Possible role of the gut microbiota–brain axis in the antidepressant effects of (R)-ketamine in a social defeat stress model
Chun Yang, Youge Qu, Yuko Fujita, Qian Ren, Min Ma, Chao Dong, Kenji Hashimoto
Translational Psychiatry December 15, 2017 DOI: 10.1038/s41398-017-0031-4 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Observational study using a chronic social defeat stress model Peer reviewed |
|---|---|
| Population | Mice subjected to chronic social defeat stress |
| Interventions | (R)-ketamine (S)-ketamine |
| Topics | Ketamine Esketamine |
| Keywords | Antidepressant Social defeat Gut flora Pharmacology Immunology Hippocampus |
| Citations | 231 |
| Key findings | Antidepressant effects of (R)-ketamine and (S)-ketamine may be partly mediated by restoration of gut microbiota, with (R)-ketamine more potently affecting Mollicutes and Butyricimonas levels. |
Abstract
Accumulating evidence suggests that the gut microbiota-brain axis plays a role in the pathogenesis of depression, thereby contributing to the antidepressant actions of certain compounds. (R)-ketamine has a greater potency and longer-lasting antidepressant effects than (S)-ketamine. Here, we investigated whether the gut microbiota plays a role in the antidepressant effects of these two ketamine enantiomers. The role of the gut microbiota in the antidepressant effects of ketamine enantiomers in a chronic social defeat stress (CSDS) model of depression was examined using 16S ribosomal RNA gene sequencing of fecal samples. At the phylum level, CSDS-susceptible mice showed alterations in the levels of Tenericutes and Actinobacteria; however, neither ketamine enantiomers influenced these alterations. At the class level, both ketamine enantiomers significantly attenuated the increase in the levels of Deltaproteobacteria in the susceptible mice after CSDS. Furthermore, (R)-ketamine, but not (S)-ketamine, significantly attenuated the reduction in the levels of Mollicutes in the susceptible mice. At the genus level, both ketamine enantiomers significantly attenuated the decrease in the levels of Butyricimonas in the susceptible mice. Notably, (R)-ketamine was more potent than (S)-ketamine at reducing the levels of Butyricimonas in the susceptible mice. In conclusion, this study suggests that the antidepressant effects of two enantiomers of ketamine in CSDS model may be partly mediated by the restoration of the gut microbiota. Furthermore, the specific effect of (R)-ketamine on the levels of Mollicutes and Butyricimonas may explain its robust antidepressant action.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cited by 54
- Rapid‐acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective Psychiatry and Clinical Neurosciences June 19, 2019
- Ketamine: A tale of two enantiomers Journal of Psychopharmacology November 6, 2020
- Molecular mechanisms underlying the antidepressant actions of arketamine: beyond the NMDA receptor Molecular Psychiatry May 7, 2021
- Molecular mechanisms of the rapid-acting and long-lasting antidepressant actions of (R)-ketamine. Biochemical Pharmacology July 1, 2020
- Comparison of antidepressant and side effects in mice after intranasal administration of (R,S)-ketamine, (R)-ketamine, and (S)-ketamine. Pharmacology, Biochemistry, and Behavior June 1, 2019
and 49 more in the library
Cites 23
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Archives of General Psychiatry March 1, 1994
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial American Journal of Psychiatry August 28, 2013
- A Randomized Add-on Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Bipolar Depression Archives of General Psychiatry August 1, 2010
and 18 more in the library