The incidence of neutropenia and agranulocytosis in patients treated with clozapine in the UK and Ireland

Atkin, K; Kendall, Frank M.; Freeman, Hugh; Lieberman, Harris R.; O'Sullivan, D

doi:10.1016/0924-977x(96)88099-0

Cited by 4 publications

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“…Agranulocytosis is a potentially fatal blood dyscrasia characterized by a dramatic decrease in neutrophil count. Therefore, patients on clozapine are required to monitor their neutrophil count weekly for the first 6-12 months after which the frequency of monitoring is often decreased (1). Little is known about the mechanism of drug-induced agranulocytosis and how clozapine causes this idiosyncratic drug reaction.…”

Section: Introductionmentioning

confidence: 99%

“…Clozapine is an atypical dibenzodiazepine antipsychotic lacking extrapyramidal side effects. Despite its unique effectiveness in treating refractory schizophrenia, its use is limited because of the propensity to cause agranulocytosis in ∼0.8% of patients , . Agranulocytosis is a potentially fatal blood dyscrasia characterized by a dramatic decrease in neutrophil count.…”

Section: Introductionmentioning

confidence: 99%

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Testing the Hypothesis that Vitamin C Deficiency Is a Risk Factor for Clozapine-Induced Agranulocytosis Using Guinea Pigs and ODS Rats

Wilson

Uetrecht

2008

Chem. Res. Toxicol.

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The use of clozapine is limited by a relatively high incidence of drug-induced agranulocytosis. Clozapine is oxidized by bone marrow cells to a reactive nitrenium ion. Although many idiosyncratic drug reactions are immune-mediated, the fact that patients with a history of clozapine-induced agranulocytosis do not immediately develop agranulocytosis on rechallenge suggests that some other factor may be responsible for the idiosyncratic nature of this reaction. The reactive nitrenium ion is very rapidly reduced back to clozapine by vitamin C, and many schizophrenic patients are vitamin C deficient. We set out to test the hypothesis that vitamin C deficiency is a major risk factor for clozapine-induced agranulocytosis using a vitamin C deficient guinea pig model. Although the vitamin C deficient guinea pigs did not develop agranulocytosis, the amount of clozapine covalent binding in these animals was less than we had previously observed in samples from rats and humans. Therefore, we studied ODS rats that also cannot synthesize vitamin C. Vitamin C deficient ODS rats also did not develop agranulocytosis, and furthermore, although covalent binding in the bone marrow was greater than that in the guinea pig, it was not increased in the vitamin C deficient ODS rats relative to ODS rats that had adequate vitamin C in their diet. Therefore, it is very unlikely that vitamin C deficiency is a major risk factor for clozapine-induced agranulocytosis.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Testing the Hypothesis that Vitamin C Deficiency Is a Risk Factor for Clozapine-Induced Agranulocytosis Using Guinea Pigs and ODS Rats

Wilson

Uetrecht

2008

Chem. Res. Toxicol.

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Induction of Metabolism-Dependent and -Independent Neutrophil Apoptosis by Clozapine

et al. 2000

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Clozapine, an atypical antipsychotic used in the treatment of refractory schizophrenia, causes neutropenia and agranulocytosis in 3 and 0.8% of patients, respectively. Clozapine undergoes bioactivation to a chemically reactive nitrenium ion, which has been shown to cause neutrophil cytotoxicity. To define further the mechanism of cell death, we have investigated the toxicity of clozapine, its stable metabolites, and its chemically reactive nitrenium ion to neutrophils and lymphocytes. Clozapine was able to induce neutrophil apoptosis at therapeutic concentrations (1-3 microM) only when it was bioactivated to the nitrenium ion. The parent drug caused apoptosis at supratherapeutic concentrations (100-300 microM) only. Neutrophil apoptosis induced by the nitrenium ion, but not by the parent drug itself, was inhibited by antioxidants and genistein and was accompanied by cell surface haptenation (assessed by flow cytometry) and glutathione depletion. Dual-color flow cytometry showed that neutrophils that were haptenated were the same cells that underwent apoptosis. No apoptosis of lymphocytes was evident with the nitrenium ion or the parent drug, despite the fact that the former caused cell surface haptenation, glutathione depletion, and loss of membrane integrity. Demethylclozapine, the major stable metabolite in vivo, showed a profile that was similar to, although less marked than that observed with clozapine. N-oxidation of clozapine or replacement of the nitrogen (at position 5) by sulfur produced compounds that were entirely nontoxic to neutrophils. In conclusion, the findings of the study expand on potential mechanisms of clozapine-induced cytotoxicity, which may be of relevance to the major forms of toxicity encountered in patients taking this drug.

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Mechanism of Clozapine-Induced Agranulocytosis

Pirmohamed

Park

1997

CNS Drugs

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Clozapine is an atypical antipsychotic agent that has several advantages over conventional antipsychotics, not least of which is its superior efficacy. However, the high risk of agranulocytosis (0.8% of patients) associated with clozapine therapy has resulted in restricted indications for its use.The mechanism of clozapine-induced agranulocytosis is not clear. The target cells affected are the myeloid precursors, although the mature neutrophil may also be targeted simultaneously. There is no convincing evidence of direct toxicity of the parent compound or its stable metabolites (demethyl-clozapine and clozapine N-oxide). Clozapine is also metabolised by liver microsomes, peripheral blood neutrophils and their bone marrow precursors to a chemically reactive intermediate that has been postulated to be a nitrenium ion. This toxic metabolite has been shown to covalently bind to neutrophil proteins, suggesting that it may be involved in the pathogenesis of the toxicity. However, it is not clear how toxicity is mediated. The nitrenium ion may bind to essential cellular proteins and disrupt neutrophil function or, alternatively, it may act as a hapten and initiate an immune reaction resulting in immune-mediated destruction of the neutrophil. Indirect evidence exists to support both mechanisms, although clear direct evidence is still lacking. The role of cytokines and apoptosis in the pathogenesis of the agranulocytosis is unclear.The reason why only approximately 1% of individuals who are treated with clozapine are affected by agranulocytosis has not been elucidated. Evidence exists to implicate both the major histocompatibility complex antigens and heat shock protein variants in determining individual susceptibility, although more patients of different ethnic backgrounds need to be studied.The ultimate aim of research into clozapine-induced agranulocytosis should be to either prospectively predict which individuals are going to develop agranulocytosis and/or to develop analogues that retain efficacy but are not toxic. The former is complicated by the fact that predisposition may be multifactorial, and thus prediction may require multiple tests that may be of statistical but not absolute validity. The latter depends on identifying the mechanism of toxicity and the chemical characteristics of clozapine that are responsible for the toxicity. This knowledge may allow rational design of new analogues that do not cause agranulocytosis.

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The incidence of neutropenia and agranulocytosis in patients treated with clozapine in the UK and Ireland

Cited by 4 publications

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Testing the Hypothesis that Vitamin C Deficiency Is a Risk Factor for Clozapine-Induced Agranulocytosis Using Guinea Pigs and ODS Rats

Testing the Hypothesis that Vitamin C Deficiency Is a Risk Factor for Clozapine-Induced Agranulocytosis Using Guinea Pigs and ODS Rats

Induction of Metabolism-Dependent and -Independent Neutrophil Apoptosis by Clozapine

Mechanism of Clozapine-Induced Agranulocytosis

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