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Clozapine-induced agranulocytosis


Drug-induced agranulocytosis is a potentially life-threatening, idiosyncratic reaction characterized by a profound decrease in neutrophil count and susceptibility to infection. Among the many causative agents, antipsychotic drug Clozapine ( Clozaril ) occupies a unique place due to its role in treatment-refractory schizophrenia ( TRS ), where it is often the only effective treatment.
Clozapine-induced agranulocytosis ( CLIA ) is an obstacle to Clozapine use in a much larger number of patients with schizophrenia.

Clozapine, a dibenzodiazepine atypical antipsychotic drug, was introduced for treatment of schizophrenia in Europe in 1971, rapidly gaining popularity due to its efficacy and virtual absence of extrapyramidal side effects. However, its propensity to cause neutropenia and agranulocytosis was soon recognized, leading to its withdrawal.

A double-blind, randomized trial, which has demonstrated superior efficacy of Clozapine over Chlorpromazine in treatment-refractory schizophrenia, led to its reintroduction in 1989 in Europe and in 1990 in the USA. However, Clozapine use is largely restricted to treatment-resistant cases and blood count monitoring, mandatory for the entire duration of treatment, has been introduced in most countries.

The National Institute for Clinical Excellence 2014 guidelines has stated that Clozapine is the drug of choice for treatment-resistant psychosis, defined as failure to respond to at least two other trials of antipsychotic drugs.
Treatment resistance, thus defined, affects approximately one-third of patients with schizophrenia.
There is evidence that Clozapine is superior to any other antipsychotic in reducing hospitalizations and all-cause mortality.

Despite the reduction of the incidence of Clozapine-induced agranulocytosis due to blood monitoring programs, and reduced mortality from drug-induced agranulocytosis, psychiatrists may be reluctant to prescribe a drug with a potentially fatal side effect.
Additional burden of regular blood testing discourages both patients and clinicians from choosing Clozapine.
Due to these concerns, Clozapine remains underutilized in patients with treatment-refractory schizophrenia. ( Xagena )

Mijovic A, MacCabe JH, Ann Hematol 2020; 99: 2477-2482

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