Efficacy and Safety of Repeated Subcutaneous Ketamine Injections for Treatment Resistant Depression - The KADS Study: A Randomised, Double-Blind, Comparator-Controlled Trial

Colleen K. Loo, Nicholas Glozier, David Barton, Bernhard T. Baune, Natalie Mills, Paul B. Fitzgerald, Paul Glue, Shanthi Sarma, Veronica Galvez-Ortiz, Dusan Hadzi-Pavlovic, Angelo Alonzo, Vanessa Dong, Donel M. Martin, Stevan Nikolin, Philip Bowden Mitchell, Michael Berk, Gregory Carter, Maree Hackett, John Leyden, Sean HoodAndrew Somogyi, Kyle Lapidus, Elizabeth Stratton, Kirsten Gainsford, Deepak Garg, Nicollette Thornton, Celia Fourrier, Karyn Richardson, Demi Rozakis, Anish Scaria, Cathrine Mihalopoulos, Mary Lou Chatterton, William McDonald, Philip Boyce, Paul Holtzheimer, Frank A. Kozel, Patricio Riva-Posse, Anthony Rodgers

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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.
Original languageEnglish
Pages (from-to)1-9
Number of pages9
JournalThe British Journal of Psychiatry
DOIs
Publication statusE-pub ahead of print - 14 Jul 2023

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