Targeting glutamate signalling in depression: progress and prospects
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Updated: Mar 6, 2026

Animal Models of Depression - Chronic Despair Model CDM
Published on: September 23, 2021
James W Murrough1, Chadi G Abdallah2, Sanjay J Mathew3
1Mood 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.
Abstract:
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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