Ketamine Fails To Outperform Control in Hospital Depression Trial

Ketamine has been hailed as a fast-acting antidepressant, but a new trial from Trinity College Dublin and Queen’s University Belfast casts doubts on its efficacy in hospital settings.

In the study, ketamine showed no significant advantage over the control. The results raise serious questions about ketamine’s real-world value as an adjunctive therapy.

Why is ketamine being considered for depression?

Depression is a major driver of global ill health, impacting an estimated 5.7% of the adult population worldwide. The World Health Organization has recognized the condition as a leading cause of disability globally. Despite its prevalence, treatment for depression remains far from perfect. Conventional antidepressants fail in around one-third of patients, leaving a substantial “treatment gap.”

Ketamine has emerged as a promising candidate for the treatment of depression. Unlike standard antidepressants, ketamine acts on glutamate signalling by blocking N-methyl-D-aspartate (NMDA) receptors. Single, low-dose intravenous ketamine infusions can relieve symptoms within hours, although benefits often fade after a few days. Evidence from open-label and small trials suggests that repeated infusions might prolong benefit.

“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,” said the authors of the new study.

Earlier studies on ketamine’s benefits tended to be small, uncontrolled or poorly blinded. One major issue with investigating ketamine is its distinctive dissociative effects (changes in perception, altered consciousness), which make it hard to mask treatment assignment.

To address these weaknesses, the KARMA-Dep 2 trial was designed to offer a more rigorous test. Its goal was to assess whether serial ketamine infusions outperform an active psychoactive control (midazolam) when added to standard inpatient care.

Investigating ketamine’s effects in a rigorous trial

The KARMA-Dep 2 study was an investigator-led, double-blind, randomized clinical trial in which 65 adults hospitalized with moderate-to-severe depression took part. All met DSM-5 criteria for a major depressive episode, either unipolar or bipolar. Participants were randomly assigned to one of two groups: up to eight infusions of ketamine or midazolam, given twice weekly over four weeks.

Those in the ketamine arm received 0.5 mg per kg of body weight by intravenous infusion over 40 minutes. The midazolam group received 0.045 mg per kg. Midazolam, a sedative with short-term psychoactive effects, was chosen to mimic some of ketamine’s sensations and help preserve the study's blind. All participants continued their usual treatments, including medication, psychotherapy and inpatient support.

A change in depression severity was measured by the Montgomery–Åsberg Depression Rating Scale (MADRS). Other measures tracked self-rated symptoms, cognition, quality of life, cost and safety.

The team found that ketamine did not outperform midazolam. There were also no significant differences in any secondary outcomes.

Both groups improved over time, likely reflecting the benefits of comprehensive inpatient care. Remission rates were 43.8% for ketamine and 30% for midazolam.

Side effects were similar, mainly fatigue, sleep problems and mild liver test changes.

What the results mean for ketamine therapy in practice

Under rigorous trial conditions, repeated ketamine infusions did not provide any extra benefit beyond standard inpatient care, contrasting with earlier trials that reported large antidepressant effects. The results suggest that ketamine’s impact on depression may have been overstated, possibly due to unblinding and expectancy effects.

“Our initial hypothesis was that repeated ketamine infusions for people hospitalized with depression would improve mood outcomes. However, we found this not to be the case,” said corresponding author Dr. Declan McLoughlin, a research professor of psychiatry at Trinity College Dublin and Consultant Psychiatrist at St Patrick’s Mental Health Services. “Under rigorous clinical trial conditions, adjunctive ketamine provided no additional benefit to routine inpatient care during the initial treatment phase or the six-month follow-up period.”

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The study also underlines the challenge of maintaining blinding in trials involving psychoactive drugs. Most participants and raters correctly guessed their treatment, which can amplify placebo effects.

“Our trial highlights the importance of reporting the success, or lack thereof, of blinding in clinical trials,” said lead author Dr. Ana Jelovac, a research fellow at Trinity College Dublin. “Such problems can lead to enhanced placebo effects and skewed trial results that can over-inflate real treatment effects.”

Recruitment disruptions during COVID-19 meant the study enrolled fewer participants than planned, which may have reduced statistical power.

Despite these limits, the study calls for recalibrated expectations of ketamine’s antidepressant efficacy and points to the need for innovative trial designs.

“Previous estimates of ketamine’s antidepressant efficacy may have been overstated, highlighting the need for recalibrated expectations in clinical practice,” said McLoughlin. 

Reference: Jelovac A, McCaffrey C, Terao M, et al. Serial ketamine infusions as adjunctive therapy to inpatient care for depression. JAMA Psychiatry. 2025. doi: 10.1001/jamapsychiatry.2025.3019

This article is a rework of a press release issued by Trinity College Dublin. Material has been edited for length and content.