PMID- 29516301 OWN - NLM STAT- MEDLINE DCOM- 20190311 LR - 20240327 IS - 1179-1934 (Electronic) IS - 1172-7047 (Print) IS - 1172-7047 (Linking) VI - 32 IP - 3 DP - 2018 Mar TI - Convergent Mechanisms Underlying Rapid Antidepressant Action. PG - 197-227 LID - 10.1007/s40263-018-0492-x [doi] AB - Traditional pharmacological treatments for depression have a delayed therapeutic onset, ranging from several weeks to months, and there is a high percentage of individuals who never respond to treatment. In contrast, ketamine produces rapid-onset antidepressant, anti-suicidal, and anti-anhedonic actions following a single administration to patients with depression. Proposed mechanisms of the antidepressant action of ketamine include N-methyl-D-aspartate receptor (NMDAR) modulation, gamma aminobutyric acid (GABA)-ergic interneuron disinhibition, and direct actions of its hydroxynorketamine (HNK) metabolites. Downstream actions include activation of the mechanistic target of rapamycin (mTOR), deactivation of glycogen synthase kinase-3 and eukaryotic elongation factor 2 (eEF2), enhanced brain-derived neurotrophic factor (BDNF) signaling, and activation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors (AMPARs). These putative mechanisms of ketamine action are not mutually exclusive and may complement each other to induce potentiation of excitatory synapses in affective-regulating brain circuits, which results in amelioration of depression symptoms. We review these proposed mechanisms of ketamine action in the context of how such mechanisms are informing the development of novel putative rapid-acting antidepressant drugs. Such drugs that have undergone pre-clinical, and in some cases clinical, testing include the muscarinic acetylcholine receptor antagonist scopolamine, GluN2B-NMDAR antagonists (i.e., CP-101,606, MK-0657), (2R,6R)-HNK, NMDAR glycine site modulators (i.e., 4-chlorokynurenine, pro-drug of the glycine(B) NMDAR antagonist 7-chlorokynurenic acid), NMDAR agonists [i.e., GLYX-13 (rapastinel)], metabotropic glutamate receptor 2/3 (mGluR(2/3)) antagonists, GABA(A) receptor modulators, and drugs acting on various serotonin receptor subtypes. These ongoing studies suggest that the future acute treatment of depression will typically occur within hours, rather than months, of treatment initiation. FAU - Zanos, Panos AU - Zanos P AUID- ORCID: 0000-0002-1968-8648 AD - Department of Psychiatry, University of Maryland School of Medicine, Rm. 934F MSTF, 685 W. Baltimore St., Baltimore, MD, 21201, USA. panoszanos1986@gmail.com. FAU - Thompson, Scott M AU - Thompson SM AD - Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA. AD - Department of Physiology, University of Maryland School of Medicine, St. BRB 5-007, 655 W. Baltimore St., Baltimore, MD, 21201, USA, Baltimore, MD, 21201, USA. FAU - Duman, Ronald S AU - Duman RS AD - Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA. AD - Department of Neurobiology, Yale University School of Medicine, New Haven, CT, USA. FAU - Zarate, Carlos A Jr AU - Zarate CA Jr AD - Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA. FAU - Gould, Todd D AU - Gould TD AD - Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD, USA. AD - Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA. AD - Department of Psychiatry, University of Maryland School of Medicine, Rm. 936 MSTF, 685 W. Baltimore St., Baltimore, MD, 21201, USA. LA - eng GR - R01 MH107615/MH/NIMH NIH HHS/United States GR - R01 MH093897/MH/NIMH NIH HHS/United States GR - MH107615/MH/NIMH NIH HHS/United States GR - R01 MH086828/MH/NIMH NIH HHS/United States GR - MH086828/MH/NIMH NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Review PL - New Zealand TA - CNS Drugs JT - CNS drugs JID - 9431220 RN - 0 (Antidepressive Agents) SB - IM MH - Antidepressive Agents/*therapeutic use MH - Depressive Disorder, Major/*drug therapy MH - Humans MH - *Time Factors PMC - PMC6005380 MID - NIHMS973129 EDAT- 2018/03/09 06:00 MHDA- 2019/03/12 06:00 PMCR- 2018/06/18 CRDT- 2018/03/09 06:00 PHST- 2018/03/09 06:00 [pubmed] PHST- 2019/03/12 06:00 [medline] PHST- 2018/03/09 06:00 [entrez] PHST- 2018/06/18 00:00 [pmc-release] AID - 10.1007/s40263-018-0492-x [pii] AID - 10.1007/s40263-018-0492-x [doi] PST - ppublish SO - CNS Drugs. 2018 Mar;32(3):197-227. doi: 10.1007/s40263-018-0492-x.