Despite the growing burden of major depressive disorder (MDD) on the society, therapeutic management that is mostly based on the conventional monoaminergic mechanisms, is significantly delimited especially from low response rate and time lag for treatment response; thus, often prolonging the distress for patients. The mechanistic exploration of drug candidates that could exert antidepressant effects rapidly has highlighted the significance of modulating mammalian target of rapamycin (mTOR) pathway in MDD. Fast acting antidepressants acts at different receptors, subunits and sites, including NMDA, AMPA, m1ACh, mGluR2/3 and GluN2B to enhance mTOR function, leading to increase in synaptic protein synthesis, synaptogenesis and spine-remodeling, which in turn contribute to the rapid antidepressant effects. This review focuses on the preclinical and clinical evidences on the fast acting antidepressants that can modulate mTOR pathway. It can be understood that modulating mTOR pathway for rapid onset of antidepressant effect in MDD is not without challenges as some of the drugs have failed in advanced stages of clinical trials. However, considering the recent approval of esketamine as a breakthrough in decades, fast acting antidepressants in the mTOR pathway may have promising prospects in the drug discovery pipeline.

尽管重度抑郁症 (MDD) 给社会带来的负担越来越大，但主要基于传统单胺能机制的治疗管理受到明显限制，尤其是低反应率和治疗反应的时间滞后；因此，往往会延长患者的痛苦。对可快速发挥抗抑郁作用的候选药物的机制探索突出了调节 MDD 中哺乳动物雷帕霉素靶点 (mTOR) 通路的重要性。速效抗抑郁药作用于不同的受体、亚基和位点，包括 NMDA、AMPA、m1ACh、mGluR2/3 和 GluN2B，以增强 mTOR 功能，导致突触蛋白合成、突触发生和脊柱重塑增加，进而促进快速抗抑郁作用。本综述重点关注可调节 mTOR 通路的速效抗抑郁药的临床前和临床证据。可以理解，调节mTOR通路以在MDD中快速发挥抗抑郁作用并非没有挑战，因为一些药物在临床试验的晚期阶段已经失败。然而，考虑到最近批准的艾氯胺酮是几十年来的一项突破，mTOR 途径中的速效抗抑郁药可能在药物发现管道中具有广阔的前景。