Ketamine and its enantiomers have a long history in anesthesia and are now gaining attention for rapid-acting antidepressant effects in severe depression. Esketamine, the (S)-enantiomer, received approval in the U.S. and Europe in 2019 as a nasal spray for depression, but concerns about long-term efficacy, addiction, and suicide risk persist. In rodent models, arketamine, the (R)-enantiomer, shows superior and longer-lasting antidepressant effects with fewer side effects than esketamine, though human research on arketamine is limited. The article reviews the historical use of ketamine and its enantiomers in anesthesia and psychiatry and explores future directions.
Ketamine and its enantiomer esketamine show promise for managing both depression and pain in cancer patients. Sub-anesthetic intravenous doses can alleviate postoperative depressive symptoms with a tolerable safety profile. Research on non-intravenous routes for depression in this population is limited. Intravenous ketamine is effective for acute postoperative pain, while alternative routes like local infiltration and intramuscular injection yield mixed results but may suit patients who avoid IV. Evidence for ketamine in chronic cancer pain is inconsistent. Overall, ketamine offers a promising approach for depression and pain in oncologic patients.
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.