Mechanism of antidepressant action of ketamine and differences between its two enantiomers.
Journal of anesthesia and translational medicine September 1, 2025 Junbiao Zhan, Yuxi Zhang, Hao Tian et al.
Ketamine, a racemate of S-ketamine and R-ketamine, produces rapid and sustained antidepressant effects in rodent models and patients with treatment-resistant depression at subanesthetic doses. Its mechanisms involve glutamate receptors (NMDAR, AMPAR, mGluR5), molecular pathways (mTOR, ERK-CREB, PI3K/Akt), metabolites, opioid receptors, inflammation, and monoamines. S-ketamine has received FDA approval as a novel antidepressant. In rodent depression models (forced swimming test, novelty suppressed feeding, chronic social defeat stress, learned helplessness), R-ketamine showed more potent and prolonged effects without psychotomimetic side effects or abuse potential, though its clinical effects remain unclear. This review overviews ketamine's antidepressant mechanisms and differences between the two enantiomers.