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

• Published in: British journal of psychiatry Vol. 223; no. 6; pp. 533 - 541
• Main Authors: Loo, Colleen, Glozier, Nick, Barton, David, Baune, Bernhard T., Mills, Natalie T., Fitzgerald, Paul, Glue, Paul, Sarma, Shanthi, Galvez-Ortiz, Veronica, Hadzi-Pavlovic, Dusan, Alonzo, Angelo, Dong, Vanessa, Martin, Donel, Nikolin, Stevan, Mitchell, Philip B., Berk, Michael, Carter, Gregory, Hackett, Maree, Leyden, John, Hood, Sean, Somogyi, Andrew A., Lapidus, Kyle, Stratton, Elizabeth, Gainsford, Kirsten, Garg, Deepak, Thornton, Nicollette L. R., Fourrier, Célia, Richardson, Karyn, Rozakis, Demi, Scaria, Anish, Mihalopoulos, Cathrine, Chatterton, Mary Lou, McDonald, William M., Boyce, Philip, Holtzheimer, Paul E., Kozel, F. Andrew, Riva-Posse, Patricio, Rodgers, Anthony
• Format: Journal Article
• Language: English
• Published: Cambridge, UK Cambridge University Press 01.12.2023
• Subjects: Antidepressants; Australia; Blood pressure; Depression; Depressive Disorder, Treatment-Resistant - drug therapy; Dosage; Drug dosages; Efficacy; Emotional disorders; General Adult; Humans; Ketamine; Ketamine - adverse effects; Mental depression; Midazolam; Midazolam - adverse effects; Multicenter studies; Original; Original Article; Pharmacists; Psychiatry; Refractory depression; Regression analysis; Regulatory approval; Remission; Remission (Medicine); Safety; Side effects; Australia; New Zealand; affective disorders; major depressive disorder; Ketamine/esketamine; clinical drug studies; neuroscience
• ISSN: 0007-1250; 1472-1465
• DOI: 10.1192/bjp.2023.79

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. 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. 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. 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% . 2.0%; OR = 12.1, 95% CI 2.1-69.2, = 0.005), but not different in cohort 1 (remission rate 6.3% . 8.8%; OR = 1.3, 95% CI 0.2-8.2, = 0.76). Ketamine was well tolerated. Acute adverse effects (psychotomimetic, blood pressure increases) resolved within 2 h. 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.