Identification of an Optimal Dose of Intravenous Ketamine for Late-Life Treatment-Resistant Depression: A Bayesian Adaptive Randomization Trial
Marijn Lijffijt, Nicholas Murphy, Sidra Iqbal, C. Green, Tabish Iqbal, Lee C. Chang, Colin N. Haile, Lorna C. Hirsch, N. Ramakrishnan, Dylan A. Fall, Alan C. Swann, R. A. Al Jurdi, S. Mathew
Neuropsychopharmacology November 27, 2021 DOI: 10.1038/s41386-021-01242-9 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized controlled trial (Bayesian adaptive randomization, double-blind, active placebo-controlled) Peer reviewed |
|---|---|
| Sample size | 33 |
| Population | Medication-free US military veterans aged 55-72 (mean 62; 10 female) with late-life treatment-resistant depression |
| Interventions | Ketamine Midazolam |
| Dose | ketamine 0.1 mg/kg, 0.25 mg/kg, or 0.5 mg/kg; midazolam 0.03 mg/kg |
| Duration | 40-minute intravenous infusion; follow-up to day 28 |
| Measures | Montgomery-Åsberg Depression Rating Scale (MADRS), resting electroencephalography gamma and alpha power |
| Topics | Depression Esketamine Ketamine |
| Key findings | Ketamine 0.5 mg/kg produced higher day-7 treatment response rates (70%) than midazolam (46%), with a posterior probability of 0.89 favoring ketamine 0.5 mg/kg; response persisted at day 28 (82% vs 37%). The 0.1 and 0.25 mg/kg doses were terminated for inferiority. The authors suggest 0.5 mg/kg is an effective initial IV ketamine dose in late-life treatment-resistant depression, though further studies in people older than 75 are needed. |
Abstract
Evidence supporting specific therapies for late-life treatment-resistant depression (LL-TRD) is necessary. This study used Bayesian adaptive randomization to determine the optimal dose for the probability of treatment response (≥50% improvement from baseline on the Montgomery-Åsberg Depression Rating Scale) 7 days after a 40 min intravenous (IV) infusion of ketamine 0.1 mg/kg (KET 0.1), 0.25 mg/kg (KET 0.25), or 0.5 mg/kg (KET 0.5), compared to midazolam 0.03 mg/kg (MID) as an active placebo. The goal of this study was to identify the best dose to carry forward into a larger clinical trial. Response durability at day 28, safety and tolerability, and effects on cortical excitation/inhibition (E/I) ratio using resting electroencephalography gamma and alpha power, were also determined. Thirty-three medication-free US military veterans (mean age 62; range: 55–72; 10 female) with LL-TRD were randomized double-blind. The trial was terminated when dose superiority was established. All interventions were safe and well-tolerated. Pre-specified decision rules terminated KET 0.1 (N = 4) and KET 0.25 (N = 5) for inferiority. Posterior probability was 0.89 that day-seven treatment response was superior for KET 0.5 (N = 11; response rate = 70%) compared to MID (N = 13; response rate = 46%). Persistent treatment response at day 28 was superior for KET 0.5 (response rate = 82%) compared to MID (response rate = 37%). KET 0.5 had high posterior probability of increased frontal gamma power (posterior probability = 0.99) and decreased posterior alpha power (0.89) during infusion, suggesting an acute increase in E/I ratio. These results suggest that 0.5 mg/kg is an effective initial IV ketamine dose in LL-TRD, although further studies in individuals older than 75 are required.
Comparable studies
Other randomized controlled trials on ketamine for depression, most cited first.