R (−)-ketamine shows greater potency and longer lasting antidepressant effects than S (+)-ketamine

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Highlights

  • Ketamine shows a rapid and long-lasting antidepressant effect.

  • Both isomers of ketamine showed antidepressant effect in mice.

  • R-ketamine, but not S-ketamine, showed antidepressant effect at day 7.

  • R-Ketamine would be a potent and safe antidepressant relative S-ketamine.

Abstract

The N-methyl-d-aspartate (NMDA) receptor antagonist ketamine is one of the most attractive antidepressants for treatment-resistant major depressive disorder (MDD). Ketamine (or RS (±)-ketamine) is a racemic mixture containing equal parts of R (−)-ketamine and S (+)-ketamine. In this study, we examined the effects of R- and S-ketamine on depression-like behavior in juvenile mice after neonatal dexamethasone (DEX) exposure. In the tail suspension test (TST) and forced swimming test (FST), both isomers of ketamine significantly attenuated the increase in immobility time, seen in DEX-treated juvenile mice at 27 and 29 h respectively, after ketamine injections. In the 1% sucrose preference test (SPT), both isomers significantly attenuated the reduced preference for 1% sucrose consumption in DEX-treated juvenile mice, 48 h after a ketamine injection. Interestingly, when immobility times were tested by the TST and FST at day 7, R-ketamine, but not S-ketamine, significantly lowered the increases in immobility seen in DEX-treated juvenile mice. This study shows that a single dose of R-ketamine produced rapid and long-lasting antidepressant effects in juvenile mice exposed neonatally to DEX. Therefore, R-ketamine appears to be a potent and safe antidepressant relative to S-ketamine, since R-ketamine may be free of psychotomimetic side effects.

Introduction

Growing evidence suggests that glutamatergic neurotransmission via the N-methyl-d-aspartate (NMDA) receptor plays key roles in the neurobiology and treatment of major depressive disorder (MDD) (Hashimoto, 2009, Hashimoto, 2011, Hashimoto, 2013, Hashimoto et al., 2007, Hashimoto et al., 2013, Heresco-Levy and Javitt, 1998, Javitt, 2004, Maeng and Zarate, 2007, Pittenger et al., 2007, Zarate et al., 2010). The NMDA receptor antagonist ketamine shows rapid and robust antidepressant effects in MDD patients including treatment-resistant MDD (Berman et al., 2000) and in patient with treatment-resistant MDD (Zarate et al., 2006). A recent study using a large sample size demonstrated that a single infusion of ketamine showed rapid antidepressant effect in patients with treatment resistant MDD compared to the active placebo midazolam (Murrough et al., 2013). Interestingly, these antidepressant effects are not evident until after ketamine's psychotomimetic effects have disappeared (Berman et al., 2000, Zarate et al., 2006). Furthermore, the clinical benefits after a single dose of ketamine can last for a little as one to two days, or in excess of two weeks (Berman et al., 2000, Krystal et al., 2013, Zarate et al., 2006). These findings currently make ketamine one of the most attractive antidepressants for treatment-resistant MDD (Domino, 2010, Duman et al., 2012, Krystal et al., 2013, Lapidus et al., 2013, Li et al., 2010, Machado-Vieira et al., 2009, Murrough, 2012, Rush, 2013, Zarate et al., 2013).

Ketamine (or RS (±)-ketamine) is a racemic mixture containing equal parts of R (−)-ketamine and S (+)-ketamine. S-ketamine has an approximately 4-fold greater affinity for the NMDA receptor than the R-isomer (Domino, 2010). Furthermore, S-ketamine shows an approximately 3–4 fold greater anesthetic potency and greater undesirable psychotomimetic side effects, compared with the R-isomer (Domino, 2010, Kohrs and Durieux, 1998). These findings strengthened the general acceptance that the anesthetic and psychotomimetic actions of ketamine are mediated primarily via the blockade of NMDA receptors (Domino, 2010, Kohrs and Durieux, 1998). However, no studies have examined the effects of R-ketamine in patients with MDD, as to date, most clinical studies on ketamine's antidepressant effects have utilized racemic mixtures. Therefore, it would be of great interest to identify which ketamine isomers confer antidepressant effects.

Very recently, we reported that neonatal dexamethasone (DEX) exposure caused depression-like behavior in juvenile mice, suggesting that this paradigm may be a new animal model of pediatric depression (Li et al., 2014). In this study, we examined the effects of R- and S-ketamine on depression-like behavior in juvenile mice after neonatal DEX exposure.

Section snippets

Animals

Male and female ICR mice (9 weeks old) were purchased from SLC Japan (Hamamatsu, Shizuoka, Japan). The mice were housed in groups of 3 or 5 per cage, under a controlled 12/12-hour light–dark cycle (lights on from 7:00 AM to 7:00 PM), at a room temperature of 23 ± 1 °C and humidity of 55 ± 5%. Mice were given free access to water and food pellets. Experimental procedures were approved by the Animal Care and Use Committee of Chiba University.

Drugs

R- and S-ketamine hydrochloride were prepared by

Results

Mice showed no differences [F (3, 39) = 0.260, p = 0.854] in locomotion after a single administration of R- or S-ketamine (Fig. 2B). The ANOVA analysis highlighted a significant difference [TST: F (3, 32) = 9.231, p = 0.001, FST: F (3, 30) = 5.618, p = 0.004] among the four groups. In the TST and FST, both isomers of ketamine significantly attenuated the increase in immobility time, seen in DEX-treated juvenile mice at 27 and 29 h respectively, after ketamine injections (Fig. 2C and D). Furthermore, R

Discussion

In this study, we found that a dose of 10 mg/kg of R- or S-ketamine induced antidepressant effects in juvenile mice exposed neonatally to DEX (days 1–3). In the TST and FST, the antidepressant effects of both isomers were detected some 27 to 29 h after a single dose. Interestingly, the antidepressant effects of R-ketamine could be detected 7 days after a single treatment, unlike S-ketamine, indicating that R-ketamine possessed a longer lasting action. It is unlikely that this detectable disparity

Acknowledgments

This study was supported by a grant from Grants-in-Aid for Scientific Research on Innovative Areas of the Ministry of Education, Culture, Sports, Science and Technology, Japan (to K.H., Grant number: 24116006). Dr. Su-xia Li was supported by JSPS Invitation Fellowship Program for Research in Japan (Long Term).

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