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.
Journal of Neuroinflammation
April 10, 2020
Jing Wu, Jianjun Yang, Yan Cao et al.
140 citations
General anesthesia induced by ketamine or sevoflurane disrupts iron metabolism, causing iron overload in hippocampal neurons and brain tissue. This iron overload triggers ferroptosis, a form of iron-dependent cell death, leading to cognitive deficits in young rats and aged mice. The iron chelator deferiprone reduces mitochondrial dysfunction, ferroptosis, and cognitive impairment. The mechanism involves NMDAR-RASD1 signaling activating DMT1, which mediates iron uptake. Disturbed iron metabolism may contribute to anesthesia-related neurotoxicity and cognitive decline.
Scientific Reports
June 5, 2017
Ze-Min Xie, Xingming Wang, Ning Xu et al.
69 citations
Rats with neuropathic pain that also developed depression-like behaviors had higher levels of pro-inflammatory cytokines (interleukin-1β and interleukin-6) and an imbalance between pro- and anti-inflammatory cytokines, along with lower levels of brain-derived neurotrophic factor in the prefrontal cortex, compared to rats without depression-like behaviors and sham-operated controls. A single dose of ketamine reversed both the depression-like behaviors and the elevated serum levels of IL-1β and IL-6. These findings suggest that changes in inflammatory cytokines and BDNF may underlie depression caused by neuropathic pain, and that serum cytokines could serve as biomarkers for ketamine's antidepressant effects.
Journal of Anesthesia and Translational Medicine
July 11, 2024
Kenji Hashimoto, Mingming Zhao, Tingting Zhu et al.
32 citations
Ketamine and its enantiomers have a long history in anesthesia and are now gaining attention for rapid-acting antidepressant effects in severe depression. Esketamine, the (S)-enantiomer, received approval in the U.S. and Europe in 2019 as a nasal spray for depression, but concerns about long-term efficacy, addiction, and suicide risk persist. In rodent models, arketamine, the (R)-enantiomer, shows superior and longer-lasting antidepressant effects with fewer side effects than esketamine, though human research on arketamine is limited. The article reviews the historical use of ketamine and its enantiomers in anesthesia and psychiatry and explores future directions.
European journal of pharmacology
March 15, 2025
Mingming Zhao, Akifumi Eguchi, Rumi Murayama et al.
6 citations
Intermittent MDMA administration (10 mg/kg, three times weekly for 6 weeks) reduced demyelination in the corpus callosum of mice treated with cuprizone, a chemical that induces myelin loss. The effect appears linked to changes in gut bacteria and metabolites, including β-D-allose, L-sorbose, and carnitine, which correlated negatively with specific microbes such as Romboutsia. These findings suggest MDMA may influence brain demyelination through the gut-brain axis, though further research is needed to clarify the roles of gut microbiota and metabolites.
Psychedelics.
October 14, 2025
Mingming Zhao, Jianjun Yang, Kenji Hashimoto
MDMA (ecstasy) is a unique entactogen that increases serotonin in the brain by reversing the serotonin transporter, and also affects catecholamine and oxytocin pathways. In clinical trials, MDMA-assisted psychotherapy has led to substantial improvements in treatment-resistant PTSD, though regulatory approval has been delayed due to concerns about unblinding and protocol rigor. Early placebo-controlled studies suggest benefits for autism spectrum disorder, eating disorders with comorbid PTSD, and anxiety from life-threatening illness. Large observational studies link MDMA use with lower depression rates, reduced suicidal ideation, and improved posttrauma coping, but causal inference is limited.