Differential effects of ketamine enantiomers on EEG parameters including the gamma-delta shift phenomenon.

In rats, the (S)-enantiomer of ketamine (esketamine) produces a fourfold stronger wake-promoting effect and a twofold stronger increase in gamma brainwave power during wakefulness compared to the (R)-enantiomer (arketamine). Only esketamine enhances delta power during NREM sleep after gamma activity normalizes, a pattern called the gamma-delta shift. This shift, previously proposed as a marker of antidepressant activity for racemic ketamine, appears specific to esketamine. The findings help clarify which enantiomer drives the EEG changes and suggest that the gamma-delta shift may serve as a biomarker for antidepressant effects, relevant to treatment-resistant depression.

Study at a glance

Abstract

Ketamine consists of two enantiomers, (R)-ketamine and (S)-ketamine, which exhibit distinct pharmacological properties. Currently, only the (S)-enantiomer has been approved for the treatment of major depressive disorder, whereas recent clinical studies have failed to demonstrate an antidepressant effect for (R)-ketamine. The quantitative electroencephalography (qEEG) gamma-enhancing effect of racemic ketamine has been reported before; moreover, a previous study has described a phenomenon that shows a temporal shift between the elevation of qEEG gamma and qEEG delta power, which we named as gamma-delta shift. It has been proposed as a marker of the antidepressant activity of racemic ketamine. To determine which enantiomer is responsible for these effects and in which sleep-wake states these changes occur, we compared the effects of the two enantiomers together with the separation of the different sleep-wake stages and examining dose dependency across a broad frequency spectrum. In Wistar rats, frontoparietal EEG and muscle activity were recorded following intraperitoneal administration of (S)-ketamine (7.5, 15 and 30 mg kg-1) or (R)-ketamine (7.5, 15, 30 and 60 mg kg-1) or vehicle at the beginning of the passive phase. Wake-inducing and NREM sleep-reducing effects of (S)-ketamine were fourfold stronger compared to (R)-ketamine. The gamma power increase induced by (S)-ketamine during wakefulness was twice as strong as that of (R)-ketamine. Additionally, once gamma activity normalized, only (S)-ketamine enhanced delta power during non-rapid eye movement (NREM) sleep and induced the gamma-delta shift. These findings indicate that the gamma-delta shift phenomenon is specific to (S)-ketamine.