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
Alonzo, A., Barton, D., Baune, B. T., Berk, M., Boyce, P., Carter, G. T., Chatterton, M. L., Dong, V., Fitzgerald, P. B., Fourrier, C., Gainsford, K., Galvez-Ortiz, V., Garg, D., Glozier, N., Glue, P., Hackett, M., Hadzi-Pavlovic, D., Holtzheimer, P. E., Hood, S., Kozel, F. A., Lapidus, K., Leyden, J., Loo, C., Martin, D., McDonald, W., Mihalopoulos, C., Mills, N. T., Mitchell, P. B., Nikolin, S., Richardson, K., Riva-Posse, P., Rodgers, A., Rozakis, D., Sarma, S., Scaria, A., Somogyi, A. A., Stratton, E., Thornton, N. L. R.
This Phase III, double-blind, randomised trial (n=174) evaluated the acute efficacy and safety of a 4-week course of ketamine (35-63mg/70kg) in participants with treatment-resistant depression (TRD). The study found that ketamine was more efficacious than midazolam (1.75mg/70kg) in the flexible-dose cohort (remission rate 19.6% vs 2.0%), demonstrating that adequately dosed subcutaneous racemic ketamine is both effective and safe in treating TRD over 4 weeks.
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.