The Synaptic Biology and Cognition Laboratory, The Florey, Parkville, Victoria, Australia.
Florey Department of Neuroscience and Mental Health, Parkville, Victoria, Australia.
Expert Opin Investig Drugs. 2023 Jul-Dec;32(12):1113-1121. doi: 10.1080/13543784.2023.2288074. Epub 2023 Dec 28.
Successful phase 3 trials of KarXT in people with schizophrenia herald a new era of treating the disorder with drugs that do not target the dopamine D2 receptor. The active component of KarXT is xanomeline, a muscarinic (CHRM) M1 and M4 agonist, making muscarinic receptors a viable target for treating schizophrenia.
This review covers the process of taking drugs that activate the muscarinic M1 and M4 receptors from conceptualization to the clinic and details the mechanisms by which activating the CHRM1 and 4 can affect the broad spectrum of symptoms experienced by people with schizophrenia.
Schizophrenia is a syndrome which means drugs that activate muscarinic M1 and M4 receptors, as was the case for antipsychotic drugs acting on the dopamine D2 receptor, will not give optimal outcomes in everyone within the syndrome. Thus, it would be ideal to identify people who are responsive to drugs activating the CHRM1 and 4. Given knowledge of the actions of these receptors, it is possible treatment non-response could be restricted to sub-groups within the syndrome who have deficits in cortical CHRM1 or those with one of the cognitive endophenotypes that may be identifiable by changes in the blood transcriptome.
KarXT 在精神分裂症患者中的成功 3 期试验标志着一个新时代的到来，即用非多巴胺 D2 受体靶向药物治疗该疾病。KarXT 的活性成分是 xanomeline，一种毒蕈碱（CHRM）M1 和 M4 激动剂，这使得毒蕈碱受体成为治疗精神分裂症的一个可行靶点。
本综述涵盖了从概念到临床阶段将激活毒蕈碱 M1 和 M4 受体的药物的开发过程，并详细介绍了激活 CHRM1 和 4 可以影响精神分裂症患者广泛症状的机制。
精神分裂症是一种综合征，这意味着激活毒蕈碱 M1 和 M4 受体的药物，如作用于多巴胺 D2 受体的抗精神病药物，在该综合征中的每个人身上都不会产生最佳效果。因此，理想情况下是确定对激活 CHRM1 和 4 的药物有反应的人。鉴于对这些受体作用的了解，治疗无反应可能仅限于综合征内皮质 CHRM1 缺陷的亚组或可能通过血液转录组变化来识别的认知表型之一的人。
