Is There a Relationship Between Clozapine and Obsessive-Compulsive Disorder?: A Retrospective Chart Review S. Nassir Ghaemi, Carlos A. Zarate, Jr., Anand P. Popli, Srinivasan S. Pillay, and Jonathan O. Cole The emergence of obsessive-compulsive symptoms during clozapine treatment has been reported in re- cent case studies, yet the incidence and significance of this finding is still unclear pending reliable data from a larger sample of patients. Hospital records of 142 randomly selected inpatients started on clozapine treatment at McLean Hospital before July 1, 1992, were reviewed retrospectively. Based on a limited retrospective chart review, there were no definitive cases of patients who developed obsessive-compul- sive disorder (OCD) or whose OCD worsened as a result of clozapine treatment. Although some fluctua- tion of OCD symptoms may have occurred in two cases, it is unclear whether those symptoms were related to treatment with clozapine (or other psycho- tropic drugs) or to undulations in the natural history of OCD. No definitive relationship between OCD symp- toms and clozapine treatment could be established in this limited study. Further clarification of this matter awaits outcome research using prospective methodolo- gies. Copyright © 1995 by W.B. Saunders Company C OZAPINE is an atypical antipsychotic agent introduced in the United States in 1989. Recent reports of the emergence of obsessive- compulsive symptoms during clozapine treat- ment 1-4 have led to speculation that the effect may be due to clozapine's antagonism of seroto- nin-2 receptors. This phenomenon also has been reported with the newer serotonin-2- dopamine-2 receptor antagonist, risperidone, s-6 As for clozapine, Patil 1 reported two patients with schizophrenia (aged 24 and 34 years, with 6- to 15-year duration of illness) with no prior history of obsessive-compulsive symptoms, who developed "transient obsessive-compulsive symptoms" of checking or fear of contamination after 8 to 12 weeks of clozapine treatment (dosages not given). These symptoms resolved spontaneously in 1 to 3 weeks despite continued clozapine treatment. In other reports, 2,3 after 10 weeks to I year of treatment with clozapine (300 to 800 mg/d), three patients with schizophrenia (aged 30 to 39) developed obsessive-compulsive symptoms (compulsive list-making or obsessions about having a car accident, falling out of a window, or having "repetitive cursing thoughts"), which persisted but responded to treatment with fluox- etine. In a review of treatment with clozapine (mean dose, 630 _+ 145 mg/d) in 49 patients with schizophrenia (mean duration, 18.0 _+ 6.0 years), Baker et al. 4 noted that five (10.2%) had devel- oped "either de novo obsessive-compulsive symptoms or exacerbation of preexistent symp- toms." We conducted a descriptive retrospective analysis to evaluate the incidence of emergence of obsessive-compulsive symptoms during treat- ment with clozapine. METHOD We obtained the names of all patients who were admitted to McLean Hospital before July 1, 1992, and started on clozapine treatment. To determine the sample size needed to reject the null hypothesis that clozapine treatment is not associated with the occurrence of obsessive-compulsive symptoms, we conducted a power analysis based on the report of a possible incidence rate of 10.2%. 4 We deter- mined that this study would be a descriptive one, not a comparison of groups, with a dichotomous variable (occur- rence of obsessive-compulsive symptoms). The power analy- sis7 analyzed the required sample size if the expected proportion of the incidence of obsessive-compulsive symp- toms in patients treated with clozapine was 0.10. The desired precision of the confidence interval was specified as .10 (.05 below and .05 above). At a confidence level of 95%, a sample size of 139 patients would have been required to find a 10% incidence of obsessive-compulsive symptoms with clozapine treatment. Based on this power analysis, we then randomly selected 142 patients and reviewed their medical records. We re- viewed all hospital records before and during clozapine treatment. We also reviewed records for all subsequent From the Psychopharmacology Program and Affective Disor- ders Program, Laboratories for Psychiatric Research, and Bipolar and Psychotic Disorders Program, McLean Hospital Division of Massachusetts General Hospital, Belmont, and Consolidated Department of Psychiatry, Harvard Medical School, Boston, MA. Address reprint requests to S. Nassir Ghaemi, M.D., WACC- 815, Massachusetts General Hospital, 15 Parkman St, Boston, MA 02114. Copyright © 1995 by W.B. Saunders Company 0010-440X/95/3604-0004503.00/0 ComprehensivePsychiatry, Vol. 36, No. 4 (July/August), 1995: pp 267-270 267