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Original Research

Cardiovascular Disease Mortality in Patients With Chronic Schizophrenia Treated With Clozapine: A Retrospective Cohort Study

Deanna L. Kelly, PharmD, BCPP; Robert P. McMahon, PhD; Fang Liu, MS;       Raymond C. Love, PharmD, BCPP; Heidi J. Wehring, PharmD, BCPP;       Joo-Cheol Shim, MD, PhD; Kimberly R. Warren, PhD; and Robert R. Conley, MD

Published: January 12, 2010

Article Abstract

Background: Cardiovascular disease (CVD) mortality in schizophrenia is more frequent than in the general population. Whether second-generation antipsychotics (SGAs) increase risk of CVD morbidity and mortality has yet to be determined.

Method: We conducted a retrospective cohort
study using an administrative database to identify patients with DSM-III– or DSM-IV-diagnosed schizophrenia, treated in Maryland, who started clozapine treatment (n‘ ‰=‘ ‰1,084) or were never treated with clozapine (initiated on risperidone; n‘ ‰=‘ ‰602) between 1994 and 2000. Deaths between 1994 and 2004 were identified by the Social Security Death Index, and death records were obtained.

Results: During the 6- to 10-year follow-up period, there were 136 deaths, of which 43 were attributed to CVD. Cardiovascular disease mortality in patients aged younger than 55 years at medication start was approximately 1.1% (clozapine, 1.1%; risperidone, 1.0%) in both groups at 5 years and 2.7% (clozapine) and 2.8% (risperidone) at 10 years (χ21‘ ‰=‘ ‰0.12, P‘ ‰=‘ ‰.73). Patients who started treatment at ages ≥‘ ‰55 years had CVD mortality of 8.5% (clozapine) and 3.6% (risperidone) at 5 years and 16.0% (clozapine) and 5.7% (risperidone) at 10 years (χ21‘ ‰=‘ ‰2.13, P‘ ‰=‘ ‰.144). In a Cox regression model, patients aged ≥‘ ‰55 years were at greater risk of mortality than younger patients (hazard ratio‘ ‰=‘ ‰4.6, P‘ ‰<‘ ‰.001); whites were at greater risk than nonwhites (HR‘ ‰=‘ ‰2.1, P‘ ‰=‘ ‰.046); however, SGA treatment (HR‘ ‰=‘ ‰1.2; 95% CI, 0.6-2.4; P‘ ‰=‘ ‰.61) and sex (HR‘ ‰=‘ ‰0.9, P‘ ‰=‘ ‰.69) were not statistically significant predictors of CVD, nor was there a significant age × clozapine interaction (χ21‘ ‰=‘ ‰1.52, P‘ ‰=‘ ‰.22). Age-, race-, and gender-adjusted standardized mortality ratios were significantly elevated (clozapine, 4.70; 95% CI, 3.19-6.67; risperidone, 2.88; 95% CI, 1.38-5.30) compared to year 2000 rates for the Maryland general population but did not differ by antipsychotic group (χ21‘ ‰=‘ ‰1.42, P‘ ‰=‘ ‰.23).

Conclusions: The risk of CVD mortality in
schizophrenia does not differ between clozapine
and risperidone in adults despite known differences
in risk profiles for weight gain and metabolic side effects. However, we cannot rule out an increased risk of CVD mortality among those starting treatment at ages 55 years or older.

Submitted: September 17, 2008; accepted January 2, 2009.

Online ahead of print: January 12, 2010.

Corresponding author: Deanna L. Kelly, PharmD, BCPP, Maryland Psychiatric Research Center, University of Maryland School of Medicine, Box 21247, Baltimore, MD 21228 (

Volume: 71

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