Clozapine Rechallenge After Excluding the High-Risk Clozapine-Induced Agranulocytosis Genotype of HLA-DQB1 6672G>C

To the Editor: Although clozapine is considered the most effective antipsychotic for treatment-resistant schizophrenia, it is underutilized because of the risk of clozapine-induced agranulocytosis and neutropenia. While drug interactions, benign ethnic neutropenia, and medical comorbidity can often contribute to clozapine-induced agranulocytosis, most patients who develop neutropenia or agranulocytosis do not restart clozapine after its discontinuation. While treating a patient with a history of robust response to discontinued clozapine, we incorporated a newly available genetic test to help with the decision to attempt a clozapine rechallenge.

Case Report

A 33-year-old Caucasian woman with treatment-resistant schizoaffective disorder developed neutropenia after 8 years of clozapine treatment. The patient had achieved relative stability while taking quetiapine, 400 mg/day; extended-release divalproex, 1500 mg/day; and clozapine, 300 mg/day. After discontinuing clozapine because of neutropenia that was discovered after routine testing (absolute neutrophil count, 600 cells/mm³; WBC, 2,800 cells/mm³), she experienced worsening psychosis and catatonic symptoms that led to hospitalization. During the hospitalization, the hematology consultant opined that her low absolute neutrophil count was due to clozapine therapy, so clozapine was not restarted. Over the next 5 months, the patient did not respond to pharmacologic treatments or ECT.

Because of the patient's previous positive response to clozapine, we considered a clozapine rechallenge. Based on recent findings of the association of a single-nucleotide polymorphism (6672G>C) in the major histocompatibility complex class II, DQ beta 1 gene (MHC HLA-DQB1) with increased risk of clozapine-induced agranulocytosis (1), the genotyping for this polymorphism was performed (PGxPredict:CLOZAPINE test, PGxHealth, Newton, Mass.). Results showed no high risk for clozapine-induced agranulocytosis genotype (HLA-DQB1 6672G>C). Even in the absence of genetic testing, this patient may have been at lower risk for repeat neutropenia based on the preceding 8 years of successful clozapine therapy without neutropenia. Although this test does not eliminate all risks for clozapine-induced agranulocytosis, this information was helpful in supporting the decision to restart clozapine. The patient has sustained a positive response after 14 months of clozapine therapy without agranulocytosis; recent values were absolute neutrophil count, 2,200 cells/mm³, and WBC, 5,000 cells/mm³.

Discussion

The odds of developing clozapine-induced agranulocytosis are 16.9 higher in patients carrying the C instead of the G DQB1 genotype (1). This single-nucleotide polymorphism has no known functionality and may be linked to other polymorphisms with causality for clozapine-induced agranulocytosis. In fact, other human leukocyte antigen variants associated with hypersensitivity to several drugs have been found (1). In a previous report (2), of the 53 patients rechallenged with clozapine, 38% redeveloped a blood dyscrasia that was usually more severe and occurred during the first 10 weeks following rechallenge; however, 55% were able to continue taking clozapine. Although the test identifies only a subset of individuals who may develop clozapine-induced agranulocytosis, the absence of the C genotype in patients being considered for clozapine rechallenge can help in the clinical risk and benefits assessment.