The neurobiological mechanism underlying ketamine’s rapid-acting antidepressant effect

Abstract

Depression is one of the most common disabling mental disorders. However, first-line treatments for depression are typically slow-acting. Ketamine, a glutamatergic modulator with rapid antidepressant effects, has proven effective in treating both refractory depression and suicidal tendencies. The neurobiological mechanisms underlying the effects of antidepressants have become a research hotspot; yet, the exact processes remain unclear. Brain imaging studies have provided important evidence from macroscopic perspectives, such as brain structure and function, while biochemical studies have made significant discoveries from microscopic perspectives, including proteomics and genomics. Previous reviews have summarized a broad range of biomarkers related to the ketamine response, encompassing studies in imaging, electrophysiology, metabolism, immunology, genetics, and neurotrophy. In this review, we systematically summarize a number of potential biomarkers for predicting and modulating the efficacy of ketamine, from both macroperspectives (such as neuroimaging and neuroelectrophysiological markers) and microperspectives (such as neurobiochemical and genetic markers). Although research in this area is still in its infancy, these biomarkers can help clinicians identify whether ketamine intervention is needed for treatment-resistant depression, thereby reducing the burden on patients and society. However, the majority of biomarkers are still in the preclinical exploratory stage, and existing findings are limited. To realize the clinical application of these biomarkers, future studies should combine biomarkers of different types to investigate the relationships and interactions between them. This approach aims to optimize clinical outcomes by enhancing the involvement of biological targets in new models.