Translational Psychiatry
September 1, 2015
Chun Yang, Yukihiko Shirayama, J-C Zhang et al.
600 citations
R-ketamine, a stereoisomer of the anesthetic ketamine, produces a more potent and longer-lasting antidepressant effect than S-ketamine (esketamine) in mouse models of depression, without causing psychotomimetic side effects or abuse liability. In the social defeat stress and learned helplessness models, R-ketamine more effectively restored decreased dendritic spine density, brain-derived neurotrophic factor (BDNF)-TrkB signaling, and synaptogenesis in the prefrontal cortex, CA3, and dentate gyrus of the hippocampus. Neither isomer affected these measures in the nucleus accumbens. S-ketamine, but not R-ketamine, caused hyperlocomotion, prepulse inhibition deficits, rewarding effects, and loss of parvalbumin-positive cells in the medial prefrontal cortex and dentate gyrus. R-ketamine appears to be a safe, long-lasting antidepressant.
Translational Psychiatry
December 15, 2017
Chun Yang, Youge Qu, Yuko Fujita et al.
231 citations
The gut microbiota-brain axis is implicated in depression, and (R)-ketamine shows more potent and longer-lasting antidepressant effects than (S)-ketamine. In a chronic social defeat stress mouse model of depression, fecal 16S ribosomal RNA gene sequencing revealed that both enantiomers attenuated increases in Deltaproteobacteria levels. (R)-ketamine, but not (S)-ketamine, also reversed reductions in Mollicutes levels. At the genus level, both enantiomers attenuated decreases in Butyricimonas, with (R)-ketamine being more potent. These findings suggest that the antidepressant actions of ketamine enantiomers may be partly mediated by restoring gut microbiota, with (R)-ketamine's specific effects on Mollicutes and Butyricimonas potentially explaining its superior efficacy.
Scientific Reports
November 10, 2017
Youge Qu, Chun Yang, Qian Ren et al.
126 citations
In a mouse model of depression induced by chronic social defeat stress, (R)-ketamine, but not the related NMDAR antagonist lanicemine, reversed depression-like behavior and partially restored the composition of gut bacteria, including Bacteroidales, Clostridiales, Ruminococcaceae, and Clostridium. The findings suggest that the antidepressant effects of (R)-ketamine may be partly mediated by its ability to normalize gut microbiota alterations.
The International Journal of Neuropsychopharmacology
October 7, 2016
Chao Dong, Ji-Chun Zhang, Wei Yao et al.
116 citations
MGS0039, a metabotropic glutamate 2/3 receptor antagonist, produces rapid and sustained antidepressant effects in mice subjected to social defeat stress, similar to the well-known antidepressant ketamine. A single dose of either drug reversed depression-like behaviors—reducing immobility in tail suspension and forced swimming tests within 1–2 days and restoring sucrose preference over 3–7 days. Both compounds also reversed reductions in brain-derived neurotrophic factor, TrkB signaling, glutamate receptor subunits, and spine density in the prefrontal cortex, dentate gyrus, and CA3 region of the hippocampus, but not in the nucleus accumbens. These findings suggest that MGS0039 may offer a novel antidepressant mechanism through lasting synaptic changes in specific brain regions.
Psychopharmacology
August 3, 2016
Bangkun Yang, Ji-Chun Zhang, Mei Han et al.
93 citations
R-ketamine and rapastinel, both NMDA receptor antagonists, produced rapid antidepressant effects in mice susceptible to social defeat stress. A single injection of either compound (10 mg/kg) reduced immobility in the tail suspension and forced swimming tests and increased sucrose preference for up to seven days. R-ketamine, but not rapastinel, restored reduced BDNF-TrkB signaling, PSD-95, and GluA1 levels in the prefrontal cortex, dentate gyrus, and CA3 of the hippocampus. Neither compound altered the elevated levels of these proteins in the nucleus accumbens. A lower intravenous dose of R-ketamine (3 mg/kg) maintained antidepressant effects after seven days, whereas rapastinel did not, indicating R-ketamine produces a longer-lasting antidepressant effect.