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

At a dose matching the concentration found effective for depression in humans, the anesthetic (R,S)-ketamine increased gamma power in the EEG of rhesus macaques, replicating clinical findings. The enantiomer (R)-ketamine produced a similar rise in gamma power but had weaker effects on EEG features linked to side effects. Ketamine metabolites caused only mild EEG changes, suggesting they contribute little to ketamine's EEG effects. The results indicate (R)-ketamine may have a broader therapeutic range and lower risk of adverse effects than (R,S)-ketamine.

Study at a glance

Abstract

(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 an 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 nonhuman 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.NEW & NOTEWORTHY (R,S)-Ketamine, used to treat depression, induces side effects. This study investigated the effects of (R,S)-ketamine, its enantiomers, and metabolites on EEG metrics which may be related to the antidepressant effects and side effects of (R,S)-ketamine. Findings suggest that (R)-ketamine may have a lower risk of adverse effects and a broader effective dose range compared with (R,S)-ketamine.