Association between initial 30-day cumulative clozapine dose and risk of agranulocytosis: A nationwide register-based...

Clozapine-induced agranulocytosis (CIA) is traditionally considered an idiosyncratic, dose-independent reaction. However, emerging evidence suggests that clozapine-related inflammatory events may exhibit dose-dependent characteristics, leading us to hypothesize that CIA risk may similarly relate to early cumulative exposure.

Using Japan's nationwide Clozaril Patient Monitoring Service database (2009-2024), the 30-day cumulative dose following initiation was calculated for all treated patients. Participants were stratified into quartiles (Q1-Q4). CIA was defined as two consecutive absolute neutrophil counts <500/mm³. The incidence of CIA was compared across quartiles using Kaplan-Meier survival curves and Cox proportional hazards models adjusted for age and sex.

Among 18,189 patients (mean age 42.9 [SD 12.7]; 46.4% female), 138 (0.76%) developed CIA, with no cases occurring within the first 30 days. The incidence rates of CIA in Q1, Q2, Q3, and Q4 were 0.44%, 0.66%, 0.74%, and 1.20%, respectively. Compared with Q1, hazard ratios (HRs) over 180 days were 1.78 (95% confidence interval [CI] 0.96-3.30; P = 0.0659), 2.01 (95% CI 1.10-3.66; P = 0.0233), and 3.07 (95% CI 1.74-5.42; P < 0.001) for Q2, Q3, and Q4, respectively. Male sex and age >40 years were identified as independent risk factors. E-values for Q4 HR were 5.59 (point estimate) and 2.88 (95% CI), indicating high robustness against unmeasured confounders such as co-medications.

Higher early cumulative clozapine exposure was associated with increased CIA risk. These findings suggest that early exposure may serve as a clinically relevant marker of CIA risk, although causal inference is limited and further research is needed.