Randomized Trial of Ketamine Masked by Surgical Anesthesia in Depressed Patients
Theresa R. Lii, Ashleigh E. Smith, Josephine R. Flohr, Robin L. Okada, Cynthia A. Nyongesa, Lisa J. Cianfichi, Laura M Hack, Alan F. Schatzberg, Boris D. Heifets
medRxiv Preprint Server April 28, 2023 preprint DOI: 10.1101/2023.04.28.23289210 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized controlled trial Placebo-controlled |
|---|---|
| Sample size | 40 |
| Population | Adult patients with major depressive disorder |
| Intervention | Ketamine |
| Dose | 0.5 mg/kg |
| Duration | 3 days post-infusion |
| Topics | Esketamine Ketamine |
| Keywords | Mood improvement Psychiatric medication Mental health intervention Therapeutic approach Drug trial Pharmacological investigation Novel drug delivery Anesthetic administration Mood disorder management Chronic depression relief Mental illness treatment Unconscious administration Sedation therapy Controlled environment treatment Blinded study |
| Citations | 28 |
| Registration | NCT03861988 |
| Key findings | A single dose of intravenous ketamine (0.5 mg/kg) delivered during surgical anesthesia had no greater effect than placebo in acutely reducing the severity of depressive symptoms. |
Abstract
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 as usual 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 did not find statistical separation of ketamine from placebo. 36.8% of participants guessed their treatment assignment correctly; both groups allocated their guesses in similar proportions. One serious adverse event occurred in each group, unrelated to ketamine administration.
Conclusion: In adults with major depressive disorder, a single dose of intravenous ketamine delivered during surgical anesthesia had no greater effect than placebo in acutely reducing the severity of depressive symptoms. 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 )