Mr. S, age 43, has schizophrenia and been stable on clozapine for 6 years after several other antipsychotic regimens failed. Mr. S also has a history of hypertension, dyslipidemia, and gastroesophageal reflux disorder. His medication regimen includes clozapine, 400 mg/d, lisinopril, 20 mg/d, atorvastatin, 40 mg/d, omeprazole, 40 mg/d, and a multivitamin. During routine blood monitoring, Mr. S shows a significant drop in absolute neutrophil count (ANC) (750/µL) (reference range, 1,500 to 8,000 µL). Mr. S , who is African American, has no history of benign ethnic neutropenia (BEN) or ANC <1,000/µL. While reviewing his chart, clinicians note that Mr. S had an ANC of 1,350/µL3 years earlier in 2013. Because a complete workup reveals no other cause for this lab abnormality, we determine that is clozapine-induced. Mr. S’s physician asks about treatment options that would allow him to stay on clozapine.
Because of clozapine’s efficacy in treatment-resistant schizophrenia, many psychiatrists aim to
Clozapine-induced neutropenia
Clozapine was approved in 1989 for managing treatment-resistant schizophrenia after demonstrating better efficacy than chlorpromazine.1 However, the adverse effects of neutropenia (white blood cell count [WBC] <3,000/μL) and agranulocytosis (ANC <500/μL3) leading to death were reported in later studies.2,3 One study in the United Kingdom and Ireland reported a prevalence of 2.9% for neutropenia and 0.8% for agranulocytosis among patients taking clozapine.3 Because of this risk, the FDA mandated WBC and ANC monitoring before initiating clozapine and periodically thereafter. In October 2015, the Risk Evaluation and Mitigation Strategies program for clozapine updated recommended ANC levels and eliminated WBC monitoring. ANC monitoring frequencies are summarized in the Table.1
The exact mechanism of clozapine-induced neutropenia is unknown, although it is possible it stems from the drug’s effect on white blood cell precursors.2 Neutropenia typically appears within 3 months of clozapine initiation; however, delayed cases have been reported. Additionally, the risk is higher in certain patient populations (African heritage, Yemenite, West Indians, and Arab). Patients with a lower ANC at clozapine initiation and advanced age appear to be at higher risk.2
Filgrastim
The use of granulocyte-colony stimulating factor, such as filgrastim, often is viewed as a “rescue” treatment. Filgrastim’s mechanism of action is related to neutrophil production and proliferation. Several articles from the 1990s reported efficacy in the short-term management of low WBC or ANC. However, few articles, mainly case reports, have looked at long-term use of these agents. One article examined 3 patients, average age 45, who developed neutropenia during clozapine treatment.4 Filgrastim at an average dosage of 0.6 to 0.9 mg/week was used successfully. The dosage was reduced to 0.3 mg/week in 1 patient, although neutropenia returned.