Based on a synthesis of the currently available prospective and naturalistic data, it appears that clozapine does, in fact, have a protective effect against suicide for individuals with either schizophrenia or schizoaffective disorder. Suicide is a significant contributor to premature mortality for individuals with schizophrenia, and the lifetime risk of suicide for people with schizophrenia is 4.9% (Palmer, Pankratz, and Bostwick 2005). In 2018, the overall age-adjusted suicide rate in the US was 14.8 per 100,000 (Centers for Disease Control and Prevention). Clozapine is the only medication with an indication by the US Food and Drug Administration (FDA) for reduction in the risk of recurrent suicidal behavior in schizophrenia or schizoaffective disorder (DailyMed – US National Library of Medicine 2019).
The FDA indication is based on the findings from the International Suicide Prevention Trial (InterSePT), which randomized 980 individuals with schizophrenia or schizoaffective disorder deemed at high risk for suicide (based on a prior attempt or hospitalization to avoid an attempt within 3 years or with recent suicidal ideation) to either olanzapine or clozapine (Meltzer et al. 2003). In this study, individuals on clozapine were found to have significantly less suicidal behaviors over a two year period than those taking olanzapine, independent of the reduction in positive symptoms of psychosis. Naturalistic studies lead us toward similar conclusions. In a 20-year follow up study using data from a nationwide Finnish registry of individuals with schizophrenia (Taipale et al. 2020), in comparison to individuals receiving other antipsychotics, clozapine had the lowest risk of mortality from suicide (hazard ratio 0.21, 95% confidence interval 0.15 – 0.29). Outside of suicide, there is data suggesting clozapine may reduce mortality in comparison to other antipsychotic medications. For example, in a meta-analysis of 24 mortality studies including 1327 deaths of any cause (Vermeulen et al. 2019), individuals continuously treated with clozapine had a significantly lower mortality rate compared to other antipsychotics (mortality rate ratio = 0.56, 95% CI = 0.36-0.85).
Consensus criteria for treatment resistant schizophrenia, developed by the Treatment Response and Resistance in Psychosis (TRRIP) workgroup, include failure of two or more antipsychotic medication trials at a therapeutic dose for at least six weeks (Howes et al. 2017). At this point a clozapine trial is warranted. However, if individuals are demonstrating ongoing suicidal ideation or have had serious suicide attempts without meeting TRS criteria, clozapine should be considered more promptly in the treatment algorithm (American Psychiatric Association 2019).