Association between initial 30‐day cumulative clozapine dose and risk of agranulocytosis: A nationwide register‐based cohort study

Aims 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. Methods 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/mm 3 . The incidence of CIA was compared across quartiles using Kaplan–Meier survival curves and Cox proportional hazards models adjusted for age and sex. Results 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. Conclusions 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.