Sial Omar K, Parise Eric M, Parise Lyonna F, Gnecco Tamara, Bolaños-Guzmán Carlos A
Texas A&M University: Department of Psychological and Brain Sciences, 4325 TAMU, College Station, TX, 77843, USA.
Fishberg Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, New York, NY, 10029, USA.
Behav Brain Res. 2020 Apr 6;383:112508. doi: 10.1016/j.bbr.2020.112508. Epub 2020 Feb 1.
Two decades ago, the observation of a rapid and sustained antidepressant response after ketamine administration provided an exciting new avenue in the search for more effective therapeutics for the treatment of clinical depression. Research elucidating the mechanism(s) underlying ketamine's antidepressant properties has led to the development of several hypotheses, including that of disinhibition of excitatory glutamate neurons via blockade of N-methyl-d-aspartate (NMDA) receptors. Although the prominent understanding has been that ketamine's mode of action is mediated solely via the NMDA receptor, this view has been challenged by reports implicating other glutamate receptors such as AMPA, and other neurotransmitter systems such as serotonin and opioids in the antidepressant response. The recent approval of esketamine (Spravato™) for the treatment of depression has sparked a resurgence of interest for a deeper understanding of the mechanism(s) underlying ketamine's actions and safe therapeutic use. This review aims to present our current knowledge on both NMDA and non-NMDA mechanisms implicated in ketamine's response, and addresses the controversy surrounding the antidepressant role and potency of its stereoisomers and metabolites. There is much that remains to be known about our understanding of ketamine's antidepressant properties; and although the arrival of esketamine has been received with great enthusiasm, it is now more important than ever that its mechanisms of action be fully delineated, and both the short- and long-term neurobiological/functional consequences of its treatment be thoroughly characterized.
二十年前，氯胺酮给药后出现快速且持续的抗抑郁反应这一现象，为寻找更有效的临床抑郁症治疗方法开辟了一条令人兴奋的新途径。阐明氯胺酮抗抑郁特性背后机制的研究催生了几种假说，包括通过阻断N-甲基-D-天冬氨酸（NMDA）受体来解除对兴奋性谷氨酸能神经元的抑制作用这一假说。尽管普遍的认识是氯胺酮的作用方式仅通过NMDA受体介导，但这一观点受到了一些报告的挑战，这些报告表明其他谷氨酸受体（如AMPA）以及其他神经递质系统（如5-羟色胺和阿片类物质）也参与了抗抑郁反应。艾氯胺酮（Spravato™）近期获批用于治疗抑郁症，引发了人们对更深入了解氯胺酮作用机制及安全治疗用途的兴趣再度高涨。本综述旨在介绍我们目前对氯胺酮反应中涉及的NMDA和非NMDA机制的认识，并探讨围绕其立体异构体和代谢产物的抗抑郁作用及效力的争议。关于我们对氯胺酮抗抑郁特性的理解，仍有许多未知之处；尽管艾氯胺酮的问世备受欢迎，但现在比以往任何时候都更重要的是，要全面阐明其作用机制，并彻底明确其治疗的短期和长期神经生物学/功能后果。
