Subacute effects of ketamine on neural correlates of reward processing

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.