PMID- 29532791
OWN - NLM
STAT- MEDLINE
DCOM- 20190404
LR  - 20190404
IS  - 1476-5578 (Electronic)
IS  - 1359-4184 (Print)
IS  - 1359-4184 (Linking)
VI  - 23
IP  - 4
DP  - 2018 Apr
TI  - Mechanisms of ketamine action as an antidepressant.
PG  - 801-811
LID - 10.1038/mp.2017.255 [doi]
AB  - Clinical studies have demonstrated that a single sub-anesthetic dose of the 
      dissociative anesthetic ketamine induces rapid and sustained antidepressant 
      actions. Although this finding has been met with enthusiasm, ketamine's 
      widespread use is limited by its abuse potential and dissociative properties. 
      Recent preclinical research has focused on unraveling the molecular mechanisms 
      underlying the antidepressant actions of ketamine in an effort to develop novel 
      pharmacotherapies, which will mimic ketamine's antidepressant actions but lack 
      its undesirable effects. Here we review hypotheses for the mechanism of action of 
      ketamine as an antidepressant, including synaptic or GluN2B-selective 
      extra-synaptic N-methyl-D-aspartate receptor (NMDAR) inhibition, inhibition of 
      NMDARs localized on GABAergic interneurons, inhibition of NMDAR-dependent burst 
      firing of lateral habenula neurons, and the role of 
      alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor activation. We 
      also discuss links between ketamine's antidepressant actions and downstream 
      mechanisms regulating synaptic plasticity, including brain-derived neurotrophic 
      factor (BDNF), eukaryotic elongation factor 2 (eEF2), mechanistic target of 
      rapamycin (mTOR) and glycogen synthase kinase-3 (GSK-3). Mechanisms that do not 
      involve direct inhibition of the NMDAR, including a role for ketamine's 
      (R)-ketamine enantiomer and hydroxynorketamine (HNK) metabolites, specifically 
      (2R,6R)-HNK, are also discussed. Proposed mechanisms of ketamine's action are not 
      mutually exclusive and may act in a complementary manner to exert acute changes 
      in synaptic plasticity, leading to sustained strengthening of excitatory 
      synapses, which are necessary for antidepressant behavioral actions. 
      Understanding the molecular mechanisms underpinning ketamine's antidepressant 
      actions will be invaluable for the identification of targets, which will drive 
      the development of novel, effective, next-generation pharmacotherapies for the 
      treatment of depression.
FAU - Zanos, P
AU  - Zanos P
AD  - Department of Psychiatry, University of Maryland School of Medicine, Baltimore, 
      MD, USA.
FAU - Gould, T D
AU  - Gould TD
AD  - Department of Psychiatry, University of Maryland School of Medicine, Baltimore, 
      MD, USA.
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.
LA  - eng
GR  - R01 MH107615/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
DEP - 20180313
PL  - England
TA  - Mol Psychiatry
JT  - Molecular psychiatry
JID - 9607835
RN  - 0 (Antidepressive Agents)
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (NR2B NMDA receptor)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - 690G0D6V8H (Ketamine)
RN  - EC 2.7.11.26 (Glycogen Synthase Kinase 3)
SB  - IM
MH  - Animals
MH  - Antidepressive Agents/metabolism/pharmacology
MH  - Brain-Derived Neurotrophic Factor
MH  - Depression/drug therapy
MH  - Depressive Disorder/drug therapy
MH  - Glycogen Synthase Kinase 3
MH  - Humans
MH  - Interneurons/metabolism
MH  - Ketamine/*metabolism/*pharmacology
MH  - Neuronal Plasticity/drug effects
MH  - Neurons/metabolism
MH  - Receptors, N-Methyl-D-Aspartate/metabolism
MH  - Synapses/metabolism
PMC - PMC5999402
MID - NIHMS973128
COIS- Conflicts of interest P.Z. and T.D.G. are listed as co-authors in a patent 
      applications related to the pharmacology and use of (2S,6S)- and 
      (2R,6R)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, 
      suicidal ideation and post-traumatic stress disorders.
EDAT- 2018/03/14 06:00
MHDA- 2019/04/05 06:00
PMCR- 2018/06/13
CRDT- 2018/03/14 06:00
PHST- 2017/06/23 00:00 [received]
PHST- 2017/09/19 00:00 [revised]
PHST- 2017/10/27 00:00 [accepted]
PHST- 2018/03/14 06:00 [pubmed]
PHST- 2019/04/05 06:00 [medline]
PHST- 2018/03/14 06:00 [entrez]
PHST- 2018/06/13 00:00 [pmc-release]
AID - mp2017255 [pii]
AID - 10.1038/mp.2017.255 [doi]
PST - ppublish
SO  - Mol Psychiatry. 2018 Apr;23(4):801-811. doi: 10.1038/mp.2017.255. Epub 2018 Mar 
      13.