Potential Antidepressive Effects of R-ketamine in Patients with Treatment Resistance Depression

Ketamine, long used as an anesthetic, also reduces depressive symptoms at lower doses, especially in people with treatment-resistant depression (TRD) for whom standard antidepressants often fail. Pre-clinical studies of ketamine's two mirror-image forms—R-ketamine and S-ketamine—suggested that R-ketamine might work faster, last longer, and cause fewer side effects and less risk of abuse. However, early clinical trials testing R-ketamine for TRD have not yet shown clear antidepressant benefits, even though the drug appeared safe and tolerable. This review compares the two enantiomers and concludes that while R-ketamine looked promising in animal studies, it did not consistently reduce depression in human trials, making its effectiveness uncertain.

Study at a glance

Abstract

Ketamine has a long history as an anesthetic but has recently demonstrated antidepressant effects at sub-anesthetic doses (Matveychuk et al., 2020). For individuals with treatment-resistant depression (TRD), typical antidepressants are frequently ineffective, whereas ketamine’s unique mechanisms have demonstrated promising results in reducing depressive symptoms where other treatments have failed (Voineskos et al., 2020; Matveychuk et al., 2020). Pre-clinical investigation of the ketamine enantiomers, R- and S-ketamine, revealed that R-ketamine may be more effective than S-ketamine due to its rapid-acting, long-lasting antidepressant-like effects with fewer psychotomimetic side effects and abuse liability (Chang et al., 2019; Yang et al., 2015; Bonaventura et al., 2021; Koncz et al., 2023). However, early clinical trials assessing R-ketamine to treat TRD have not yet produced significant antidepressant effects despite promising safety and tolerability profiles (Leal et al., 2023). This review compares the antidepressant efficacy, abuse liability, and safety profiles of ketamine enantiomers, focusing on the antidepressant success of R-ketamine in pre-clinical and clinical trials for TRD. Although R-ketamine did present promising results for treating TRD in pre-clinical trials, it did not demonstrate consistent significant antidepressant effects in clinical trials, making it difficult to conclude its effects in treating depression.