RCT · 2025
Oral ketamine for depression: small trial missed its main goal, pooled evidence more positive
- Original title
- Oral ketamine for the treatment of major depressive and bipolar disorder, a randomized controlled trial and meta-analysis.
- Authors
- Silberbauer LR, Eggerstorfer B, Michenthaler P, et al.
- Journal
- Journal of affective disorders, 2025
- Molecules
- Ketamine
- Conditions
- Depression, Bipolar depression
- Participants
- 45
- Evidence grade
- Moderate
- Source
- Read the original paper
The question
Can ketamine taken by mouth reduce symptoms of a moderate to severe depressive episode, and what does the wider trial evidence show?
What they did
Forty-five patients with a moderate to severe depressive episode were randomly assigned to either oral ketamine (1 mg/kg) or midazolam solution (0.03 mg/kg) as an active comparator, given six times over two weeks. Neither the patients nor the researchers knew who received which treatment. Depression was measured with the MADRS, a standard clinician-rated symptom scale. The authors also pooled results from randomized trials of oral ketamine, covering 592 patients in total.
What they found
The trial’s main outcome, reduction in MADRS score after one week, did not reach statistical significance. Response rates favoured ketamine, with a number needed to treat of 4.6 (95% confidence interval 2.4 to 62.6) at that time point, meaning roughly one extra responder for every five people treated, though the range around that estimate was very wide. Treatment was well tolerated, and no serious adverse events were reported; blood tests showed lower levels of ketamine than of its breakdown product norketamine. In the pooled analysis of 592 patients, oral ketamine showed a number needed to treat of 4.89 (95% CI 3.41 to 8.66) for response and 9.16 (95% CI 5.49 to 27.59) for remission.
The fine print
The trial included only 45 people and missed its primary endpoint, so its individual result is inconclusive. The confidence interval around the response benefit stretched from 2.4 to 62.6, meaning the true effect could be substantial or negligible. Midazolam is an active comparator rather than an inert placebo, and the abstract reports only short-term (one week) results for the main outcome. This summary is based on the abstract alone.
What it means
This small trial did not show a clear advantage for oral ketamine on its main measure, but the combined evidence from randomized trials suggests it can improve depression symptoms and was tolerated without serious adverse events in this study.
Evidence grade: Moderate. A small double-blind randomized trial (45 people) that did not meet its primary endpoint, paired with a meta-analysis of randomized trials totalling 592 patients.
This summary is based on the study’s published abstract.