PMID- 23534055
OWN - NLM
STAT- MEDLINE
DCOM- 20130327
LR  - 20141114
IS  - 1535-7228 (Electronic)
IS  - 0002-953X (Linking)
VI  - 169
IP  - 11
DP  - 2012 Nov
TI  - Synaptic mechanisms underlying rapid antidepressant action of ketamine.
PG  - 1150-6
AB  - Recent clinical studies have demonstrated that a single subpsychotomimetic dose 
      of ketamine, an ionotropic glutamatergic N-methyl-D-aspartate (NMDA) receptor 
      antagonist, produces a rapid antidepressant response in patients with major 
      depressive disorder, with effects lasting up to 2 weeks. Despite enthusiasm about 
      this unexpected efficacy of ketamine, its widespread use as a fast-acting 
      antidepressant in routine clinical settings is curtailed by its abuse potential 
      as well as possible psychotomimetic effects. However, the ability of ketamine to 
      produce a rapid and long-lasting antidepressant response in patients with 
      depression provides a unique opportunity for investigation of mechanisms that 
      mediate these clinically relevant behavioral effects. From a mechanistic 
      perspective, it is easy to imagine how activation of NMDA receptors may trigger 
      cellular and behavioral responses; it is relatively more difficult, however, to 
      envision how transient blockade of one of the key pathways for neuronal 
      communication produces a persistent beneficial effect. The authors discuss recent 
      work linking ketamine's mechanism of action to homeostatic synaptic plasticity 
      processes activated after suppression of NMDA-mediated glutamatergic 
      neurotransmission. They focus on their recent work demonstrating that 
      ketamine-mediated blockade of NMDA receptors at rest deactivates eukaryotic 
      elongation factor 2 (eEF2) kinase, resulting in reduced eEF2 phosphorylation and 
      desuppression of rapid dendritic protein translation, including BDNF 
      (brain-derived neurotrophic factor), which then contributes to synaptic 
      plasticity mechanisms that mediate longterm effects of the drug. The authors also 
      explore possible molecular strategies to target spontaneous neurotransmitter 
      release selectively to help uncover novel presynaptic avenues for the development 
      of fast-acting antidepressants and possibly psychoactive compounds with 
      effectiveness against other neuropsychiatric disorders.
FAU - Kavalali, Ege T
AU  - Kavalali ET
AD  - Department of Neuroscience, University of Texas Southwestern Medical Center, 
      Dallas, USA. ege.kavalali@utsouthwestern.edu
FAU - Monteggia, Lisa M
AU  - Monteggia LM
LA  - eng
GR  - MH066198/MH/NIMH NIH HHS/United States
GR  - MH070727/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  - United States
TA  - Am J Psychiatry
JT  - The American journal of psychiatry
JID - 0370512
RN  - 0 (Antidepressive Agents)
RN  - 0 (Neurotransmitter Agents)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - 690G0D6V8H (Ketamine)
SB  - IM
CIN - Am J Psychiatry. 2012 Nov;169(11):1137-40. PMID: 23128919
MH  - Animals
MH  - Antidepressive Agents/*pharmacology
MH  - Brain/*drug effects
MH  - Disease Models, Animal
MH  - Humans
MH  - Ketamine/*pharmacology
MH  - Mice
MH  - Neuronal Plasticity/drug effects
MH  - Neurotransmitter Agents/metabolism
MH  - Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors
MH  - Signal Transduction/drug effects
MH  - Synapses/*drug effects
MH  - Synaptic Transmission/*drug effects
MH  - Synaptic Vesicles/drug effects
EDAT- 2013/03/28 06:00
MHDA- 2013/03/28 06:01
CRDT- 2013/03/28 06:00
PHST- 2013/03/28 06:00 [entrez]
PHST- 2013/03/28 06:00 [pubmed]
PHST- 2013/03/28 06:01 [medline]
AID - 10.1176/appi.ajp.2012.12040531 [doi]
PST - ppublish
SO  - Am J Psychiatry. 2012 Nov;169(11):1150-6. doi: 10.1176/appi.ajp.2012.12040531.