Trial of Ketamine Masked by Surgical Anesthesia in Depressed Patients
This triple-masked, randomised, placebo-controlled trial (n=40) of adults with major depressive disorder (MDD) found no short-term effect on depression severity (measured by MADRS) after a single dose of intravenous ketamine (35mg/70kg) compared to placebo (saline) during anaesthesia for routine surgery.
Authors
- Boris Heifets
- Alan Schatzberg
Published
Abstract
Background
Ketamine may have antidepressant properties, but its acute psychoactive effects complicate successful masking in placebo-controlled trials.
Methods
In a triple-masked, randomized, placebo-controlled trial, 40 adult patients with major depressive disorder were randomized to a single infusion of ketamine (0.5 mg/kg) or placebo (saline) during anesthesia for routine surgery. The primary outcome was depression severity measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) at 1, 2, and 3 days post-infusion. The secondary outcome was the proportion of participants with clinical response (≥50% reduction in MADRS scores) at 1, 2, and 3 days post-infusion. After all follow-up visits, participants were asked to guess which intervention they received.
Results
Mean MADRS scores did not differ between groups at screening or pre-infusion baseline. The mixed-effects model showed no evidence of effect of group assignment on post-infusion MADRS scores at 1 to 3 days post-infusion (-5.82, 95% CI -13.3 to 1.64, p=0.13). Clinical response rates were similar between groups (60% versus 50% on day 1) and comparable to previous studies of ketamine in depressed populations. Secondary and exploratory outcomes found no evidence of benefit for ketamine. 36.8% of participants guessed their treatment assignment correctly; both groups allocated their guesses in similar proportions.
Conclusion
A single dose of intravenous ketamine compared to placebo has no short-term effect on the severity of depression symptoms in adults with major depressive disorder. This trial successfully masked treatment allocation in moderate-to-severely depressed patients using surgical anesthesia. While it is impractical to use surgical anesthesia for most placebo-controlled trials, future studies of novel antidepressants with acute psychoactive effects should make efforts to fully mask treatment assignment in order to minimize subject-expectancy bias. (ClinicalTrials.gov number, NCT03861988)
Research Summary of 'Trial of Ketamine Masked by Surgical Anesthesia in Depressed Patients'
Introduction
Ketamine is a dissociative anaesthetic that has shown rapid-acting antidepressant effects in patients with major depressive disorder (MDD), including treatment-resistant cases. Prior randomised trials using a single intravenous infusion of 0.5 mg/kg report rapid therapeutic onset and measurable response and remission rates within 24 hours. However, the drug’s obvious acute psychoactive effects make participant masking difficult in placebo-controlled trials, creating a risk of subject-expectancy bias that could inflate apparent treatment effects. This concern applies broadly to other fast-acting psychoactive therapeutics as well. Lii and colleagues designed a randomised, triple-masked, placebo-controlled trial that used routine surgical anaesthesia to conceal administration of ketamine or saline, with the primary aim of determining whether a single 0.5 mg/kg infusion of ketamine given during maintenance anaesthesia produces greater short-term antidepressant effects than placebo. The hypothesis was that ketamine would reduce depressive symptoms more than inert saline within the first 3 days post-infusion in adults with moderate-to-severe MDD. The study therefore addresses both efficacy and the feasibility of rigorous masking in ketamine trials.
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Study Details
- Study Typeindividual
- Journal
- Compound
- Topics
- Authors
- APA Citation
Lii, T. R., Smith, A. E., Flohr, J. R., Okada, R. L., Nyongesa, C. A., Cianfichi, L. J., Hack, L. M., Schatzberg, A. F., & Heifets, B. D. (2023). Trial of Ketamine Masked by Surgical Anesthesia in Depressed Patients. Nature Mental Health, 1(11), 876-886. https://doi.org/10.1038/s44220-023-00140-x
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Nagele, P., Duma, A., Kopec, M. et al. · Biological Psychiatry (2015)
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