SUSTAINED PHARMACODYNAMIC EFFECTS OF ESKETAMINE ON CORTICAL EXCITABILITY AND RESTING-STATE BRAIN ACTIVITY: A RANDOMIZED, PLACEBO-CONTROLLED TRIAL

Aim

Acute pharmacodynamic effects of esketamine have been well characterized; however, reliable pharmacodynamic measures capturing delayed effects—potentially related to its antidepressant efficacy emerging beyond 24 hours—remain limited. We hypothesized that delayed effects arising after esketamine clearance are mechanistically distinct from acute, peak-concentration–driven psychomimetic and CNS-depressant effects. To address this, we investigated pharmacodynamic biomarkers reflecting acute, delayed, and sustained central nervous system (CNS) effects of esketamine, used as a tool compound for rapid-acting antidepressant activity, using Transcranial Magnetic Stimulation (TMS) and resting-state pharmaco-electroencephalography (pEEG), with the goal of informing biomarker strategies for delayed antidepressant effects in early-phase drug trials.

Methods

In this randomized, double-blind, double-dummy, placebo-controlled, four-way crossover study, 16 healthy participants received a therapeutic intravenous (IV) dose of esketamine (0.40 mg/kg 40-minute IV), oral low-dose of esketamine (0.20 mg/kg), oral highdose of esketamine (0.45 mg/kg), or placebo. Neurophysiological assessments were conducted from baseline up to 7 days post-dose using TMS combined with electromyography (TMS-EMG) and electroencephalography (TMS-EEG), alongside resting-state pEEG and plasma concentrations of parent drug and metabolites. Outcomes were analyzed using mixedeffects ANCOVA and cluster-based permutation testing.

Results

IV esketamine produced an acute significant reduction in motor-evoked potential amplitude (estimated difference [ED]: −430.17 μV; 95% CI: −806.74 to −53.61; p = 0.03), alongside sustained attenuation of long-interval intracortical inhibition (LICI₅₀) persisting beyond drug exposure (ED: +57.83%; 95% CI: 14.24 to 101.43; p = 0.01). TMS-EEG revealed acute modulation of TMS-evoked potentials across all active treatments, whereas delayed effects were observed only following IV and high-dose oral esketamine. Restingstate pEEG demonstrated acute reductions in alpha, beta, and delta power during eyes-closed conditions and a sustained increase in delta power during eyes-open conditions following IV and high-dose oral dosing.

Conclusion

TMS-and pEEG-derived measures reveal delayed and sustained pharmacodynamic CNS effects of esketamine persisting up to 7 days post-dose. These findings indicate a temporally dissociable pharmacodynamic profile, distinct from acute, exposure-driven CNS effects, which may be relevant to its delayed antidepressant efficacy.