{"id":"doi:10.1038/tp.2015.136","kind":"article","title":"R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects","authors":["Yang C","Shirayama Y","Zhang JC","Ren Q","Yao W","Ma M","Dong C","Hashimoto K"],"author_count":8,"year":2015,"published":"2015-09-01","venue":"Translational psychiatry","cited_by":493,"doi":"10.1038/tp.2015.136","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1038/tp.2015.136","archive_url":"https://space-kitty.com/papers/doi:10.1038/tp.2015.136","updated":null,"pmid":"26327690","pmcid":"PMC5068814","openalex_id":null,"pdf_url":"https://europepmc.org/articles/PMC5068814/pdf","abstract":"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.","abstract_license":"CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)","license":"CC-BY","is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":[],"details":null,"provenance":"europepmc","attribution":"Abstract of \"R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects\" by Yang C, Shirayama Y, Zhang JC et al., https://doi.org/10.1038/tp.2015.136, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified.","topics":[{"slug":"psychiatric-therapeutics","name":"Novel Psychiatric Therapeutics","domain_slug":"neuroscience"}],"cited_in_dossiers":[]}