Leukocytosis associated with clozapine treatment: A case series and systematic review of the literature

Background and Objectives: Clozapine is the only antipsychotic approved for treatment-resistant schizophrenia. Despite its superior efficacy profile as compared with other antipsychotics, clozapine remains underutilized. Clozapine monitoring systems clearly describe the proposed management of clozapine-induced neutropenia; however, no specific mention is made of how to interpret neutrophilic leukocytosis, despite that being a relatively frequent finding. Prescribers unfamiliar with this molecule may misjudge its clinical significance, potentially leading to untimely treatment interruption. Here, we systematically review the literature on the risk of neutrophilic leukocytosis during clozapine treatment, and describe eight additional cases among our patient cohort. Materials and Methods: We performed a systematic review of the literature on PubMed and Embase using the PRISMA 2020 guidelines, and selected all original reports describing either (1) the prevalence of neutrophilic leukocytosis during clozapine treatment, or (2) the clinical significance of neutrophilic leukocytosis. We described eight additional cases of neutrophilic leukocytosis during clozapine treatment while attending an outpatient psychiatric clinic. Results: Our research ultimately yielded the selection of 13 articles included in this systematic review. The case series highlighted the presence of stable and clinically unremarkable neutrophilia during a follow-up ranging from one to ten years. Conclusions: Existing evidence indicates that leukocytosis associated with clozapine treatment can be considered as an asymptomatic and benign condition, suggesting that no change in clozapine treatment is needed upon its detection.