Clozapine-Associated Neutropenia among People on Clozapine in Japan: A Nationally Representative Retrospective Cohort...

Clozapine is the most effective antipsychotic for treatment-resistant schizophrenia, but use is constrained by potentially life-threatening neutropenia and mandatory hematological monitoring. Evidence from Western cohorts suggests risk is concentrated early in treatment, yet data from Japan where monitoring is stringent, remain limited.

Retrospective study including all patients prescribed clozapine from July 2009-January 2020 in Japan. Mild neutropenia was defined as absolute neutrophil count (ANC) 1.0-1.5 × 109/L, and serious neutropenia as ANC <1.0 × 109/L. Cumulative incidence of first mild and serious neutropenia was estimated using competing-risks methods. Associations with serious neutropenia were examined using Fine-Gray regression, including 2-week titration rate.

The cohort comprised 8263 individuals contributing 764 180 blood tests, with a median follow-up of 102 weeks. Overall, 3.0% patients experienced mild neutropenia and 2.2% had serious neutropenia. Among clozapine-naïve patients, cumulative incidence was 1.8% for mild and 1.6% for serious neutropenia at 18 weeks, rising to 3.1% and 2.5% at 104 weeks, respectively. Faster clozapine titration rate was associated with higher incidence of serious neutropenia (sub-distribution hazard ratio [sHR] 1.22, 95% CI, 1.02-1.45 per 50 mg dosage increase at 2-weeks), as was older age (sHR 1.05, 95% CI, 1.04-1.06), while prior clozapine exposure was associated with lower incidence (sHR 0.27, 95% CI, 0.09-0.86).

In Japan, neutropenia among clozapine-treated patients accrued predominantly within the first 1-2 years, with faster titration in the first 2-weeks being associated with a 22% increase in serious neutropenia risk per 50 mg. These findings support risk-stratified, less intensive monitoring approaches beyond the first 2 years.