Sustained pharmacodynamic effects of S-ketamine on cortical excitability and resting-state brain activity: A randomized, placebo-controlled trial.

Abstract

<h4>Aims</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusion</h4>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.

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