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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\u2019s 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\u2013placebo, placebo\u2013ketamine, or lamotrigine\u2013ketamine treatment. Resting-state fMRI was acquired at baseline, during ketamine\/placebo infusion, and 24\u2009h 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\u2009+\u2009FPN 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\u2009h. 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\u2019s mechanism of action.<\/jats:p>","DOI":"10.1038\/s41398-026-04392-w","type":"journal-article","created":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T14:58:50Z","timestamp":1787065130000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Ketamine\u2019s impact on rumination-related brain dynamics: insights from a randomized controlled fMRI trial"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9747-5015","authenticated-orcid":false,"given":"Marvin S.","family":"Meiering","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5402-6394","authenticated-orcid":false,"given":"David","family":"Weigner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1185-1789","authenticated-orcid":false,"given":"Matti","family":"G\u00e4rtner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luisa","family":"Carstens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7552-4082","authenticated-orcid":false,"given":"Christian","family":"Keicher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerd","family":"Luippold","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Wunder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Weigand","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Grimm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,18]]},"reference":[{"key":"4392_CR1","doi-asserted-by":"publisher","first-page":"576","DOI":"10.1016\/j.jad.2020.06.050","volume":"276","author":"RS McIntyre","year":"2020","unstructured":"McIntyre RS, Carvalho IP, Lui LMW, Majeed A, Masand PS, Gill H, et al. 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KG. Simone Grimm has served as a consultant to and received research support from Boehringer Ingelheim Pharma GmbH & Co. KG. Andreas Wunder was an employee of Boehringer Ingelheim Pharma GmbH & Co. KG. Gerd Luippold is an employee of Boehringer Ingelheim Pharma GmbH & Co. KG. Christian Keicher is an employee of Charite\u0301 Research Organisation. The authors declare no conflict of interest.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"All methods were performed in accordance with relevant guidelines and regulations. All participants gave written informed consent to participate in the study. The study was approved by the Independent Ethics Committee, Landesamt f\u03cbr Gesundheit und Soziales, and the Federal Institute for Drugs and Medical Devices (BfArM; 4043918). The study is registered at ClinicalTrials.gov (NCT04156035). 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