The rapid-onset antidepressant effect of ketamine: More surprises?

J Clin Pharm Ther. 2018 Apr;43(2):308-311. doi: 10.1111/jcpt.12656. Epub 2017 Nov 26.


What is known and objective: An effective rapid-onset treatment for major depressive disorder could save lives. Extensive preclinical and clinical data demonstrate such an action of ketamine. However, the presumptive mechanism of action, inhibition of NMDA (N-methyl-D-aspartate) receptors, has recently been challenged. Elucidation of the mechanism is important clinically for drug discovery and for understanding the (patho)physiology of depression.

Comment: The best-known pharmacologic property of ketamine is non-competitive inhibition of the NMDA subtype of glutamate receptor. Although other mechanisms have been postulated, this action has been assumed the major one that accounts for ketamine's antidepressant effect. However, a ketamine metabolite and a different mechanism have now been claimed to be necessary and sufficient for the effect.

What is new and conclusion: A metabolite has been proposed to be responsible for the antidepressant action of ketamine, via activation of non-NMDA receptors. It will be important to determine which of the competing views is correct.

Keywords: AMPA receptor; NMDA receptor; antidepressant; ketamine; metabolite.

MeSH terms

  • Antidepressive Agents / therapeutic use*
  • Depression / drug therapy
  • Depression / metabolism
  • Depressive Disorder, Major / drug therapy*
  • Depressive Disorder, Major / metabolism
  • Drug Discovery / methods
  • Humans
  • Ketamine / therapeutic use*
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors


  • Antidepressive Agents
  • Receptors, N-Methyl-D-Aspartate
  • Ketamine