[Ketamine's antidepressant effect: focus on ketamine mechanisms of action]

Encephale. 2014 Feb;40(1):48-55. doi: 10.1016/j.encep.2013.09.002. Epub 2014 Jan 13.
[Article in French]


Background: In recent years, discovery of ketamine's fast and powerful antidepressant effects for treatment-resistant depression (TRD) has led to rethinking of the pathophysiology of depression. Numerous studies in humans and animals have focused on mechanisms of action underlying this effect, producing a number of explanatory pathways.

Method: The aim of this article is to summarize the various hypotheses underlying rapid antidepressant action of ketamine and therefore to better understand the mechanisms underlying depression and antidepressant action.

Results: Ketamine unique antidepressant properties have led to many studies on its neurobiological grounds. Intracellular signaling pathways such as mTOR, GSK3 or eEF2 seem to play a key role and are associated with an increased synaptic plasticity. Other hypotheses are discussed such as ketamine effects on neuro-inflammation, the role of anterior cingulate cortex in brain changes induced by ketamine, and the potential benefits of analgesic properties of ketamine in depressive disorders.

Conclusion: Our review highlights the potential role of the glutamatergic system in the pathophysiology and treatment of mood disorders. Understanding which pathways underlie the fast antidepressant effect of ketamine paves the way for the development of new antidepressants.

Keywords: Dépression; Dépression résistante; Glutamate; Ketamine; Kétamine; Major depressive disorder; NMDA; NMDA receptors; Treatment-resistant depression.

Publication types

  • Review

MeSH terms

  • Animals
  • Antidepressive Agents / adverse effects
  • Antidepressive Agents / therapeutic use*
  • Brain / drug effects*
  • Brain / physiopathology
  • Depressive Disorder, Treatment-Resistant / diagnosis
  • Depressive Disorder, Treatment-Resistant / drug therapy*
  • Depressive Disorder, Treatment-Resistant / physiopathology
  • Depressive Disorder, Treatment-Resistant / psychology
  • Elongation Factor 2 Kinase / physiology
  • Glycogen Synthase Kinase 3 / physiology
  • Gyrus Cinguli / drug effects
  • Gyrus Cinguli / physiopathology
  • Humans
  • Ketamine / adverse effects
  • Ketamine / therapeutic use*
  • Neuronal Plasticity / drug effects
  • Neuronal Plasticity / physiology
  • Receptors, Neurotransmitter / drug effects
  • Receptors, Neurotransmitter / physiology
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology
  • TOR Serine-Threonine Kinases / physiology


  • Antidepressive Agents
  • Receptors, Neurotransmitter
  • glutamine receptor
  • Ketamine
  • MTOR protein, human
  • EEF2K protein, human
  • TOR Serine-Threonine Kinases
  • Elongation Factor 2 Kinase
  • Glycogen Synthase Kinase 3