions of the fear network, such as baso-

1985; Schweizer et al. 1986; Tiller et al. 1988; Okasha SAD

were positively associated with improvements in anx-

Specific Phobia Glucocorticoids in the treatment of specific phobia.

baseline cortisol levels are normal or pathologically ele-

Glucocorticoids in the treatment of PTSD. Based on

as brief laboratory stressors induce increases in natural

show a high level of antineural antibodies against the

findings should be viewed cautiously given the small

Electrophysiological studies in GAD studies did not

et al. 1998) and is a predictor of mortality (Dekker

Mental Disorders (DSM)-IV and DSM-5 excluding clinical et al. 1997).

Neurocognition performance than controls, but this finding did not

ticipants per group were excluded.

(Chamberlain et al. 2007b).

Increasing efforts are being made to find reliable bio-

evaluation of escitalopram. Am J Geriatr Psychiatry. Disord. 116:192–200.

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