Clozapine-induced neutropenia: Prevalence and associated factors

Introduction: Clozapine is the gold-standard therapy for resistant schizophrenia. However, its use is limited by risks such as clozapine-induced agranulocytosis (CIA) and neutropenia (CIN), requiring strict monitoring. This study aimed to estimate the prevalence and mortality of CIA and CIN at GHU Paris Psychiatrie & Neurosciences and identify risk factors. Methods: This retrospective study used data from the health data warehouse. We selected all patients treated with clozapine between January 1, 2019, and December 31, 2024. Based on the absolute neutrophil count (ANC), we identified cases of CIA (ANC < 500/mm 3 ) and CIN, classified as mild (ANC = (1000–1499/mm 3 )) or moderate (ANC = (500–999/mm 3 )). We then investigated risk factors using ordinal adjacent categories regression. Results: Among 1768 patients treated with clozapine, we identified 5 cases of CIA (prevalence: 0.28%), with no fatalities, and 163 cases of CIN (prevalence: 9.22%), including 36 moderate cases. African origins increased the risk of mild neutropenia (OR: 2.617; 95% CI: 1.327–5.163), while a higher ANC before treatment introduction decreased the risk (OR: 0.352; 95% CI: 0.229–0.542). Regarding the progression from mild to moderate neutropenia, receiving an anxiolytic treatment and being older than 49 years old significantly decreased the risk (OR: 0.189, 95% CI: 0.042–0.86; OR: 0.139, 95% CI: 025–0.772, respectively). Treatment was discontinued in 44% of the patients with neutropenia, and 53% were rechallenged with clozapine. Conclusion: Our study provides further evidence that CIA is a rare side effect. Given the benefits of clozapine and the rarity of agranulocytosis, our results suggest a looser approach to hematological monitoring and support the new French and US guidelines.