Synaptic mechanisms underlying rapid antidepressant action of ketamine

Ege T Kavalali, Lisa M Monteggia

Research output: Contribution to journalArticle

150 Citations (Scopus)

Abstract

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 long-term 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 compoundswith effectiveness against other neuropsychiatric disorders.

Original languageEnglish (US)
Pages (from-to)1150-1156
Number of pages7
JournalAmerican Journal of Psychiatry
Volume169
Issue number11
DOIs
StatePublished - Nov 1 2012

Fingerprint

Ketamine
Antidepressive Agents
N-Methyl-D-Aspartate Receptors
Neuronal Plasticity
Elongation Factor 2 Kinase
Peptide Elongation Factor 2
Aptitude
Brain-Derived Neurotrophic Factor
Major Depressive Disorder
Protein Biosynthesis
N-Methylaspartate
Synaptic Transmission
Neurotransmitter Agents
Communication
Phosphorylation
Antidepressants
Depression
Pharmaceutical Preparations
Plasticity

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Arts and Humanities (miscellaneous)

Cite this

Synaptic mechanisms underlying rapid antidepressant action of ketamine. / Kavalali, Ege T; Monteggia, Lisa M.

In: American Journal of Psychiatry, Vol. 169, No. 11, 01.11.2012, p. 1150-1156.

Research output: Contribution to journalArticle

Kavalali, Ege T ; Monteggia, Lisa M. / Synaptic mechanisms underlying rapid antidepressant action of ketamine. In: American Journal of Psychiatry. 2012 ; Vol. 169, No. 11. pp. 1150-1156.
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