Research progress on the mechanism of rapid antidepressant action of hydronorketamine

Abstract

Major depressive disorder is a mental illness characterized by depressed mood, lack of engagement in pleasurable activities, anhedonia, and cognitive-behavioral disorders. Currently, traditional pharmacological treatments for depression have a delayed therapeutic onset and low treatment effectiveness. (2R, 6R)-HNK, as a key metabolite of ketamine, can not only exert rapid and lasting antidepressant effects but also has no side effects such as hallucination and addiction caused by ketamine, which has potential clinical application values. Studies have found that the antidepressant effect of (2R, 6R)-HNK is closely related to the regulation mechanism of glutamate receptor and synaptic plasticity. Besides, the changes of downstream signaling pathways include the upregulation of brain-derived neurotrophic factor (BDNF) expression, dephosphorylation of eukaryotic elongation factor 2 (eEF2), and activation of the mammalian target of rapamycin (mTOR) play a key role in the antidepressant process of the drug. Understanding the molecular mechanisms underpinning (2R, 6R)-HNK's antidepressant effects will be invaluable for the identification of targets, which will drive the development of novel, effective, next-generation pharmacotherapies for the treatment of depression. Key words: Depression; (2R, 6R)-hydronorketamine; Glutamate; Antidepressant