Summary: A large, randomized, double-blind clinical trial found that repeated low-dose ketamine infusions provided no additional benefit over standard inpatient care for people hospitalized with major depression. When compared with an active psychoactive placebo (midazolam), ketamine produced no meaningful advantages on clinician-rated or self-reported depression scales, cognition, healthcare costs, or quality of life.
Investigators warn that earlier reports of ketamine’s antidepressant effects may have been exaggerated by unblinding and placebo-related influences. The new findings underscore the need for rigorous, well-controlled trials before expanding ketamine’s clinical use for depression.
Key Facts:
- No additional benefit: In this trial, ketamine did not outperform midazolam on primary or key secondary outcomes.
- Blinding challenges: Most participants and assessors correctly guessed treatment allocation, which could have inflated perceived effects in prior studies.
- Clinical implication: Results call for more cautious expectations about ketamine’s role in routine depression care and for careful evaluation of its costs, safety, and long-term effects.
Source: TCD
Overview of the trial
The KARMA-Dep 2 trial—conducted by teams at St Patrick’s Mental Health Services, Trinity College Dublin, and Queen’s University Belfast and led by Declan McLoughlin—tested whether serial adjunctive ketamine infusions improve outcomes for adults hospitalized with a major depressive episode. The trial results were published in JAMA Psychiatry.
Depression is a leading cause of disability worldwide. In Ireland in 2023 there were 15,631 adult admissions to psychiatric services; depressive disorders accounted for the largest share (about 24%). Around 30% of people with depression do not respond adequately to conventional antidepressants, which has motivated research into alternative mechanisms and treatments.
Ketamine, a dissociative anaesthetic given intravenously at low, sub-anaesthetic doses, acts on glutamatergic systems rather than classic monoamine targets. Single ketamine infusions have been reported to produce rapid antidepressant effects that typically fade within days. Because of this short-lived benefit, some clinicians have adopted repeated infusions off-label in the hope of sustaining improvement, but robust evidence from placebo-controlled trials has been limited.
Design and procedures
KARMA-Dep 2 was an investigator-led, double-blind, randomized, midazolam-controlled pragmatic trial run at an academic centre in Ireland from September 2021 to August 2024 and funded by the Health Research Board. Eligible adults (age ≥18) were hospitalized with a DSM-5 major depressive episode (unipolar or bipolar) and had a baseline Montgomery-Åsberg Depression Rating Scale (MADRS) score of 20 or higher.
Participants were randomized 1:1 to receive up to eight intravenous infusions over four weeks, given twice weekly, of either ketamine (0.5 mg/kg) or midazolam (0.045 mg/kg) as an adjunct to usual inpatient pharmacotherapy and routine psychiatric care. Participants were followed for six months after treatment.
Primary and secondary outcomes
- The primary outcome was change in depression severity measured by the observer-rated MADRS from baseline to end of treatment.
- Secondary outcomes included self-reported depression severity (QIDS-SR-16), cognition, safety and tolerability, health care costs, and quality of life.
Main findings
Of 65 randomized participants (mean age 53.5 years; 59.7% male), 62 were included in the final analysis. At the end of the treatment course there was no statistically significant difference between the ketamine and midazolam groups on the MADRS primary outcome (adjusted mean difference −3.16 points; 95% CI, −8.54 to 2.22; P = .25). Self-reported depression scores (QIDS-SR-16) also showed no between-group difference (adjusted mean difference −0.002; 95% CI, −2.71 to 2.71; P > .99).
No significant differences emerged between groups on secondary measures of cognition, cost-effectiveness, or quality of life. Importantly, most patients and raters correctly guessed which treatment had been administered, indicating incomplete blinding and a risk that placebo-related factors influenced results.
Interpretation and implications
Lead investigator Declan McLoughlin noted that, contrary to the initial hypothesis, adjunctive serial ketamine infusions provided no measurable advantage over a psychoactive comparison drug when added to standard inpatient care, either during the short treatment phase or across six months of follow-up. The authors emphasize that earlier estimates of ketamine’s antidepressant efficacy may have been inflated by problems maintaining the blind and by placebo effects.
Co‑author Ana Jelovac highlighted the broader trial-methodology lesson: in studies of treatments with striking subjective effects—such as ketamine, some psychedelics, or brain stimulation therapies—rigorous assessment of whether blinding was successful is essential to avoid overestimating efficacy.
Key Questions Answered
A: The trial tested whether repeated low-dose ketamine infusions improve depression outcomes when added to standard inpatient care.
A: There was no significant difference between patients receiving ketamine and those given a psychoactive placebo (midazolam) across primary clinical measures and quality-of-life outcomes.
A: Despite increasing off-label use of ketamine for depression, this rigorously controlled trial suggests its benefits may be smaller than previously reported and highlights the importance of careful evaluation before widespread clinical adoption.
A: Many participants and raters accurately guessed treatment allocation, which can enhance placebo effects and affect perceived treatment benefit.
About this research
Author: Ciara O’Shea
Source: TCD
Contact: Ciara O’Shea – TCD
Image: The image is credited to Neuroscience News
Original Research: Closed access. “Serial Ketamine Infusions as Adjunctive Therapy to Inpatient Care for Depression” by Declan McLoughlin et al., JAMA Psychiatry. ClinicalTrials.gov Identifier: NCT04939649
Abstract
Serial Ketamine Infusions as Adjunctive Therapy to Inpatient Care for Depression
Importance
Serial ketamine infusions are being used off-label for major depression, but robust, psychoactive placebo-controlled evidence for both short- and long-term efficacy and safety is limited.
Objective
To evaluate 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.
Design, Setting, and Participants
KARMA-Dep 2 was a double-blind, randomized, midazolam-controlled pragmatic trial in an academic centre in Ireland (September 2021–August 2024). Adults hospitalized with a DSM-5 major depressive episode and MADRS ≥20 were eligible.
Interventions
Participants were randomized 1:1 to up to eight twice-weekly intravenous infusions of ketamine (0.5 mg/kg) or midazolam (0.045 mg/kg) as adjuncts to usual inpatient care and followed for six months.
Main Outcomes and Measures
Primary outcome: change in MADRS score from baseline to end of treatment. Secondary outcomes: self-reported depression, safety, tolerability, costs, and quality of life.
Results
Sixty-five participants were randomized (mean age 53.5 years; 59.7% male); 62 were analyzed. End-of-treatment MADRS scores did not differ significantly between groups (adjusted mean difference −3.16; 95% CI, −8.54 to 2.22; P = .25). QIDS-SR-16 scores and other secondary outcomes showed no between-group differences. Most patients and raters accurately guessed treatment allocation.
Conclusions and Relevance
Serial adjunctive ketamine infusions were not more effective than serial midazolam infusions in reducing depressive symptoms among inpatients receiving routine psychiatric care. These results highlight the importance of rigorous controls and blinding when evaluating treatments with prominent subjective effects.