Mechanism of antidepressant action of ketamine and differences between its two enantiomers

Ketamine has been widely used since its discovery, and in addition to its anesthetic effects, in recent years it has been found to exhibit rapid and sustained antidepressant effects in rodent models and in patients with treatment-resistant depression (TRD) at subanesthetic doses. The antidepressant mechanism of ketamine has also been intensively studied, involving glutamate receptors such as NMDAR, AMPAR, mGluR5, molecular pathways such as mTOR, ERK-CREB, PI3K/Akt, metabolites, and other related pathways such as opioid receptors, inflammation, and monoamines. Ketamine is a racemate containing equal amounts of S-ketamine and R-ketamine. S-ketamine has recently been approved by the U.S. Food and Drug Administration (FDA) as an antidepressant with a novel mechanism of action. In rodent models of depression, such as the forced swimming test (FST), the novelty suppressed feeding (NSF) test, the chronic social defeat stress (CSDS) and the learned helplessness (LH) test, R-ketamine showed more potent and prolonged antidepressant effects. Moreover, R-ketamine was free of psychotomimetic side effects and abuse tendencies, but its clinical effects are still unclear. The enantiomers of ketamine have been known to have pharmacological and clinical differences since the late 1970s and have been studied further. The exploration of the two enantiomers of ketamine for antidepressant effects may lead to a deeper understanding of new antidepressant ideas, and this review provides an overview of the mechanism of ketamine's antidepressant action in recent years as well as the differences in the effects of the two enantiomers.