Comparison of antidepressant and side effects in mice after intranasal administration of (R,S)-ketamine, (R)-ketamine, and (S)-ketamine

The N-methyl-d-aspartate receptor (NMDAR) antagonist (R,S)-ketamine produces rapid and sustained antidepressant effects in treatment-resistant patients with depression although intranasal use of (R,S)-ketamine in ketamine abusers is popular. In March 5, 2019, nasal spray of (S)-ketamine for treatment-resistant depression was approved as a new antidepressant by the US Food Drug Administration. Clinical study of (R)-ketamine is underway. In a chronic social defeat stress (CSDS) model, we compared the antidepressant effects of (R,S)-ketamine, (R)-ketamine, and (S)-ketamine after a single intranasal administration. Furthermore, we also compared the side effects (i.e., locomotion, prepulse inhibition (PPI), abuse liability) of these three compounds in mice. The order of potency of antidepressant effects after a single intranasal administration was (R)-ketamine > (R,S)-ketamine > (S)-ketamine. In contrast, the order of locomotor activity and prepulse inhibition (PPI) deficits after a single intranasal administration was (S)-ketamine > (R,S)-ketamine > (R)-ketamine. In the conditioned place preference (CPP) test, both (S)-ketamine and (R,S)-ketamine increased CPP scores in mice after repeated intranasal administration, in a dose dependent manner. In contrast, (R)-ketamine did not increase CPP scores in mice. These findings suggest that intranasal administration of (R)-ketamine would be a safer antidepressant than (R,S)-ketamine and (S)-ketamine. •Antidepressant and side effects of intranasal administration of (R,S)-ketamine and its two enantiomers were compared.•The order of potency of antidepressant effects was (R)-ketamine > (R,S)-ketamine > (S)-ketamine.•The order of side effects was (S)-ketamine > (R,S)-ketamine > (R)-ketamine.•(R)-ketamine would be a safer antidepressant than (R,S)-ketamine and (S)-ketamine.