Shafique, HanaDemers, Julie C.Biesiada, JuliaGolani, Lalit K.Cerne, RokSmith, Jodi L.Szostak, MartaWitkin, Jeffrey M.2024-08-272024-08-272024-06-20Shafique H, Demers JC, Biesiada J, et al. (R)-(-)-Ketamine: The Promise of a Novel Treatment for Psychiatric and Neurological Disorders. Int J Mol Sci. 2024;25(12):6804. Published 2024 Jun 20. doi:10.3390/ijms25126804https://hdl.handle.net/1805/42968NMDA receptor antagonists have potential for therapeutics in neurological and psychiatric diseases, including neurodegenerative diseases, epilepsy, traumatic brain injury, substance abuse disorder (SUD), and major depressive disorder (MDD). (S)-ketamine was the first of a novel class of antidepressants, rapid-acting antidepressants, to be approved for medical use. The stereoisomer, (R)-ketamine (arketamine), is currently under development for treatment-resistant depression (TRD). The compound has demonstrated efficacy in multiple animal models. Two clinical studies disclosed efficacy in TRD and bipolar depression. A study by the drug sponsor recently failed to reach a priori clinical endpoints but post hoc analysis revealed efficacy. The clinical value of (R)-ketamine is supported by experimental data in humans and rodents, showing that it is less sedating, does not produce marked psychotomimetic or dissociative effects, has less abuse potential than (S)-ketamine, and produces efficacy in animal models of a range of neurological and psychiatric disorders. The mechanisms of action of the antidepressant effects of (R)-ketamine are hypothesized to be due to NMDA receptor antagonism and/or non-NMDA receptor mechanisms. We suggest that further clinical experimentation with (R)-ketamine will create novel and improved medicines for some of the neurological and psychiatric disorders that are underserved by current medications.en-USAttribution 4.0 InternationalMajor depressive disorderRapid-acting antidepressantInflammationKetamine(R)-ketamineSubstance use disorderArticle