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.

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针对抑郁症的谷氨酸信号：进展和前景

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定义为一种快速起作用的抗抑郁药，催化了谷氨酸信号调节剂作为抑郁症新型治疗剂的研究。在这篇综述中，我们讨论了用于治疗抑郁症的调节剂的开发进展，并考察了最近的临床前和转化研究，这些研究调查了靶向谷氨酸盐的抗抑郁药的作用机理。关于该药物开发系列的未来前景，仍然存在根本性问题，包括有关安全性和耐受性，功效，剂量反应关系和治疗机制的问题。