Serial Ketamine Infusions as Adjunctive Therapy to Inpatient Care for Depression: The KARMA-Dep 2 Randomized Clinical Trial.
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Authors
Jelovac, Ana
McCaffrey, Cathal
Terao, Masashi
Shanahan, Enda
Whooley, Emma
McDonagh, Kelly
McDonogh, Sarah
Loughran, Orlaith
Shackleton, Ellie
Igoe, Anna
Issue Date
2025-10-22
Type
Journal Article
Language
en
Keywords
Alternative Title
Abstract
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.
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.
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 (≥18 years) hospitalized with a DSM-5 major depressive episode (unipolar or bipolar) and baseline Montgomery-Åsberg Depression Rating Scale (MADRS) score ≥20.
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.
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.
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, -3.16 points, 95% CI, -8.54 to 2.22; P = .25; Cohen d, -0.29). Similarly, there was no significant between-group difference between Quick Inventory of Depressive Symptoms, Self-Report, scores (adjusted mean difference, -0.002; 95% CI, -2.71 to 2.71; P > .99; Cohen d, -0.0004). 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.
Serial adjunctive ketamine infusions were not more effective than serial midazolam infusions in reducing depressive symptoms in inpatients receiving usual psychiatric care.
ClinicalTrials.gov Identifier: NCT04939649.
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.
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 (≥18 years) hospitalized with a DSM-5 major depressive episode (unipolar or bipolar) and baseline Montgomery-Åsberg Depression Rating Scale (MADRS) score ≥20.
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.
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.
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, -3.16 points, 95% CI, -8.54 to 2.22; P = .25; Cohen d, -0.29). Similarly, there was no significant between-group difference between Quick Inventory of Depressive Symptoms, Self-Report, scores (adjusted mean difference, -0.002; 95% CI, -2.71 to 2.71; P > .99; Cohen d, -0.0004). 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.
Serial adjunctive ketamine infusions were not more effective than serial midazolam infusions in reducing depressive symptoms in inpatients receiving usual psychiatric care.
ClinicalTrials.gov Identifier: NCT04939649.
Description
Citation
Jelovac A, McCaffrey C, Terao M, Shanahan E, Whooley E, McDonagh K, McDonogh S, Loughran O, Shackleton E, Igoe A, Thompson S, Mohamed E, Nguyen D, O'Neill C, Walsh C, McLoughlin DM. Serial Ketamine Infusions as Adjunctive Therapy to Inpatient Care for Depression: The KARMA-Dep 2 Randomized Clinical Trial. JAMA Psychiatry. 2025 Oct 22. doi: 10.1001/jamapsychiatry.2025.3019. Epub ahead of print. PMID: 41123905.
Publisher
License
Journal
JAMA psychiatry
Volume
Issue
PubMed ID
ISSN
2168-6238