TY - JOUR
T1 - Efficacy and safety of a 4-week course of repeated subcutaneous ketamine injections for treatment-resistant depression (KADS study)
T2 - randomised double-blind active-controlled trial
AU - Loo, Colleen
AU - Glozier, Nick
AU - Barton, David
AU - Baune, Bernhard T.
AU - Mills, Natalie T.
AU - Fitzgerald, Paul
AU - Glue, Paul
AU - Sarma, Shanthi
AU - Galvez-Ortiz, Veronica
AU - Hadzi-Pavlovic, Dusan
AU - Alonzo, Angelo
AU - Dong, Vanessa
AU - Martin, Donel
AU - Nikolin, Stevan
AU - Mitchell, Philip B.
AU - Berk, Michael
AU - Carter, Gregory
AU - Hackett, Maree
AU - Leyden, John
AU - Hood, Sean
AU - Somogyi, Andrew A.
AU - Lapidus, Kyle
AU - Stratton, Elizabeth
AU - Gainsford, Kirsten
AU - Garg, Deepak
AU - Thornton, Nicollette L.R.
AU - Fourrier, Célia
AU - Richardson, Karyn
AU - Rozakis, Demi
AU - Scaria, Anish
AU - Mihalopoulos, Cathrine
AU - Chatterton, Mary Lou
AU - McDonald, William M.
AU - Boyce, Philip
AU - Holtzheimer, Paul E.
AU - Kozel, F. Andrew
AU - Riva-Posse, Patricio
AU - Rodgers, Anthony
N1 - Funding Information:
The study was funded by a competitive research grant from the Australian National Health and Medical Research Council (APP1105089).
Funding Information:
C.L. is on the Clinical Advisory Board for Douglas Pharmaceuticals and has received fees for the following: Janssen Cilag advisory board, Medical Director of Neurostimulation and Interventional Psychiatry at Ramsay Health Care. In the past 36 months, N.G. has received speaker's bureau honoraria from Servier Laboratories, Janssen and Lundbeck, and served on Advisory Boards for Servier Laboratories, Esia, Seqirus and Lundbeck. D.B. is a Director and part owner of Neurotrials Victoria Pty Ltd trading as Neurocentrix and Neurocentrix TMS Pty Ltd; he serves on the advisory board for Eli Lilly and Janssen, and is currently supported by grant funding from Praxis, Janssen, Eli Lilly, Biogen and NHMRC; he has served on speaker panels for Servier, Janssen and Eli Lilly in the past 12 months; he is an investigator on the Janssen Quality of Life Esketamine study. B.T.B. has received grants and served as consultant, advisor or CME speaker for: AstraZeneca, Bristol-Myers Squibb, Janssen, Lundbeck, Otsuka, Servier, the NHMRC, the Fay Fuller Foundation, and the James and Diana Ramsay Foundation. In the past 3 years, P.F. has received equipment for research from Neurosoft, Nexstim and Brainsway Ltd; he has served on scientific advisory boards for Magstim and LivaNova and received speaker fees from Otsuka; he is a founder and board member for TMS Clinics Australia and Resonance Therapeutics. Within the last 36 months, P.G. has attended a Janssen New Zealand advisory board, and is named on a patent for a controlled release ketamine tablet developed by Douglas Pharmaceuticals. In the past 36 months, D.M. has received research consulting fees from Douglas Pharmaceuticals for a clinical trial involving ketamine. P.B.M. has received remuneration from Janssen (Australia) and Sanofi (Hangzhou) for lectures or advisory board membership within the past 3 years. M.B. has received honoraria EPA Warsaw, Lundbeck, Controversias Barcelona, Servier, Medisquire, HealthEd, ANZJP, European Psychiatric Association, Janssen, Medplan, Milken Institute, Abbott India, ASCP, Allori for Eisai, Otsuka, St Bio Pharma and Sandoz in the past 3 years. G.C. has received educational and travel support from Servier, Astra Zeneca, Otsuka Australia, Merck Sharp & Dohme, and Janssen-Cilag in the past 5 years; he also served on an advisory board for the AFFINITY trial. S.H. has received speaker and consultancy fees from Janssen and Servier, served on advisory boards for Janssen and Lundbeck. A.A.S. is a director of the Australian Medicines Handbook Pty Ltd (unpaid) and has received funding support by the Australian and New Zealand College of Anaesthetists to investigate ketamine for chronic postsurgical pain. K.L. has received contracts for research involving ketamine and other antidepressants and equipment support from ALTO Neuroscience, Cybin and Brainsway; he has received grants/contracts, as well as consulting and manuscript writing fees, from Fisher Wallace, consulting fees (including advisory panel payments and travel funds) from Janssen and consulting fees from Third Bridge; he owns stocks in Validose and has a patent issued for a device developed by the company that could deliver ketamine as well as other drugs; he also owns stocks in Journey Clinical and is a Medical Director for this company; he owns Affective Care, which is a company providing antidepressant treatments, and owns several companies involved in medical care, including depression treatment (Psychiatric Care, Anxiety Psychiatry, Marham and Sol2rise); companies owned by him own equity in Woolsey Pharmaceuticals, Enalare Therapeutics and Cecilia Health. D.G. is the founder and director of TMS Gold Coast and Synergy Specialist Clinic in Gold Coast, Australia. N.L.R.T. has received payment from Janssen for consulting services and participation in an advisory panel. W.M.M. was the uncompensated chair of the DSMB for the MED KET study under review; he is on the board of and has received travel support from Skyland Trail; he is on the Board of 3Keys and is a paid consultant for Signant Health and Sage Therapeutics; he has received past funding from Soterix, Neuronetics, NeoSync and Cervel Neurotherapeutics. P.B. has received speaker fees from Servier and Janssen, educational support from Servier and Lundbeck, is on an advisory board for Incite Health, has been a consultant for Servier, inhaleRx and Greenhorn industries, and has served as DSMC Chair for Douglas Pharmaceuticals. P.E.H. has received consulting fees from Abbott and payment for expert testimony from Ficksman & Conley, LLP, Harry S. Cohen & Associates, Cole, Scott and Kissane, PA, and Shaw Science Partners Inc. F.A.K. has patents as an inventor through the Medical University of South Carolina on fMRI Detection of Deception, with patents pending for Guided rTMS Inhibition of Deception and Optimizing VNS dose with rTMS; he receives loan equipment from Neuronetics and NIRx. P.R.-P. has received honoraria for consulting for Janssen Pharmaceuticals, Abbott Neuromodulation and LivaNova Inc.
Publisher Copyright:
Copyright © The Author(s), 2023. Published by Cambridge University Press on behalf of the Royal College of Psychiatrists.
PY - 2023/12/14
Y1 - 2023/12/14
N2 - 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.
AB - 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.
KW - affective disorders
KW - clinical drug studies
KW - Ketamine/esketamine
KW - major depressive disorder
KW - neuroscience
UR - http://www.scopus.com/inward/record.url?scp=85166637623&partnerID=8YFLogxK
U2 - 10.1192/bjp.2023.79
DO - 10.1192/bjp.2023.79
M3 - Article
C2 - 38108319
AN - SCOPUS:85166637623
SN - 0007-1250
VL - 223
SP - 533
EP - 541
JO - British Journal of Psychiatry
JF - British Journal of Psychiatry
IS - 6
ER -
