R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects

TLDR

Ketamine is a rapid‑onset, sustained antidepressant but its clinical use is limited by psychotomimetic side effects and abuse liability. The study aimed to compare the therapeutic mechanisms of the R‑ and S‑ketamine stereoisomers. Behavioral and side‑effect tests, together with analyses of BDNF‑TrkB signaling and synaptogenesis in key brain regions, were used to assess each stereoisomer. R‑ketamine produced a more potent and sustained antidepressant effect than S‑ketamine, increased BDNF‑TrkB signaling and synaptogenesis in the PFC, CA3, and DG, and did not elicit psychotomimetic side effects or PV‑cell loss, indicating it is a potent, long‑lasting, and safe antidepressant.

Abstract

Although the efficacy of racemate ketamine, a rapid onset and sustained antidepressant, for patients with treatment-resistant depression was a serendipitous finding, clinical use of ketamine is limited, due to psychotomimetic side effects and abuse liability. Behavioral and side-effect evaluation tests were applied to compare the two stereoisomers of ketamine. To elucidate their potential therapeutic mechanisms, we examined the effects of these stereoisomers on brain-derived neurotrophic factor (BDNF)-TrkB signaling, and synaptogenesis in selected brain regions. In the social defeat stress and learned helplessness models of depression, R-ketamine showed a greater potency and longer-lasting antidepressant effect than S-ketamine (esketamine). Furthermore, R-ketamine induced a more potent beneficial effect on decreased dendritic spine density, BDNF-TrkB signaling and synaptogenesis in the prefrontal cortex (PFC), CA3 and dentate gyrus (DG) of the hippocampus from depressed mice compared with S-ketamine. However, neither stereoisomer affected these alterations in the nucleus accumbens of depressed mice. In behavioral tests for side effects, S-ketamine, but not R-ketamine, precipitated behavioral abnormalities, such as hyperlocomotion, prepulse inhibition deficits and rewarding effects. In addition, a single dose of S-ketamine, but not R-ketamine, caused a loss of parvalbumin (PV)-positive cells in the prelimbic region of the medial PFC and DG. These findings suggest that, unlike S-ketamine, R-ketamine can elicit a sustained antidepressant effect, mediated by increased BDNF-TrkB signaling and synaptogenesis in the PFC, DG and CA3. R-ketamine appears to be a potent, long-lasting and safe antidepressant, relative to S-ketamine, as R-ketamine appears to be free of psychotomimetic side effects and abuse liability.