PMID- 26327690 OWN - NLM STAT- MEDLINE DCOM- 20160511 LR - 20220408 IS - 2158-3188 (Electronic) IS - 2158-3188 (Linking) VI - 5 IP - 9 DP - 2015 Sep 1 TI - R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects. PG - e632 LID - 10.1038/tp.2015.136 [doi] AB - 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. FAU - Yang, C AU - Yang C AD - Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan. FAU - Shirayama, Y AU - Shirayama Y AD - Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan. AD - Department of Psychiatry, Teikyo University Chiba Medical Center, Ichihara, Japan. FAU - Zhang, J-c AU - Zhang JC AD - Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan. FAU - Ren, Q AU - Ren Q AUID- ORCID: 0000-0003-2982-8824 AD - Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan. FAU - Yao, W AU - Yao W AD - Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan. FAU - Ma, M AU - Ma M AD - Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan. FAU - Dong, C AU - Dong C AD - Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan. FAU - Hashimoto, K AU - Hashimoto K AD - Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150901 PL - United States TA - Transl Psychiatry JT - Translational psychiatry JID - 101562664 RN - 0 (Antidepressive Agents) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Hallucinogens) RN - 690G0D6V8H (Ketamine) SB - IM EIN - Transl Psychiatry. 2020 Aug 21;10(1):295. PMID: 32826855 MH - Analysis of Variance MH - Animals MH - Antidepressive Agents/*pharmacology MH - Behavior, Animal/drug effects MH - Blotting, Western MH - Brain-Derived Neurotrophic Factor/drug effects MH - *Hallucinogens MH - Ketamine/*pharmacology MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Rats MH - Rats, Sprague-Dawley PMC - PMC5068814 COIS- Dr Hashimoto is an inventor on a filed patent application on 'The use of R-ketamine in the treatment of psychiatric diseases' by Chiba University. Dr Hashimoto has served as a scientific consultant to Astellas and Taisho, and he has also received research support from Abbvie, Dainippon Sumitomo, Mochida, Otsuka and Taisho. Dr Shirayama has received research support from Eli Lilly, Eisai, MSD, Otsuka, Pfizer, Taisho, Takeda and Mitsubishi-Tanabe. The remaining authors declare no conflict of interest. EDAT- 2015/09/04 06:00 MHDA- 2016/05/12 06:00 PMCR- 2015/09/01 CRDT- 2015/09/02 06:00 PHST- 2015/07/28 00:00 [received] PHST- 2015/07/30 00:00 [revised] PHST- 2015/07/30 00:00 [accepted] PHST- 2015/09/02 06:00 [entrez] PHST- 2015/09/04 06:00 [pubmed] PHST- 2016/05/12 06:00 [medline] PHST- 2015/09/01 00:00 [pmc-release] AID - tp2015136 [pii] AID - 10.1038/tp.2015.136 [doi] PST - epublish SO - Transl Psychiatry. 2015 Sep 1;5(9):e632. doi: 10.1038/tp.2015.136.