The pharmacology underlying the unique antipsychotic efficacy of clozapine.

IF 5.5 3区 医学 Q1 CLINICAL NEUROLOGY
Gavin P Reynolds
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引用次数: 0

Abstract

Clozapine is unique in being the only recourse for people with schizophrenia not responding to conventional pharmacotherapy with dopamine D2 antagonists and partial agonists. Yet, after half a century of use, the underlying mechanism of clozapine's relatively greater efficacy remains elusive. There have been many hypotheses relating to various neurotransmitter receptors that have not withstood further study, and some that have not been fully investigated. The recent introduction of the xanomeline-trospium combination for the treatment of schizophrenia has renewed interest in muscarinic receptor mechanisms; like xanomeline, clozapine and particularly its metabolite norclozapine reportedly have partial agonist actions at some muscarinic receptor subtypes. In their recent article, Morrison et al. draw attention to this by highlighting hypersalivation, a common feature of clozapine treatment that is not shared by other antipsychotic agents which they suggest to be a result of muscarinic receptor agonism. However the relatively weak muscarinic activity of clozapine, low brain availability of norclozapine and clinical findings from xanomeline combine to provide little support for muscarinic mechanisms underlying the greater efficacy of clozapine. An alternative hypothesis is that of alpha2 adrenergic receptor antagonism, a feature of clozapine pharmacology that may also contribute to clozapine-induced hypersalivation. Clinical findings with adjunctive alpha2 antagonists demonstrate clozapine-like improvements in antipsychotic efficacy, while both preclinical studies with specific alpha2C antagonists and the relatively high and selective antagonism of alpha2C receptors by clozapine provide support for this mechanism for clozapine's unique efficacy.

氯氮平独特抗精神病疗效的药理学基础。
氯氮平是精神分裂症患者对多巴胺D2拮抗剂和部分激动剂的常规药物治疗无效的唯一选择。然而,经过半个世纪的使用,氯氮平相对更有效的潜在机制仍然难以捉摸。有许多关于各种神经递质受体的假设还没有经受住进一步的研究,有些还没有得到充分的研究。最近引入的治疗精神分裂症的黄嘌呤-trospium组合重新引起了对毒蕈碱受体机制的兴趣;与xanomeline一样,氯氮平及其代谢物去氯氮平据报道对某些毒蕈碱受体亚型具有部分激动作用。在他们最近的文章中,Morrison等人强调了氯氮平治疗的一个共同特征——唾液分泌过多,这是其他抗精神病药物所没有的,他们认为这是毒蕈碱受体激动作用的结果。然而,氯氮平相对较弱的毒蕈碱活性,去氯氮平的低脑可利用性和xanomeline的临床结果结合起来,几乎没有支持氯氮平更有效的毒蕈碱机制。另一种假说是α 2肾上腺素能受体的拮抗作用,这是氯氮平药理学的一个特征,也可能导致氯氮平诱导的唾液分泌过多。辅助alpha2拮抗剂的临床研究结果显示,氯氮平具有类似氯氮平的抗精神病疗效改善,而特异性alpha2C拮抗剂的临床前研究和氯氮平对alpha2C受体相对较高的选择性拮抗作用均支持氯氮平独特疗效的这一机制。
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来源期刊
Journal of Psychopharmacology
Journal of Psychopharmacology 医学-精神病学
CiteScore
8.60
自引率
4.90%
发文量
126
审稿时长
3-8 weeks
期刊介绍: The Journal of Psychopharmacology is a fully peer-reviewed, international journal that publishes original research and review articles on preclinical and clinical aspects of psychopharmacology. The journal provides an essential forum for researchers and practicing clinicians on the effects of drugs on animal and human behavior, and the mechanisms underlying these effects. The Journal of Psychopharmacology is truly international in scope and readership.
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