Clozapine, Mortality, and Self-Harm in Treatment-Resistant Schizophrenia


New evidence bolsters the reputation of clozapine as the “gold-standard” antipsychotic for patients with treatment-resistant schizophrenia.

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Clozapine is the “gold-standard” antipsychotic for patients with treatment-resistant schizophrenia. However, it remains underutilized for several reasons, including concerns about potential adverse effects and the need for serial blood monitoring.

Schizophrenia is associated with a dramatic burden of increased premature mortality.1 A large Finnish study found that during the first 11 years of treatment, clozapine was associated with significantly decreased all-cause and suicide mortality compared with other antipsychotics.2Study designWimberley and colleagues3 investigated mortality and self-harm associated with clozapine and other antipsychotics in patients with treatment-resistant schizophrenia. The authors studied a cohort of all individuals born in Denmark after January 1, 1955, who were 18 or older and received a first diagnosis of schizophrenia after January 1, 1996. Subjects met criteria for treatment resistance by June 1, 2013, defined as either: (1) filled a prescription for clozapine, or (2) had psychiatric hospitalization within 18 months of antipsychotic treatment after at least 2 previous periods of antipsychotic treatment for at least 6 weeks with different agents. Data were extracted from several Danish registers.

The authors studied all-cause and cause-specific mortality, as well as recorded episodes of self-harm (including suicide attempt, cutting, and poisoning). They compared periods of clozapine and no clozapine treatment for cohort members. The median follow-up period was 7 years (maximum, 17 years). Data were analyzed using Cox proportional hazards regression. Analyses were adjusted for age; sex; calendar year; history of self-harm; comorbid substance use, medical disorders, and psychiatric disorders; area of residence; and cumulative clozapine treatment.

The cohort consisted of 2370 individuals with treatment-resistant schizophrenia. The median age at meeting criteria for treatment resistance was 30; 46% were female. During the follow-up period, 158 subjects (7%) died, 602 (25%) had at least one episode of self-harm, and 1372 (58%) initiated clozapine treatment for a median of 3 periods of 10 months each.

The absence of clozapine treatment was associated with significant all-cause mortality compared with clozapine treatment (hazard ratio [HR] = 1.88). Estimates were even higher for no antipsychotic versus clozapine treatment (HR = 2.50). All-cause mortality rates were highest after clozapine discontinuation, particularly within the first year (HR = 2.65). Non-clozapine antipsychotic treatment was associated with a significantly increased risk of self-harm compared with clozapine treatment (HR = 1.36). Sensitivity analyses did not change the pattern of findings.

The authors noted that strengths of the study included the population-based, longitudinal design; extensive registry data; and within-subject approach of comparing periods of treatment with clozapine, other antipsychotics, and no antipsychotics. They also noted that information on antipsychotic treatment during periods of psychiatric hospitalization was not available.

The bottom line
This study found that in patients with treatment-resistant schizophrenia, clozapine treatment was associated with decreased all-cause mortality and self-harm. Discontinuation of clozapine treatment was also associated with increased mortality risk.


Dr. Miller is Associate Professor in the Department of Psychiatry and Health Behavior at Augusta University in Augusta, GA, and Schizophrenia Section Editor and Editorial Board Member for Psychiatric Times. He reports no conflicts of interest concerning the subject matter of this article.


1. Laursen TM, Nordentoft M, Mortensen PB. Excess early mortality in schizophrenia. Annu Rev Clin Psychol. 2014;10:425-448.
2. Tiihonen J, Lönnqvist J, Wahlbeck K, et al. 11-year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study). Lancet. 2009;374:620-627.
3. Wimberley T, MacCabe JH, Laursen TM. Mortality and self-harm in association with clozapine in treatment-resistant schizophrenia. Am J Psychiatry. 2017.

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