A historical review of antidepressant effects of ketamine and its enantiomers

Pharmacol Biochem Behav. 2020 Mar;190:172870. doi: 10.1016/j.pbb.2020.172870. Epub 2020 Feb 5.


The robust antidepressant effects of (R,S)-ketamine are among the most important discoveries in mood research over the last half century. Off-label use of (R,S)-ketamine, which is an equal mixture of (R)-ketamine and (S)-ketamine, has become especially popular in the United States (US) for treatment-resistant depression. On March 5, 2019, the US Food and Drug Administration approved an (S)-ketamine nasal spray for use in treatment-resistant depression, though its use has been limited to certified medical offices or clinics. On December 19, 2019, (S)-ketamine nasal spray was approved for the same indication in Europe. However, despite its potential for benefit, there are several concerns about the efficacy of (S)-ketamine nasal spray. Accumulating evidence from preclinical studies show that (R)-ketamine has greater potency and longer lasting antidepressant effects than (S)-ketamine in animal models of depression, and that (R)-ketamine has fewer detrimental side effects than either (R,S)-ketamine or (S)-ketamine. As such, clinical studies of (R)-ketamine in humans are now underway by Perception Neuroscience Ltd. In this article, we review the brief history of (R,S)-ketamine and its two enantiomers as novel antidepressants. We also discuss the mechanisms of ketamine's antidepressant actions.

Keywords: Antidepressant; Arketamine; Enantiomer; Esketamine; Ketamine.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antidepressive Agents / chemistry*
  • Antidepressive Agents / pharmacology
  • Antidepressive Agents / therapeutic use*
  • Depression / drug therapy*
  • Depressive Disorder, Treatment-Resistant / drug therapy*
  • Humans
  • Ketamine / chemistry*
  • Ketamine / pharmacology
  • Ketamine / therapeutic use*
  • Stereoisomerism
  • Treatment Outcome


  • Antidepressive Agents
  • Esketamine
  • Ketamine