Department of Psychiatry, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Curr Pharm Biotechnol. 2012 Jun;13(8):1572-86. doi: 10.2174/138920112800784880.
The concept that the efficacy of all antipsychotic drugs (APDs) can be explained by their action on dopamine (DA) D2 receptors is most challenged by drugs such as clozapine which target serotonin (5-HT)2A receptors as an essential component of their efficacy and tolerability. The 5-HT2A receptor, along with 5-HT1A, 5-HT 2C, 5-HT 6 or 5-HT 7 receptors, all of which are components of the mechanism of action of clozapine, represent important targets for treating multiple aspects of schizophrenia, especially psychosis and cognitive impairment. The class of atypical antipsychotic drugs (APDs), of which clozapine is the prototype, share in common more effective 5-HT 2A receptor inverse agonism and weaker interference with D2 receptor stimulation, either through D2 receptor blockade or partial D2 receptor agonism. This has led to development of a selective 5-HT2A antagonist, ACP-103 (pimavanserin), which has been found to be effective as monotherapy in L-DOPA psychosis and has promise as an add-on agent for sub-effective doses of atypical APDs. We review here the extensive preclinical evidence to support the importance of 5-HT2A receptor inverse agonism to the action of clozapine and related atypical APDs, and evidence supporting the potential of selective 5-HT2A, 5-HT 6 , and 5-HT 7, antagonists, 5-HT1A partial agonists and 5-HT2C agonists for development of drugs which ameliorate psychosis or cognitive impairment.
所有抗精神病药物（APD）的疗效都可以通过其对多巴胺（DA）D2 受体的作用来解释，这一概念最受氯氮平等药物的挑战，氯氮平等药物将血清素（5-HT）2A 受体作为其疗效和耐受性的重要组成部分。5-HT2A 受体与 5-HT1A、5-HT2C、5-HT6 或 5-HT7 受体一起，都是氯氮平作用机制的组成部分，它们都是治疗精神分裂症多个方面的重要靶点，尤其是精神病和认知障碍。氯氮平为原型的非典型抗精神病药物（APD）类药物具有共同的特点，即更有效的 5-HT2A 受体反向激动作用和对 D2 受体刺激的较弱干扰，无论是通过 D2 受体阻断还是部分 D2 受体激动作用。这导致了选择性 5-HT2A 拮抗剂 ACP-103（pimavanserin）的开发，它已被发现作为单药治疗 L-DOPA 精神病有效，并有望作为非典型 APD 亚有效剂量的附加药物。我们在这里回顾了广泛的临床前证据，以支持 5-HT2A 受体反向激动作用对氯氮平和相关非典型 APD 的重要性，以及支持选择性 5-HT2A、5-HT6 和 5-HT7 拮抗剂、5-HT1A 部分激动剂和 5-HT2C 激动剂开发改善精神病或认知障碍的药物的潜力。
