Major depressive disorder (MDD) is among the most disabling medical illnesses worldwide and ranks first among all mental health, substance and neurological disorders in terms of disability-adjusted life years 1,2 . The consequences of untreated or partially treated depres- sion are enormous for patients, their families, health- care systems and society 3 . A substantial proportion of patients with MDD do not respond to current treat- ments, despite many antidepressant trials and augmenta- tion strategies 4,5 : up to ~20% of patients with MDD have treatment-resistant depression (TRD; usually defined as a failure to respond to two or more antidepressant med- ication trials) 3 . Moreover, the peak efficacy of first-line antidepressants, such as serotonin-selective reuptake inhibitors (SSRIs), is delayed, with lag times of several weeks to months before benefit. Although the mono- amine systems (including the serotonin, noradrenaline and dopamine systems) have long been the focus of depression research and treatment, there is now a gen- eral consensus that drug discovery must move beyond the monoamine systems to improve patient outcomes. In particular, the glutamate system has emerged as a vibrant area of investigation 6,7 . The ubiquity and complexity of the glutamate sys- tem poses considerable obstacles for drug discovery efforts, in large part owing to the potential for seizure induction and other tolerability-related issues. However, motivated by the recognition that glutamate and its spe- cific receptor subtypes serve fundamental roles in the regulation of synaptic plasticity and affect basic human processes of mood, cognition, learning and reward, sev- eral early-stage clinical neuropsychiatric programmes have been initiated for compounds that target different components of the glutamate system. Such compounds include modulators of ionotropic receptors (including N-methyl-d-aspartate receptors (NMDARs) and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs)), metabotropic glutamate receptor (mGluR) modulators, glycine transporter 1 (GlyT1) inhibitors and glutamate release inhibitors 8 . The NMDAR-blocking agent ketamine — an anaes- thetic that has been available for human use since the 1960s — was reported in 2000 to induce profound clinical improvements in the core symptoms of depression within several hours of treatment 9 ; this was an unexpected find- ing that was later hailed as “arguably the most important discovery [in mood disorders] in half a century” (REF. 10). Moreover, this discovery triggered vigorous research in both industry and academia to understand the role of glutamate signalling in depression pathophysiology and to develop novel treatments. Investigational drugs that target components of the glutamate system have begun to enter phase II and phase III trials. This Review eval- uates the role of glutamate signalling in depression and discusses the potential of ketamine and other glutamate- signalling modulators as novel antidepressant agents. We critically review the limitations of existing studies of the clinical effects and hypothesized mechanisms of action of glutamate-based antidepressant candidates, and detail progress in this area. We evaluate evidence concerning the role of the NMDAR versus other molecular targets in the antidepressant mechanism of action of ketamine and other candidate glutamate modulators, and conclude with a discussion of the challenges of glutamate modu- lation for novel drug development and opportunities for new directions. 1 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. 2 Clinical Neuroscience Division, VA National Center for PTSD; Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06511, USA. 3 Mental Health Care Line, Michael E. DeBakey VA Medical Center; Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, Texas 77030, USA. Correspondence to J.W.M.  james.murrough@mssm.edu doi:10.1038/nrd.2017.16 Published online 17 Mar 2017 Synaptic plasticity Activity- or experience- dependent changes in synaptic structure and function that are relatively long-lasting (that is, persisting beyond the initial electrochemical event). Targeting glutamate signalling in depression: progress and prospects James W. Murrough 1 , Chadi G. Abdallah 2 and Sanjay J. Mathew 3 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. REVIEWS 472 | JULY 2017 | VOLUME 16 www.nature.com/nrd ©2017MacmillanPublishersLimited,partofSpringerNature.Allrightsreserved.