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

I read with great interest the recent article by Kishimoto et al. (2016) about meta-analysis of the antidepressant effects of the N-methyl-d-aspartate receptor (NMDA-R) antagonist ketamine (racemate) and non-ketamine NMDA-R antagonists (traxoprodil, lanicemine, rapastinel) in patients with major depressive disorder (MDD) and bipolar disorder. The authors examined the time trajectory of efficacy of ketamine and non-ketamine NMDA-R antagonists. The greater reduction in depressive symptoms by ketamine infusion started as early as within 40–60 min, peaking on day 1, and lasting until days 5–8, with maintenance of superior remission and response status until days 3–5 and 7, respectively. Effect sizes of ketamine ranged from medium to high (−0.38 to −1.00). In contrast to ketamine, single infusion of non-ketamine NMDA-R antagonists was only significantly superior to placebo at one assessment time point (days 5–8) with a small to medium effect size (−0.37). Together, it is likely that non-ketamine NMDA-R antagonists have smaller effect sizes than ketamine, although the reason underlying this difference remains unclear.

Ketamine (or RS-ketamine) (K _i = 0.53 µ m for NMDA-R) is a racemic mixture containing equal parts of R-ketamine and S-ketamine (esketamine). Esketamine shows an approximately 3- to 4-fold greater anaesthetic potency and greater undesirable psychotomimetic side effects, compared with R-ketamine (Domino, 2010). This is related to the fact that esketamine (K _i = 0.30 µ m) has an approximately 4-fold greater affinity for NMDA-R relative to R-ketamine (K _i = 1.4 µ m) (Fig. 1) (Ebert et al. 1997). We reported that R-ketamine showed greater potency and longer-lasting antidepressant effects than esketamine in animal models of depression (Zhang et al. 2014; Yang et al. 2015). It is therefore unlikely that NMDA-R has a major role in the long-lasting antidepressant effects of R-ketamine, although antagonism at this receptor may promote its rapid antidepressant action (Hashimoto, 2014; Zhang et al. 2014; Yang et al. 2015). Unlike esketamine, R-ketamine does not induce psychotomimetic side effects and abuse potential in rodents (Yang & Hashimoto, 2014; Yang et al. 2015). Furthermore, a single dose of esketamine, but not R-ketamine, resulted in loss of parvalbumin (PV)-immunoreactivity in the prefrontal cortex (Yang et al. 2015). A recent study using [¹¹C]raclopride and positron emission tomography showed a marked reduction of dopamine D_2/3 receptor binding in the conscious monkey striatum after single infusion of esketamine, but not R-ketamine (Hashimoto et al. 2016). Singh et al. (2015) reported that psychotomimetic side effects were the highest at 40 min after single infusion of esketamine although a rapid-onset antidepressant effect was shown in treatment-resistant patients with MDD. Considering the role of dopamine release in psychosis, it is likely that marked release of dopamine from presynaptic terminals in the striatum could be associated with psychotomimetic side effects in humans after a single infusion of ketamine or esketamine.

Fig. 1. 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, 2016). A clinical study using esketamine showed marked psychotomimetic side effects in major depressive disorder patients after administration of esketamine (Singh et al. 2015). Since the psychotomimetic effects of ketamine are known to be associated with N-methyl-d-aspartate receptor (NMDA-R) antagonism, it is likely that the use of R-ketamine is safer than esketamine or ketamine in the treatment of depression. The values in the parentheses are K _i values for NMDA-R in the brain (Ebert et al. 1997).

The authors also pointed out that the transient efficacy lasting 1 week post-infusion of ketamine has stimulated multi-infusion studies (Kishimoto et al. 2016). Studies using repeated ketamine (or esketamine) infusions resulted in the marked psychotomimetic side effects after an each infusion although antidepressant effects were shown (Aan het Rot et al. 2010; Murrough et al. 2013; Singh et al. 2015). Interestingly, there was no difference in dissociative, psychotomimetic, or high feeling between responders and non-responders (Murrough et al. 2013), suggesting that ketamine's antidepressant effects are not associated with its psychotomimetic effects. Recently, we reported that repeated, intermittent administration of esketamine, but not R-ketamine, caused loss of PV-immunoreactivity in the prefrontal cortex of mouse brain (Yang et al. 2016). Since loss of PV-immunoreactivity in the prefrontal cortex may be associated with psychosis and γ-oscillation deficits in schizophrenia (Gonzalez-Burgos et al. 2015), it is possible that repeated administration of esketamine or ketamine may have long-lasting detrimental side effects in the prefrontal cortex of humans.

In conclusion, the use of R-ketamine in the treatment of depression would provide a new therapeutic approach by reducing the detrimental side effects of ketamine.