A historical review of antidepressant effects of ketamine and its enantiomers.

Summary

The antidepressant effects of (R,S)-ketamine, a mixture of (R)-ketamine and (S)-ketamine, are a major advance in mood research. Off-label use for treatment-resistant depression has grown in the US, and in 2019 the FDA and European authorities approved (S)-ketamine nasal spray for this condition, but only in certified medical settings. Preclinical evidence indicates that (R)-ketamine may be more potent and longer-lasting as an antidepressant than (S)-ketamine, with fewer side effects. Clinical trials of (R)-ketamine in humans are now underway. This article reviews the history of these compounds and discusses the mechanisms behind ketamine's antidepressant actions.

Study at a glance

Abstract

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.