Why is Clozapine uniquely Effective in Treatment Resistant Schizophrenia?

IF 9.6 1区 医学 Q1 NEUROSCIENCES
Robin M Murray, Alice Egerton, Yueming Gao, Anthony A Grace, Oliver Howes, Sameer Jauhar, Stefan Leucht, Eric Y H Chen, James H MacCabe, Robert A McCutcheon, Sridhar Natesan, David Taylor
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Abstract

Much is known about the use, benefits, and side-effects, of clozapine in treatment resistant schizophrenia (TRS). However, why clozapine is more effective than other antipsychotics in TRS remains unclear. This paper addresses this question. TRS patients show glutamate abnormalities, and clozapine has widespread effects on glutamate. However, these actions have not been proven different to those of other antipsychotics. Immune dysfunction is also reported in TRS, and clozapine has anti-inflammatory actions, but these have not been correlated with clinical improvement. Currently, there is much interest in muscarinic abnormalities in psychosis. Unlike most antipsychotics, clozapine has important effects on muscarinic receptors, particularly M1 and M4, and its major metabolite, N-desmethylclozapine, is a full agonist at M1. These effects are likely crucial to clozapine's effectiveness. In addition, clozapine's lower D2 receptor occupancy has been postulated to allow gradual resolution of dopamine receptor supersensitivity in the minority of patients with TRS who initially respond to antipsychotics but become resistant following long-term dopamine blockade. This hypothesis, however, remains controversial. Clozapine's multi-receptor profile enables it to have beneficial actions on the non-psychotic symptoms common in TRS: its ability to bind to histamine H1, serotonin 5-HT1A and GABA-B receptors offers an explanation for its anxiolytic actions while effects on 5-HT1A, 5-HT2A and 5-HT7 receptors likely underly its antidepressant properties. Clozapine shares these properties with olanzapine and quetiapine but its affinity for muscarinic receptors may be the mechanism by which it is more effective in TRS.

为什么氯氮平对治疗难治性精神分裂症特别有效?
关于氯氮平在治疗难治性精神分裂症(TRS)中的使用、益处和副作用,我们已经知道很多。然而,为什么氯氮平在TRS中比其他抗精神病药物更有效尚不清楚。本文解决了这个问题。TRS患者表现为谷氨酸异常,氯氮平对谷氨酸有广泛影响。然而,这些作用并没有被证明与其他抗精神病药物不同。TRS中也有免疫功能障碍的报道,氯氮平具有抗炎作用,但这些与临床改善无关。目前,人们对精神病中的毒蕈碱异常非常感兴趣。与大多数抗精神病药物不同,氯氮平对毒蕈碱受体,特别是M1和M4有重要作用,其主要代谢物n -去甲基氯氮平是M1的完全激动剂。这些影响可能对氯氮平的有效性至关重要。此外,氯氮平较低的D2受体占用率被认为可以使少数最初对抗精神病药物有反应但在长期多巴胺阻断后变得耐药的TRS患者的多巴胺受体超敏感逐渐消退。然而,这一假设仍然存在争议。氯氮平的多受体特征使其对TRS中常见的非精神病性症状具有有益作用:其与组胺H1, 5-HT1A和GABA-B受体结合的能力解释了其抗焦虑作用,而对5-HT1A, 5-HT2A和5-HT7受体的作用可能是其抗抑郁特性的基础。氯氮平与奥氮平和喹硫平具有这些特性,但其对毒蕈碱受体的亲和力可能是其在TRS中更有效的机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Biological Psychiatry
Biological Psychiatry 医学-精神病学
CiteScore
18.80
自引率
2.80%
发文量
1398
审稿时长
33 days
期刊介绍: Biological Psychiatry is an official journal of the Society of Biological Psychiatry and was established in 1969. It is the first journal in the Biological Psychiatry family, which also includes Biological Psychiatry: Cognitive Neuroscience and Neuroimaging and Biological Psychiatry: Global Open Science. The Society's main goal is to promote excellence in scientific research and education in the fields related to the nature, causes, mechanisms, and treatments of disorders pertaining to thought, emotion, and behavior. To fulfill this mission, Biological Psychiatry publishes peer-reviewed, rapid-publication articles that present new findings from original basic, translational, and clinical mechanistic research, ultimately advancing our understanding of psychiatric disorders and their treatment. The journal also encourages the submission of reviews and commentaries on current research and topics of interest.
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