Differential effects of ketamine enantiomers on EEG parameters including the gamma-delta shift phenomenon.
Szabolcs Koncz, Dóra Pothorszki, Noémi Papp, Donát Pál, György Bagdy
British Journal of Pharmacology June 1, 2026 DOI: 10.1111/bph.70399 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental animal study Peer reviewed |
|---|---|
| Population | Wistar rats |
| Interventions | (S)-ketamine (R)-ketamine |
| Dose | 7.5, 15 and 30 mg kg-1 for (S)-ketamine; 7.5, 15, 30 and 60 mg kg-1 for (R)-ketamine |
| Topics | Esketamine Ketamine |
| Keywords | Arousal Biomarker Qeeg Sleep–wake stage Treatment‐resistant depression |
| Citations | 2 |
| Key findings | The gamma-delta shift phenomenon is specific to (S)-ketamine, not (R)-ketamine. |
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.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cites 25
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms Pharmacological Reviews June 26, 2018
- R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Translational Psychiatry September 1, 2015
- Pharmacological and behavioral divergence of ketamine enantiomers: implications for abuse liability Molecular Psychiatry April 15, 2021
and 20 more in the library