Activation of σ1-Receptors by R-Ketamine May Enhance the Antidepressant Effect of S-Ketamine

Ketamine is a racemic mixture of S-ketamine and R-ketamine, each with distinct pharmacological activities. S-ketamine blocks NMDA channels and acts as an opioid μ-receptor agonist, while R-ketamine binds to σ1-receptors and is believed to act as an agonist. In patients with major depressive disorder, S-ketamine nasal spray shows clear antidepressant activity, but compared to intravenous racemic ketamine, its response rate, duration of action, and anti-suicidal activity appear less pronounced. The σ1-activity of R-ketamine may enhance pathways through which S-ketamine produces antidepressant effects and provide its own antidepressant activity, potentially explaining the superior effect of racemic ketamine over S-ketamine alone.

Study at a glance

Abstract

Ketamine is a racemic mixture composed of two enantiomers, S-ketamine and R-ketamine. In preclinical studies, both enantiomers have exhibited antidepressant effects, but these effects are attributed to distinct pharmacological activities. The S-enantiomer acts as an NMDA-channel blocker and as an opioid μ-receptor agonist, whereas the R-enantiomer binds to σ1-receptors and is believed to act as an agonist. As racemate, ketamine potentially triggers four biochemical pathways involving the AGC-kinases, PKA, Akt (PKB), PKC and RSK that ultimately lead to inhibitory phosphorylation of GSK3β in microglia. In patients with major depressive disorder, S-ketamine administered as a nasal spray has shown clear antidepressant activity. However, when compared to intravenously infused racemic ketamine, the response rate, duration of action and anti-suicidal activity of S-ketamine appear to be less pronounced. The σ1-protein interacts with μ-opioid and TrkB-receptors, whereas in preclinical experiments σ1-agonists reduce μ-receptor desensitization and improve TrkB signal transduction. TrkB activation occurs as a response to NMDA blockade. So, the σ1-activity of R-ketamine may not only enhance two pathways via which S-ketamine produces an antidepressant response, but it furthermore provides an antidepressant activity in its own right. These two factors could explain the apparently superior antidepressant effect observed with racemic ketamine compared to S-ketamine alone.