Ketamine as a Rapid-Acting Antidepressant: A Scoping Review of Mechanisms and Efficacy in Treatment-Resistant Depression.

Ketamine is a rapid-acting antidepressant, especially for treatment-resistant depression, working through multiple targets in the glutamatergic system. It blocks NMDA receptors, which disinhibits dopamine reward pathways and increases BDNF expression via eEF2K suppression, activating the mTOR pathway and enhancing synaptic plasticity. Neuroimaging shows ketamine rapidly reshapes prefrontal-limbic connectivity and normalizes brain activity. It has a fast onset and broad therapeutic window, but enantiomers and metabolites differ in effects. Long-term safety, dependence risk, and cognitive effects require monitoring. Future work should explore synergistic treatments and safer ketamine derivatives for precision psychiatry.

Study at a glance

Abstract

Ketamine has emerged as a promising rapid-acting antidepressant with distinct advantages for the treatment of treatment-resistant depression (TRD). Its therapeutic effects are mediated through multi-target modulation of the glutamatergic system. Unlike conventional antidepressants, ketamine exerts a markedly faster onset of action; however, its long-term safety profile and potential risk of dependence require rigorous evaluation. This scoping review aims to systematically summarize recent advances in research on ketamine's role in depression treatment. This review synthesizes current evidence regarding ketamine's molecular mechanisms of action, neuroimaging correlates, pharmacological characteristics, and associated ethical considerations. By primarily antagonizing N-methyl-d-aspartate receptors, ketamine rapidly disinhibits the mesolimbic dopamine reward pathway and upregulates brain-derived neurotrophic factor (BDNF) expression via eukaryotic elongation factor 2 kinase (eEF2K) suppression, thereby activating the mammalian target of rapamycin (mTOR) pathway and enhancing synaptic plasticity. Neuroimaging studies further reveal that ketamine induces rapid remodeling of prefrontal-limbic functional connectivity, modulates default mode network activity, and promotes the normalization of cerebral metabolism and structure. Pharmacologically, ketamine exhibits a rapid onset of action and a relatively broad therapeutic window, though notable pharmacodynamic and pharmacokinetic differences exist between its enantiomers and active metabolites, which warrants further investigation. Ketamine displays rapid onset and high efficacy in the management of TRD; nevertheless, its long-term safety, risk of dependence, and potential cognitive effects necessitate close clinical monitoring. Future research should prioritize the exploration of synergistic treatment regimens and the development of novel ketamine derivatives with improved target specificity and safety profiles to advance the application of precision psychiatry. Collectively, this review provides a foundational reference to guide clinical practice and inform subsequent mechanistic studies on ketamine-based antidepressant therapies.