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Original Research

The Protective Effect of Clozapine on Suicide: A Population Mortality Study of Statewide Autopsy Records in Maryland

Brian J. Lee, MD, PhDa; Robert O. Cotes, MDb; Ramin Mojtabai, MD, PhDa,c; Russell L. Margolis, MDa; Frederick C. Nucifora, Jr, DO, PhDa,‡; and Paul S. Nestadt, MDa,c,‡,*

Published: March 15, 2023


Objective: Clozapine is the most efficacious antipsychotic medication, but it is underutilized and its mechanism of action is still poorly understood. One aspect of its unique efficacy that requires further study is its effect on suicidality. A randomized controlled trial, the InterSePT study, yielded evidence that clozapine reduces suicidality more than olanzapine, after which it became the only medication indicated for recurrent suicidal behavior in schizophrenia and schizoaffective disorder. We present here the first study of population mortality data to investigate the effect of clozapine on suicide.

Methods: We reviewed statewide autopsy records of Maryland’s Office of the Chief Medical Examiner, which performs uniquely comprehensive death investigations that include full toxicologic panels with postmortem blood levels of antipsychotics. Our study compared clozapine- and olanzapine-positive decedents across demographic, clinical, and manner-of-death outcomes using contingency table analysis and logistic regression.

Results: Of 53,144 decedents from 2003 to 2021, 621 had clozapine or olanzapine detected on autopsy, with the two groups showing no demographic differences. Decedents with clozapine were significantly less likely to have died by suicide than by accident compared to those with olanzapine (odds ratio = 0.47; 95% CI, 0.26–0.84; P = .011).

Conclusions: Our study thus adds more naturalistic evidence to the growing literature on the beneficial effect of clozapine on suicidality. Our findings also highlight the utility of statewide autopsy records, an untapped resource for investigating the potential protective effect of psychiatric medications on suicide at a population level.

Volume: 84

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