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

Abstract

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 & 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.

Fig. 1. Major metabolisms of ketamine enantiomers.

Arketamine is metabolized to (R)-norketamine that is metabolized to (2 R,6 R)-hydroxynorketamine (HNK). In addition, arketamine is also metabolized to (2 R,6 R)-hydroxyketamine that is metabolized (2 R,6 R)-HNK. Esketamine is metabolized to (S)-norketamine that is metabolized to (2 S,6 S)-HNK. In addition, esketamine is metabolized to (2 S,6 S)-hydroxyketamine that is metabolized to (2 S,6 S)-HNK. Ki values for NMDAR are presented in parenthesis [46, 49].

Fig. 2. Proposed signaling pathways underlying the antidepressant-like actions of arketamine and TGF-β1.

Arketamine induces the expression of TGF-β1 in the microglia through unidentified mechanisms. Arketamine-induced TGF-β1 or TGF-β1 bind to its receptor TGF-β receptor 1/2 in　the microglia. Subsequently, released BDNF binds to its receptor TrkB, resulting in MEK–ERK–CREB signaling pathway, leading to synaptogenesis and antidepressant actions. MEK: mitogen-activated protein kinase, ERK: extracellular signal-regulated kinase, CREB: cAMP response element binding protein.

Fig. 3. Role of brain–gut–microbiota axis and brain–spleen axis in the stress-related psychiatric disorders and beneficial effects by arketamine.

Repeated stress caused gut microbiota dysbiosis and an increase in spleen size and weight, resulting in abnormalities in immune system. Stress-induced neuroinflammation might be mediated by the brain–gut–microbiota axis and the brain–spleen axis through the vagus nerve. Interestingly, arketamine could ameliorate the abnormalities of gut microbiota, abnormal functions of the spleen, and depressive symptoms in patients with stress-related disorders. A slight modification from the previous report [44]. Some materials of the figure have been designed using resources from Freepik.com.

Fig. 4. Potential of arketamine for cognitive impairments in psychiatric disorders and other diseases.

Preclinical findings suggest that arketamine would be a new therapeutic drug for cognitive impairments in psychiatric disorders, neurodegenerative disorders such as Parkinson’s disease, osteoporosis, IBDs (ulcerative colitis and Crohn’s disease), and stroke. Importantly, patients with these diseases have depressive symptoms as comorbidity. IBD is a risk factor for PD [180]. Some materials of the figure have been designed using resources from Freepik.com.