Long-term outcomes of delayed clozapine initiation in treatment-resistant schizophrenia: A multicenter retrospective cohort study

Abstract

Abstract Background Clozapine is the only antipsychotic medication with proven efficacy against treatment-resistant schizophrenia. This multicenter retrospective cohort study aimed to evaluate the impact of a delay in clozapine initiation on long-term outcomes. Methods Patients who initiated clozapine treatment between July 2009 and December 2018 were included in this study. According to the length of time from the diagnosis of schizophrenia to the clozapine initiation, the patients were categorized into one of three groups: early (≤ 9 years), intermediate (10–19 years), and late (≥ 20 years) initiation. The endpoints were psychiatric rehospitalization, all-cause clozapine discontinuation, and treatment failure at 3 years. Hazard ratios (HR) and 95% confidence interval (CI) were estimated using the Fine and Gray method or the Cox proportional hazards model. Results The incidence rates of rehospitalization at 3 years according to the cumulative incidence function were 32.3% for early, 29.7% for intermediate, and 62.2% for late initiation, respectively. Late initiation had a significantly higher risk of rehospitalization than both early (HR, 2.94; 95% CI, 1.01– 8.55; P = 0.016 by the Gray's test) and intermediate initiation (HR, 3.13; 95% CI, 1.34–7.30; P = 0.0025 by the Gray's test). The incidence rate of all-cause clozapine discontinuation at 3 years using the Kaplan–Meier method were 13.0% for early, 10.6% for intermediate, and 20.1% for late initiation. The risk of all-cause clozapine discontinuation was not significantly among the groups. The late initiation group showed significantly increased risk of treatment failure only when using univariate analysis. The late initiation group had more patients discontinuing because of death due to physical diseases than the other groups. Conclusions The study suggests that clozapine should be initiated promptly in patients with treatment-resistant schizophrenia to prevent psychiatric rehospitalization during long-term treatment. Further studies of higher quality, with appropriate consideration of patient characteristics, and with larger sample sizes are needed.