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.
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.
Neuropharmacology
August 14, 2022
Ji-Chun Zhang, Wei Yao, Kenji Hashimoto
88 citations
The NMDAR antagonist (R,S)-ketamine produces rapid and sustained antidepressant effects in treatment-resistant major depressive disorder and other psychiatric conditions. (R,S)-ketamine is a racemic mixture of (R)-ketamine (arketamine) and (S)-ketamine (esketamine), with esketamine having greater NMDAR affinity. An esketamine nasal spray was approved in 2019 for treatment-resistant depression. Preclinical studies indicate arketamine has greater potency and longer-lasting antidepressant-like effects than esketamine in rodents, despite lower NMDAR binding affinity, and causes fewer side effects such as psychotomimetic and dissociative effects and abuse liability. An open-label study showed rapid and sustained antidepressant effects of arketamine in treatment-resistant MDD patients, and a phase 2 trial is underway. This review covers the history, molecular mechanisms, and future directions of arketamine.
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.