Proportion and Reasons for Clozapine Discontinuation: A Systematic Review and Meta-Analysis

Abstract Background and Hypothesis: Clozapine is the only recommended medication for treatment-resistant schizophrenia. Understanding reasons for clozapine discontinuation is important, as once clozapine is stopped, treatment options are limited. Study Design: We conducted a systematic review and proportional meta-analysis of observational studies to identify the prevalence of clozapine discontinuation and to identify reasons for clozapine discontinuation. We systematically searched PubMed and Scopus databases from 1988 until November 2025. We included English language observational studies which reported on clozapine-treated cases and reasons for clozapine discontinuation. Study quality and risk of bias were assessed using the National Heart, Lung and Blood Institute Study Quality Assessment Tool. Study Results: Forty-five studies met inclusion criteria. The pooled proportion of clozapine discontinuation was 34% (95% CI, 29%-40%, n = 8136, 41 studies (n = 22 323), I2 = 98.43%). The pooled proportion of discontinuation in the total population due to non-adherence (all reasons) was 11% (95% CI, 8%-16%, n = 1418, 34 studies, I2 = 97.27%); side effects 11% (95% CI, 8%-13%, n = 2754, 40 studies, I2 = 96.12%); and ineffectiveness, 7% (95% CI, 5%-9%, n = 1355, 31 studies, I2 = 96.26%). Conclusions: The most common reasons for clozapine discontinuation are non-adherence and side effects. By identifying and addressing these issues, clozapine continuation and thus clinical outcomes can be optimized. Lack of consistency in reporting reasons for discontinuation may indicate incomplete representation of reasons and could affect the findings of our study.