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Ketamine’s impact on rumination-related brain dynamics: insights from a randomized controlled fMRI trial

Marvin Sören Meiering, David Weigner, Matti Gärtner, Luisa Carstens, Christian Keicher, Gerd Luippold, Andreas Wunder, Anne Weigand, Simone Grimm

Translational Psychiatry August 18, 2026 DOI: 10.1038/s41398-026-04392-w (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics Randomized controlled trial Placebo-controlled Double-blind Peer reviewed
Sample size 75
Population Healthy adults
Interventions Ketamine Lamotrigine
Duration 24 hours post-infusion
Topics Esketamine Ketamine
Key findings Ketamine acutely reduced the occurrence rate of a hybrid DMN+FPN coactivation pattern associated with rumination, with larger decreases in individuals reporting higher rumination; effects were transient and returned to baseline after 24 hours. Lamotrigine pretreatment nominally attenuated ketamine-induced changes, suggesting partial glutamatergic mediation.

Abstract

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. 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. 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 h. Exploratorily, ketamine also reduced engagement of a canonical somatomotor CAP during infusion. Lamotrigine pretreatment nominally attenuated ketamine-induced changes across analyses. Ketamine transiently alters dynamic brain states implicated in rumination and somatosensory processing, and preliminary evidence suggests partial glutamatergic mediation. These findings provide insights into ketamine's mechanism of action.

Comparable studies

Other randomized controlled trials on ketamine, most cited first.

Study Year Design Participants
Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Healthy human subjects recruited from the community 1994 Randomized controlled trial n = 19
Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial Patients with treatment-resistant major depression experiencing a major depressive episode 2013 Randomized controlled trial n = 73
Remifentanil-induced Postoperative Hyperalgesia and Its Prevention with Small-dose Ketamine Patients undergoing major abdominal surgery 2005 Randomized controlled trial n = 75
Efficacy of Intravenous Ketamine for Treatment of Chronic Posttraumatic Stress Disorder Patients with chronic PTSD related to a range of trauma exposures 2014 Randomized controlled trial n = 41
Ketamine-Induced Deficits in Auditory and Visual Context-Dependent Processing in Healthy Volunteers Healthy volunteers 2000 Single-blind placebo-controlled study n = 20

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Esketamine Ketamine Default mode network