Colony-Stimulating Factors Can Help Treat, Prevent Clozapine-Induced Neutropenia or Leukopenia

A case report has revealed that clozapine with intermittent colony-stimulating factors (CSFs) helped treat leukopenia and neutropenia in a patient with chronic paranoid schizophrenia who responds only to clozapine.

Clozapine is one of the oldest antipsychotic medications and has been proven to be successful for treatment-resistant schizophrenia. However, unlike newer antipsychotic medications, clozapine has been associated with many adverse events (AEs) including neutropenia and leukopenia, which may lead to agranulocytosis. Discontinuation of clozapine from these associated AEs becomes an issue, especially in patients with no alternative treatment regimens.

CSFs are cytokines that proliferate and differentiate myeloid precursor cells and are used for hematological related disorders. Their use in clozapine-associated neutropenia has been reported by Lister and Karst in a case report of a patient with chronic paranoid schizophrenia.

The patient in this case study is a 55-year old white male with chronic paranoid schizophrenia who has failed multiple antipsychotic regimens and has been stable on clozapine for over 20 years. After a prolonged period of treatment with clozapine, he reported developing leukopenia and the drug was withdrawn. Following discontinuation of clozapine, the patient decompensated, and clozapine was re-challenged. Within 4 days of treatment, the patient suffered from leukopenia again and was switched to many alternative treatments including olanzapine, risperidone, paliperidone, quetiapine, ziprasidone, iloperidone, and asenapine, all which were ineffective.

Retrial of clozapine was attempted again, this time with the addition of lithium. Lithium is known to increase white blood cell (WBC) and absolute neutrophil count (ANC), which may help with clozapine-induced neutropenia. When the patient developed neutrophilia and leukocytosis, clozapine was initiated again and titrated up to control patient symptoms. The patient was stabilized on a new regimen of 100 mg clozapine every morning and 200 mg at bedtime along with lithium 900 mg at bedtime.

After 2 months, the patient became neutropenic again, so lithium was discontinued and clozapine was held. A review of the patient’s medications revealed no other culprits and alternative causes, including morning pseudoneutropenia, were ruled out. This time, CSF therapy was recommended to manage the patient’s neutropenia and leukopenia. Initially, the patient was treated with G-CSF (filgrastim). WBC and ANC recovered within 4 days and clozapine was restarted. Six weeks later, leukopenia and neutropenia recurred, and GM-CSF (sargramostim) was started, due to formulary considerations. Intermittent use of GM-CSF has stabilized the patient’s clinical decompensation and the reinitiating of clozapine has controlled schizophrenia.

In some patients where clozapine is the only option for severe treatment-resistant schizophrenia, the use of intermittent or prophylactic G-CSF or GM-CSF has proven to successfully prevent clozapine discontinuation. Future placebo-controlled clinical trials will be required to provide conclusive evidence.

Reference

Lister J, Karst A. Utilization of G-CSF and GM-CSF as an alternative to discontinuation in clozapine-induced neutropenia or leukopenia: a case report and discussion. Ment Health Clin. 2018;8(5):250-255. doi: 10.9740/mhc.2018.09.250.