title: Targeting glutamate signalling in depression: progress and prospects.
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.
authors.affiliation: 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.
authors.forename: James W
authors.initials: JW
authors.lastname: Murrough
authors.affiliation: Clinical Neuroscience Division, VA National Center for PTSD; Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06511, USA.
authors.forename: Chadi G
authors.initials: CG
authors.lastname: Abdallah
authors.affiliation: 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.
authors.forename: Sanjay J
authors.initials: SJ
authors.lastname: Mathew
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000503:physiopathology; D015195:Drug Design; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D007649:Ketamine / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000928:Antidepressive Agents; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D007649:Ketamine