Antipsychotics and New-Onset Obsessive-Compulsive Disorder in Schizophrenia

Comorbidity or medication adverse effect? Researchers performed a nested case-control study of new-onset obsessive-compulsive disorder following antipsychotic use in schizophrenia.



“Mr Harris” is a 30-year-old male with a 5-year history of schizophrenia. His primary psychotic symptoms included auditory hallucinations and persecutory delusions. In the first year after the onset of his illness, he developed an obsessive fear of contamination and compulsive hand washing and bathing. He failed trial (adequate dose and duration) of 2 different second-generation and 1 first-generation antipsychotic. During a psychiatric hospitalization, he was subsequently started on clozapine, which was titrated to 300 mg/day. His auditory hallucinations remitted, and his persecutory delusions were significantly reduced. However, his compulsive hand washing and bathing worsened within 3 months of clozapine treatment. He was aware that his fears of contamination were excessive, but he was unable to resist acting on them. Adjunctive treatment with clomipramine 50 mg/day significantly decreased his obsessive thoughts and compulsive behaviors.

Many patients with schizophrenia have comorbid obsessive-compulsive symptoms (OCS) or obsessive-compulsive disorder (OCD), with a pooled prevalence of 30% and 12%, respectively.1 There is some evidence that a greater duration of illness may be associated with a higher prevalence of comorbid OCS or OCD.2 Furthermore, OCS or OCD may be present as a prodromal symptom or co-occurring symptom in schizophrenia, or as an adverse effect of antipsychotics. Cross-sectional studies are limited by their inability to investigate the temporal relationship between antipsychotic exposure and OCS/OCD.

The Current Study

Accordingly, Park and colleagues3 investigated the association between antipsychotic use and the risk of new-onset OCD in patients with schizophrenia using a nationwide cohort in Korea.

The authors used a nationwide medical claims database that covers about 98% of the Korean population. Patients aged 15 to 60 with a first diagnosis of schizophrenia between January 2010 and December 2018 (index date) were included. Patients with a diagnosis of schizophrenia or exposure to any antipsychotic within 2 years before the index date were excluded. Patients diagnosed with OCD before schizophrenia or within 2 weeks of the first schizophrenia diagnosis were also excluded, as were patients without an antipsychotic prescription during the observation period.

The authors used a nested case-control design to avoid potential biases (eg length bias due to antipsychotic exposure). Patients with schizophrenia, but without OCD were matched to patients with schizophrenia and OCD in a 4:1 ratio based on age, sex, date of schizophrenia diagnosis, observation period, location, and level of medical facility. Age of schizophrenia diagnosis was trichotomized into early-onset (age 15 to 20), intermediate-onset (age 21 to 44), and late-onset (age 45 to 60). The authors analyzed the 9 most frequently prescribed antipsychotics in Korea: olanzapine, risperidone, quetiapine, aripiprazole, clozapine, haloperidol, chlorpromazine, amisulpride, and paliperidone. Logistic regression analysis was used to estimate the risk of newly diagnosed OCD, calculating odds ratios (ORs) and 95% confidence intervals (CIs), with haloperidol set as the reference, and adjusting for type of health insurance and presence of previous psychiatric illness.

Among approximately 50,000 patients newly diagnosed with schizophrenia during the study period, 775 cases of new-onset OCD and 3100 matched controls were identified. The mean subject age was 31, and the sample was 54% male. Compared to haloperidol, clozapine was associated with significant increased odds of OCD (OR=2.9, 95% CI 1.6-5.0). Furthermore, risks of clozapine and new-onset OCD were significant in the early- and intermediate-onset groups, but not the late-onset schizophrenia group (although there were only n=3 subjects in this group). Among the 35 patients prescribed clozapine with new-onset OCD, the mean time from clozapine initiation to OCD diagnosis was 1.9 years, and the mean clozapine dose was 146 mg. There was no difference in the risk of OCD between all other antipsychotics and haloperidol.

Study Conclusions

The authors concluded that clozapine was associated with almost threefold increased odds (versus haloperidol) of new-onset OCD inpatients with schizophrenia, with no significant difference in risk for other antipsychotics. Strengths of the study include the population-based representative sample. Study limitations include the inability to assess the frequency of subthreshold OCS, which are more common than OCD and may require clinical attention. Data on other potential risk factors, such as genetics/family history of OCD and severity of psychotic symptoms, were not available.

The Bottom Line

There is reliable evidence for the risk of OCD associated with commonly prescribed antipsychotics, particularly clozapine (and within the first 2 years of treatment).

Dr Miller is professor in the Department of Psychiatry and Health Behavior, Augusta University, Augusta, Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for Psychiatric TimesTM. The author reports that he receives research support from Augusta University, the National Institute of Mental Health, and the Stanley Medical Research Institute.


1. Swets M, Dekker J, van Emmerik-van Oortmerssen K, et al. The obsessive compulsive spectrum in schizophrenia, a meta-analysis and meta-regression exploring prevalence rates. Schizophr Res. 2014;152(2-3):458-468.

2. Schirmbeck F, Swets M, de Haan L. Epidemiology: prevalence and clinical characteristics of obsessive-compulsive disorder and obsessive-compulsive symptoms in patients with psychotic disorders. In: de Haan L, Schiirmbeck F, Zink M, eds. Obsessive-Compulsive Symptoms in Schizophrenia. Springer; 2015:47-61.

3. Park CI, Han M, Jung I, et al. A nationwide nested case-control study of new-onset obsessive-compulsive disorder following antipsychotic use in schizophrenia. Acta Psychiatr Scand. 2021. Online ahead of print.