Comparative EEG analysis of the effects of ketamine enantiomers and metabolites in rhesus macaques.

(R,S)-Ketamine, a dissociative anesthetic, has shown rapid and sustained antidepressant effects at lower doses than those required for anesthetic effects in patients with treatment-resistant depression. However, its use is limited because it causes side effects, including psychotomimetic symptoms and dependence. The enantiomer (R)-ketamine was reported to promote antidepressant-like effects in rodents with a potentially lower risk for adverse effects compared with (S)-ketamine. This study compared the effects of (R)-ketamine, (S)-ketamine, their metabolites, and another N-methyl-D-aspartate antagonist, MK-801, on the electroencephalograms (EEGs) of rhesus macaques across a wide range of doses. The results showed that the dose level of (R,S)-ketamine, corresponding to the clinically effective antidepressant concentration in humans, produced increase in gamma power as reported in clinical trials. Compared with (S)-ketamine, (R)-ketamine produced a comparable increase in gamma power but had weaker effects on EEG features thought to be associated with adverse effects. The EEG changes induced by the ketamine metabolites were relatively mild, indicating a minimal contribution to the EEG effects of ketamine. This comprehensive EEG evaluation in a non-human primate, together with measurements of plasma drug concentrations, when interpreted in comparison with existing clinical data, provide increased translational insight into the dose-dependent neurophysiological characteristics of (R,S)-ketamine, its enantiomers and metabolites. EEG-based comparisons of (R)-ketamine with (R,S)-ketamine and (S)-ketamine suggest that (R)-ketamine exhibits neurophysiological features consistent with a potentially broader therapeutic range for antidepressant effects.