Molecular Psychiatry
May 7, 2021
Wei Yan, Lijia Chang, Kenji Hashimoto
242 citations
The antidepressant effects of the drug (R,S)-ketamine, a mixture of (R)-ketamine (arketamine) and (S)-ketamine (esketamine), are not primarily due to blocking the N-methyl-D-aspartate receptor (NMDAR), despite initial assumptions. Preclinical studies in rodents show arketamine has more potent and longer-lasting antidepressant-like effects than esketamine, even though arketamine binds less strongly to NMDAR. Clinical trials with other NMDAR-blocking compounds failed to produce robust antidepressant effects in humans, indicating rodent findings do not always translate. The exact molecular mechanisms remain unclear. This review covers recent findings on these mechanisms, the possible roles of the brain-gut-microbiota and brain-spleen axes, and arketamine's potential for treating cognitive impairment, Parkinson's disease, osteoporosis, inflammatory bowel diseases, and stroke.
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.
Pharmacology, Biochemistry and Behavior
February 5, 2020
Yan Wei, Lijia Chang, K. Hashimoto
157 citations
The antidepressant effects of (R,S)-ketamine, a mixture of (R)-ketamine and (S)-ketamine, are a major advance in mood research. Off-label use for treatment-resistant depression has grown in the US, and in 2019 the FDA and European authorities approved (S)-ketamine nasal spray for this condition, but only in certified medical settings. Preclinical evidence indicates that (R)-ketamine may be more potent and longer-lasting as an antidepressant than (S)-ketamine, with fewer side effects. Clinical trials of (R)-ketamine in humans are now underway. This article reviews the history of these compounds and discusses the mechanisms behind ketamine's antidepressant actions.
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
August 28, 2019
Jiancheng Zhang, Youge Qu, Lijia Chang et al.
56 citations
A single injection of (R)-ketamine (10 mg/kg) rapidly reversed the loss of dendritic spines in the medial prefrontal cortex and hippocampus of mice that had become susceptible after chronic social defeat stress. Spine density was measured three hours after treatment and was significantly increased in the prelimbic area of the medial prefrontal cortex, the Cornu Ammonis3 region, and the dentate gyrus of the hippocampus. The findings suggest that (R)-ketamine's rapid restoration of spine density in these brain regions may underlie its fast-acting antidepressant effects.
Pharmacology Biochemistry and Behavior
December 5, 2022
Youge Qu, Lijia Chang, Li Ma et al.
42 citations
In mice treated with lipopolysaccharide (LPS) to induce depression-like behavior, both lisuride (a non-hallucinogenic psychedelic analog) and (R)-ketamine (a novel antidepressant) reduced immobility in the forced swimming test and prevented loss of dendritic spine density in the prelimbic region of the medial prefrontal cortex, CA3, and dentate gyrus of the hippocampus. DOI, a hallucinogenic psychedelic with potent 5-HT2AR agonism, did not improve these measures. The findings suggest that the antidepressant-like effect of lisuride is not linked to 5-HT2AR-related psychedelic effects, and that 5-HT2AR may not play a major role in rapid antidepressant actions of psychedelics.
Neurobiology of disease
September 1, 2024
Lijia Chang, Yan Wei, Youge Qu et al.
22 citations
In mice susceptible to chronic social defeat stress, removing the spleen reduces arketamine's antidepressant-like effects. RNA sequencing of the prefrontal cortex revealed that the oxidative phosphorylation (OXPHOS) pathway mediates this effect. Inhibiting OXPHOS with oligomycin A reversed the spleen removal's suppressive effect. Specific OXPHOS genes—COX11, UQCR11, and ATP5e—may be involved. Transforming growth factor β1 (TGF-β1) and COX11 appear to modulate the suppression; activating the TGF-β1 receptor with SRI-01138 alleviated it. Cutting the subdiaphragmatic vagus nerve also counteracted the inhibitory effect of splenectomy. These results suggest that arketamine's antidepressant-like effects involve the OXPHOS pathway and TGF-β1 in the prefrontal cortex, communicated through a spleen-brain axis via the vagus nerve.
Neuropharmacology
May 1, 2023
Xiayun Wan, Akifumi Eguchi, Lijia Chang et al.
A single injection of arketamine (10 mg/kg) reduced anhedonia-like behavior and reversed the loss of femoral neck cortical and total bone mineral density in mice susceptible to chronic social defeat stress. The abundance of certain gut microbiota and plasma metabolites differed between arketamine-treated and saline-treated susceptible mice, and these microbial and metabolite abundances correlated with bone mineral density. The findings suggest arketamine may improve both depressive symptoms and bone density through a gut-microbiota-bone-brain axis, indicating potential as a therapy for depressed patients with low bone mineral density.
Brain Research Bulletin
February 1, 2022
Yan Wei, Tong Wang, Lei Liao et al.
The spleen filters blood and supports the immune system. New evidence shows it also influences brain function in health and disease through immune modulation. In mice, systemic inflammation or chronic social defeat stress causes spleen enlargement (splenomegaly). The antidepressant arketamine can reverse both splenomegaly and depression-like behaviors in stressed mice. A direct brain-to-spleen pathway exists: neurons in the paraventricular nucleus and central amygdala regulate humoral immune defense. Vagal nerve signaling also contributes to brain-spleen communication. This review summarizes recent findings on the brain-spleen axis.