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, J. 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
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.