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

Background and Purpose 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. Experimental Approach 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. Key Results 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. Conclusion and Implications These findings indicate that the gamma‐delta shift phenomenon is specific to (S)‐ketamine.