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The discovery of robust antidepressant actions exerted by the  N -methyl-D-aspartate receptor (NMDAR) antagonist ( R,S )-ketamine has been a crucial breakthrough in mood disorder research. ( R,S )-ketamine is a racemic mixture of equal amounts of ( R )-ketamine (arketamine) and ( S )-ketamine (esketamine). In 2019, an esketamine nasal spray from Johnson &amp; Johnson was approved in the United States of America and Europe for treatment-resistant depression. However, an increasing number of preclinical studies show that arketamine has greater potency and longer-lasting antidepressant-like effects than esketamine in rodents, despite the lower binding affinity of arketamine for the NMDAR. In clinical trials, non-ketamine NMDAR-related compounds did not exhibit ketamine-like robust antidepressant actions in patients with depression, despite these compounds showing antidepressant-like effects in rodents. Thus, the rodent data do not necessarily translate to humans due to the complexity of human psychiatric disorders. Collectively, the available studies indicate that it is unlikely that NMDAR plays a major role in the antidepressant action of ( R,S )-ketamine and its enantiomers, although the precise molecular mechanisms underlying antidepressant actions of ( R,S )-ketamine and its enantiomers remain unclear. In this paper, we review recent findings on the molecular mechanisms underlying the antidepressant actions of ( R,S )-ketamine and its potent enantiomer arketamine. Furthermore, we discuss the possible role of the brain–gut–microbiota axis and brain–spleen axis in stress-related psychiatric disorders and in the antidepressant-like action of arketamine. Finally, we discuss the potential of arketamine as a treatment for cognitive impairment in psychiatric disorders, Parkinson’s disease, osteoporosis, inflammatory bowel diseases, and stroke.

Molecular mechanisms underlying the antidepressant actions of arketamine: beyond the NMDA receptor