| Ketamine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, has gained increasing attention for its rapid antidepressant effects in treatment-resistant depression (TRD) and acute suicidal ideation. Its mechanisms include NMDA receptor blockade, AMPA receptor activation, and upregulation of BDNF/mTOR signaling, while its enantiomers and metabolites exhibit distinct pharmacological profiles. Intranasal esketamine has been approved in the United States, Europe, and China for TRD, demonstrating rapid efficacy in alleviating depressive symptoms and suicidal thoughts. By contrast, R-ketamine shows greater durability and potentially superior safety in preclinical and early clinical studies. This review summarizes recent advances in the pharmacology, pharmacokinetics, and clinical applications of ketamine and its enantiomers in depressive disorders, bipolar disorder, substance use disorders, post-traumatic stress disorder, and obsessive–compulsive disorder. Although ketamine offers broad therapeutic promise, concerns regarding dissociation, cognitive impairment, and abuse liability underscore the need for careful clinical monitoring and further research. |