Masakazu Hatano

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 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 and all-cause clozapine discontinuation within 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 within three 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 psychiatric rehospitalization than early initiation (HR, 2.94; 95% CI, 1.01- 8.55; P = 0.016 by the Gray's test). The risk of psychiatric rehospitalization was not significantly different between the early and intermediate initiation groups. The incidence rate of all-cause clozapine discontinuation within three years using the Kaplan-Meier method was 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 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 prospective studies with appropriate consideration of confounding factors and large sample sizes are needed to strengthen the evidence.

Among antipsychotics, clozapine is associated with a high risk of seizures. This study aimed to generate novel hypotheses regarding trends in the onset of clozapine-induced seizures using the JADER (Japanese Adverse Drug Event Report) database. Seizures were defined according to the Standardized MedDRA Queries (SMQ) for convulsions (SMQ20000079). Trends in the onset of clozapine-induced seizures were assessed using multivariate logistic regression analysis with covariates of sex, age, clozapine dose, antipsychotic polypharmacy, concomitant medications, and history of convulsive disorder. In addition, we assessed the time-to-onset of clozapine-induced seizures using the median time, interquartile range, and Weibull shape parameter. The JADER database registered 2,745 cases of adverse events with clozapine, and 1,784 cases were included in the analysis after excluding cases for which clinical information was not available. Medium (200-400 mg) and high (> 400 mg) doses of clozapine had a significantly higher reporting rate of seizures than low doses (< 200 mg) (adjusted reporting odds ratio [aROR] = 3.05, 95% confidence interval [CI]: 1.86-4.99 and aROR = 9.81, 95% CI: 6.06-15.89, respectively). Younger age, antipsychotic polypharmacy, and concomitant use of lithium were also significantly associated with reports of seizures. The time-to-onset analysis of 222 cases of clozapine-induced seizures showed that the median time was 134 (interquartile range, 72-295) days. The 95% CI of the WSP β-value for clozapine-induced seizures included 1 and was classified as a random failure type. In conclusion, the results suggest that clozapine-induced seizures are dose-dependent adverse events that should be monitored with consideration of the effects of age and concomitant medications. Further epidemiological research is needed to strengthen and validate our hypotheses.