Antidepressant Potential of ( R)-Ketamine in Rodent Models: Comparison with ( S)-Ketamine

J Pharmacol Exp Ther. 2017 Apr;361(1):9-16. doi: 10.1124/jpet.116.239228. Epub 2017 Jan 23.


The rapid-acting and long-lasting antidepressant effects of (R,S)-ketamine have recently gained much attention. Although (S)-ketamine has been studied as an active isomer, recent evidence suggests that (R)-ketamine exhibits longer-lasting antidepressant effects than (S)-ketamine in rodents. However, the antidepressant potential of (R)-ketamine has not been fully addressed. In the present study, we compared the antidepressant effects of (R)-ketamine with those of (S)-ketamine in animal models of depression, including a model that is refractory to current medications. Both (R)-ketamine and (S)-ketamine exhibited antidepressant effects at 30 minutes as well as at 24 hours after administration in forced-swimming and tail-suspension tests in mice. At 48 hours after administration, however, (R)-ketamine still exerted a significant antidepressant effect in the tail-suspension test, whereas the effect of (S)-ketamine was no longer observed. Moreover, (R)-ketamine, but not (S)-ketamine, significantly reversed the depressive-like behavior induced by repeated treatments with corticosterone in rats at 24 hours after a single administration. This effect was attenuated by an α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor antagonist, suggesting the involvement of AMPA receptor stimulation in the effects. Both (R)-ketamine and (S)-ketamine exhibited practically the same exposure levels in plasma, brain, and cerebrospinal fluid in mice and rats, and both compounds were rapidly eliminated from plasma (<4-8 hours). The present results confirmed the previous findings that (R)-ketamine exerted longer-lasting antidepressant effects than (S)-ketamine in animal models of depression. Moreover, our study is the first to demonstrate that (R)-ketamine exerted a sustained antidepressant effect even in a model that is refractory to currently prescribed antidepressants.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Antidepressive Agents / chemistry*
  • Antidepressive Agents / pharmacology
  • Antidepressive Agents / therapeutic use*
  • Depression / drug therapy*
  • Depression / psychology
  • Dose-Response Relationship, Drug
  • Hindlimb Suspension / methods
  • Hindlimb Suspension / psychology
  • Ketamine / chemistry*
  • Ketamine / pharmacology
  • Ketamine / therapeutic use*
  • Locomotion / drug effects
  • Locomotion / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred ICR
  • Rats
  • Rats, Sprague-Dawley
  • Stereoisomerism
  • Swimming / psychology


  • Antidepressive Agents
  • Ketamine