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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)

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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.

Study Year Design Participants
Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial Patients with treatment-resistant major depression experiencing a major depressive episode 2013 Randomized controlled trial n = 73
Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study Adults with moderate to severe nonpsychotic depression and a history of nonresponse to... 2019 Phase 3, double-blind, active-controlled, multicenter randomized controlled trial n = 227
Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression Adults with treatment-resistant depression who achieved stable remission or stable... 2019 Phase 3, multicenter, double-blind, randomized withdrawal study n = 297
Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression Adults with DSM-IV-TR diagnosis of major depressive disorder and history of inadequate... 2017 Phase 2, double-blind, doubly randomized, delayed-start, placebo-controlled study n = 67
Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of Symptoms of Depression and Suicidality in Patients at Imminent Risk for Suicide: Results of a Double-Blind, Randomized, Placebo-Controlled Study Depressed patients at imminent risk for suicide 2018 Randomized controlled trial n = 68

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