Ketamine as an antidepressant: overview of its mechanisms of action and potential predictive biomarkers

TLDR

Ketamine, first used as an anesthetic, has emerged over the past two decades as a rapid‑acting treatment for major depressive disorder, offering antidepressant effects within hours and potential anti‑suicidal benefits, contrasting with the weeks‑long onset of traditional antidepressants. This review aims to summarize ketamine’s pharmacology, toxicology, clinical trial evidence, and proposed mechanisms and biomarkers for predicting therapeutic response. The authors discuss ketamine’s glutamate‑mediated actions at NMDA and AMPA receptors, downstream BDNF and mTOR signaling, and related biomarkers for monitoring response.

Abstract

Ketamine, a drug introduced in the 1960s as an anesthetic agent and still used for that purpose, has garnered marked interest over the past two decades as an emerging treatment for major depressive disorder. With increasing evidence of its efficacy in treatment-resistant depression and its potential anti-suicidal action, a great deal of investigation has been conducted on elucidating ketamine’s effects on the brain. Of particular interest and therapeutic potential is the ability of ketamine to exert rapid antidepressant properties as early as several hours after administration. This is in stark contrast to the delayed effects observed with traditional antidepressants, often requiring several weeks of therapy for a clinical response. Furthermore, ketamine appears to have a unique mechanism of action involving glutamate modulation via actions at the N-methyl-D-aspartate (NMDA) and [Formula: see text]-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, as well as downstream activation of brain-derived neurotrophic factor (BDNF) and mechanistic target of rapamycin (mTOR) signaling pathways to potentiate synaptic plasticity. This paper provides a brief overview of ketamine with regard to pharmacology/pharmacokinetics, toxicology, the current state of clinical trials on depression, postulated antidepressant mechanisms and potential biomarkers (biochemical, inflammatory, metabolic, neuroimaging sleep-related and cognitive) for predicting response to and/or monitoring of therapeutic outcome with ketamine.