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Clozapine, a highly effective antipsychotic medication, is associated with rare but potentially life-threatening neutropenia. In February 2025, the US Food and Drug Administration (FDA) eliminated its clozapine Risk Evaluation and Mitigation Strategies (REMS) program, which required documented absolute neutrophil count (ANC) lab results prior to clozapine dispensation. Considering the FDA decision, the purpose of this study was to examine the prevalence and patient-level factors associated with clozapine-associated neutropenia in a large, diverse, US-based integrated health system.

This was a retrospective cohort study of adult Kaiser Permanente Northern California members who initiated clozapine therapy between January 2021 and December 2022. Data were extracted from KPNC's electronic health record, including sociodemographic and clinical characteristics, medication fills, and ANC values. The main outcome was any neutropenic event within two years of clozapine initiation, classified as mild (ANC = 1000-1499/μL) or severe (ANC < 1000/μL).

Among 402 patients, 10 (2.5%) experienced neutropenia within 24 months of starting clozapine. Eight cases were mild, and two were severe, with one resulting in death. Race differed significantly between those who experienced neutropenia and those who did not (p = 0.038). The mean clozapine dose at the time of neutropenia was 192.5 mg, with significant differences between mild and severe cases (p = 0.015). Logistic regression analyses showed no significant associations between neutropenia and patient-level sociodemographic or clinical characteristics.

Clozapine-related neutropenia was rare and typically transient, but it can be life-threatening. Continued adherence to the manufacturer's recommendations for ANC monitoring is warranted to ensure patient safety.