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

This vehicle-controlled mouse study (n=40) compared the antidepressant efficacy between R(-) and S(+) isomer forms of ketamine (10mg/kg) and found that both forms produce rapid antidepressant effects, but only R-ketamine produces long-lasting antidepressant effects persisting 7 days after a single infusion.

Abstract

“Introduction: 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.

Methods: In this study, we examined the effects of R- and S-ketamine on depression-like behavior in juvenile mice after neonatal dexamethasone (DEX) exposure.

Results: 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.

Discussion: 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.”

Authors: Ji-chun Zhang , Su-xia Li & Kenji Hashimoto

Summary

1. Introduction

Several studies have demonstrated that glutamatergic neurotransmission via the N-methyl-D-aspartate (NMDA) receptor plays key roles in the neurobiology and treatment of major depressive disorder (MDD), and that ketamine can have rapid and robust antidepressant effects in patients with treatment-resistant MDD.

Ketamine is an anesthetic and psychotomimetic drug that acts by blocking NMDA receptors. However, no studies have examined the effects of R-ketamine on patients with MDD.

Neonatal dexamethasone exposure caused depression-like behavior in juvenile mice. Rand S-ketamine reduced this behavior.

2.1. Animals

Male and female ICR mice were purchased from SLC Japan and were housed in groups of 3 or 5 per cage under a controlled 12/12-hour light – dark cycle.

2.2. Drugs

R-andS-ketamine hydrochloride were prepared by recrystallization of RS-ketamine and D-()-tartaric acid, and the purity of these isomers was determined by high-performance liquid chromatography.

2.3. Treatment

Breeding procedure consisted of housing three to four females with one male for 14 days, and injecting DEX into neonatal mice on days 1, 2, and 3. Male juvenile mice were injected with vehicle and Ror S-ketamine on day 36.

2.5. Tail suspension test (TST)

Mouse tails were wrapped with tape from base to tip and mice were fixed upside down on a hook. Their immobility time was recorded.

2.6. Forced swimming test (FST)

Mice were placed in a cylinder containing 15 cm of water, and their activity time was measured. The immobility time was calculated and scored for 6 min.

2.7. Sucrose preference test (SPT)

Mice were habituated to a 1% sucrose solution for 48 h before the test day, and their sucrose preference was determined.

2.8. Statistical analysis

Data were analyzed using one-way ANOVA, followed by the post hoc LSD test.

3. Results

Mice showed no differences in locomotion after a single administration of R-orS-ketamine, but both isomers of ketamine significantly attenuated the increase in immobility time, seen in DEX-treated juvenile mice at 27 and 29 h after ketamine injections.

We performed TST and FST at day 7 after ketamine administration, and found that R-ketamine, but not S-ketamine, significantly lowered the increases in immobility seen in DEX-treated juvenile mice.

4. Discussion

We found that R-orS-ketamine induced antidepressant effects in juvenile mice exposed neonatally to DEX. The antidepressant effects of R-ketamine were detected 7 days after a single dose, unlikeS-ketamine, indicating that R-ketamine possessed a longer lasting action.

Recently, we reported that neonatal DEX exposure causes depression-like behavior in juvenile mice. The NMDA GluN2B receptor antagonist Ro 63-1908 can prevent depression-like behavior in juvenile mice after neonatal DEX exposure.

PET studies demonstrated that S-ketamine increased cerebral metabolic rates of glucose in the frontal cortex and thalamus, and that these effects were mainly induced by its S-isomer.

R-ketamine produced a state of relaxation and well being in all subjects, even though it produced only a marginally significant change in mood scores. It also exhibited weak affinity for sigma-1 receptor chaperone, suggesting a possible role for this chaperone in its action. A recent study demonstrated that RS-dehydronorketamine, a metabolite of RS-ketamine, is a negative allosteric modulator of the nicotinic acetylcholine receptor.

A case report showed that S-ketamine had a slightly weaker antidepressant effect than RS-ketamine, and an open label study and another case report suggested that RS-ketamine may have greater antidepressant potency than S-ketamine.

In conclusion, R-ketamine produced rapid and long-lasting antidepressant effects in juvenile mice exposed neonatally to DEX. R-ketamine is free of psychotomimetic side effects.