Subacute effects of ketamine on neural correlates of reward processing

Abstract

Objectives Ketamine’s prohedonic properties have been linked to enhanced reward-related brain activation during the early post-infusion phase. Its effects during the subacute period (∼2-24 h post-infusion), when psychotomimetic symptoms fade and neuroplastic adaptations emerge, are less well characterised. This study assessed ketamine’s subacute effects on reward processing using the Monetary Incentive Delay (MID) task. Methods In a randomised, placebo-controlled, crossover study, 28 healthy participants received 0.5 mg/kg racemic ketamine or placebo via 40-minute intravenous infusion. Functional magnetic resonance imaging (fMRI) was acquired ∼5 h post-infusion. Plasma concentrations of ketamine and norketamine were obtained for individual area under the curve (AUC) estimation. Analyses focused on the contrast between expected and actual trial outcomes. Results At five hours post-infusion, ketamine did not significantly modulate MID task-related brain activation, despite pronounced subjective drug effects. Pharmacokinetic modelling confirmed expected ketamine and norketamine profiles, but neither drug exposure (AUC) nor subjective measures correlated with neural activation. Conclusions Prohedonic effects of ketamine may not sufficiently manifest in MID task-related activation in healthy individuals ∼5 hours after infusion. The lack of significant effects provides valuable extension of the existing literature, as ketamine’s effects might be confined to a more acute time window or differ in clinical populations.