The Antidepressant Actions of Ketamine and its Enantiomers

Summary

Ketamine shows rapid antidepressant effects in treatment-resistant depression, but side effects and misuse risk limit its use. Its two enantiomers, (S)- and (R)-ketamine, work through different mechanisms: (S)-ketamine affects mTORC1 signaling, while (R)-ketamine affects ERK signaling. Preclinical studies suggest divergent pathways, and clinical research indicates (R)-ketamine has a milder side effect profile and reduces depression scores. However, recent randomized controlled trials found (R)-ketamine had no significant antidepressant efficacy compared to placebo, so caution is needed when interpreting its therapeutic potential. Further research is required to optimize dosing, route, and administration for each enantiomer.

Study at a glance

Abstract

Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist first developed as an anesthetic, has shown significant promise as a medication with rapid antidepressant properties in treatment-resistant depression. However, concerns such as adverse side effects and potential misuse liability have limited its widespread use. Racemic ketamine has two enantiomers—(S)- and (R)-ketamine—that appear to have disparate underlying mechanisms. This brief review summarizes some of the most recent preclinical and clinical research regarding the convergent and divergent prophylactic, immediate, and sustained antidepressant effects of (S)- and (R)-ketamine while addressing potential differences in their side effect and misuse liability profiles. Preclinical research suggests divergent mechanisms underlying (S)- and (R)-ketamine, with (S)-ketamine more directly affecting mechanistic target of rapamycin complex 1 (mTORC1) signaling and (R)-ketamine more directly affecting extracellular signal-related kinase (ERK) signaling. Clinical research suggests that (R)-ketamine has a milder side effect profile than (S)-ketamine and decreases depression rating scale scores, but recent randomized, controlled trials found that it had no significant antidepressant efficacy compared to placebo, suggesting that caution is warranted in interpreting its therapeutic potential. Future preclinical and clinical research is needed to maximize the efficacy of each enantiomer, either by optimizing dose, route of administration, or administration paradigm.