Antidepressant Potential of (R)-Ketamine in Rodent Models: Comparison with (S)-Ketamine

Abstract

The rapid-acting and long-lasting antidepressant effects of ()-ketamine have recently gained much attention. Although ()-ketamine has been studied as an active isomer, recent evidence suggests that ()-ketamine exhibits longer-lasting antidepressant effects than ()-ketamine in rodents. However, the antidepressant potential of ()-ketamine has not been fully addressed. In the present study, we compared the antidepressant effects of ()-ketamine with those of ()-ketamine in animal models of depression, including a model that is refractory to current medications. Both ()-ketamine and ()-ketamine exhibited antidepressant effects at 30 minutes as well as at 24 hours after administration in forced-swimming and tail-suspension tests in mice. At 48 hours after administration, however, ()-ketamine still exerted a significant antidepressant effect in the tail-suspension test, whereas the effect of ()-ketamine was no longer observed. Moreover, ()-ketamine, but not ()-ketamine, significantly reversed the depressive-like behavior induced by repeated treatments with corticosterone in rats at 24 hours after a single administration. This effect was attenuated by an -amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor antagonist, suggesting the involvement of AMPA receptor stimulation in the effects. Both ()-ketamine and ()-ketamine exhibited practically the same exposure levels in plasma, brain, and cerebrospinal fluid in mice and rats, and both compounds were rapidly eliminated from plasma (<4-8 hours). The present results confirmed the previous findings that ()-ketamine exerted longer-lasting antidepressant effects than ()-ketamine in animal models of depression. Moreover, our study is the first to demonstrate that ()-ketamine exerted a sustained antidepressant effect even in a model that is refractory to currently prescribed antidepressants.

Mechanisms of ketamine action as an antidepressant

“…( S )-ketamine has ~4-fold greater affinity/potency at inhibiting the NMDAR compared to its ( R )-ketamine enantiomer 13, 111–115 . Hashimoto and colleagues were the first to report superior and longer-lasting antidepressant actions of ( R )-ketamine compared with ( S )-ketamine in rodent models 116–118 . These findings were subsequently replicated by Zanos et al .…”

“…(2016), who showed that ( S )-ketamine’s antidepressant behavioral actions require higher doses compared to those of ( R )-ketamine 13 . The superiority of ( R )-ketamine does not seem to be related to a U-shaped dose response of the drugs, as it has been shown superior to ( S )-ketamine with up to a 30-fold range of doses in multiple mouse tests of antidepressant efficacy 13, 118 . Importantly, administration of equal, antidepressant-relevant, doses of ( R )- and ( S )-ketamine in mice did not yield different levels of these enantiomers in the brain of mice 13 , indicating that the antidepressant superiority of ( R )-ketamine in rodent models is not due to greater brain exposure.…”

Convergent Mechanisms Underlying Rapid Antidepressant Action

“…Moreover, ( S )-ketamine decreased escape failures in the learned helplessness paradigm [45] and reduced high behavioral despair in the forced-swim test following repeated corticosterone administration [65] in rodents. These behavioral actions of ( S )-ketamine in rodent tests require higher doses compared to the ( R )-ketamine enantiomer [45, 64, 65], indicating that ( R )-ketamine is a more potent antidepressant compared to the ( S )-ketamine enantiomer, at least in rodents [66]. The ( S )-ketamine enantiomer is currently in Phase III clinical trials for the treatment of treatment-resistant depression and suicidal ideation after receiving the FDA Fast Track Designation (Clinical Trial ID: NCT02417064).…”

“…For example, ( R )-ketamine has a ~4-fold lower affinity/potency for blocking the NMDAR compared to ( S )-ketamine, but is a more potent antidepressant than ( S )-ketamine in the 24-h forced-swim test, the learned helplessness and novelty-suppressed feeding tests, as well as in reversing anhedonia following chronic social defeats in rodents [45, 64, 65, 99, 100]. …”

Intracellular Signaling Pathways Involved in ( S )- and ( R )-Ketamine Antidepressant Actions

“…Subsequent studies have confirmed superiority of ( R )-ketamine over ( S )-ketamine in rodent antidepressant-relevant behavioral outcomes using up to a 30-fold range of doses (4, 5). Notably, the difference in antidepressant potency is not due to bioavailability differences since administration of equal doses of these enantiomers does not yield different drug concentrations in the brains of rodents (4, 5). Given that ( S )-ketamine is a stronger inhibitor of the NMDAR, yet ( R )-ketamine is a more potent antidepressant, these preclinical findings indicate it is unlikely ketamine exerts its antidepressant actions merely via inhibition of the NMDAR.…”