R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects.
Although the efficacy of racemate ketamine, a rapid onset and sustained antidepressant, for patients with treatment-resistant depression was a serendipitous finding, clinical use of ketamine is limited, due to psychotomimetic side effects and abuse liability. Behavioral and side-effect evaluation tests were applied to compare the two stereoisomers of ketamine. To elucidate their potential therapeutic mechanisms, we examined the effects of these stereoisomers on brain-derived neurotrophic factor (BDNF)-TrkB signaling, and synaptogenesis in selected brain regions. In the social defeat stress and learned helplessness models of depression, R-ketamine showed a greater potency and longer-lasting antidepressant effect than S-ketamine (esketamine). Furthermore, R-ketamine induced a more potent beneficial effect on decreased dendritic spine density, BDNF-TrkB signaling and synaptogenesis in the prefrontal cortex (PFC), CA3 and dentate gyrus (DG) of the hippocampus from depressed mice compared with S-ketamine. However, neither stereoisomer affected these alterations in the nucleus accumbens of depressed mice. In behavioral tests for side effects, S-ketamine, but not R-ketamine, precipitated behavioral abnormalities, such as hyperlocomotion, prepulse inhibition deficits and rewarding effects. In addition, a single dose of S-ketamine, but not R-ketamine, caused a loss of parvalbumin (PV)-positive cells in the prelimbic region of the medial PFC and DG. These findings suggest that, unlike S-ketamine, R-ketamine can elicit a sustained antidepressant effect, mediated by increased BDNF-TrkB signaling and synaptogenesis in the PFC, DG and CA3. R-ketamine appears to be a potent, long-lasting and safe antidepressant, relative to S-ketamine, as R-ketamine appears to be free of psychotomimetic side effects and abuse liability.
Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.
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Yang
Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.|Department of Psychiatry, Teikyo University Chiba Medical Center, Ichihara, Japan.
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Shirayama
Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.
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Zhang
Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.
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http://orcid.org/0000-0003-2982-8824
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Ren
Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.
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Yao
Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.
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Ma
Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.
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Dong
Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.
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Hashimoto
D000704:Analysis of Variance; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D015153:Blotting, Western; D019208:Brain-Derived Neurotrophic Factor / Q000187:drug effects; D006213:Hallucinogens; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D017207:Rats, Sprague-Dawley
D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D006213:Hallucinogens; D007649:Ketamine