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.
Pharmacology, Biochemistry and Behavior
June 1, 2019
Lijia Chang, Kai Zhang, Yaoyu Pu et al.
174 citations
In a mouse model of chronic social defeat stress, a single intranasal dose of (R)-ketamine produced stronger antidepressant effects than (R,S)-ketamine or (S)-ketamine. Conversely, (S)-ketamine caused the greatest increase in locomotor activity and deficits in prepulse inhibition, followed by (R,S)-ketamine, while (R)-ketamine showed the least. In conditioned place preference tests, repeated intranasal (S)-ketamine and (R,S)-ketamine increased preference scores dose-dependently, indicating abuse liability, whereas (R)-ketamine did not. These findings suggest intranasal (R)-ketamine may be a safer antidepressant option.
Translational Psychiatry
January 27, 2020
Kai Zhang, Chun Yang, Lijia Chang et al.
120 citations
In mice with depression-like symptoms from chronic social defeat stress, (R)-ketamine produced more potent and longer-lasting antidepressant effects than (S)-ketamine. RNA sequencing of the prefrontal cortex showed that transforming growth factor (TGF)-β signaling may explain these differences. (R)-ketamine, but not (S)-ketamine, reversed reduced expression of Tgfb1 and its receptors in the prefrontal cortex and hippocampus. Blocking TGF-β1 with inhibitors or a neutralizing antibody prevented (R)-ketamine's antidepressant effects. Depleting microglia also blocked these effects. Recombinant TGF-β1 itself produced rapid and lasting antidepressant effects in mice, suggesting a microglial TGF-β1-dependent mechanism and potential for new human antidepressants.
Progress in neuro-psychopharmacology & biological psychiatry
January 10, 2025
Dan Xu, Akifumi Eguchi, Rumi Murayama et al.
4 citations
Repeated oral administration of MDMA (10 mg/kg/day for 14 days) to male rats significantly altered gut microbiota composition in the small intestine, cecum, and colon, with distinct effects in each region. Analysis of microbial functional capabilities indicated shifts in several metabolic pathways. Untargeted metabolomics showed that MDMA changed levels of two metabolites in the colon—ferulic acid and methylmalonic acid—without affecting levels in blood, small intestine, or cecum. Methylmalonic acid levels in the colon positively correlated with the bacteria Lawsonibacter and Oscillibacter. These results suggest that repeated MDMA treatment can modify gut microbiota across intestinal regions, which may contribute to its pharmacological effects.
Behavioural Brain Research
August 1, 2019
Zhongwei Xiong, Yuko Fujita, Kai Zhang et al.
(R)-ketamine, but not its final metabolite (2R,6R)-hydroxynorketamine (HNK), produced rapid and sustained antidepressant effects in mice susceptible to chronic social defeat stress. It also improved elevated plasma levels of the inflammatory bone marker RANKL, restored the reduced OPG/RANKL ratio, and attenuated decreased bone mineral density in these mice. These findings suggest (R)-ketamine may have beneficial effects on both depression-like behavior and bone abnormalities in susceptible mice, indicating it could be a potential therapeutic drug for bone metabolism problems in depressed patients.