Clozapine rechallenge after neutropenia: a retrospective cohort study in the UK

Background: Clozapine is contraindicated in patients with a history of neutropenia suspected to be clozapine-induced agranulocytosis. Under exceptional circumstances, patients may be rechallenged with clozapine under an off-licence agreement. The evidence regarding clozapine rechallenge after suspected clozapine-induced neutropenia remains sparse and conflicting. In this observational study, we aimed to review the outcomes of patients rechallenged with clozapine using data from the two largest clozapine manufacturers in the UK.

Methods: We analysed data of patients in the UK and Ireland rechallenged on clozapine after they registered on the Central Non-Rechallenge Database (CNRD), provided by the Clozaril Patient Monitoring Service and Zaponex Treatment Access System, between Jan 1, 2013, and Dec 12, 2025. Unsuccessful rechallenge was defined as reregistration on the CNRD within 6 months. We calculated incidence proportion and incidence rates of severe neutropenia (agranulocytosis) using both threshold-based and pattern-based criteria. Demographic characteristics, details of each clozapine trial, and factors associated with unsuccessful rechallenge were examined. People with lived experience were not involved in the research or writing of this study.

Findings: Of the 4719 patients registered on the CNRD, 1296 (27%) were rechallenged on clozapine, of whom 435 (34%) patients met the revised CNRD criteria. The cohort was predominantly male (278 [64%] male patients vs 157 [36%] female patients), with a median age of 34 years (IQR 25–46) at clozapine initiation, and was ethnically diverse: 321 (74%) White patients, 70 (16%) Black patients, 30 (7%) Asian patients, and 14 (3%) patients of other ethnicities. Median duration of follow-up was 2·2 years (IQR 0·5–4·9) or 1336 person-years. Within 6 months of rechallenge, 29 (7%) patients were re-registered on the CNRD having had a further neutropenic episode, and 87 (20%) patients had less than 6 months of rechallenge follow-up. Unsuccessful rechallenge within 6 months was associated with higher baseline absolute neutrophil count (hazard ratio [HR] 1·38 per 1 × 10⁹/L [95% CI 1·09–1·61]), male sex (HR 2·16 [95% CI 1·11–4·02]), and increasing age (HR 1·06 per year [95% CI 1·01–1·11]).

Interpretation: Clozapine rechallenge can be successful in a select group of patients after mandated clozapine cessation for suspected clozapine-induced neutropenia.