(R)-(-)-Ketamine: The Promise of a Novel Treatment for Psychiatric and Neurological Disorders.

NMDA receptor antagonists show promise for neurological and psychiatric conditions such as neurodegenerative diseases, epilepsy, traumatic brain injury, substance use disorder, and major depressive disorder. (S)-ketamine was the first rapid-acting antidepressant approved for medical use. Its stereoisomer, (R)-ketamine (arketamine), is under development for treatment-resistant depression and has shown efficacy in multiple animal models. Two clinical studies reported efficacy in treatment-resistant depression and bipolar depression, though a sponsor study failed to meet primary endpoints; post hoc analysis indicated efficacy. (R)-ketamine is less sedating, produces fewer psychotomimetic or dissociative effects, and has lower abuse potential than (S)-ketamine. Its antidepressant mechanisms may involve NMDA receptor antagonism and non-NMDA receptor pathways. Further clinical research may lead to improved treatments for underserved neurological and psychiatric disorders.

Study at a glance

Abstract

NMDA 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.