1. 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
- Author
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Loo, C ; https://orcid.org/0000-0003-3267-0554, Glozier, N, Barton, D, Baune, BT, Mills, NT, Fitzgerald, P, Glue, P, Sarma, S, Galvez-Ortiz, V, Hadzi-Pavlovic, D ; https://orcid.org/0000-0002-2059-3865, Alonzo, A ; https://orcid.org/0000-0003-3304-4387, Dong, V, Martin, D ; https://orcid.org/0000-0002-8452-0390, Nikolin, S ; https://orcid.org/0000-0003-4440-9273, Mitchell, PB ; https://orcid.org/0000-0002-7954-5235, Berk, M, Carter, G, Hackett, M ; https://orcid.org/0000-0003-1211-9087, Leyden, J, Hood, S, Somogyi, AA, Lapidus, K, Stratton, E, Gainsford, K, Garg, D, Thornton, NLR, Fourrier, C, Richardson, K, Rozakis, D, Scaria, A, Mihalopoulos, C, Chatterton, ML, Mcdonald, WM, Boyce, P, Holtzheimer, PE, Kozel, FA, Riva-Posse, P, Rodgers, A ; https://orcid.org/0000-0003-1282-1896, Loo, C ; https://orcid.org/0000-0003-3267-0554, Glozier, N, Barton, D, Baune, BT, Mills, NT, Fitzgerald, P, Glue, P, Sarma, S, Galvez-Ortiz, V, Hadzi-Pavlovic, D ; https://orcid.org/0000-0002-2059-3865, Alonzo, A ; https://orcid.org/0000-0003-3304-4387, Dong, V, Martin, D ; https://orcid.org/0000-0002-8452-0390, Nikolin, S ; https://orcid.org/0000-0003-4440-9273, Mitchell, PB ; https://orcid.org/0000-0002-7954-5235, Berk, M, Carter, G, Hackett, M ; https://orcid.org/0000-0003-1211-9087, Leyden, J, Hood, S, Somogyi, AA, Lapidus, K, Stratton, E, Gainsford, K, Garg, D, Thornton, NLR, Fourrier, C, Richardson, K, Rozakis, D, Scaria, A, Mihalopoulos, C, Chatterton, ML, Mcdonald, WM, Boyce, P, Holtzheimer, PE, Kozel, FA, Riva-Posse, P, and Rodgers, A ; https://orcid.org/0000-0003-1282-1896
- 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.
- Published
- 2023