Department of Pharmacology and Therapeutics, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Bydgoszcz, Poland.
Curr Opin Hematol. 2018 Jan;25(1):22-28. doi: 10.1097/MOH.0000000000000391.
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.
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.
氯氮平诱导的粒细胞缺乏症/粒细胞减少症（CIAG）是一种罕见的病症，但后果可能是致命的。尽管进行了多项实验，但发病机制仍未完全阐明。目前的理论认为活性氧物质-亚硝鎓离子是 CIAG 的最重要因素。在本次综述中，将讨论 CIAG 的发病机制和监测。
CIAG 的发病机制似乎具有自身免疫背景，而不是毒性。氯氮平具有很高的生化活性，能转化为亚硝鎓离子。氯氮平的主要代谢产物-N-去甲基氯氮平的作用正在下降。亚硝鎓离子主要由白细胞中的 CYP3A4、CYP2D6 和髓过氧化物酶系统合成。CIAG 发病机制的一个重要组成部分是人类白细胞抗原基因的遗传异常，以及与凋亡和泛素化相关的基因。氯氮平的监测方案因国家而异。源自美国的氯氮平风险评估和缓解策略在血液参数阈值方面最为宽松。因此，它为医生提供了继续治疗的机会，并在 CIAG 发作后重新使用该药物。
每位出现 CIAG 发作的患者都应进行个体化评估，特别注意危险因素和药物相互作用。在此基础上，应决定是否重新开始氯氮平治疗或停止治疗。
