快速起效抗抑郁药物的潜在靶标

Progress in potential targets for fast-onset antidepressants

抑郁症已成为全球性严重的公共卫生问题和突出的社会问题。现有一线抗抑郁药物绝大多数基于单胺策略研发,普遍存在效率不高、起效缓慢(2~6周)以及导致认知功能损伤、性功能障碍等诸多缺陷。尤其是其临床起效的延迟效应,会大大降低患者的临床依从性,从而增加患者自杀及自残风险。因此,开发快速起效、低毒副作用的新一代抗抑郁药物已成为国内外药学家的重点研究方向。近年来,关于抑郁症的发病机制和药物治疗靶标的研究取得了可喜进展,抗抑郁药物研究从传统的增加脑内去甲肾上腺素5-羟色胺(NE/5-HT)等单胺水平,逐渐深入到调控神经系统适应性和可塑性变化,尤其是发现了N-甲基-D-天门冬氨酸(NMDA)受体、α-氨基-3羟基-5甲基-4异噁唑丙酸(AMPA)受体、M胆碱受体等在内的一系列基于非单胺递质的潜在的快速起效抗抑郁药物分子靶标。围绕着这些潜在靶标,本文对广义的快速抗抑郁药物进行总结和分析,综述其靶标价值及作用机制,旨在对新型快速起效抗抑郁药物的研发提供参考。

Depression has become a serious global public health concern and a prominent social problem.Moreover,the majority of first-line antidepressants that target monoamine neurotransmitter function have significant limitations（ie,low response rates,a time-lag of weeks for a response,cognitive impairment and sexual dysfunction）,particularly with the delayed onset of clinical effects which will reduce the patients′clinical compliance and increase the patients′risk of suicide and self-harm.All this highlights a major unmet need for a new generation of antidepressants with fast onset action and low toxic side effects.There has been great progress in the study on pathogenesis of depression and drug targets so far.Recent research has shifted from increasing the level of monoamine neurotransmitter（NE/5-HT）to focusing on regulating the adaptive and plastic change of the nervous system,especially the discovery of new potential fast-onset non-monoaminergic targets including NMDA receptor,AMPA receptor and M choline receptor.This article reviews the investigation into generalized fast antidepressants and their potential targets,in the hope of providing critical information for the development of fastonset antidepressants.