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February 9, 2026BMJ Mental Health1 citationsOpen Access

Risk of neutropenia-related hospitalisation among clozapine initiators

ASAmeet SarpatwariBrigham and Women's Hospital MMMufaddal MahesriBrigham and Women's Hospital JLJoyce Lii

Key Points

To compare the risk of neutropenia-related hospitalisations between clozapine and olanzapine initiators in adults with schizophrenia or schizoaffective disorder.
Used claims data from Medicaid and commercial health insurance databases.
Included adults with a diagnosis of schizophrenia or schizoaffective disorder who initiated clozapine or olanzapine.
Employed propensity score matching (1:1) to control for confounding factors.
Primary outcome was hospitalisation for neutropenia, assessed through both as-treated and intention-to-treat analyses.
Clozapine cohort had 12 neutropenia-related hospitalisations at 6 months (incidence rate: 2.21 per 1000 person-years).
Olanzapine cohort had <11 hospitalisations (incidence rate: 0.18 per 1000 person-years).
Incidence rate ratio (IRR) for clozapine versus olanzapine was 12.18.
IRRs were 5.77 at 1 year, 5.50 at 2 years, and 5.40 at 3 years post-initiation.
Intention-to-treat analyses showed attenuated associations but retained significance.

Abstract

Background Clozapine is highly effective for treatment-resistant schizophrenia but has been associated with an increased risk of agranulocytosis. As a result, until 2025, the Food and Drug Administration required patients receiving clozapine to undergo regular blood testing to monitor for neutropenia as part of a Risk Evaluation and Mitigation Strategy (REMS) programme. Objective This study sought to compare the risk of neutropenia-related hospitalisations between clozapine and olanzapine initiators. Methods The study cohort was nested in claims data from Medicaid and two commercial health insurance databases and consisted of adults initiating clozapine or olanzapine who had a recorded diagnosis of schizophrenia or schizoaffective disorder and ≥1 dispensing of a different antipsychotic in the 6 months before initiation. Propensity score matching (1:1) was used to mitigate confounding. The primary outcome was hospitalisation with a neutropenia diagnosis in the primary position. Both as-treated and intention-to-treat analyses were implemented. Findings After propensity score matching, there were 16 873 initiators in each group. At 6 months postinitiation, there were 12 neutropenia-related hospitalisations among the clozapine cohort (incidence rate: 2.21 per 1000 person-years; 95% CI 1.25 to 3.89) and <11 among the olanzapine cohort (0.18; 95% CI 0.03 to 1.29), corresponding to an incidence rate ratio (IRR) of 12.18 (95% CI 1.58 to 93.71). The IRRs were 5.77 (95% CI 1.29 to 25.76) at 1 year, 5.50 (95% CI 1.23 to 24.55) at 2 years and 5.40 (95% CI 1.21 to 24.13) at 3 years postinitiation. Associations remained but were attenuated in intention-to-treat analyses. Conclusions Clozapine initiators had an elevated risk of neutropenia-related hospitalisation, especially during the first 6 months of treatment, although the absolute risk was low. Clinical implications Despite removal of the REMS programme, it is important for prescribers to monitor patients for neutropenia after initiating clozapine.

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