Curr Psychiatry Rep (2014) 16:510
DOI 10.1007/s11920-014-0510-8
GENETIC DISORDERS (W BERRETTINI, SECTION EDITOR)
Second Generation Antipsychotic-Induced
Obsessive-Compulsive Symptoms in Schizophrenia: A Review
of the Experimental Literature
Trehani M. Fonseka & Margaret A. Richter &
Daniel J. Müller
Published online: 26 September 2014
# Springer Science+Business Media New York 2014
Abstract Second generation antipsychotics (SGAs) have
been implicated in the de novo emergence and exacerbation
of obsessive-compulsive symptoms (OCS) in patients with
schizophrenia. Among SGAs, clozapine, olanzapine, and ris-
peridone are the most prominent agents associated with these
sequelae, according to case reports. Comorbid OCS can im-
pede recovery by compromising treatment benefits, medica-
tion compliance, and clinical prognoses. Previous reviews of
SGA-induced OCS have predominantly focused on descrip-
tive case reports, with limited attention paid toward experi-
mental findings. To address this paucity of data, we sought to
review the effects of SGAs on OCS in schizophrenia in the
experimental literature, while addressing the role of different
treatment (duration, dose, serum levels) and pharmacogenetic
factors. Our findings suggest that clozapine confers the
greatest risk of OCS in schizophrenia, with 20 to 28 % of
clozapine-treated patients experiencing de novo OCS, in ad-
dition to 10 to 18 % incurring an exacerbation of pre-existing
OCS. Clozapine can also yield full threshold obsessive-
compulsive disorder (OCD), in some cases. Olanzapine is
another high risk drug for secondary OCS which occurs in
11 to 20 % of schizophrenic patients receiving olanzapine
This article is part of the Topical Collection on Genetic Disorders
T. M. Fonseka : D. J. Müller (*)
Campbell Family Mental Health Research Institute, Center for
Addiction and Mental Health, 250 College Street, Toronto, ON M5T
1R8, Canada
e-mail: daniel.mueller@camh.ca
M. A. Richter
Frederick W. Thompson Anxiety Disorders Centre, Department of
Psychiatry, Sunnybrook Health Sciences Centre, University of
Toronto, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada
M. A. Richter : D. J. Müller
Department of Psychiatry, University of Toronto, Toronto, ON,
Canada
therapy. At this time, there is insufficient experimental evi-
dence to characterize the effects of other SGAs on OCS.
Despite some experimental support for the involvement of
longer treatment duration and genetic factors in mediating
drug-induced OCS, more research is needed to clearly eluci-
date these associations. Based on these results, schizophrenic
patients should be routinely monitored for OCS throughout
the course of SGA treatment, particularly when clozapine or
olanzapine is administered.
Keywords Second generation antipsychotic . Clozapine .
Olanzapine . Obsessive-compulsive disorder . Schizophrenia .
Side effect
Introduction
Schizophrenia is a highly impairing psychiatric disorder char-
acterized by a chronic course, and according to diagnostic
systems, a global lifetime prevalence rate in the range of 1-4
cases per 1000 persons [1–3]. Clinical improvement of schizo-
phrenic symptoms is primarily achieved through treatment
with antipsychotic medication. Unlike first-generation anti-
psychotics (FGAs), pharmacologically distinct second-
generation antipsychotics (SGAs) have been shown to induce
obsessive-compulsive symptoms (OCS) in schizophrenic pa-
tients despite their comparatively superior clinical efficacy. In
fact, case reports most frequently implicate clozapine,
olanzapine, and risperidone in mediating secondary OCS [4]
which are phenomenologically similar to OCS in primary
obsessive-compulsive disorder (OCD) [5]. However, an ex-
amination of SGA-induced OCS within the experimental lit-
erature is lacking, as previous reviews have predominantly
focused on results from descriptive studies which lack the
scientific parameters to clearly discern treatment-specific ef-
fects. The characterization of this drug-induced phenotype is
510, Page 2 of 17
clinically relevant in that it can inform clinical practice and
effective treatment strategies. Thus, this review will summa-
rize findings from experimental studies that examine the ef-
fects of SGAs on OCS prevalence and severity in schizo-
phrenic patients while addressing the role of treatment (dura-
tion, dose, serum levels) and pharmacogenetic factors as po-
tential mediators.
Methods
To assess the effects of SGAs on the induction and exac-
erbation of OCS in schizophrenia, a literature search in
OVID Medline, Embase, and PsycINFO databases was
performed. Search terms included (‘schizophrenia’ OR
‘psychosis’ OR ‘psychotic’) AND (‘obsessive compulsive
disorder’ OR ‘OCD’ OR ‘obsession’ OR ‘compulsion’)
AND (‘atypical antipsychotic’ OR ‘neuroleptic drug’ OR
‘second generation antipsychotic’ OR ‘clozapine’ OR
‘olanzapine’ OR ‘risperidone’ OR ‘quetiapine’). Results
were restricted to experimentally-designed, peer-reviewed
articles published in English from 1960 to 2014. Studies
involving pre-clinical or descriptive methodology were
excluded. No secondary restrictions based on demographic
(e.g., age, gender, ethnicity) or clinical (e.g., symptom
severity, comorbid psychiatric or medical conditions) pa-
tient variables or experimental design parameters (e.g.,
sample size, assessment method, dose or duration of treat-
ment) were included. The search yielded 127 articles
which were individually reviewed for concordance with
refinement criteria.
A total of 15 studies were selected for review of
clozapine-induced OCS, nine for olanzapine-induced OCS,
and six for risperidone-induced OCS. Due to an insufficient
number of experimental studies, separate investigations of
additional SGAs were not permitted. All included studies
had the following data extracted, where possible: (a) sam-
ple characteristics including psychiatric diagnoses, age, gen-
der, and in/outpatient status, (b) treatment information in-
cluding duration, dose, and serum levels, (c) study design
parameters including data collection methodology, sample
size, and use of comparison groups, and (d) OCS outcomes
including prevalence and severity estimates. Studies were
primarily naturalistic in design, and involved longitudinal,
cross-sectional and/or retrospective data collection. Study
participants had a diagnosis of either schizophrenia,
schizoaffective or schizophreniform disorder. Most studies
had treatment comparison arms, with two studies including
one or more of the following comparison conditions: treat-
ment-absent, healthy control, healthy sibling or placebo-
controlled. Treatment dose and duration were typically
variable.
Curr Psychiatry Rep (2014) 16:510
Epidemiology of OCS in Schizophrenia
Epidemiological studies report that approximately 25 to 64 %
of schizophrenic patients experience OCS, of which 8 to 26 %
meet criteria for clinically significant OCD, according to the
Diagnostic and Statistical Manual of Mental Disorders (DSM)
[6–14]. Despite variable rates, the majority of studies have
assessed OCD using comparable assessment methods includ-
ing the Structured Clinical Interview for Axis I DSM Disor-
ders (SCID) or the Mini-International Neuropsychiatric Inter-
view (MINI), in conjunction with the Yale–Brown Obsessive
Compulsive Scale (Y-BOCS). To address the heterogeneity of
rates across epidemiological studies, a meta-analysis by
Achim et al. [15] examined pooled prevalence rates of anxiety
disorders within schizophrenia, identifying a mean rate of
12.1 % for obsessive- compulsive disorders. Similarly, a more
recent combinatorial meta-analysis and meta-regression by
Swets et al. [16•] identified adjusted mean rates of 13.6 %
for OCD and 30.3 % for OCS in schizophrenia. These esti-
mates are higher than typically observed in the general popu-
lation where lifetime OCD and OCS prevalence rates are 0.3
to 3 %, and 21 to 25 %, respectively [17–22].
The increased risk of OCS comorbidity in schizophrenia
may be a consequence of similar neurobiological dysfunction,
particularly within frontal lobe and basal ganglia circuits, in
both schizophrenia and OCD [23–25]. However, only 1.7 to
14 % of OCD patients report psychotic symptoms and 4 to
12 % present with comorbid schizophrenia [21, 26, 27].
Alternate theories propose that OCS are part of the pathology
of schizophrenia. However, comorbid OCS are not consistent-
ly observed throughout the course of schizophrenic disorders,
being more prominent in chronic or late stage schizophrenia.
As such, prevalence estimates in prodromal or first-episode
patients are low, with rates around 9 % for OCS and 1.5 % for
OCD [28, 29]. The low incidence of OCS and OCD in early
stage schizophrenia may result from drug-naivety or short-
term treatment duration. Although the basis for this comor-
bidity has yet to be clearly defined, epidemiological findings
suggest that antipsychotics may contribute to the risk of OCS
in schizophrenia.
Clinical Presentation of OCS in Schizophrenia
Clinical Features of OCS and OCD
OCS are characterized by two main clinical features: obses-
sions and compulsions. Obsessions are intrusive thoughts,
images, doubts or urges of a persistent and recurrent nature
that provoke significant anxiety [30]. Obsessional thought
content generally focuses on themes such as contamination,
aggression, perfectionism, blasphemy, and sexuality [31, 32].
Patients attempt to ignore or suppress these preoccupations or
Curr Psychiatry Rep (2014) 16:510 Page 3 of 17, 510

neutralize them through compulsions. Patients often retain
insight into the nature of their obsessions, as evidenced by
an understanding that thought content is unreasonable or
excessive [30]. Compulsions are repetitive behaviors or men-
tal rituals, such as excessive cleaning or hand-washing,
counting, hoarding, arranging, or checking, that patients feel
compelled to perform in response to obsessions [30, 33, 34].
OCS are considered clinically sub-threshold until symptoms
become significantly time consuming (>1 hour/day) and/or
functionally impairing or distressing to thereby warrant a
threshold diagnosis of OCD [35]
schizoaffective disorder or delusional disorder, compulsions
may even be performed in response to delusions [42]. Simi-
larly, schizophrenia can occur with obsessive-compulsive fea-
tures, whether they manifest as full-threshold OCD or sub-
threshold OCS. This constellation of symptoms has been
clinically referred to as schizo-obsessive disorder [45]. The
clinical interface between OCD and schizophrenia creates a
spectrum of phenotypes where worsened prognostic outcomes
are associated with greater comorbid overlap (refer to Fig. 1).
Prognosis of OCS in Schizophrenia

OCS in schizophrenia alter the course of the disorder, as

Clinical Comparisons between OCD and Schizophrenia
evidenced by distinct changes in prognostic outcomes. In
some studies, OCS comorbidity has been argued to have a
OCD and schizophrenia can often be clinically differentiated by
protective effect against positive and negative symptoms,
distinguishing between obsessions and delusions which, despite
particularly within first-episode patients [12, 46, 47]. Howev-
both being thought disorders, are fundamentally different in their
er, the majority of evidence supports a worsened trajectory.
respective content and structure (refer to Table 1). In schizophre-
Most studies have found that schizophrenic patients with
nia, delusions are incorrect beliefs that patients highly regard as
comorbid OCS experience higher rates of positive [9,
truth despite existence of contradictory evidence, in most cases.
48–51] and negative symptoms [10, 48, 51, 52], earlier age
Hence, patients with delusions defend their beliefs, and resist
of psychosis onset [53], longer illness duration [53], use of
changing them or accepting alternate perspectives [36–38]. De-
more extensive clinical treatments [52], and longer and more
lusional content is often bizarre and, although mainly persecu-
frequent hospitalizations [14, 52] compared to non-comorbid
tory or referential, can be somatic, religious, or grandiose [39].
patients. OCS-comorbid patients also have greater impair-
Patients with schizophrenia also perceive their thoughts to orig-
ments in motor [6, 54] and cognitive function, with the latter
inate from an external source [40]. This differs from obsessions
evidenced by poorer neurocognitive performance on tasks of
which are comparatively more realistic in content. OCD patients
executive function [51, 52, 55], visual-spatial skills, delayed
also believe obsessions are a product of their own mind, typi-
nonverbal memory, impulse inhibition, and cognitive shifting
cally have insight (or recognition that these thoughts are exag-
[56, 57]. In addition, greater psychiatric comorbidity occurs
gerated or irrational), and often try to resist them due to their
with OCS in schizophrenia, particularly higher rates of axis II
irrational and excessive nature [30, 35, 41].
Despite the distinct clinical nature of OCD and schizophre-
nia, there can be a certain degree of overlap between these
diagnostic phenotypes that adds to the heterogeneity of these
disorders, clinically. For example, although patients with
OCD are traditionally defined as maintaining insight into both
the absurdity and/or origin of their obsessions and/or compul-
sions, a subtype has been identified where such insight is
deficient. This absence of awareness, termed OCD without
insight, leads to a delusional or overvalued justification of
behaviors [42–44]. In cases where psychotic symptoms are
more prominent, such as when primary OCD is accompanied
by a full-threshold psychotic disorder like schizophrenia,

Table 1 Clinical differences between obsessions and delusions

Obsessions Delusions

Degree of conviction Low High

Resistance to change Low High
Fig. 1 Different clinical phenotypes exist between primary schizophre-
Thought content Exaggerated, realistic Often bizarre nia (SCZ) and obsessive-compulsive disorder (OCD). Worsened prog-
Perceived thought origin Internal External nostic outcomes follow in the directions of comorbid OCD and SCZ,
where clinical and functional impairment is greatest
510, Page 4 of 17
disorders [58], body dysmorphic disorder, and tic disorders
[59, 60], suicidal ideation and suicide attempts [61, 62], and
emotional discomfort and depression [9, 50, 51, 61], including
greater depressive severity [63]. These worsened outcomes
have been shown to lead to greater functional impairment in
the areas of increased social isolation [9], and lower levels of
the following: social functioning [11, 63], marriage and co-
habitation [14], and independent living, employment, and age-
appropriate functioning [9, 14, 42, 49, 52]. Overall, the clin-
ical and functional consequences of comorbid OCS in schizo-
phrenia are high.
Mechanisms of SGA-induced OCS in Schizophrenia
Sociodemographic Risk Factors of SGA-Induced OCS
SGA-induced OCS have been associated with certain risk
factors in clinical reports. A review of 28 case reports by Ke
et al. [64] found a greater incidence of SGA-induced OCS
within males compared to females, at a rate of 6:1. Of these
cases, despite an age range of 19 to 56 years, most patients
were in their 20s and 30s. However, the small number of
reviewed cases limits the inferences that can be made. In
contrast, experimental studies have primarily found no differ-
ence between schizophrenic patients with versus without
drug-induced OCS/OCD on sociodemographic variables such
as age, sex, ethnicity, education or family history [48, 53, 54,
65•].
Genetic Models of SGA-Induced OCS
Schizophrenia and OCD are both highly heritable and com-
plex polygenic diseases [66–69]. To date, various candidate
genes involved in serotonergic, dopaminergic and glutamater-
gic systems have, both individually and synergistically, been
implicated in the risk of OCD. In particular, candidate gene
studies have identified the involvement of multiple genetic
variants from serotonergic system-related genes such as 5-
HTTLPR (serotonin-transporter-linked polymorphic region)
and HTR2A (serotonin receptor 2A) in OCD. Variants from
the genes encoding catechol-O-methyltransferase (COMT)
and monoamine oxidase A (MAOA) have been associated
with OCD in certain cases. The glutamatergic gene SLC1A1
(excitatory amino-acid transporter 3) has been implicated in
association and linkage studies, and there is limited evidence
for association for the dopaminergic genes DAT1 (dopamine
active transporter 1) and DRD3 (dopamine receptor D3) in
this phenotype. For further details on the genetic basis of
OCD, refer to Pauls et al. [68].
Some of these same genes have been implicated in the
differential risk for drug-induced OCS/OCD, according to
Curr Psychiatry Rep (2014) 16:510
preliminary candidate gene studies. Ryu et al. [70] investigat-
ed SLC1A1, in addition to the glutamatergic DLGAP3 (disks
large associated protein 3) gene, for this association in clini-
cally stable schizophrenic patients. Results showed that
DLGAP3 rs7525948 interacted with SLC1A1 rs2228622 to
significantly predict SGA-emergent OCS, with carriers of
each risk genotype having a 30.2-fold increase in OCS sus-
ceptibility compared to patients with neither risk genotype. A
similar epistatic model was tested among clozapine-treated
schizophrenic patients by Cai et al. [65•]. Results revealed
that SLC1A1 rs2228622A also interacted with the GRIN2B
rs890T allele to predict OCS. Finally, Kwon et al. [71] further
characterized this phenotype by examining sequence varia-
tions in the SCL1A1 gene in Korean schizophrenic patients.
Results showed that the odds of experiencing SGA-induced
OCS was almost four times higher in patients with the A/C/G
haplotype at rs2228622–rs3780413–rs3780412 than patients
with the G/C/A reference haplotype. Individual trends of
association were also observed for rs2228622 and
rs3780412. However, Shirmbeck et al. [72•] could not repli-
cate these findings when tested in a European sample. This
may suggest that, although SCL1A1 is a hypothesized risk
gene for SGA-induced OCS, its effects may differ between
ethnic groups. Further hypothesis-driven and/or hypothesis-
free genome-wide association studies (GWAS), in addition to
studies of gene function, are needed to more clearly discern
the genetic basis of SGA-induced OCS.
Neurotransmitter Dysregulation in OCD and Serotonin
Hypothesis of SGA-Induced OCS
Central serotonin (5HT) dysregulation has been most strongly
implicated in the pathophysiology of OCD. Several studies
report a deficit of serotonin in specific brain regions, in addi-
tion to elevated peripheral 5HT metabolites, in both pre-
clinical and clinical models of OCD [73, 74]. The role of the
serotonergic system is further supported by the therapeutic
effects of selective serotonin reuptake inhibitors (SSRIs) on
OCD through normalization of aberrant serotonin levels [73,
75, 76]. SSRIs, such as fluvoxamine and fluoxetine, achieve
this effect by blocking 5HT reuptake into pre-synaptic neu-
rons by acting at the site of the serotonin transporter [77, 78] to
enhance synaptic 5HT availability and facilitate post-synaptic
binding [79] (refer to Fig. 2a). SSRIs have also been reported
to reduce 5HT turnover as evidenced through lowered cere-
brospinal levels of the central 5HT metabolite 5-
hydroxyindoleacetic acid (5-HIAA) [79]. Similar serotonergic
effects have been observed for tricyclic antidepressants such
as clomipramine, and lowering of platelet and whole blood
5HT levels has been postulated to reduce OCD symptomatol-
ogy [80]. Alterations of additional neurotransmitters, such as
dopamine [81, 82] and glutamate [83], have also been impli-
cated in the neurobiology of OCD, but the exact mechanism of
Curr Psychiatry Rep (2014) 16:510
their effects is not fully understood. Thus, while different
neurotransmitter systems are altered during antipsychotic
treatment, the serotonergic antagonism of most SGAs appears
to be the most likely mechanism involved in antipsychotic-
induced OCS (described in more detail below).
Pharmacodynamic Properties of SGAs and OCS
Antipsychotic drugs, which broadly include FGAs and SGAs,
are pharmacologically designed to act antagonistically at the
dopamine D2 receptor. This property, particularly within the
mesolimbic dopamine pathway, is predominantly responsible
for mediating the antipsychotic effects of these drugs. Despite
this similarity, SGAs are pharmacologically distinct from
FGAs as defined by the strength of their D2 receptor blockade,
in addition to their unique antagonism of the serotonin 5HT2A
receptor (refer to Fig. 2b) [84]. Most SGAs achieve antipsy-
chotic response through preferential occupancy of 5HT2 over
D2 receptors, as observed in vitro and in vivo [85, 86]. Kapur
et al. [85] showed that clozapine, olanzapine, and risperidone
all have a higher 5HT2 binding affinity relative to D2, accord-
ing to their respective 5HT2/D2 occupancy ratios of 20:1,
12:1, and 11:1. Similar pharmacodynamic profiles have been
observed for ziprasidone [87] and quetiapine [88]. However,
aripiprazole is uniquely characterized by lower 5HT2 over D2
receptor occupancy [89]. Nevertheless, SGAs can show pat-
terns of increased D2 binding when administered at higher
doses [90, 91]. SGAs also rapidly dissociate from the D2
receptor when competing with endogenous dopamine [92].
This differs from predominantly dopaminergic FGAs which
have comparatively lower dissociation rates at these sites [93].
The enhanced antiserotonergic binding profile of SGAs is
the hypothesized mechanism through which these drugs in-
duce and exacerbate OCS. This theory receives support from
multiple lines of evidence. For one, Ma et al. [94] found that
clozapine-induced antagonism of the 5HT system altered se-
rum serotonin to levels comparable to OCD. Second, SGA-
induced OCS are often remedied through adjunctive pharma-
cotherapy with SSRIs, which are traditionally prescribed to
treat OCD [53]. Finally, FGA treatment studies have demon-
strated that predominantly dopaminergic agents, such as hal-
operidol, typically yield OCS prevalence and severity esti-
mates that differ from SGAs [48]. For example, FGAs com-
monly have no effect or improve OCD symptoms, and can be
co-administered with SSRIs to improve treatment-refractory
OCD [95, 96]. Similar treatment benefits have been observed
for predominantly dopaminergic SGAs like amisulpride [97],
and the partial dopamine/serotonin agonist aripiprazole
[98–100]. Although other prototypical SGAs like clozapine,
olanzapine, risperidone and quetiapine have, in some cases,
been reported to improve OCS in both primary OCD
[101–103] and schizophrenia [104, 105], this may be a con-
sequence of high drug dosing which, as mentioned previously,
Page 5 of 17, 510
can shift D2 receptor binding affinities. The next section will
summarize experimental evidence on the effects of SGAs in
drug-induced OCS/OCD.
Clozapine-induced OCS in Schizophrenia
Evidence of clozapine-emergent and exacerbated OCS has
been documented in numerous case reports [106–109], case
series [64, 110–112] and chart reviews [113–115]. These
descriptive studies provide preliminary support for a dose-
dependent relationship between clozapine and OCS, evi-
denced by worsened OCS severity with increased clozapine
dose [111, 116], and improved OCS with clozapine dose
reductions [110, 116]. Dose reductions facilitated by augmen-
tation with valproic acid have also been shown to improve
OCS outcomes [117, 118]. Case reports further document OCS
remission upon clozapine cessation [107, 113, 119], initiation
of adjunctive SSRIs [108, 116, 120–122], and maintenance use
of electroconvulsive therapy [123]. In contrast, a small number
of reports have documented OCS improvement subsequent to
clozapine treatment [104, 124], with one report of de novo
OCS occurring in response to clozapine withdrawal [125].
Clozapine-Induced De Novo OCS vs. OCS Exacerbation
Most experimental studies have broadly examined clozapine-
related OCS (discussed below) without distinguishing be-
tween rates of de novo versus exacerbated OCS. However,
some experimental investigations have examined these two
OCS subtypes separately (refer to Table 2). Lin et al. [126]
reported an overall OCS prevalence rate of 38.2 % among 102
schizophrenic patients treated with clozapine. Subtype analy-
ses revealed that 28.4 % of all patients experienced de novo
onset, having no history of OCS prior to treatment. Of these
cases, six developed full threshold de novo OCD, which was
5.9 % of the total sample. Only 9.8 % of patients reported a
prior history of OCS that worsened with clozapine treatment,
one of which developed OCD (1 %). Ertugrul et al. [127]
found a higher overall OCS prevalence rate of 76 % among 50
clozapine-treated schizophrenic patients. The de novo OCS
rate was comparable at 20 %, while the rate of OCS exacer-
bation was almost double at 18 %. A similar de novo OCS rate
of 26.7 % was reported by Lim et al. [128]. Mahendran et al.
[129] showed that out of all cases of de novo OCS among
schizophrenic patients receiving SGA treatment, clozapine
accounted for 22 %. Overall, these studies suggest that cloza-
pine can induce and worsen OCS at a rate of 20 to 28 % and 10
to 18 %, respectively.
These findings also suggest that clozapine can, albeit less
frequently, induce full threshold OCD. Further support for
these effects is derived from De Haan et al. [115] who noted
that 9.8 % of clozapine-treated patients developed de novo
510, Page 6 of 17
Fig. 2 a. SSRIs (in green) block
reuptake of serotonin (in purple)
into the pre-synaptic nerve
terminal. This results in increased
5HT in the synaptic cleft and
increased post-synaptic binding.
b. SGAs, like clozapine and
olanzapine (in blue) block
serotonin from binding to its
receptor (in red) which impedes
5HT binding
OCD unlike patients treated with other antipsychotics who
experienced no such effects. However, in contrast to these de
novo outcomes, clozapine reduced pre-treatment OCD to sub-
threshold levels in this sample. Similarly, Doyle et al. [130•]
observed that 22 % of clozapine-treated schizophrenic patients
had clinically significant OCS, of which3 % had OCS pre-
treatment and 19 % had de novo onset. Interestingly, the
resultant OCS profile of this clozapine-treated schizophrenic
sample differed from primary OCD controls, in that the former
was more often characterized by cognitive rather than behav-
ioral OCS.
Overall, the comparable de novo OCS rates across studies
suggest this outcome may be relatively quick to onset and stable
across conditions. This is in contrast to variable rates of OCS
exacerbation which may indicate this outcome is a consequence
of other treatment parameters, such as duration or dose. Inter-
individual variation in OCS outcomes may also be explained by
genetic differences across patients. Cai et al. [65•] examined the
effects of OCD risk variants on clozapine-induced OCS in 250
schizophrenic patients. Among the 57.6 % of patients
exhibiting OCS, there was a greater frequency of the GRIN2B
rs890T allele compared to in the non-OCS group. A marginally
significant association was also observed for the SLC1A1
rs2228622A allele. In addition, interactions between SLC1A1
and GRIN2B variants significantly elevated the risk of OCS in
this sample. This study is difficult to interpret, however, as
polymorphic variants in these genes may play a role in risk of
OCD generally, and so might be expected to show association
with development of OCS in individuals with schizophrenia
regardless of treatment. Nevertheless, more studies examining
the de novo and exacerbated OCS/OCD subtypes are required
to further elucidate the effects of clozapine.
Clozapine Effects on OCS General Prevalence and Severity
Studies have also documented the effects of clozapine on gen-
eral estimates of OCS prevalence and severity. Sa et al. [48]
examined these correlates by comparing treatment effects of
Curr Psychiatry Rep (2014) 16:510
clozapine versus haloperidol among 60 schizophrenic patients.
Higher rates of clinically significant OCD were reported among
clozapine cases, but haloperidol-treated patients had a greater
incidence of OCS. However, neither finding reached signifi-
cance possibly due to the relatively low sample size. Results
also showed that significantly greater OCS severity was associ-
ated with clozapine use compared to haloperidol. Ongur and
Goff (2005) [50] identified similar associations by characteriz-
ing treatment profiles in patients divided according to OCS
severity. Results showed that patients with severe compulsive
symptoms were more likely to be treated with clozapine and/or
olanzapine than patients without any OCS.
Schirmbeck et al. [57] expanded the number of treatment
comparisons by examining the effects of clozapine and
olanzapine (group I) relative to aripiprazole and amisulpride
(group II) on SGA-induced OCS in a group of 70 patients.
Clozapine cases predominated in group I at a rate of 66.7 %.
Results showed that OCS prevalence and severity were sig-
nificantly higher within group I compared to group II.
Clozapine-treated patients also had more pronounced control-
ling and checking behaviors compared to olanzapine cases.
Schirmbeck et al. [131•] subsequently modified study param-
eters to include a 12-month longitudinal design, and still
found comparable results. At baseline, OCS prevalence and
severity was higher in group I than group II, as was the
severity of obsessions and compulsions, separately. The same
pattern of findings was found after 12 months, in addition to a
trend toward persisting or worsened OCS in group I relative to
baseline. These results suggest that Schirmbeck et al. not only
found evidence of the effects of clozapine to induce OCS but
also its propensity to maintain and/or worsen OCS over time.
Scheltema Bedouin et al. [53] also conducted treatment
comparisons but examined schizophrenic patients receiving
clozapine, olanzapine, risperidone or no treatment, and includ-
ed two additional psychiatrically healthy comparison arms
which separately involved controls and siblings. OCS preva-
lence was higher in patients compared to controls or siblings.
OCS prevalence was also highest within the clozapine group
Table 2 Effects of clozapine, olanzapine, and risperidone on OCS in schizophrenia

Reference Treatment Study population Study design OCS outcomes

Doyle et al. (2014) [130•]
Cai et al. (2013) [65•]
CLZ (n=62) n=97 outpatients Cross-sectional, Observational, 22 % of CLZ-treated SCZ patients had clinically
SCZ (n=62) Stratification by diagnosis significant OCS: 3 % pre-treatment OCS,
OCD (n=35) 19 % de novo
58 males, 39 females CLZ dose not correlated with OCS severity
OCS in SCZ characterized by cognitive rather than
behavioralOCS compared to in OCD
CLZ n=250 outpatients Genetic, Greater frequency of GRIN2B rs890T in OCS-group
Curr Psychiatry Rep (2014) 16:510

Schirmbeck et al. (2013) [131•]
Grassi et al. (2013) [132]
Scheltema Bedouin et al. (2012) [53]
Schirmbeck et al. (2011) [57]
Sa et al. (2009) [48]
Mukhopadhaya et al. (2009) [54]
Van Nimwegen et al. (2008) [144]
Mahendran et al. (2007) [129]
SCZ Stratification by OCS status SLC1A1 and GRIN2B interact to increase risk of
121 males, 129 females OCS and increase OCS severity
Group I: n=75 outpatients Longitudinal, Higher OCS prevalence in Group I vs. II at baseline
CLZ (n=26), OLZ (n=15) SCZ (n=73) Naturalistic, Higher OCS severity in Group I vs. II
Group II: SZA (n=2) Stratification by treatment
APZ (n=18), AMS (n=16) 53 males, 22 females Persisting or worsened OCS in Group I over timeNS
CLZ (n=30) n=60 outpatients Cross-sectional, CLZ associated with higher prevalence and
Other APs (n=30) SCZ Naturalistic, severityNS of OCD compared to other SGA-
34 males, 26 females Stratification by treatment treated patients
CLZ (n=71) n=543 in/outpatients Cross-sectional, Higher OCS prevalence within treatment conditions
OLZ (n=196) SCZ (and related disorders) Naturalistic, vs. controls or siblings
RSP (n=149) 429 males, 114 females Stratification by treatment OCS prevalence: 38.9 % CLZ, 23.2 % RSP,
No AP (n=107) Control group (n=575 ) 20.1 % OLZ, 19.6 % No AP. NS severity
Sibling group (n=979) differences.
Higher OCS prevalence associated with longer
duration of CLZ but not OLZ or RSP treatment
Group I: n=70 outpatients Cross-sectional, Higher OCS prevalence and severity in Group I vs. II
CLZ (n=26), OLZ (n=13) SCZ (n=68) Naturalistic, OCS severity positively correlated with CLZ dose
Group II: SZA (n=2) Stratification by treatment and duration but not serum levels
APZ (n=16), AMS (n=15) 50 males, 20 females
OCS severity did not correlate with OLZ duration,
dose or serum levels
CLZ (n=40) n=60 outpatients Cross-sectional, Naturalistic, Higher OCD prevalence in CLZ vs. HALNS
HAL (n=20) SCZ Stratification by treatment Higher OCS prevalence in HAL vs. CLZNS
45 males, 15 females
Higher OCS severity with CLZ vs. HAL
CLZ n=59 outpatients Cross-sectional, Naturalistic, Higher CLZ dose among OCS comorbid vs.
SCZ (n=56) Stratification by OCS status non-comorbid patientsNS
SZA (n=3)
37 males, 22 females
OLZ (n=59) n=122 in/outpatients Randomized, Greater decline in OCS severity in OLZ vs.
(5, 10, 15, 20 mg) SCZ (n=110) Double-blind, RSP treated patients
RSP (n=63) SZA (n=5) Stratification by treatment
(1.25, 2.5, 3.75, 5 mg) SZP (n=7)
111 males, 11 females
CLZ, OLZ, n=303 outpatients Retrospective, De novo OCS in 3 % of all SGA-treated patients
RSP, QUET SCZ, SZA Cross-sectional,
Page 7 of 17, 510
Table 2 (continued)

Reference Treatment Study population Study design OCS outcomes

180 males, 123 females Stratification by treatment De novo cases: CLZ accounted for 22 %, OLZ
for 44 %, and RSP for 33 %
510, Page 8 of 17

Lim et al. (2007) [128] CLZ (n=75), OLZ (n=27) n=209 outpatients Cross-sectional , Naturalistic, De novo OCS: 26.7 % for CLZ, 11.1 % for OLZ,
APZ (n=10), AMS (n=17) SCZ (n=198) Stratification by treatment and 3.4 % for RSP
RSP (n=59), QUET (n=2) SZA (n=11)
ZPR (n=19)
Lin et al. (2006) [126] CLZ n=102 outpatients Retrospective, Naturalistic, OCS in 38.2 % of total sample: 28.4 % de novo OCS
SCZ Stratification by OCS status vs.9.8 % exacerbated OCS
59 males, 43 females Higher plasma CLZ and norclozapine among OCS
comorbid vs. non-comorbid patients
Longer CLZ treatment duration among OCS comorbid
vs. non-comorbid patients
Ertugrul et al. (2005) [127] CLZ n=50 outpatients Cross-sectional, OCS in 76 % of total sample: 20 % de novo OCS
SCZ Naturalistic, vs.18 % exacerbated OCS
28 males, 22 females Stratification by OCS status No association between OCS and CLZ
dose or duration
Ongur and Goff (2005) [50] CLZ n=118 outpatients Cross-sectional, Higher rate of CLZ/OLZ treatment among
OLZ SCZ, SZA Naturalistic, severe compulsions vs. symptom-free patients
Any AP 89 males, 29 females Stratification by treatment
De Haan et al. (2004) [115] CLZ n=200 Chart Analysis, 9.8 % of CLZ patients developed de novo OCD
Other AP SCZ (n=152) Naturalistic, CLZ reduced pre-treatment OCD to sub-threshold
SZA (n=36) Stratification by treatment levels
SZP (n=12)
158 males, 42 females
Veznedaroglu et al. (2003) [154] RSP n=40 Single Blind, RSP decreased OCS severity over two months
SCZ Prospective
Drop-Out (n=4)
20 males, 16 females
De Haan et al. (2002) [143] OLZ (n=63) n=113 inpatients Longitudinal, Higher OCS severity at baselineNS and week 6 for
RSP (n=43) Excluded (n=7) Naturalistic, OLZ vs. RSP
SCZ (n=97) Stratification by treatment Higher OCD incidence at week 6 for OLZ vs. RSP
SZA (n=9)
Higher OCS severity associated with longer OLZ
SZP (n=7)
duration
92 males, 21 females
De Haan et al. (1999) [113] CLZ n=121 Retrospective, Higher onset and exacerbation of obsessions in CLZ-
Other APs Recent-onset SCZ or related disorder Cohort, treated vs. other AP-treated patients
Stratification by treatment
Baker et al. (1996) [145] OLZ 1 mg (n=11) n=25 Double-blind, NS difference between OLZ vs. placebo on OCS
OLZ 10 mg (n=7) SCZ Stratification by treatment
Placebo (n=7)

NS=result not statistically significant at p<0.05

CLZ=clozapine, OLZ=olanzapine, APZ=aripiprazole, AMS=amisulpride, RSP=risperidone, QUET=quetiapine, ZPR=ziprasidone, HAL=haloperidol, AP=antipsychotic, SCZ=schizophrenia,
SZA=schizoaffective disorder, SZP=schizophreniform disorder, OCD=obsessive-compulsive disorder, OCS=obsessive-compulsive symptoms
Curr Psychiatry Rep (2014) 16:510
Curr Psychiatry Rep (2014) 16:510
(38.9 %) compared to risperidone (23.2 %), olanzapine
(20.1 %), or no treatment (19.6 %). OCS severity did not
significantly differ between treatment groups, a finding which
contrasts with previous studies. Grassi et al. [132] conducted
further SGA treatment comparison among 60 schizophrenic
patients. In the total sample where 26.6 % of patients met
criteria for OCD, patients treated with clozapine had a trend
toward a higher prevalence and severity of OCD compared to
other SGA-treated patients. This prevalence difference be-
came significant after controlling for duration of illness, dura-
tion of antipsychotic treatment, use of antidepressant medica-
tion, and schizophrenic symptom severity. Similar findings
have been observed within recent-onset schizophrenia after
De Haan et al. [113] reported greater obsessional symptom
onset and exacerbation among clozapine-treated patients rel-
ative to patients treated with other antipsychotics. These ob-
served differences in OCS severity across studies may be a
partial consequence of genetic variability between subjects.
Cai et al. [20] showed that the AA genotype at SLC1A1
rs2228622 and TT genotype at GRIN2B rs890 interacted
within clozapine-treated schizophrenic patients to predict
greater OCS severity compared to patients that had any other
genotypic combination at these loci. Nevertheless, overall
trends suggest that clozapine may have more potent OCS
effects as compared to other antipsychotics.
Effects of Clozapine Treatment Duration on OCS
Scheltema Bedouin et al. [53] examined the effects of cloza-
pine treatment duration on OCS finding a significantly higher
OCS prevalence among patients treated for >6 months versus
<6 months. Lin et al. [126] also observed significantly longer
clozapine treatment length in OCS-comorbid versus non-
comorbid schizophrenic cases. However, Ertugrul et al.
[127] did not find any association between these variables.
Treatment duration has also been found to positively correlate
with OCS severity, as observed by Schirmbeck et al. [57].
Overall, results suggest that prolonged clozapine use may be
associated with greater OCS prevalence and severity, but
further investigations are warranted.
Effects of Clozapine Dose and Serum Levels on OCS
Lin et al. [126] examined the association between OCS and
plasma concentrations of clozapine and its metabolites
norclozapine and clozapine-N-oxide. Results showed greater
plasma concentrations of clozapine and norclozapine in OCS-
comorbid versus non-comorbid cases. No significant differ-
ence was observed for clozapine-N-oxide. These findings
occurred despite similar dosing between groups. Similar in-
vestigations were completed by Schirmbeck et al. [57] but in
regards to OCS severity. Results showed that OCS severity
was correlated with clozapine dose but not serum levels.
Page 9 of 17, 510
However, Mukhopadhaya et al. [54], Ertugrul et al. [127],
and Doyle et al. [130•] did not find an association between
clozapine dose and OCS. Study outcomes suggest that cloza-
pine dose may not be directly related to OCS prevalence or
severity. Instead, effects may be indirectly mediated through
differences in rates of clozapine metabolism.
Olanzapine-induced OCS in Schizophrenia
As with clozapine, case reports provide insight into the effects
of olanzapine therapy on de novo [133, 134] and worsened
[133, 135, 136] OCS, with some reports documenting
olanzapine-induced OCD [136–138]. However, some studies
also report therapeutic benefits of adjunctive olanzapine ther-
apy in OCS reduction among treatment refractory OCD pa-
tients [139–142] and even among schizophrenia patients with
OCS [105].
Effects of Olanzapine Treatment on OCS Prevalence
and Severity
As mentioned previously, Schirmbeck et al. [57] investigated
the combined effects of olanzapine and clozapine (group I) on
OCS as compared to aripiprazole and amisulpride (group II).
Although olanzapine cases comprised only one third (33.3 %)
of group I, results showed that OCS prevalence and severity
were significantly higher in group I over group II. Similar
observations were reported in the aforementioned studies by
Schirmbeck et al. [131•] and Ongur and Goff [50]. However,
due to mixed treatment conditions, it is possible that these
findings are primarily driven by the effects of clozapine. Thus,
to more clearly discern the role of olanzapine, treatment-
stratified analyses are required.
In studies that have individually assessed the effects of
olanzapine (refer to Table 2), prevalence estimates of OCS
have been identified as ranging between 11 % and 20 %,
according to Lim et al. [128] and Scheltema Bedouin et al.
[53]. OCS severity outcomes have been variable. De Haan
et al. [143] assessed this clinical correlate in adolescent in-
patients who were already treated with or randomized to
treatment with olanzapine or risperidone. Results showed that
OCS severity did not differ between SGAs among the subset
of patients that were randomly assigned or switched to SGA
treatment. However, among the subset of patients that main-
tained use of their initial SGA, the olanzapine group showed a
trend toward higher OCS severity than the risperidone group
at baseline, with a significant difference emerging after
6 weeks. At week 6, the incidence of OCD was also higher
among olanzapine-treated versus risperidone-treated patients.
These results indicate that olanzapine may have a stronger
510, Page 10 of 17
long-term propensity to induce OCS compared to in the short-
term.
Despite similar study parameters, these results differ from
those of Van Nimwegen et al. [144] after longitudinally ex-
amining OCS severity in adolescents treated with olanzapine
or risperidone over 6 weeks. Results showed that olanzapine
significantly reduced OCS severity compared to risperidone
over the study duration. In contrast, Baker et al. [145] did not
find any effects of olanzapine on OCS after conducting a 6 week,
double-blind, placebo-controlled trial. Although olanzapine ap-
pears to play some role in mediating OCS outcomes, the
direction of these effects require further investigation.
Effects of Olanzapine Treatment Duration on OCS
De Haan et al. [143] found that duration of olanzapine treat-
ment was associated with OCS severity. Results showed that
patients treated >12 weeks had significantly greater OCS
severity relative to patients treated for <12 weeks. However,
Schirmbeck et al. [57] and Scheltema Bedouin et al. [53] did
not observe any associations between length of olanzapine
treatment and OCS severity or prevalence, respectively.
Effects of Olanzapine Dose and Serum Levels on OCS
Only Schirmbeck et al. [57] examined the effects of
olanzapine dose and serum levels on OCS severity and ob-
served no correlation. Additional investigations are required
to more clearly elucidate the effects of these treatment vari-
ables on OCS during olanzapine therapy.
Risperidone-induced OCS in Schizophrenia
Risperidone has been highly studied within the descriptive
literature, with multiple case reports documenting its effects
on OCS outcomes. In particular, evidence suggests that ad-
ministration of risperidone therapy is associated with de novo
onset and exacerbation of OCS in schizophrenia [64,
146–149], with a demonstrated relationship between OCS
severity and increasing risperidone dose [150]. OCS induced
by risperidone is responsive to treatment with anti-obsessional
agents like sertraline and clomipramine [147, 150]. In con-
trast, risperidone has also been recommended as successful
augmentation therapy for refractory OCD [102, 151], with the
magnitude of efficacy influenced by symptom subtypes and
comorbid conditions [152]. Further evidence describes risper-
idone as a first-line treatment for severe OCD in patients
requiring a faster therapeutic response than typically observed
during traditional SSRI therapy [153].
Few experimental studies have examined risperidone-
induced OCS (refer to Table 2), with limited information
Curr Psychiatry Rep (2014) 16:510
available on the effects of dose, duration and serum levels.
However, studies previously described within this review
have provided some insight. Scheltema Bedouin et al. [53]
identified an OCS prevalence rate of 23.2 % among 149
risperidone-treated patients, and found that treatment duration
was not associated with OCS prevalence. Lim et al. [128]
reported a 3.4 % de novo OCS prevalence rate among risper-
idone treated patients, and Mahendran et al. [129] showed that
risperidone accounted for 33 % of all SGA-induced OCS. Van
Nimwegen et al. [144] also found that risperidone led to
increased OCS severity compared to olanzapine. Conversely,
De Haan et al. [143] found the reverse relationship, where
lower OCS prevalence and severity was observed among
patients treated with risperidone compared to olanzapine.
Similar findings were documented by Veznedaroglu et al.
[154] after finding a significant decrease in OCS severity over
two months of risperidone treatment in schizophrenia. Over-
all, experimental evidence on risperidone-induced OCS in
schizophrenia is mixed and these differences may reflect dose
effects, as observed within case reports. Therefore, future
research should strive to identify the role of such treatment
parameters in this drug-induced phenotype.
Other SGA-induced OCS in Schizophrenia
There is limited information on the effects of other SGAs on
OCS within schizophrenia, with the majority of findings re-
stricted to descriptive studies. Despite reports of inducing de
novo OCS in some patients [155], aripiprazole has been
frequently characterized as a low risk drug for OCS, and in
fact, has been frequently shown to improve OCS when ad-
ministered as an adjunctive treatment in schizophrenia [98,
100, 110, 156]. The same outcome was observed within an
experimental paradigm tested by Glick et al. [157], with
additional support derived from the previously described
works of Schirmbeck et al. [57, 131•]. In fact, Lim et al.
[128] observed that patients treated with aripiprazole did not
develop any OCS, as did none of the patients receiving
amisulpride, quetiapine or ziprasidone. However, a case report
by Kim et al. [158] documented the de novo development of
OCS after sequential treatment with aripiprazole and
ziprasidone. This same case also reported improvements in
OCS subsequent to switching to amisulpride. Furthermore,
the role of quetiapine in SGA-induced OCS is unclear as some
case reports describe its capacity to induce and exacerbate
OCS in schizophrenic patients [159–163] while others note its
therapeutic benefits within refractory OCD in some [161, 164,
165] but not all cases [166, 167]. Case reports have also
documented the capacity of paliperidone to improve
treatment-resistant OCS in schizophrenia [168], and
clothiapine to induce de novo compulsive symptoms [169].
Curr Psychiatry Rep (2014) 16:510
Discussion
Clinical Implications
A review of the experimental literature provides evidence of
the role of both olanzapine and, more robustly, clozapine in the
induction and worsening of OCS in schizophrenia. This review
also suggests that other antiserotonergic SGAs may be in-
volved in mediating OCS but their exact effects have yet to
be clearly determined. In fact, where most SGAs have been
conversely implicated in improving OCS in treatment-
refractory OCD, such reports are underreported among cloza-
pine cases [102, 151, 170]. Although antipsychotics can offer
symptomatic relief for patients diagnosed with schizophrenia,
these benefits may be offset by SGA-induced OCS. This
comorbidity may not only worsen prognostic outcomes, as
evidenced in this review, but can affect medication compli-
ance. It is therefore of critical importance that clinicians are
trained to recognize a broad spectrum of comorbid clinical
phenotypes and discern OCS from pure psychotic behaviors.
Moreover, routine monitoring of patients receiving SGA treat-
ment, particularly clozapine and olanzapine, for new onset or
worsened OCS should be incorporated into regular clinical
practice. OCS monitoring is important throughout the full
course of treatment, even among chronic schizophrenia pa-
tients, as SGA-induced OCS can worsen over time. Where
OCS occur, patients should have treatment modified to either
include an antipsychotic with a lower 5HT2 binding affinity or,
failing which, any adjunctive antidepressant that has shown
clinical efficacy in reducing OCS without further exacerbating
psychotic symptoms (e.g., fluvoxamine) [146, 171, 172].
Limitations
Methodological limitations of the reviewed literature restrict
the numbers of conclusions that can be drawn at the present
time. Due to the naturalistic and cross-sectional study design
used across most of the included studies, the following issues
should be addressed: (a) use of concomitant medications,
including multiple antipsychotics and/or antidepressants,
may have confounded the results, especially through suppres-
sion of potential OCS outcomes in cases of adjunctive SSRIs;
(b) since clozapine is routinely prescribed among treatment-
refractory patients, higher rates of OCS severity, in some
cases, may be a result of more impaired baseline psychopa-
thology than the treatment itself; (c) retrospective assessments
of OCS onset and pre-treatment symptom levels may be
subject to biased or inaccurate recall; and (d) in the absence
of longitudinal data collection, true inferences on causality
cannot be made. Despite these limitations, current experimen-
tal investigations have provided preliminary evidence on the
role of SGAs, particularly olanzapine and clozapine, in the
induction and worsening of OCS outcomes in schizophrenia.
Page 11 of 17, 510
However, to more clearly elucidate the exact role of these
agents, further research that takes these methodological limi-
tations into consideration is warranted.
Future Directions
Future studies would benefit from prospective monitoring of
OCS across time points from the start of SGA therapy. In cases
where multiple drugs are being examined, patients should be
randomized to treatment in accordance with a double-blind
design. Experimental parameters should include fixed SGA
dose and duration, where permitted, in addition to routine drug
level testing to confirm medication compliance. Serum level
quantification of drug metabolites would also permit investiga-
tions of drug serum effects on OCS. Patients should be excluded
in the event they are taking concomitant mediations, particularly
SSRIs, or should have medications tapered off and discontinued
during a minimum 2-week washout period prior to the study.
This would allow for more accurate assessments of drug-
emergent OCS outcomes and permit inferences of causality.
As mentioned previously, the clinical phenotype of SGA-
induced OCS may be under partial genetic control, according
to the results of genetic studies. To date, variations in the genes
encoding DLGAP3, SLC1A1, and GRIN2B have been impli-
cated in drug-induced OCS outcomes [65•, 70, 71]. In con-
sidering this, it may be promising to expand genetic investi-
gations to include additional variants implicated in the risk of
OCD (refer to Pauls et al. [68]). An interesting candidate is the
5HT2A gene, where variants such as C516T [173], G1438A
[174], T102C, and His452Tyr [175] have been implicated in
OCD risk and/or therapeutic response to clozapine. The Ser9Gly
polymorphism of DRD3, a gene implicated in risk for OCD, has
also been associated with response to SGAs including clozapine
and olanzapine [176]. Finally, information from this review
highlighted the potential effects of drug metabolism on OCS
outcomes. In considering that differences in drug metabolism
can, in fact, create variability in medication response [177–180],
investigations of genes encoding antipsychotic-metabolizing
enzymes, like the cytochrome P450 enzyme CYP2D6, may
inform how SGAs yield variable OCS outcomes. Overall, it
may be advantageous to genotype additional polymorphisms in
all of these gene regions to identify gene-wide effects, and/or
conduct a hypothesis-free GWAS. Additionally, it may be infor-
mative to combine genetic research with neuroimaging data,
particularly functional imaging and magnetic resonance spec-
troscopy, which can provide insight into the neurobiological
mechanisms involved in SGA-induced OCS.
Conclusions
Experimental studies, although limited, suggest that clozapine
confers the greatest risk of OCS in schizophrenia, with 20 to
510, Page 12 of 17
28 % of clozapine-treated patients experiencing de novo OCS,
in addition to 10 to 18 % incurring an exacerbation of pre-
existing OCS. Clozapine can also yield full threshold OCD, in
some cases. Olanzapine is another high risk drug for second-
ary OCS which occurs in 11 to 20 % of olanzapine-treated
patients. At this time, there is insufficient experimental evi-
dence to characterize the effects of other SGAs on OCS.
Despite some experimental support for the involvement of
longer treatment duration and genetic factors in mediating
drug-induced OCS, more research is needed to clearly eluci-
date these associations. Based on these results, routine OCS
monitoring and treatment modifications should be available
for patients throughout the course of SGA treatment, particu-
larly when administered clozapine or olanzapine. Future re-
search in functional neuroimaging and pharmacogenetics may
uncover functional pathways that can be exploited to mitigate
SGA-induced OCS effects while preserving intended treat-
ment benefits. This is of high clinical importance considering
that clozapine is the only existing pharmacotherapy that ex-
hibits superior therapeutic efficacy over other SGAs in
treatment-resistant schizophrenia, and may thus be the only
available treatment for reducing psychosis in some patients.
Compliance with Ethics Guidelines
Conflict of Interest Trehani M. Fonseka and Daniel J. Müller declare
that they have no conflict of interest. Daniel J. Müller hase received
frunding from the Canadian Institutes of Health Research (CIHR), the
Brain & Behaviour Research Foundation (USA), the Ontario Mental
Health Foundation (Canada), and the Ministry of Research and Innova-
tion of Ontario (Canada).
Margaret A. Richter has received grants from the Ontario Mental
Health Foundation, Canadian Institutes of Health Research and honoraria
payments from Lundbeck.
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
of the authors.
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