title: Glutamate receptor antagonists as fast-acting therapeutic alternatives for the treatment of depression: ketamine and other compounds.
abstract: The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has rapid and potent antidepressant effects in treatment-resistant major depressive disorder and bipolar depression. These effects are in direct contrast to the more modest effects seen after weeks of treatment with classic monoaminergic antidepressants. Numerous open-label and case studies similarly validate ketamine's antidepressant properties. These clinical findings have been reverse-translated into preclinical models in an effort to elucidate ketamine's antidepressant mechanism of action, and three important targets have been identified: mammalian target of rapamycin (mTOR), eukaryotic elongation factor 2 (eEF2), and glycogen synthase kinase-3 (GSK-3). Current clinical and preclinical research is focused on (a) prolonging/maintaining ketamine's antidepressant effects, (b) developing more selective NMDA receptor antagonists free of ketamine's adverse effects, and (c) identifying predictor, mediator/moderator, and treatment response biomarkers of ketamine's antidepressant effects.
authors.affiliation: Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institutes of Health/National Institute of Mental Health, Bethesda, Maryland 20814-9692; email: mark.niciu@nih.gov.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Niciu
authors.forename: Ioline D
authors.initials: ID
authors.lastname: Henter
authors.forename: David A
authors.initials: DA
authors.lastname: Luckenbaugh
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Zarate
authors.forename: Dennis S
authors.initials: DS
authors.lastname: Charney
mesh_terms: D000928:Antidepressive Agents / Q000494:pharmacology*; D003863:Depression / Q000188:drug therapy*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D007649:Ketamine / Q000494:pharmacology*; D020652:Peptide Elongation Factor 2 / Q000378:metabolism; D016032:Randomized Controlled Trials as Topic; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000928:Antidepressive Agents; D018691:Excitatory Amino Acid Antagonists; D020652:Peptide Elongation Factor 2; D007649:Ketamine; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3