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
{"title":"Why is Clozapine uniquely Effective in Treatment Resistant Schizophrenia?","authors":"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","doi":"10.1016/j.biopsych.2025.06.011","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":" ","pages":""},"PeriodicalIF":9.6000,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biological Psychiatry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.biopsych.2025.06.011","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
引用次数: 0
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.
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.