{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T19:46:31Z","timestamp":1791229591085,"version":"4.1.0"},"reference-count":36,"publisher":"American Medical Association (AMA)","issue":"12","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Psychiatry"],"published-print":{"date-parts":[[2025,12,1]]},"abstract":"\n Importance<\/jats:title>\n Serial ketamine infusions are being increasingly adopted as off-label treatment for major depression in routine clinical practice, yet robust psychoactive placebo-controlled trial evidence for short- and long-term efficacy and safety remains limited.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n To assess antidepressant efficacy, safety, tolerability, cost-effectiveness, and quality of life during and after serial ketamine infusions compared with midazolam as an adjunct to usual inpatient care.<\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n \n The KARMA-Dep 2 trial was an investigator-led, double-blind, randomized, midazolam-controlled, pragmatic trial conducted at an academic center in Ireland between September 2021 and August 2024. Participants included adults (\u226518 years) hospitalized with a\n DSM-5<\/jats:italic>\n major depressive episode (unipolar or bipolar) and baseline Montgomery-\u00c5sberg Depression Rating Scale (MADRS) score \u226520.\n <\/jats:p>\n <\/jats:sec>\n \n Interventions<\/jats:title>\n Participants were randomized 1:1 to receive up to 8 twice-weekly intravenous infusions of either ketamine (0.5 mg\/kg) or midazolam (0.045 mg\/kg) as an adjunct to usual-care pharmacotherapy and other aspects of routine inpatient psychiatric care. Participants were followed up for 6 months.<\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n The primary outcome was change in depression symptom severity measured by the observer-rated MADRS score from baseline to end of treatment. Secondary outcomes included self-reported depression severity, safety, tolerability, health care costs, and quality of life.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Of 65 randomized participants (mean [SD] age, 53.5 [18.6] years; 37 [59.7%] male), 62 were included in the final analysis. In the analysis of primary outcome, end-of-treatment MADRS scores did not significantly differ between the ketamine and midazolam groups (adjusted mean difference, \u22123.16 points, 95% CI, \u22128.54 to 2.22;\n P<\/jats:italic>\n \u2009=\u2009.25; Cohen\n d<\/jats:italic>\n , \u22120.29). Similarly, there was no significant between-group difference between Quick Inventory of Depressive Symptoms, Self-Report, scores (adjusted mean difference, \u22120.002; 95% CI, \u22122.71 to 2.71;\n P<\/jats:italic>\n \u2009&amp;gt;\u2009.99; Cohen\n d<\/jats:italic>\n , \u22120.0004). There were no significant between-group differences on other secondary outcomes, including cognition, cost-effectiveness, or quality of life. Most patients and raters accurately guessed treatment allocation.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n Serial adjunctive ketamine infusions were not more effective than serial midazolam infusions in reducing depressive symptoms in inpatients receiving usual psychiatric care.<\/jats:p>\n <\/jats:sec>\n \n Trial Registration<\/jats:title>\n \n ClinicalTrials.gov Identifier:\n NCT04939649<\/jats:ext-link>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jamapsychiatry.2025.3019","type":"journal-article","created":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T15:31:07Z","timestamp":1761147067000},"page":"1216","source":"Crossref","is-referenced-by-count":24,"title":["Serial Ketamine Infusions as Adjunctive Therapy to Inpatient Care for Depression"],"prefix":"10.1001","volume":"82","author":[{"given":"Ana","family":"Jelovac","sequence":"first","affiliation":[{"name":"Department of Psychiatry, School of Medicine, Trinity College Dublin, St 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