Mood and Anxiety Disorders Program, Department of Psychiatry; Fishberg Department of Neuroscience; and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
Clinical Neuroscience Division, VA National Center for PTSD; Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06511, USA.
Nat Rev Drug Discov. 2017 Jul;16(7):472-486. doi: 10.1038/nrd.2017.16. Epub 2017 Mar 17.
Major depressive disorder (MDD) is severely disabling, and current treatments have limited efficacy. The glutamate N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine was recently repurposed as a rapidly acting antidepressant, catalysing the vigorous investigation of glutamate-signalling modulators as novel therapeutic agents for depressive disorders. In this Review, we discuss the progress made in the development of such modulators for the treatment of depression, and examine recent preclinical and translational studies that have investigated the mechanisms of action of glutamate-targeting antidepressants. Fundamental questions remain regarding the future prospects of this line of drug development, including questions concerning safety and tolerability, efficacy, dose-response relationships and therapeutic mechanisms.
重度抑郁症（MDD）严重致残，目前的治疗方法疗效有限。谷氨酸 N-甲基-D-天冬氨酸受体（NMDAR）拮抗剂氯胺酮最近被重新用作快速作用的抗抑郁药，这促使人们大力研究谷氨酸信号调节剂作为治疗抑郁症的新型治疗药物。在这篇综述中，我们讨论了开发此类调节剂治疗抑郁症方面所取得的进展，并研究了针对谷氨酸的抗抑郁药的作用机制的最近的临床前和转化研究。关于这一药物开发路线的未来前景，仍存在一些基本问题，包括安全性和耐受性、疗效、剂量反应关系和治疗机制等方面的问题。
