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.

Background: The GABA_A receptor (GABAAR) potentiator, KRM-II-81, is being developed as a novel antiseizure medication with reduced potential for sedation, tolerance development, and abuse liability. Although KRM-II-81 has been shown to provide antiseizure protection against a broad array of seizure induction paradigms, seizures induced by viral vectors have not been previously studied. GABAARs with specific α subunit compositions have been studied in relation to the reduced side-effect liability of KRM-II-81; however, the role of β subunit composition has yet to be determined. Methods: In the present study, KRM-II-81 was studied against handling-induced seizures in Theiler’s murine encephalomyelitis virus (TMEV)-infected mice. Results: An intracerebral infusion of TMEV on day 0 increased the cumulative seizure burden in mice when assessed for handling-induced seizures on days 3–7. KRM-II-81 (15 mg/kg, p.o., bid) nearly completely suppressed seizures in TMEV-infected mice over the course of daily treatments. The number of the most severe seizures (stage 5, tonic/clonic seizures) in the mice was suppressed to zero by KRM-II-81. Although the selectivity of KRM-II-81 for GABAAR α2/3 receptor subtypes might imbue KRM-II-81 with a reduced side-effect liability, other mechanisms are possible, and the potentiation of β1-containing GABAARs has been implicated in inducing sedation. The role of β subunit composition has yet to be determined for KRM-II-81. In electrophysiological studies with cells transfected with α_xβ₁γ₂ or α_xβ₃γ₂, KRM-II-81 preferentially potentiated GABA responses in cells containing β3 subunits in α2/3-containing GABAARs. Conclusions: The present findings confirm the robust antiseizure activity of KRM-II-81, now extended to a virus-induction model, and suggest a possible role of reduced β1-potentiation in the low side-effect profile of KRM-II-81.