Sustained pharmacodynamic effects of S-ketamine on cortical excitability and resting-state brain activity: A randomized, placebo-controlled trial.
Catherine M K E De Cuba, Annika A De Goede, Joost C Van Mechelen, Laura Borghans, Liam Van der Aa, Erik Olofsen, Maria J Juachon, Robert J Doll, Amy L Gillespie, Catherine J Harmer, Gabriël E. Jacobs, Jules A A C Heuberger
British Journal of Clinical Pharmacology June 24, 2026 DOI: 10.1002/bcp.70649 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized controlled trial Placebo-controlled Double-blind Peer reviewed |
|---|---|
| Sample size | 16 |
| Population | Healthy participants |
| Intervention | S-ketamine |
| Dose | therapeutic intravenous dose, low and high oral dose |
| Duration | 7 days post-dose |
| Topics | Esketamine Ketamine |
| Keywords | S‐ketamine Pharmaco‐electroencephalography Transcranial magnetic stimulation |
| Key findings | Intravenous S-ketamine induced delayed pharmacodynamic effects on motor cortex inhibition and brain electrical activity that persisted up to seven days post-dose, distinct from its acute effects. |
Abstract
This study aimed to investigate a set of pharmacodynamic biomarkers reflecting acute, delayed and sustained central nervous system effects of S-ketamine, used as a tool compound for rapid-acting antidepressant activity, with the goal of informing biomarker strategies for delayed antidepressant effects. In this randomized, double-blind, double-dummy, placebo-controlled, 4-way crossover study in 16 healthy participants, we administered S-ketamine in a therapeutic intravenous dose (IV), a low and high oral dose, versus placebo. Measurements were conducted from baseline up to 7 days post-dose using Transcranial Magnetic Stimulation combined with electromyography (TMS-EMG) and encephalography (TMS-EEG), pharmaco-electroencephalography (pEEG), alongside drug and metabolite plasma concentrations. Outcomes were analysed using mixed-effects ANCOVA and cluster-based permutation testing. Post-hoc concentration-effect relationships were explored. IV S-ketamine induced an acute reduction in motor-evoked potential (MEP) amplitude and sustained attenuation of long-interval intracortical inhibition (LICI50), the latter showing a linear concentration-effect relationship with the parent compound. Acute TEP modulation was observed across all treatments, whereas delayed effects occurred only after IV and high-dose oral. pEEG showed acute reductions in alpha, beta and delta power (eyes closed) and sustained increases in delta power (eyes open) following IV and high-dose oral S-ketamine; with delta power exhibiting a less analyte-specific linear concentration-effect relationship. We provide evidence suggestive of delayed pharmacodynamic effects of S-ketamine in healthy participants sustained up to 7 days post-dose, using TMS and pEEG derived measures, which are markedly distinct from its acute effects and may be relevant to understand its antidepressant efficacy.
Comparable studies
Other randomized controlled trials on esketamine, most cited first.
Citations in the library
Cites 13
- Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial American Journal of Psychiatry August 28, 2013
- Intravenous Esketamine in Adult Treatment-Resistant Depression: A Double-Blind, Double-Randomization, Placebo-Controlled Study Biological Psychiatry November 4, 2015
- Comparative efficacy of racemic ketamine and esketamine for depression: a systematic review and meta-analysis Journal of Affective Disorders September 23, 2020
- Ketamine Decreases Resting State Functional Network Connectivity in Healthy Subjects: Implications for Antidepressant Drug Action PLoS One September 24, 2012
- Ketamine Increases Human Motor Cortex Excitability to Transcranial Magnetic Stimulation The Journal of Physiology March 1, 2003
and 8 more in the library