Department of Neuropsychiatry, Division of Neuroscience, Graduate School of Medicine, Mie University, Tsu 514-8507, Japan.
National Hospital Organization Sakakibara Hospital, 777 Sakakibara, Tsu, Mie 514-1292, Japan.
Int J Mol Sci. 2020 Sep 24;21(19):7019. doi: 10.3390/ijms21197019.
Clozapine (CLZ) is an approved antipsychotic agent for the medication of treatment-resistant schizophrenia but is also well known as one of the most toxic antipsychotics. Recently, the World Health Organization's (WHO) global database (VigiBase) reported the relative lethality of severe adverse reactions of CLZ. Agranulocytosis is the most famous adverse CLZ reaction but is of lesser lethality compared with the other adverse drug reactions of CLZ. Unexpectedly, VigiBase indicated that the prevalence and relative lethality of pneumonia, cardiotoxicity, and seizures associated with CLZ were more serious than that of agranulocytosis. Therefore, haematological monitoring in CLZ patients monitoring system provided success in the prevention of lethal adverse events from CLZ-induced agranulocytosis. Hereafter, psychiatrists must amend the CLZ patients monitoring system to protect patients with treatment-resistant schizophrenia from severe adverse CLZ reactions, such as pneumonia, cardiotoxicity, and seizures, according to the clinical evidence and pathophysiology. In this review, we discuss the mechanisms of clinical efficacy and the adverse reactions of CLZ based on the accumulating pharmacodynamic findings of CLZ, including tripartite synaptic transmission, and we propose suggestions for amending the monitoring and medication of adverse CLZ reactions associated with pneumonia, cardiotoxicity, and seizures.
氯氮平（CLZ）是一种已批准的抗精神病药物，可用于治疗治疗抵抗性精神分裂症，但也被公认为最毒的抗精神病药之一。最近，世界卫生组织（WHO）的全球数据库（VigiBase）报告了 CLZ 严重不良反应的相对致死率。粒细胞缺乏症是 CLZ 最著名的不良反应，但与 CLZ 的其他药物不良反应相比，其致死率较低。出乎意料的是，VigiBase 表明，肺炎、心脏毒性和癫痫与 CLZ 相关的患病率和相对致死率比粒细胞缺乏症更为严重。因此，CLZ 患者监测系统中的血液学监测成功预防了 CLZ 诱导的粒细胞缺乏症的致死性不良事件。此后，根据临床证据和病理生理学，精神科医生必须修改 CLZ 患者监测系统，以保护治疗抵抗性精神分裂症患者免受肺炎、心脏毒性和癫痫等严重 CLZ 反应的影响。在这篇综述中，我们根据 CLZ 的累积药效学发现，包括三突触传递，讨论了 CLZ 的临床疗效和不良反应的机制，并提出了修改与肺炎、心脏毒性和癫痫相关的 CLZ 不良反应监测和用药的建议。
