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

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.

On the Eve of Upgrading Antidepressants: (R)-Ketamine and Its Metabolites

“…In sharp contrast to this prediction, however, they found that the (R)-ketamine enantiomer has greater antidepressant efficacy in the forced swim test, the novelty-suppressed feeding test, and the learned helplessness test. These results are consistent with previous studies [12,13], in which (R)-ketamine appeared to be a more potent, long-lasting, and safe antidepressant than (S)-ketamine. MK-801, another NMDAR antagonist, also has rapid antidepressant effects but they are not maintained [14,15].…”

“…The deuterated ketamine failed to induce sustained antidepressant effects 24 h after administration, suggesting that (2S,6S;2R,6R)-HNK is necessary for such effects. Consistent with the greater antidepressant action of (R)-ketamine than (S)-ketamine [6,13], (2R,6R)-HNK, which is exclusively metabolized from (R)-ketamine, has more potent, dosedependent antidepressant actions, while (2S,6S)-HNK has antidepressant effects at higher doses.…”

Gene deficiency and pharmacological inhibition of soluble epoxide hydrolase confers resilience to repeated social defeat stress

“…Previous reports demonstrated that the prefrontal cortex (PFC), CA3, and dentate gyrus (DG) of the hippocampus, striatum, and nucleus accumbens (NAc) play a role in the depression-like behaviors in rodents after inflammation, social defeat stress, and learned helplessness (36)(37)(38)(39)(40). We examined whether sEH protein is altered in the brain tissues from mice after LPS (0.5 mg/kg) administration (Fig.…”

Letter to the Editor:R-ketamine: a rapid-onset and sustained antidepressant without risk of brain toxicity

“…Antidepressant and side effects of R-ketamine, ketamine (racemate) and esketamine in preclinical models of depression suggest that R-ketamine has greater potency and longer-lasting antidepressant effects than ketamine (racemate) and esketamine (S-ketamine) (Zhang et al 2014;Yang et al 2015). Furthermore, preclinical studies using locomotion, prepulse inhibition, conditioned place preference and parvalbumin (PV)-immunohistochemistry suggest that ketamine and esketamine, but not R-ketamine, could cause psychotomimetic effects, drug abuse potential and PV-loss in the prefrontal cortex (Yang et al 2015(Yang et al , 2016. A clinical study using esketamine showed marked psychotomimetic side effects in major depressive disorder patients after administration of esketamine (Singh et al 2015).…”