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Efficacy and safety of a 4-week course of repeated subcutaneous ketamine injections for treatment-resistant depression (KADS study): randomised double-blind active-controlled trial

Colleen Loo, N. Glozier, David Barton, Bernhard T Baune, Natalie T Mills, P. Fitzgerald, Paul Glue, Shanthi Sarma, Verònica Gálvez-Ortiz, Dusan Hadzi-Pavlovic, Angelo Alonzo, Vanessa Dong, D. Martin, Stevan Nikolin, Philip B Mitchell, Michael Berk, Gregory Carter, Maree Hackett, John Leyden, Sean Hood, Andrew A Somogyi, Kyle Lapidus, Elizabeth Stratton, K. Gainsford, D. Garg, Nicollette Thornton, C. Fourrier, Karyn Richardson, Demi Rozakis, A. Scaria, Cathrine Mihalopoulos, M. Chatterton, William M. Mcdonald, P. Boyce, Paul E. Holtzheimer, F. Kozel, P. Riva-Posse, Anthony Rodgers

The British Journal of Psychiatry July 14, 2023 DOI: 10.1192/bjp.2023.79 (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics Randomized controlled trial Double-blind Peer reviewed
Sample size 174
Population Participants with treatment-resistant depression
Interventions subcutaneous racemic ketamine midazolam
Dose 0.5–0.9 mg/kg (flexible-dose) or 0.5 mg/kg (fixed-dose) for ketamine; 0.025–0.045 mg/kg (flexible-dose) or 0.025 mg/kg (fixed-dose) for midazolam
Duration 4-week treatment period
Topics Depression Esketamine Ketamine
Citations 70
Key findings Flexible-dose subcutaneous racemic ketamine was significantly more efficacious than midazolam for treatment-resistant depression over four weeks, with a remission rate of 19.6% versus 2.0%.

Abstract

Background: Prior trials suggest that intravenous racemic ketamine is a highly effective for treatment-resistant depression (TRD), but phase 3 trials of racemic ketamine are needed.

Aims: To assess the acute efficacy and safety of a 4-week course of subcutaneous racemic ketamine in participants with TRD.

Trial Registration: ACTRN12616001096448 at www.anzctr.org.au.

Method: This phase 3, double-blind, randomised, active-controlled multicentre trial was conducted at seven mood disorders centres in Australia and New Zealand. Participants received twice-weekly subcutaneous racemic ketamine or midazolam for 4 weeks. Initially, the trial tested fixed-dose ketamine 0.5 mg/kg versus midazolam 0.025 mg/kg (cohort 1). Dosing was revised, after a Data Safety Monitoring Board recommendation, to flexible-dose ketamine 0.5–0.9 mg/kg or midazolam 0.025–0.045 mg/kg, with response-guided dosing increments (cohort 2). The primary outcome was remission (Montgomery-Åsberg Rating Scale for Depression score ≤10) at the end of week 4.

Results: The final analysis (those who received at least one treatment) comprised 68 in cohort 1 (fixed-dose), 106 in cohort 2 (flexible-dose). Ketamine was more efficacious than midazolam in cohort 2 (remission rate 19.6% v. 2.0%; OR = 12.1, 95% CI 2.1–69.2, P = 0.005), but not different in cohort 1 (remission rate 6.3% v. 8.8%; OR = 1.3, 95% CI 0.2–8.2, P = 0.76). Ketamine was well tolerated. Acute adverse effects (psychotomimetic, blood pressure increases) resolved within 2 h.

Conclusions: Adequately dosed subcutaneous racemic ketamine was efficacious and safe in treating TRD over a 4-week treatment period. The subcutaneous route is practical and feasible.

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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