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.
Biological Psychiatry
January 1, 2018
Chun Yang, Q. Ren, Y. Qu et al.
249 citations
The antidepressant effects of the two enantiomers of ketamine rely on different signaling pathways in mice. (S)-ketamine requires mTOR signaling, as blocking mTOR with rapamycin or AZD8055 eliminated its effects, while (R)-ketamine does not. Instead, (R)-ketamine requires ERK signaling; blocking ERK with SL327 eliminated its effects. (S)-ketamine restored reduced mTOR phosphorylation in the prefrontal cortex of stressed mice, whereas (R)-ketamine restored reduced ERK phosphorylation in the prefrontal cortex and hippocampal dentate gyrus. These findings indicate that mTOR activation is not necessary for (R)-ketamine's antidepressant actions.
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.
Molecular Psychiatry
November 24, 2021
W. Yao, Qianqian Cao, Shilin Luo et al.
208 citations
In a mouse model of depression, (R)-ketamine produces longer-lasting antidepressant effects than (S)-ketamine. The study identifies a molecular pathway in microglia—cells in the brain's medial prefrontal cortex—that mediates these effects. (R)-ketamine activates the ERK-NRBP1-CREB-BDNF signaling cascade in microglia, increasing BDNF transcription. Blocking this pathway with specific inhibitors or depleting microglia prevented (R)-ketamine's antidepressant-like effects and its ability to restore reduced dendritic spine density. These findings suggest that microglial signaling is essential for (R)-ketamine's antidepressant actions.
Translational Psychiatry
November 7, 2019
Chun Yang, Jianjun Yang, A. Luo et al.
189 citations
Ketamine's robust antidepressant effects in treatment-resistant depression are well established, but the exact molecular and cellular mechanisms remain unclear. While NMDAR inhibition and subsequent AMPAR activation have been proposed, (R)-ketamine, a weaker NMDAR antagonist than (S)-ketamine, produces more marked and longer-lasting antidepressant-like effects in animal models. Non-ketamine NMDAR antagonists lack similar effects in patients, suggesting other mechanisms are key. Evidence points to mTORC1 activation in the medial prefrontal cortex for (S)-ketamine, and extracellular signal-regulated kinase for (R)-ketamine. The BDNF–TrkB cascade is crucial for both enantiomers and their metabolites. This review discusses recent findings, questioning the primacy of NMDAR inhibition in ketamine's antidepressant action.
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.
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.
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.
Translational Psychiatry
February 23, 2016
H-L Sun, Z-Q Zhou, G.-F. Zhang et al.
87 citations
Ketamine produces rapid (within 0.5 hour) and sustained (up to 72 hours) antidepressant effects in rats exposed to chronic unpredictable mild stress (CUMS), a model of depression. The antidepressant action is blocked by ANA-12, a TrkB antagonist, indicating involvement of TrkB signaling. Ketamine restores reduced levels of brain-derived neurotrophic factor (BDNF) in the hippocampus and increases the ratio of phosphorylated TrkB to total TrkB. While ketamine does not affect p11 expression shortly after administration, it normalizes reduced p11 and BDNF levels 72 hours later. Knockdown of hippocampal p11 prevents ketamine's behavioral effects, suggesting p11 is essential for the sustained antidepressant response.
Neuropharmacology
September 1, 2022
Hao-Ming Hua, Chao Huang, Hanyu Liu et al.
35 citations
Ketamine's rapid antidepressant effects, a major advance in depression treatment, may involve the gut-brain axis. This review examines how ketamine and its metabolites interact with the gut microbiome and microbiota-derived molecules. The proposed mechanisms include modulation of the stress response, promotion of brain-derived neurotrophic factor (BDNF)-mediated neurogenesis, anti-inflammatory effects, and regulation of neurotransmitters. However, the exact mechanisms remain unclear.
Translational Psychiatry
September 3, 2021
Chao Huang, Yuanyuan Wang, Zifeng Wu et al.
29 citations
Ketamine acts as a rapid and long-lasting antidepressant, but its molecular mechanisms are unclear. In mice subjected to chronic social stress, microRNA miR-98-5p was downregulated in the prefrontal cortex and hippocampus. Overexpressing miR-98-5p with an agonist alleviated depression-like behaviors. Ketamine administration upregulated miR-98-5p, and inhibiting it with an antagonist blocked ketamine's antidepressant effect. This suggests a novel molecular mechanism for ketamine's action and that targeting miR-98-5p could be beneficial for depression treatment.
Science advances
July 11, 2025
Lujuan He, Xuenan Wang, Shilin Luo et al.
8 citations
Arketamine, the (R)-enantiomer of ketamine, produces faster and longer-lasting antidepressant-like effects than esketamine in mice subjected to chronic social defeat stress. Activating the proteins CREB and MeCP2 drives the production of brain-derived neurotrophic factor (BDNF) in microglia, the brain's immune cells. This microglia-derived BDNF strengthens excitatory synaptic transmission in the infralimbic region of the medial prefrontal cortex (mPFC). It also activates mPFC neurons that project to the nucleus accumbens (NAc) shell, a brain area involved in reward and mood. These mechanisms together underlie arketamine's antidepressant-like effects, highlighting the essential role of microglial BDNF in modulating this neural pathway.
Current neuropharmacology
January 16, 2025
Sen Wang, Chaoli Huang, Mengyu Wang et al.
4 citations
Depression affects about 300 million people worldwide, and its underlying mechanisms remain unclear. Changes in oligodendrocytes and myelin are implicated in depression pathology. Conventional antidepressants take weeks to work and fail for about one-third of patients. Ketamine provides rapid, sustained antidepressant effects in treatment-resistant patients. Reduced myelination is linked to depression, so repairing myelin damage may be a key mechanism behind ketamine's prolonged effects. This review summarizes the relationship between demyelination and depression and discusses how ketamine might exert antidepressant effects by repairing myelin, offering new insights into the role of myelination in antidepressant mechanisms.
Heliyon
September 15, 2024
Hao Hua, Xinghuo Fu, Wenli Wang et al.
2 citations
A bibliometric analysis of 710 publications from 2004 to October 2023 reveals growing research interest in psychedelics as treatments for depression. The analysis maps annual publication trends, authorship, countries, institutions, journals, and keywords to visualize emerging frontiers and influential factors. The authors assert that regulation of psychedelic drugs is necessary but should not impede scientific progress.
Neuroscience
March 5, 2025
Hanyu Liu, Siqi Yang, Qi Zhang et al.
Opioid-induced hyperalgesia (OIH) is a complication of pain treatment where opioids paradoxically increase pain sensitivity. Using a mouse model, about 60% of mice developed OIH after three days of morphine, shown by abnormal movement and anxiety-like behaviors. Mice whose gut microbiota were eliminated with antibiotics did not develop hyperalgesia, but those receiving fecal transplants from OIH mice did. S-ketamine, but not R-ketamine, prevented OIH. Gut microbiota analysis revealed increased Enterobacteriaceae in OIH-susceptible mice, which decreased after S-ketamine treatment. The findings suggest S-ketamine alleviates morphine-induced OIH by reducing gut Enterobacteriaceae levels.
Brain, behavior, and immunity
October 1, 2023
Xinying Zhang, Teng He, Zifeng Wu et al.
In a mouse model of depression induced by lipopolysaccharide, CD38 expression increased in the hippocampus and cortex. Pharmacological inhibition or genetic knockout of CD38 reduced neuroinflammation, microglia activation, synaptic defects, and Sirt1/STAT3 signaling, and improved depression-like behaviors. Optogenetic activation of glutamatergic neurons in the hippocampal CA3 region reduced depression susceptibility and lowered CD38 expression. The antidepressant (R)-ketamine suppressed CD38 expression and reversed synaptic defects. Hippocampal CD38 is closely linked to depressive behaviors in this inflammation model, suggesting it as a potential therapeutic target.
European Archives of Psychiatry and Clinical Neuroscience
July 14, 2018
K. Hashimoto, Chun Yang
The NMDAR antagonist (R,S)-ketamine is considered a major advance in depression treatment, but safety concerns about repeated infusions persist. (R)-ketamine shows greater potency and longer-lasting antidepressant effects than esketamine in animal models, without psychotomimetic side effects or abuse potential in rodents. Esketamine infusions cause dopamine release in monkeys and psychotomimetic symptoms in humans, suggesting a link. Phase 2 trials of intranasal esketamine found rapid reduction of depression and suicidality, with a dose-response relationship, but effects did not differ from placebo after 4 weeks in one trial. Phase 3 results were mixed: esketamine outperformed placebo in adults but not in patients 65 and older. Abuse potential remains a concern.
Clinical Psychopharmacology and Neuroscience
April 1, 2015
Chun Yang, K. Hashimoto
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