Received: 8 December 2022 Revised: 21 April 2023 Accepted: 30 April 2023

DOI: 10.1111/acps.13567

ORIGINAL ARTICLE

Antipsychotics and obsessive–compulsive

disorder/obsessive–compulsive symptoms:
A pharmacovigilance study of the FDA adverse
event reporting system

Bradley G. Burk 1 | Tilyn DiGiacomo 2 | Shea Polancich 3,4 |

Brandon S. Pruett 5,6 | Soumya Sivaraman 5,6 | Badari Birur 5,6

1
Department of Pharmacy, University of
Alabama at Birmingham Medical Center,
Birmingham, Alabama, USA
2
McWhorter School of Pharmacy, Samford
University, Birmingham, Alabama, USA
3
Department of Nursing, University of
Alabama at Birmingham Medical Center,
Birmingham, Alabama, USA
4
School of Nursing, University of Alabama
at Birmingham, Birmingham,
Alabama, USA
5 adverse drug reactions (ADRs) including OCD/OCS was obtained. The infor-
Department of Psychiatry, University of
Alabama at Birmingham Medical Center,
Birmingham, Alabama, USA
6
Department of Psychiatry and Behavioral
Neurobiology, University of Alabama at
Birmingham Heersink School of
Medicine, Birmingham, Alabama, USA
Correspondence
Bradley G. Burk, Department of
Pharmacy, University of Alabama at
Birmingham Medical Center, JT 1728,
619 19th Street South, Birmingham,
AL 35249, USA.
Email: bradleyburk@uabmc.edu
Abstract
Objective: Antipsychotics have conflicting data with respect to obsessive–
compulsive disorder/symptoms (OCD/OCS), with some reporting causality
and some reporting treatment benefits. This pharmacovigilance study aimed to
investigate reporting of OCD/OCS in association with the use of antipsychotics
in comparison to one another, as well as treatment failure using data derived
from the FDA Adverse Event Reporting System (FAERS).
Methods: Data from January 1st, 2010 to December 31st, 2020 on suspected
mation component (IC) was used to determine a disproportionality signal, and
reporting odds ratio (ROR) calculations were performed via intra-class ana-
lyses to discern differences between the evaluated antipsychotics.
Results: A total of 1454 OCD/OCS cases were utilized in IC and ROR calcula-
tions and 385,972 suspected ADRs were used as non-cases. A significant dis-
proportionality signal was seen with all second generation antipsychotics.
Relative to other antipsychotics, only aripiprazole had a significant ROR of
23.87 (95% CI: 21.01–27.13; p < 0.0001). The ROR for antipsychotic treatment
failure in those with OCD/OCS was highest with aripiprazole, and lowest with
risperidone and quetiapine. Sensitivity analyses were largely in favor of the pri-
mary findings. Our analysis appears to implicate the 5-HT1A receptor or an
imbalance between this receptor and the D2-receptor in antipsychotic
treatment-emergent OCD/OCS.
Conclusions: In contrast to prior reports noting clozapine as the antipsychotic
most commonly associated with de novo or exacerbated OCD/OCS, this phar-
macovigilance study found aripiprazole was most frequently reported for this
adverse effect. While these findings from FAERS offer a unique perspective on
OCD/OCS with different antipsychotic agents, due to the inherent limitations

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided
the original work is properly cited.
© 2023 The Authors. Acta Psychiatrica Scandinavica published by John Wiley & Sons Ltd.

Acta Psychiatr Scand. 2023;1–15. wileyonlinelibrary.com/journal/acps 1


2 BURK ET AL.
of pharmacovigilance studies they should ideally be validated through alterna-
tive prospective research studies involving direct comparisons of antipsychotic
agents.
KEYWORDS
antipsychotic, FDA adverse event reporting system, obsessive–compulsive disorder,
pharmacovigilance, reporting odds ratio
1 | INTRODUCTION
Obsessive–compulsive disorder (OCD) is characterized by
recurrent, intrusive thoughts neutralized only by rou-
tinely performing a behavior in response to the urge.1
These obsessive or compulsive symptoms gravely impair
an individuals' ability to function. The prevalence rate of
OCD is around 2%–3%. Obsessive and/or compulsive
symptoms (OCS), while characterized by the same symp-
toms as OCD, are subsyndromal, implying a lower level
of severity as compared to OCD.2 Pathophysiologically
OCD appears complex, with some research supporting
anomalies in the dopaminergic, serotonergic, and even
glutamatergic systems, possibly within the orbitofrontal
cortex, prefrontal cortex, cortico-striato-thalamo-cortical
(CSTC) pathways, reward circuit, and the limbic
regions.3–7 Neuroimaging findings also point to the CSTC
model by demonstrating hyperactivity in the prefrontal
cortex (primarily orbitofrontal cortex), anterior cingulate
cortex and caudate nucleus. Emerging imaging findings
have shown involvement of widespread associative net-
works including parietal cortex areas, limbic areas and
cerebellum.8 Dysfunction in these aforementioned areas
of the brain may lead to over-valuation of ideas with
inhibited behavioral control.
Even though prolonged administration of selective
serotonin reuptake intake inhibitors (SSRIs) is the most
effective psychopharmacological treatment of OCD,
around 40%–60% of patients fail to satisfactorily respond to
monotherapy with serotonergic drugs.9,10 The major focus
of studies on refractory OCD have emphasized the study
of psychotropic medications as adjuncts. Refractory OCD
can be addressed with different approaches including a
switch to another SSRI or clomipramine, or augmentation
with a second- or first-generation antipsychotic.9
Aripiprazole, haloperidol, and risperidone have all
shown positive results on refractory OCD as adjuvants.
The evidence is less promising with regards to quetia-
pine, olanzapine, and paliperidone.11–14 Interestingly,
despite the apparent benefit of some antipsychotics in the
treatment of refractory OCD, some antipsychotics such as
clozapine and olanzapine have classically been thought
to worsen or induce OCD or OCS, based on the large
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Significant outcomes
• OCD was reported more frequently with aripi-
prazole than with any other antipsychotic eval-
uated including those like clozapine, which
have historically been considered to be at
greatest risk for this adverse effect.
• Risperidone, paliperidone, and haloperidol had
the lowest reporting of de novo or exacerbated
OCD/OCS, while risperidone and quetiapine
had the lowest reporting of failure when used
for OCD/OCS.
• Spearman's correlation depicted a significant
strength of association for OCD/OCS with the
5-HT1A receptor as well as the 5-HT1A/D2
receptor ratio.
Limitations
• Disproportionality studies using voluntarily
reported data have inherent issues, including
reporting biases or under-reporting.
• Misclassification of OCD for alternative diag-
noses, including impulse control disorders,
may have skewed analysis.
• We did not evaluate the dose of antipsychotic
as it relates to the reporting of de-novo or exac-
erbated OCD/OCS.
number of published cases in comparison to other anti-
psychotics.15 The prevalence of developing de novo OCS
or experiencing an exacerbation of OCS secondary to clo-
zapine was estimated at 20%–28% and 10%–18%, respec-
tively.15 While other antipsychotics have published
reports on presumed OCD/OCS causality, it remains
unclear if specific agents are truly more highly correlated
with this adverse drug reaction (ADR). Although the
mechanism underlying antipsychotic-related OCD/OCS
ADRs is unclear, one possibility is that since serotonin
and dopamine often counterbalance one another through
feedback mechanisms, any inhibition of serotonin or

BURK ET AL.
serotonergic receptors, as seen with depression or
through use of certain antipsychotic medications, may
elicit OCD symptoms, perhaps through upregulation of
dopamine. Still, because OCD/OCS are frequently comor-
bid with conditions like schizophrenia and other mood
disorders treated with antipsychotics, it is important to
rule out iatrogenic causes to ensure harm reduction.16
Because of the seemingly rare occurrence of
OCD/OCS ADRs and the lack of primary clinical trial
data related to these symptoms, it is difficult to compare
the relative risk of treatment-emergent OCD/OCS with
regard to individual antipsychotics. This is where post-
marketing data may prove useful in determining a
disproportionality signal for potential correlation with
specific antipsychotic agents, and provide evidence for a
potential iatrogenic cause of de novo OCD/OCS. In this
pharmacovigilance study, we examined the signal of asso-
ciation of OCD/OCS among antipsychotic medications by
using reports to the Food and Drug Administration
Adverse Event Reporting System (FAERS) database to
calculate the Information Component (IC), a measure of
signal strength between a drug and an ADR. We also cal-
culated the reporting odds ratio (ROR) for all antipsy-
chotics reported to be associated with OCD/OCS in the
FAERS system, to discern any major differences between
the evaluated agents. The purpose of this study was to
evaluate pre-existing international data in order to pro-
vide directionality on OCD/OCS associated with antipsy-
chotics, laying the groundwork for future studies on this
topic.
2 | MATERIALS AND METHODS
2.1 | Data collection
All data were obtained from the FAERS Public Dashboard,
a worldwide pharmacovigilance database containing con-
sumer and clinician reported ADRs, which are voluntarily
reported.17 The FAERS Public Dashboard database utilizes
coding terms which adhere to the Medical Dictionary for
Regulatory Activities (MedDRA) per the International
Council for Harmonization (ICH).17 This database con-
tains 25 variables, including demographic, reporter, medi-
cation, adverse reaction, and outcome data. It is important
to note that reports to the FAERS system do not impute
causality. Further, it should be stated that information
within the FAERS system is not verified by a third party.
Any report to FAERS of [(“obsessive–compulsive disor-
der”) or (“obsessive–compulsive symptom”)] from January
1st, 2010 to December 31st, 2020 was queried, as well as
all reports of any ADR for the evaluated antipsychotics for
case/non-case analysis. These cases were downloaded, and
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3
the data were manipulated in Microsoft Excel®. All FDA-
approved antipsychotics found within FAERS with at least
1 report for OCD/OCS were included. From there, all
ADRs for the included antipsychotics of interest (i.e., those
having at least 1 report for OCD/OCS) were individually
queried for the same time period and downloaded into
Microsoft Excel®. For the purpose of this study we
excluded any other class of medications outside of antipsy-
chotics from analysis (e.g., amphetamines, antidepres-
sants, or antiepileptics), in order to examine specific
medication effects, as well as control for the effect of the
underlying disease state. In addition, only the primary sus-
pected antipsychotic was included in the analysis, to avoid
any influence from dual antipsychotic use. Lastly dedupli-
cation was performed manually based on strong case simi-
larities (e.g., patient age, sex, reaction terms, concomitant
product names, FDA received date all the same). When
duplicates were identified, one case was deleted from the
analysis.
2.2 | Statistical analysis
We utilized the IC to measure any disproportionality
between the observed number (NOBS) and expected number
(NEXP) of notifications for the drug-ADR combination.18
The IC analysis (IC = log2((NOBS + 0.5)/(NEXP + 0.5))) was
run across all FAERS ADR reports for the defined time
range correlated with the number of reports of OCD for
each antipsychotic for that same time range. A positive IC
value indicates a higher-than-expected reporting of the
ADR to FAERS. Safety signaling was calculated utilizing
the IC025, the lower threshold for statistical significance
with an IC025 greater than 0 being considered significant.
The quotient of the NOBS to the calculated NEXP, which is
also known as the relative reporting ratio (RRR), was com-
puted for any antipsychotic with a significant IC025 in
efforts to remove bias from reporting, such as historical bias
with older or newer antipsychotics that may be prescribed
less frequently (e.g., perphenazine and cariprazine, respec-
tively). The NEXP was computed using the equation
(NDRUG  NREACTION)/NTOTAL, where NDRUG is the num-
ber of notifications for the drug, regardless of the
ADR, NREACTION is the number of notifications for the
ADR, regardless of the drug, and NTOTAL is the total num-
ber of ADRs reported to FAERS over the examined time
period. The ROR and 95% confidence interval (CI) for each
antipsychotic with at least 1 report of OCD/OCS was calcu-
lated using the 2  2 contingency table ((A  D)/(B  C))
formulation (Figure 1) to determine if one specific antipsy-
chotic was more highly correlated with OCD/OCS than
another through drug-event pairing for intra-class analy-
sis.19 While the case threshold for calculating ROR is

4 BURK ET AL.
OCD Reported
Anpsychoc of Interest A C
All Other Anpsychocs B D
sometimes considered 3 reports, our threshold of 1 report
was used to reduce bias for less commonly used antipsy-
chotics, increase power of the analysis, and formulate a
more insightful opinion on first vs. second-generation anti-
psychotic OCD-reporting. The ROR provides information
on the odds of ADR occurrence with a medication relative
to reference medications. In our study, a ROR >1 suggested
OCD/OCS is more frequently reported with the drug of
interest versus the comparators (i.e., all other antipsy-
chotics of interest). All RORs with respective confidence
intervals and p-values were calculated using a free online
tool (https://www.medcalc.org/calc/odds_ratio.php), while
the IC and IC025 were computed in Microsoft Excel®.20,21
Any p-value <0.05 was considered significant.
Sensitivity analyses were performed post-hoc on the
primary outcome of ROR in order to account for factors
that may have potentially skewed our primary analysis.
This included analyzing the ROR in three separate ways:
(1) Without cases where non-implicated antipsychotics
were used concomitantly, (2) Exclusion of cases where
OCD may have been present at baseline, and (3) Exclu-
sion of an antipsychotic with an RRR an order of magni-
tude greater than any other antipsychotics. These
analyses helped to mitigate the risk of underlying disease
effects or alternative medication synergistic/antagonistic
interactions on the outcome.
2.3 | Antipsychotic treatment in OCD
Because antipsychotics have been utilized in the treat-
ment of OCD, or in the treatment of OCD comorbid with
other conditions, we simultaneously evaluated the ROR
and percent of failures with each primary suspected anti-
psychotic when used for OCD treatment. Here, the ROR
was again evaluated via intra-class analysis including
only the primary suspected medication. We queried all
ADRs for each antipsychotic of interest within the
FAERS system during the same timeframe as primary
analysis and subsequently searched for terminology con-
sistent with treatment failure or exacerbation. Therapeu-
tic failure was dictated by the reaction terms “obsessive–
compulsive symptom”, “obsessive–compulsive disorder”,
or “drug ineffective”, while exacerbation was dictated by
the reaction term “condition aggravated”, all when use
was listed for OCD treatment within FAERS. In order to
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OCD Not Reported F I G U R E 1 ROR calculation for
antipsychotics and OCD combination.
rule out the effects of other mental illnesses, ROR ana-
lyses for treatment failure were run including and exclud-
ing comorbidities. These data may be taken as a proxy
until more formal studies can be conducted on OCD
treatment with antipsychotics.
2.4 | Spearman correlation analysis of
antipsychotic-OCD mechanism
After RRR analysis was complete, we assessed the poten-
tial mechanism behind OCD secondary to antipsychotics
using Spearman correlation analysis. Human Ki data for
the most relevant receptors (5-HT1A, 5-HT2A, and D2) on
each antipsychotic of interest was compiled from the Psy-
choactive Drug Screening Program (PDSP) Ki Database.22
If multiple Ki values were reported, the values were
summed and divided by the total count to create the aver-
age Ki. The inverse of Ki (i.e., higher Ki value equals
higher affinity) was used for Spearman correlation analy-
sis against the RRR.
3 | RESULTS
Across all drugs, there were 16,388,063 total reports to the
FAERS for suspected ADRs between January 1st, 2010
and December 31st, 2020, and this was used to calculate
the NEXP and IC025 (Figure 2). In terms of OCD/OCS
reported ADRs, a total of 4506 were reported to FAERS
during the same evaluated period. Of the reported
OCD/OCS ADRs, antipsychotics were implicated in 2629
(58.3%) cases. After including only the primary suspected
antipsychotic and excluding duplicates (236 cases), a total
of 1454 reported OCD/OCS cases were found (Table 1)
and used in the primary analysis. The characteristics of
patients with OCD/OCS secondary to antipsychotics are
listed in Table 2. When looking at all other reported ADRs
for the evaluated antipsychotics after excluding OCD/OCS
cases a total of 385,972 ADRs were reported to the FAERS
during the same time period, and these were used as non-
cases. OCD/OCS constituted 0.4% of all antipsychotic
reports to FAERS during the evaluated time period.
Reports of antipsychotic treatment-emergent OCD/OCS
ranged from 0% of the total chlorpromazine reports to
2.1% of the total aripiprazole reports. Interestingly,
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BURK ET AL. 5

F I G U R E 2 Consort diagram for
antipsychotic-OCD FAERS data
inclusion/exclusion. *Deduplication was
performed manually based on strong
case similarities.
Total number of ADRs reported to FAERS between Jan. 1st,
2010 and Dec 31st, 2020
(n = 16,388,063)
Total number of ADRs (minus OCD/OCS cases) for the
evaluated anpsychocs reported to FAERS for the
same evaluated period (non-cases)
(n = 385,972)

Total number of OCD/OCS ADRs reported to Removal of reports for OCD/OCS with non-
FAERS for same evaluated period anpsychoc medicaons
(n = 4,506) (n = 1,877)

Removal of duplicate and dual

suspected primary implicated
Total number of reported medicaons
anpsychoc OCD/OCS ADRs (n = 1175)
(n = 2,629) x Duplicate reports (n = 236)*
x Dual primary suspected
anpsychocs (n = 939)

Total number of anpsychoc reports for

OCD/OCS used in IC and ROR calculaons
(n = 1,454)

T A B L E 1 Number of observed antipsychotic reports to FAERS with respective reporting odds ratio and information component
calculations.

Total number of OCD Total number of Total number OCD ROR

reports including OCD reports minus of ADRs for
duplicate and other duplicates and other antipsychotic
primary suspected primary suspected (minus OCD
Antipsychotic medications medications (NOBS)a reports) NEXP IC025 RRRb Value 95% CI
Aripiprazole 1535 1158 54,349 4.82 7.67 240.15 23.87 21.01–27.13
Asenapine 36 11 7058 0.63 2.33 17.57 0.41 0.23–0.74
Brexpiprazole 24 13 7453 0.66 2.6 19.66 0.46 0.27–0.79
Cariprazine 8 6 2381 0.21 1.78 28.4 0.67 0.30–1.49
Chlorpromazine 3 0 2935 0.26 10.93 N/A N/A N/A
Clozapine 231 72 61,088 5.42 3.22 13.28 0.28 0.22–0.35
Haloperidol 60 6 15,065 1.34 0.41 4.47 0.10 0.05–0.23
Loxapine 31 1 2353 0.21 2.7 N/A 0.11 0.02–0.79
Lurasidone 30 21 11,409 1.01 3.1 20.75 0.48 0.31–0.74
Olanzapine 180 49 38,503 3.42 3.19 14.34 0.31 0.24–0.42
Paliperidone 48 19 34,923 3.1 1.67 6.13 0.13 0.09–0.21
Perphenazine 28 2 697 0.06 0.44 N/A 0.76 0.19–3.05
Quetiapine 174 53 70,101 6.22 2.54 8.52 0.17 0.13–0.22
Risperidone 190 34 68,936 6.12 1.81 5.56 0.11 0.08–0.15
Ziprasidone 51 9 8721 0.77 1.76 11.63 0.27 0.14–0.52
Total 2629 1454 385,972 — — — — —

Note: Bolded value represents a statistically significant ROR/95% CI.

a
Includes concomitant medications not suspected to have caused OCD.
b
The relative reporting ratio (RRR) is the NOBS/NEXP.
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6 BURK ET AL.

T A B L E 2 Event characteristics as reported to FAERS for TABLE 2 (Continued)

evaluated antipsychotic-OCD ADRs.
Patients Percent
Patients Percent Characteristic (N = 1454) (%)
Characteristic (N = 1454) (%) Benzodiazepines 250
Age (avg.), y 41.8 Dopamine agonists (Anti- 27
<20 29 2 Parkinson's)
20–39 173 11.9 Mood stabilizers
40–59 226 15.5 Carbamazepine 24
≥60 49 3.4 Divalproex 63
Unknown 977 67.2 Lithium 45
Sex Oxcarbazepine 20
Female 621 42.7 Stimulants
Male 620 42.6 Amphetamine/ 34
Not specified 211 14.7 Dextroamphetamine/
Lisdexamfetamine
Severity
Methylphenidate 39
Non-serious 290 19.9
“Z-drugs” (Zolpidem, Eszopiclone, 68
Serious 1164 80.1 etc.)
Outcome
Abbreviations: ADR, adverse drug reaction; Avg, average;
Disabled 188 12.9 NaSSA, noradrenergic and specific serotonergic antidepressant;
Death 11 0.8 NDRI, norepinephrine dopamine reuptake inhibitor; OCD,
obsessive–compulsive disorder; SNRI, serotonin norepinephrine
Hospitalized 687 47.2 reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor;
Life threatening 14 1 TCA, tricyclic antidepressant.
a
Includes comorbid conditions.
Other 554 38.1
Reporter type
Consumer 1177 80.9
clozapine was on the lower end with OCD/OCS only
Healthcare professional 250 17.2
making up 0.12% of its total reported ADRs. Four first-
Not specified 27 1.9 generation antipsychotics were evaluated, and consti-
a
Indication for antipsychotic therapy tuted only 9 (0.59%) of the total primary antipsychotic
Anxiety 544 OCD/OCS cases. Of the second-generation antipsy-
Bipolar disorder 621 chotics, cariprazine comprised 6 (0.41%) cases, cloza-
pine comprised 72 (5%) cases, while aripiprazole
Major depression 720
represented 1158 (79.6%) cases.
Obsessive–compulsive disorder 159
With the exception of chlorpromazine, loxapine, and
Schizophrenia/Schizoaffective 335 perphenazine the IC025 was greater than 0 for all other
disorder
antipsychotics, indicating a significant disproportionality
Co-medication signal (Table 1). However, when comparing against all
None 901 62 other antipsychotics, the only antipsychotic with a signif-
1 76 5.2 icantly greater ROR for OCD/OCS was aripiprazole,
2 42 2.9 which had a ROR of 23.87 (95% CI: 21.01–27.13;
p < 0.0001). Similarly, aripiprazole had the largest RRR
≥3 435 29.9
for OCD/OCS reports of any antipsychotic evaluated,
Co-medication class/Agent
being an order of magnitude greater than the next near-
Antidepressants est antipsychotic, cariprazine. Apart from aripiprazole,
SSRI 267 the other two D2 partial agonists, cariprazine and brexpi-
SNRI 109 prazole, as well as lurasidone and asenapine, had the
NDRI 95 highest RRR for OCD/OCS reports while haloperidol, ris-
NaSSA 20 peridone, and paliperidone had the lowest (Table 1).
Given that the ROR and RRR for OCD/OCS were much
TCA 41
higher for aripiprazole relative to all other antipsychotics,
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BURK ET AL. 7

TABLE 3 Sensitivity analysesa excluding all concomitant medicationsb, baseline OCD diagnosisc, and aripiprazole.d

Sensitivity analysis 1 Sensitivity analysis 2 Sensitivity analysis 3

Total ROR Total ROR Total ROR

number of number of number of
OCD OCD OCD
Antipsychotic reportsb Value 95% CI reportsc Value 95% CI reportsd Value 95% CI
Aripiprazole 746 28.42 23.92–33.77 1036 21.16 18.47–24.23 — — —
Asenapine 4 0.16 0.06–0.43 10 0.28 0.15–0.53 11 1.79 0.98–3.27
Brexpiprazole 7 0.31 0.15–0.65 13 0.38 0.22–0.65 13 1.99 1.15–3.48
Cariprazine 2 0.23 0.06–0.93 5 0.42 0.17–1.0 6 2.83 1.28–6.25
Chlorpromazine 0 N/A N/A 0 N/A N/A 0 N/A N/A
Clozapine 33 0.13 0.09–0.18 65 0.19 0.15–0.25 72 1.32 1.08–1.62
Haloperidol 4 0.23 0.09–0.62 6 0.25 0.11–0.56 6 0.45 0.2–0.98
Loxapine 1 6.91 1.01–47.2 1 4.52 0.65–31.3 1 0.48 0.07–3.37
Lurasidone 16 0.44 0.27–0.73 18 0.34 0.21–0.54 21 2.06 1.37–3.12
Olanzapine 22 0.36 0.23–0.55 43 0.39 0.29–0.53 49 1.43 1.11–1.84
Paliperidone 11 0.1 0.06–0.19 17 0.13 0.08–0.2 19 0.61 0.39–0.94
Perphenazine 0 N/A N/A 0 N/A N/A 2 3.22 0.81–12.85
Quetiapine 22 0.21 0.14–0.33 43 0.21 0.16–0.29 53 0.85 0.66–1.08
Risperidone 25 0.11 0.07–0.16 30 0.12 0.08–0.17 34 0.55 0.4–0.76
Ziprasidone 8 0.41 0.21–0.83 8 0.28 0.14–0.55 9 1.16 0.61–2.2
Total 901 — — 1295 — — 296 — —

Note: Bolded value represents a statistically significant ROR/95% CI.

Abbreviations: ADR, adverse drug reaction; CI, confidence interval; N/A, not applicable; OCD, obsessive compulsive disorder; ROR, reporting odds ratio.
a
Each analysis excluded all duplicate reports and other primary suspected medications.
b
Sensitivity analysis 1: Total Number of OCD Reports Excluding Concomitant Medications correlated with Total Number of ADRs Excluding Concomitant
Medications (N = 154,588).
c
Sensitivity analysis 2: Total Number of OCD Reports Excluding Baseline OCD Diagnosis correlated with Total Number of ADRs for Antipsychotic Excluding
Baseline OCD Diagnosis (N = 221,099).
d
Sensitivity analysis 3: Total Number of OCD Reports Excluding Aripiprazole-OCD Reports correlated with Total Number of ADRs for Antipsychotics
Excluding All Aripiprazole ADRs (N = 324,850).

there was concern that it may be skewing or minimizing
the differences between the other antipsychotics. For this
reason, a sensitivity analysis was completed with aripipra-
zole excluded (Table 3). Overall, the results were largely
similar and consistent with the analysis that included aripi-
prazole though there were many more antipsychotics that
significantly separated from all other antipsychotics based
on the ROR for OCD/OCS, with brexpiprazole, cariprazine,
clozapine, lurasidone, and olanzapine having a signifi-
cantly higher ROR for OCD/OCS and haloperidol, paliperi-
done, and risperidone having a significantly lower ROR for
OCD/OCS. Additional sensitivity analyses included the
removal of concomitant medications and separately the
removal of baseline OCD diagnoses. Importantly, the ROR
results in these instances were predominantly in line with
the primary analysis wherein these factors were included
(Table 3).
We identified a total of 220 reports of primary anti-
psychotic use for OCD excluding other concomitant
suspected products and comorbid conditions (Table 4).
Of these cases, 31 (14.1%) were reported to be therapeutic
failures. The rates of therapeutic failure did not appear to
be different between the various antipsychotics, however
some medications were used more commonly than
others. When other comorbid conditions were included,
a total of 1234 cases of antipsychotic use for OCD were
found, and 248 failures were noted (20.1%). Here, thera-
peutic failure from aripiprazole use was noted 46.2% of
the time with a significantly increased ROR of 7.9 for
OCD treatment failure relative to all other antipsychotics
(Table 4). Of note, paliperidone, quetiapine, and risperi-
done all had a statistically significantly lower ROR of
OCD treatment failure relative to all other antipsychotics,
indicating a lesser likelihood of reports for treatment
failure.
Because of this large discrepancy with aripiprazole we
examined the specific reports of OCD/OCS with aripipra-
zole and also found an increased propensity for other
 8

TABLE 4 Number of reports to FAERS for primary medication use for OCD and treatment failure.a,b,c

Including comorbid conditions Excluding comorbid conditions

Number
Number (%) of (%) of
Number of reports for ROR of Number of reports for ROR of
reports for OCD OCD Fisher's reports for OCD OCD Fisher's
medication treatment treatment exact medication treatment treatment exact
Medication use for OCD failure failure 95% CI test (p) use for OCD failure failure 95% CI test ( p)
Aripiprazole 351 162 (46.2) 7.94 5.85–10.79 <0.0001 68 7 (10.3) 0.61 0.25–1.5 0.28
Asenapine 25 1 (4) 0.16 0.02–1.21 0.08 2 0 (0) 0 0.06–25.38 0.9
Brexpiprazole 31 2 (6.5) 0.27 0.06–1.13 0.07 7 0 (0) 0 0.02–6.93 0.52
Cariprazine 14 1 (7.1) 0.3 0.04–2.33 0.25 4 1 (25) 2.1 0.21–20.53 0.54
Chlorpromazine 0 0 (0) N/A N/A N/A 0 0 (0) N/A N/A N/A
Clozapine 69 9 (13) 0.58 0.28–1.19 0.14 8 2 (25) 2.1 0.41–10.93 0.38
Haloperidol 7 0 (0) 0 0–2.1 0.4 5 0 (0) 0 0.03–9.87 0.67
Loxapine 0 0 (0) N/A N/A N/A 0 0 (0) N/A N/A N/A
Lurasidone 24 5 (20.8) 1.05 0.39–2.83 0.93 5 2 (40) 4.28 0.68–26.7 0.12
Olanzapine 78 12 (15.4) 0.71 0.38–1.33 0.29 29 3 (10.3) 0.67 0.19–2.37 0.54
Paliperidone 42 3 (7.1) 0.31 0.09–0.99 0.05 8 1 (12.5) 0.87 0.1–7.3 0.89
Perphenazine 4 2 (50) 4 0.56–28.5 0.17 1 1 (100) ∞ 0.7-∞ 0.08
Quetiapine 177 21 (11.9) 0.49 0.31–0.79 0.004 20 4 (20) 1.6 0.5–5.15 0.43
Risperidone 363 24 (6.6) 0.2 0.13–0.32 <0.0001 51 8 (15.7) 1.18 0.49–2.83 0.71
Ziprasidone 49 6 (12.2) 0.54 0.23–1.29 0.17 12 2 (16.7) 1.23 0.26–5.92 0.79
Total 1234 248 (20.1) 220 31 (14.1)

Note: Bolded value represents a Fisher's exact test/95% CI.

a
Indication search included “obsessive–compulsive symptom” and “obsessive–compulsive disorder”.
b
Reaction search included “condition aggravated”, “drug ineffective”, or “obsessive–compulsive”.
c
All concomitant suspected products were excluded.
BURK ET AL.

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BURK ET AL.
reported compulsive/impulse control reactions.
OCD/OCS were co-reported with gambling disorder,
compulsive shopping, eating disorders, trichotillomania/
dermatillomania, and compulsive sexual behaviors 1090,
592, 367, 133, and 357 times, respectively. Further, to
investigate the potential impact of specific psychiatric dis-
orders on the rates of OCD/OCS cases, we evaluated the
total number of OCD/OCS cases with that diagnosis
(including and excluding comorbid disorders). As
depicted in Table 2, including comorbidities, where
OCD/OCS was reported with antipsychotic use (only pri-
mary suspected agent), depression, followed by bipolar
disorder, anxiety, then schizophrenia/schizoaffective dis-
order were the most common indications (comprising
720 (49.5%), 621 (42.7%), 544 (37.4%), and 335 (23%)
comorbidities, respectively). At baseline however, OCD
was reported in 104 of the 720 depression cases (14.4%),
93 of the 621 bipolar disorder cases (15%), 104 of the
544 anxiety cases (19.1%), and 48 of the 335 schizophre-
nia/schizoaffective disorder cases (14.3%). Using the RRR
as the correlative value against the inverse Ki affinity
values for the evaluated receptors (D2, 5-HT2A, and
5-HT1A) and receptor ratios (5-HT2A/D2 and 5-HT1A/D2),
Spearman's rank analysis identified a significant strength
of association for OCD/OCS reporting with stronger
5HT1A receptor affinity (rs = 0.77; p = 0.0008) as well as
the 5-HT1A/D2 receptor ratio (rs = 0.66; p = 0.008).22
None of the other correlations were significant.
4 | DISCUSSION
Our analysis of the FAERS reports points to disproportion-
ality safety signals for all examined second-generation
antipsychotics in the development of OCD/OCS, with
varying signal strengths, based on the IC025. By contrast,
most first-generation antipsychotics were not found to
have a disproportionality safety signal. Along with halo-
peridol, risperidone and paliperidone were associated with
low overall OCD/OCS reporting rates. Although the num-
ber of overall reports for brexpiprazole and cariprazine
were low, when evaluating the RRR our results demon-
strated that all three currently marketed D2 partial ago-
nists were among the top five agents for OCD/OCS
reporting. While clozapine has historically been presumed
to be the most likely antipsychotic to cause or exacerbate
OCD/OCS, the rates of reporting with clozapine in this
study were not dramatically higher than other second-
generation antipsychotics, being comparable to olanzapine
and quetiapine, and were far below that of aripiprazole.
Contrary to our findings, a study of 209 Korean patients
screened for OCS while on antipsychotics found 44 patients
(21.2%) displayed symptoms, most prevalently with
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9
clozapine and olanzapine (76.9% and 11.5%, respec-
tively).23 Exact percentages from specific medications can-
not be compared to our study, however, as OCD/OCS
incidence rates are not calculable from FAERS data.
A potential explanation for the beliefs surrounding cloza-
pine and OCD/OCS is the notoriety effect, wherein one
published ADR on a medication leads to accelerated report-
ing or recognition of the ADR for that medication. How-
ever, the notoriety bias did not appear to be a major factor
in the present study as it would have been expected to result
in higher rates of OCD/OCS reporting for clozapine within
FAERS. Thus, the fact that we did not identify clozapine as
the antipsychotic most associated with OCD/OCS may, in
fact, strengthen the findings of our study.
Compared with all other antipsychotics, only aripi-
prazole had a significantly higher ROR. However, we
found only 5 published case reports representing
6 patients, which identified aripiprazole as the likely
cause or exacerbation of OCD/OCS.24–28 In four cases,
including three females and one male, none of whom
had a history of OCD, all developed OCS while on 5–
15 mg/day of aripiprazole. Two of these four aripiprazole
cases described patients with schizophrenia and baseline
minor OCD symptoms, one who experienced a worsening
of OCS while on aripiprazole 10 mg/day but not while on
previously trialed clozapine or risperidone at doses of
400 and 8 mg/day, respectively.26 Further, when risperi-
done was re-initiated and aripiprazole was stopped the
patient's OCS improved. In the other case the patient suf-
fered intensifying of OCS when aripiprazole was titrated
to 30 mg/day that subsequently remitted when the medi-
cation was switched to sulpiride.21
As previously noted, OCD/OCS from aripiprazole was
commonly co-reported with gambling disorder, compul-
sive shopping, hyperphagia, and hypersexuality. In a sep-
arate study by Fusaroli et al., impulse control disorders
(ICD) from D2 partial agonists were similarly investigated
through the FAERS.29 Here, the authors found D2 partial
agonists constituted 2708 (23%) of the 11,629 total ICD
reports. Aripiprazole constituted 2545 of these reports
(94%) with the majority of time the indication for use was
a mood disorder, rather than a psychotic disorder. ICD
and OCD are often assumed to be highly comorbid due
to their similar etiology and symptom profile. Obsessive–
Compulsive and Related Disorders (OCRDs) represent a
spectrum of disorders with overlapping phenomenology
and symptomatology ranging from impulse control and
eating disorders to somatoform and neurological disor-
ders such as Tourette's syndrome. OCRD has a preva-
lence rate of up to 9.5% in the general population.30
However, 57.6% of those with OCD will additionally meet
criteria for another OCRD.31 One distinguishing feature
between ICD, tic disorder, and OCD may be whether the

10
compulsive/impulsive behavior is ego-syntonic or dys-
tonic. While compulsions are performed voluntarily in
both OCD and ICD/tic disorders, those with OCD are
performing compulsions in response to an ego-dystonic
obsession to avoid perceived bad consequences, whereas
those with ICD may sometimes, but not always, be per-
forming compulsions to satisfy an urge. Overall, the simi-
larities between these disorders may have led to
diagnostic confusion, increasing OCD reporting.
As it relates to schizophrenia, when OCD/OCS have
been reported, they occur in 40% of patients preceding
and in another 40% following psychosis onset, with the
remaining 20% reported concurrently.16 Additionally,
meta-analyses reveal that up to 12%–14% of schizophre-
nia patients meet DSM-5 criteria for OCD.16 Multiple
hypotheses have been formed surrounding the mecha-
nism of their overlap including neuropsychological
impairment, familial aggregation, and antipsychotic
use.16 Because of the high prevalence of OCD/OCS in
schizophrenia patients before initiation of antipsychotics
and the current gap in literature surrounding the often-
times multifactorial pathogenesis, correlation versus cau-
sation is difficult to discern. The overlap between
OCD/OCS in conjunction with bipolar disorder is much
more apparent, as the prevalence rate of comorbid OCD
in this population ranges from 11.1%–21%.16,32 As with
schizophrenia, OCD may also be considered as a risk fac-
tor for bipolar disorder. The comorbidity of OCD with
anxiety and depression is commonly described as a causal
relationship, as one serves as a risk factor for the other.33
One study found 53% of patients with depression
reported ≥1 OCS, while 14% reported ≥4 OCS, with
higher rates of OCS appearing correlative to depression
severity.34 In comparison to these reported percentages,
our study found that of the OCD/OCS ADR reports to
FAERS, 42.4% had comorbid depression, 36.3% had
comorbid bipolar disorder, and 19.7% had comorbid
schizophrenia. Differences in our percentages may be
accounted for by OCS not being reported within studies,
or by antipsychotic treatment. We cannot fully rule out
the possibility of disease causality, although these disease
correlations also do not fully explain differences in rates
of OCD/OCS reporting with individual antipsychotics.
However, because aripiprazole may be utilized more
commonly than other antipsychotics as an adjunctive
treatment for depression or anxiety this may have skewed
reporting.
While debated, these data taken together do appear to
align with current understanding of OCD pathophysiol-
ogy. Dopamine hyperactivity or serotonergic underactiv-
ity are thought to elicit or exacerbate OCD symptoms.
Although outside the scope of this paper, dopaminergic
agonists (e.g., pramipexole and ropinirole) constituted a
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BURK ET AL.
substantial number of OCD/OCS reports to FAERS. Dopa-
minergic partial agonists may increase dopamine signaling
within the caudate and putamen, while serotonin-2A
(5-HT2A) and 5-HT2C antagonists may indirectly increase
dopamine in the cortex and striatum through an inhibition
of GABA release.35 Thus, for antipsychotics where 5-HT2A
affinity is greater than D2 affinity (i.e., most second-
generation antipsychotics) the risk of OCD/OCS develop-
ment may be greater. Conversely, D2 antagonism may
mitigate OCD symptoms, hence the lower reporting of
OCD/OCS with all of the first-generation antipsychotics as
well as the second-generation antipsychotics risperidone
and paliperidone, which have high affinity for the D2
receptor.36 Further demonstrating the influence of
5-HT2A receptors on OCD, psilocybin and lysergic acid
diethylamide (LSD), both 5-HT2A receptor agonists,
have shown benefit for reducing compulsive-type
behaviors in both mice and humans.37–39 Separately, in
a recent pharmacovigilance-pharmacodynamic study
of FAERS, authors found significant positive associa-
tions between D3-receptor agonism and impulsivity
which may have relevance to the present study.40
Alternatively, serotonin-1A (5-HT1A) partial agonism
has been postulated as causative of OCD, through possi-
ble dopaminergic increases in the raphe nucleus and cor-
tex.40,41 Indeed, many antipsychotics are also partial
agonists at the 5-HT1A receptor. Alterations in the gluta-
matergic systems may also play a role in OCD, given the
profound efficacy of memantine in some preliminary
data.42 In total, a possible scenario outside of D2-receptor
partial agonism is multiple receptors acting to counter-
balance one another, possibly relating to 5-HT1A/D2 or
5-HT2A/D2 ratios. Spearman's correlation analysis
(Table 5) indicated that higher affinity for the 5-HT1A
receptor was associated with greater rates of OCD/OCS
reporting. While we cannot discern if this association is
secondary to partial agonistic effects for this receptor, it is
worth noting that all of the antipsychotic agents with the
highest affinity at the 5-HT1A receptor are also partial
agonists at this receptor (Table 5). Further, while the D2
receptor was not significantly correlated with OCD/OCS
risk, we cannot rule out the influence of D2 receptor par-
tial agonism since all three D2 receptor partial agonists
(aripiprazole, brexpiprazole, and cariprazine) were
among the top four agents associated with OCD/OCS
reporting based on the RRR (Table 5). Still, our finding of
a significant association between the 5-HT1A/D2 receptor
ratio for individual antipsychotics and their RRR for
OCD/OCS with agents having higher affinity for D2
receptors relative to 5-HT1A receptors being associated
with lower RRR may support the previous rationale that
greater D2 antagonism may offset the risk of OCD/OCS
from 5-HT1A agonism/partial agonism.
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BURK ET AL. 11

TABLE 5 Antipsychotic receptor profiles with corresponding OCD reporting as arranged by 5-HT1A/D2 receptor affinity (Ki).a,b

Antipsychotic RRR 5HT2A/D2 5-HT1A/D2 D2 5-HT2A 5-HT1A

Clozapine 13.28 0.01 0.29 431 5.35 123.7d
Brexpiprazole 19.66 1.57 0.4 0.3c 0.47 0.12d
Ziprasidone 11.63 0.15 0.52 4.8 0.74 2.5d
Quetiapine 8.52 0.39 1.3 245 97 320d
Aripiprazole 240.15 9.16 1.79 0.95c 8.7 1.7d
Asenapine 17.57 0.05 1.92 1.3 0.06 2.5d
c
Cariprazine 28.4 38.37 5.31 0.49 18.8 2.6d
Lurasidone 20.75 0.47 6.79 0.994 0.47 6.75d
Olanzapine 14.34 0.03 28.65 72 2 2063
Risperidone 5.56 0.05 118.49 3.57 0.17 423
Loxapine N/A 0.6 223.64 11 6.6 2460
Paliperidone 6.13 0.69 385.63 1.6 1.1 617
Chlorpromazine N/A 0.38 432.64 7.2 2.75 3115
Perphenazine N/A 7.32 550.33 0.765 5.6 421
Haloperidol 4.47 26.5 963.5 2 53 1927
Spearman's Rho ( p-value)e — 0.09 (0.75) 0.66 (0.007) 0.41 (0.13) 0.16 (0.58) 0.77 (0.0008)

Note: Bolded value represents a Spearman's Rho and p-value.

a
Ki data derived from PDSP Ki database.21
b
Some Ki depicted as average values.
c
D2 partial agonist.
d
5-HT1A partial agonist.
e
Spearman's Rho (rs) with 2-tailed p-values were calculated using the inverse of Ki values.

Selective serotonin reuptake inhibitors and clomipra-
mine have commonly been the mainstays of treatment
for OCD. Benefit from these medications again supports
the dopamine–serotonin imbalance theory, as increases
in serotonin may decrease dopamine hyperactivity. How-
ever, between 25% and 60% of patients with OCD have
residual symptoms with first-line treatment options.42,43
Antipsychotics have been trialed as augmenting agents
for those failing serotonergic agonist treatment, with
varying success. The FGAs haloperidol and pimozide
have been shown to be beneficial for refractory OCD
when used in combination with an antidepressant.44,45
A 2006 meta-analysis by Bloch et al. found the number
needed to treat with antipsychotic augmentation for
OCD patients failing 12 weeks of maximal therapy with a
serotonergic agent was 4.5 (95% CI: 3.2–7.7), but nearly
one-third of patients still exhibited refractory symp-
toms.46 While aripiprazole was not included in this analy-
sis, risperidone and haloperidol appeared efficacious, but
olanzapine and quetiapine did not.46 In a separate meta-
analysis, Dold et al. found risperidone to be the treatment
of choice for antipsychotic augmentation in OCD.47 In
more recent meta-analyses, aripiprazole has also been
shown to have significant impact on OCD symp-
toms.12,48,49 Of note, Zhou et al. found comorbid
depression to be a possible predictor of antipsychotic fail-
ure in their network meta-analysis.49 Perhaps in
depressed patients, where there is not elevated striatal
dopamine, using aripiprazole can increase dopamine sig-
naling, inducing OCS, but in patients with schizophrenia
where there is already elevated striatal dopamine the pro-
pensity is less likely.
We only found minimal data comparing antipsy-
chotics to one-another for OCD treatment. Comparative
studies on aripiprazole versus other antipsychotics have
found mixed results. One trial found olanzapine was as
effective as aripiprazole for OCD treatment, while
another found quetiapine to be as effective.50,51 Only a
2011 study by Selvi et al. found risperidone to be more
effective than aripiprazole for SSRI-refractory OCD.52
Unfortunately, most other data compare antipsychotics
to placebo, therefore more head-to-head studies are
required to determine efficacy from individual antipsy-
chotics for treatment of OCD. Ultimately, in patients with
primary OCD, it is highly conceivable that strong block-
ade of dopamine D2 receptors with an antipsychotic
could mitigate symptoms. This is in line with our finding
of lower rates of antipsychotic therapeutic failure report-
ing for FGAs and high D2 affinity SGAs (i.e., risperidone
and paliperidone) when used for primary OCD treatment

12
(Table 4). Indeed, a meta-regression analysis found
higher affinity for the D2/3 receptor was more highly
associated with treatment success.53 Paradoxically, those
without OCD may experience de novo or exacerbated
OCD/OCS from antipsychotics. However, these data do
not account for comorbid conditions. In those with
comorbid conditions, our data showed that OCD treat-
ment failure reporting was most prevalent with aripipra-
zole. This appears in direct contrast to published reports
where aripiprazole was successful in the treatment of
OCS comorbid with schizophrenia.54,55 While publication
bias may be an explanation for this discrepancy it cannot
be discounted that our findings might reflect the high
rates of aripiprazole prescribing overall, especially in
depression, which encompassed a larger proportion of
comorbidities present in the reports for OCD than did
schizophrenia.
Even fewer data exist for treatment of OCD secondary
to antipsychotics. A case series of 7 patients with
clozapine-induced OCS were treated with a mean dose of
about 23 mg aripiprazole for 9.7 weeks with significant
decreases in Yale Brown Obsessive Compulsive Rating
Scale (YBOCS) scores.56 Similarly, aripiprazole 15 mg
was shown to be of benefit in reducing YBOCS scores in
a female with schizophrenia with OCS induced by olan-
zapine. It has been hypothesized that low antipsychotic
doses, where 5-HT2A receptor antagonism may outweigh
D2 receptor antagonism, may precipitate OCD.36 Thus,
one proposed strategy has been to increase the dose of
the antipsychotic, possibly by shifting the balance in
favor of D2 antagonism rather than 5-HT1A/2A.57 Alterna-
tively, addition of an SSRI may be of benefit.58
4.1 | Limitations
Disproportionality studies have inherent issues, including
reporting biases or under-reporting. A masking-effect may
have resulted in specific antipsychotics not demonstrating
a significant ROR for OCD/OCS due to over-reporting of
other non-OCD/OCS ADRs.59 We cannot comment on the
prevalence of de novo OCD or OCS exacerbation, nor can
we comment on the severity of de-novo or exacerbated
OCS as the data provided via the FAERS Public Dash-
board is categorical in nature and does not report on any
formal rating scales, if such scales were even used. While
the majority of the reports were from consumers and not
healthcare practitioners we do not believe this strongly
influenced the outcome of the study, as aripiprazole still
constituted the largest number of antipsychotic reports,
even from healthcare practitioners. However, we cannot
fully discount that a misclassification of ICD as OCD may
have occurred through consumer unawareness of the
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BURK ET AL.
nuances between these disorders. We did not evaluate the
influence of multiple medications on OCD/OCS, in favor
of solely investigating the primary antipsychotic impli-
cated. As noted previously, interactions between antipsy-
chotics may lessen or increase OCD/OCS rates, thus
further research is needed. However, it is worth noting
that when concomitant medications were removed in a
sensitivity analysis, the ROR findings were largely in keep-
ing with the results from the primary analysis (Table 3)
suggesting that use of multiple medications was unlikely
to have confounded our primary findings. While doses and
treatment durations are reported to FAERS within the
quarterly data, as we assessed data from the Public Dash-
board which does not include these parameters we were
not able to assess the potential relationships between these
factors and the reporting of antipsychotic treatment-
emergent OCD/OCS.
In this study we did not conduct sensitivity analyses
on the influence of the underlying disease on
antipsychotic-emergent OCD/OCS (save the influence of
baseline OCD/OCS). Rather, we chose to broadly assess
the rates of OCD/OCS reporting based on all indications
combined in order to maximize the power of our study to
detect disproportionality signals. Furthermore, sensitivity
analyses would likely be more informative if conducted
in a longitudinal correlative study rather than voluntarily
submitted pharmacovigilance data. It cannot be disre-
garded that an element of unreported baseline OCD/OCS
or reporter error of misclassifying side effect with indica-
tion may have skewed our findings. Another potential
confound is the relative rates that specific antipsychotic
agents were prescribed for OCD/OCS. However, it should
be noted that the number of FAERS reports of risperi-
done used for treatment of OCD/OCS is very similar to
the number of reports of aripiprazole for this indication
despite very divergent RORs of OCD treatment failure
for these two agents (Table 4) suggesting that these
confounds are less likely to have influenced these find-
ings. Lastly, while certain illicit substances, such as
cocaine or methamphetamine, can induce OCD/OCS
and are more commonly abused by those with schizo-
phrenia, bipolar disorder, or depression, use of these
substances are not communicated to FAERS, so we
cannot rule these out as the cause for some reports.
However, we have no reason to believe that any poten-
tial effect of concomitant stimulant abuse would not be
evenly distributed across all antipsychotics examined
in this study, and thus, we would not expect this to sig-
nificantly impact our findings.
To conclude, our findings are likely to be of critical
importance for not only furthering the understanding of
OCD pathophysiology, but enhancing patient and clinician
awareness of OCD/OCS secondary to antipsychotic

BURK ET AL.
treatment. Our analyses identify D2 partial agonism,
5-HT1A potency and partial agonism, and potency of D2
receptor blockade relative to 5-HT1A blockade as key fea-
tures associated with increased reporting of antipsychotic-
induced or exacerbated OCD/OCS. Contrary to previously
published reports showing greater numbers of de novo or
exacerbated OCD/OCS with clozapine and olanzapine, we
did not find a substantially increased reporting of
OCD/OCS with these agents relative to other SGAs.
Rather, aripiprazole and other D2 receptor partial agonists
had the most reports of de novo OCD/OCS. These findings
from FAERS will hopefully lay the groundwork for future
studies on this topic and should ideally be validated
through prospective research studies involving direct com-
parisons of antipsychotic agents.
A U T H O R C ON T R I B U T I O NS
Bradley G. Burk designed and performed the research.
Bradley G. Burk, Tilyn DiGiacomo, and Badari Birur
wrote the original manuscript and subsequent revisions.
Shea Polancich and Brandon S. Pruett contributed to data
analysis. Badari Birur, Soumya Sivaraman, and Brandon
S. Pruett reviewed the original manuscript and subse-
quent revisions for accuracy.
FUNDING INFORMATION
This work (research, review, or writing) required no
funding of any type from any agency in the public, com-
mercial, or not-for-profit sectors.
CONFLICT OF INTEREST STATEMENT
The authors declare no conflicts of interest.
P EE R R EV IE W
The peer review history for this article is available at
https://www.webofscience.com/api/gateway/wos/peer-
review/10.1111/acps.13567.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are
available in FDA Adverse Event Reporting System
(FAERS) Public Dashboard at https://fis.fda.gov/sense/app/
95239e26-e0be-42d9-a960-9a5f7f1c25ee/sheet/33a0f68e-
845c-48e2-bc81-8141c6aaf772/state/analysis, reference
number 17. These data were derived from the following
resources available in the public domain: FDA, https://fis.
fda.gov/sense/app/95239e26-e0be-42d9-a960-9a5f7f1c25ee/
sheet/33a0f68e-845c-48e2-bc81-8141c6aaf772/state/analysis.
E TH IC S ST A T EME N T
An IRB review was not conducted, nor required, for this
pharmacovigilance study wherein no patient-specific data
is available.
16000447, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/acps.13567 by Cochrane Mexico, Wiley Online Library on [20/06/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
13
ORCID
Bradley G. Burk https://orcid.org/0000-0002-2681-3785
Brandon S. Pruett https://orcid.org/0000-0001-9760-
1635
Soumya Sivaraman https://orcid.org/0000-0002-3848-
9839
Badari Birur https://orcid.org/0000-0003-1258-7585
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How to cite this article: Burk BG, DiGiacomo T,
Polancich S, Pruett BS, Sivaraman S, Birur B.
Antipsychotics and obsessive–compulsive disorder/
obsessive–compulsive symptoms: A
pharmacovigilance study of the FDA adverse event
reporting system. Acta Psychiatr Scand. 2023;1‐15.
doi:10.1111/acps.13567