Clozapine-induced agranulocytosis/granulocytopenia: mechanisms and monitoring

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Purpose of review

Clozapine-induced agranulocytosis/granulocytopenia (CIAG) is an uncommon condition, but potentially fatal in consequences. The pathogenesis, despite multiple experiments, is not fully elucidated. The current theory suggests reactive oxygen species – nitrenium ion as the most important factor of CIAG. In this review, mechanism and monitoring of CIAG will be discussed.

Recent findings

The mechanism of CIAG seems to have an autoimmune background, rather than toxic. Clozapine has a high potential to undergo biochemical activation to nitrenium ion. The role of the primary metabolite of clozapine – N-desmethylclozapine – is in decline. Nitrenium ion is mainly synthesized by CYP3A4, CYP2D6, and myeloperoxidase system in leukocytes. An important component of CIAG pathogenesis is genetic aberration in human leukocyte antigen genes, and also genes associated with apoptosis and ubiquitination. Clozapine monitoring regimes differ between countries. US-derived clozapine Risk Evaluation and Mitigation Strategy is the most tolerant in the aspect of blood parameter thresholds. Therefore, it provides the opportunities for physician to continue the treatment and also to rechallenge the drug after the episode of CIAG.


Each patient with the episode of CIAG should be assessed individually, with special attention to risk factors and drug–drug interactions. Upon that, the decision about clozapine rechallenge or withdrawal should be made.

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