Ketamine’s Impact on Rumination-Related Brain Dynamics: Insights From a Randomized Controlled fMRI Trial

Introduction: Rumination has been associated with aberrant dynamics of a coactivation pattern (CAP) comprising the default mode (DMN) and frontoparietal (FPN) networks. Ketamine exerts rapid antidepressant effects and may influence these dynamics via glutamatergic mechanisms. In a randomized, double-blind, placebo-controlled fMRI study, we investigated ketamine’s effects on dynamic CAPs associated with rumination and examined whether inhibition of glutamatergic release through lamotrigine attenuates these effects.Methods: Seventy-five healthy adults were randomized to placebo–placebo, placebo–ketamine, or lamotrigine–ketamine treatment. Resting-state fMRI was acquired at baseline, during ketamine/placebo infusion, and 24 h post-infusion. Whole-brain CAP analysis identified seven recurring network configurations. Occurrence rates were examined for group differences, while controlling for age, sex, and drug plasma concentrations. Rumination was assessed using a validated self-report questionnaire.Results: A hybrid DMN+FPN CAP showed a positive association with rumination at baseline. Ketamine acutely reduced the occurrence rate of this hybrid CAP compared to placebo, with larger decreases in individuals reporting higher rumination. These effects were transient, returning to baseline after 24 hours. Exploratorily, ketamine also reduced engagement of a canonical somatomotor CAP during infusion. Lamotrigine pretreatment nominally attenuated ketamine-induced changes across analyses.Conclusion: Ketamine transiently alters dynamic brain states implicated in rumination and somatosensory processing, and these effects appear partially modulated by glutamatergic mechanisms. These findings provide insights into ketamine’s mechanism of action.