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

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

doi:10.1192/bjp.2023.79

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

Br J Psychiatry. 2023 Dec;223(6):533-541. doi: 10.1192/bjp.2023.79.

Authors

Colleen Loo¹, Nick Glozier², David Barton³, Bernhard T Baune⁴, Natalie T Mills⁵, Paul Fitzgerald⁶, Paul Glue⁷, Shanthi Sarma⁸, Veronica Galvez-Ortiz⁹, Dusan Hadzi-Pavlovic¹⁰, Angelo Alonzo¹¹, Vanessa Dong¹¹, Donel Martin¹¹, Stevan Nikolin¹¹, Philip B Mitchell¹⁰, Michael Berk¹², Gregory Carter¹³, Maree Hackett¹⁴, John Leyden¹⁵, Sean Hood¹⁶, Andrew A Somogyi¹⁷, Kyle Lapidus¹⁸, Elizabeth Stratton¹⁹, Kirsten Gainsford²⁰, Deepak Garg⁸, Nicollette L R Thornton², Célia Fourrier²¹, Karyn Richardson²², Demi Rozakis²³, Anish Scaria¹⁴, Cathrine Mihalopoulos²⁴, Mary Lou Chatterton²⁵, William M McDonald²⁶, Philip Boyce²⁷, Paul E Holtzheimer²⁸, F Andrew Kozel²⁹, Patricio Riva-Posse²⁶, Anthony Rodgers¹⁴

Affiliations

¹ Black Dog Institute, University of New South Wales, Randwick, New South Wales, Australia; and George Institute for Global Health, Newtown, New South Wales, Australia.
² Central Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia; and Australian Research Council Centre of Excellence for Children and Families over the Life Course, University of Sydney, Sydney, New South Wales, Australia.
³ Australian Centre for Heart Health, Royal Melbourne Hospital, North Melbourne, Victoria, Australia; and NeuroCentrix, South Carlton, Victoria, Australia.
⁴ Department of Psychiatry, University of Münster, Münster, Germany; Department of Psychiatry, Melbourne Medical School, University of Melbourne, Melbourne, Victoria, Australia; and Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.
⁵ Discipline of Psychiatry, University of Adelaide, Adelaide, South Australia, Australia.
⁶ Australian National University School of Medicine and Psychology, Canberra, Australian Capital Territory, Australia.
⁷ Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
⁸ Mental Health and Specialist Services, Gold Coast Health, Bond University, Robina, Queensland, Australia.
⁹ Department of Psychiatry and Mental Health, Hospital Universitari Parc Tauli, Sabadell, Spain; and Institut Investigacio I Innovacio Parc Tauli, Sabadell, Spain.
¹⁰ Discipline of Psychiatry and Mental Health, University of New South Wales, Sydney, New South Wales, Australia.
¹¹ Discipline of Psychiatry and Mental Health, University of New South Wales, Sydney, New South Wales, Australia; University of New South Wales, Randwick, New South Wales, Australia; and George Institute for Global Health, Newtown, New South Wales, Australia.
¹² Institute for Mental and Physical Health and Clinical Translation (IMPACT), School of Medicine, Barwon Health, Deakin University, Geelong, Australia.
¹³ College of Health, Medicine and Wellbeing, School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia.
¹⁴ George Institute for Global Health, Newtown, New South Wales, Australia.
¹⁵ Royal North Shore Hospital, St Leonards, New South Wales, Australia; and Northern Sydney Anaesthetic Research Institute, St Leonards, New South Wales, Australia.
¹⁶ Division of Psychiatry, University of Western Australia, Perth, Western Australia, Australia.
¹⁷ Discipline of Pharmacology, School of Biomedicine, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, Australia.
¹⁸ Affective Care, Northwell Health, New York, New York, USA.
¹⁹ Faculty of Medicine and Health, Central Clinical School, University of Sydney, Sydney, New South Wales, Australia.
²⁰ Epworth Centre for Innovation in Mental Health, Epworth Healthcare and Monash University, Camberwell, Victoria, Australia.
²¹ Discipline of Psychiatry, University of Adelaide, Adelaide, South Australia, Australia; and Lysosomal Health in Ageing, Hopwood Centre for Neurobiology, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
²² BrainPark, Turner Institute for Brain and Mental Health, Monash University, Clayton, Victoria, Australia; and Epworth Centre for Innovation in Mental Health, Epworth Healthcare and Monash University, Camberwell, Victoria, Australia.
²³ NeuroCentrix, Noble Park, Victoria, Australia.
²⁴ School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia; and School of Health and Social Development, Deakin University, Geelong, Australia.
²⁵ School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.
²⁶ Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia, USA.
²⁷ Specialty of Psychiatry, Westmead Institute of Medical Research, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia.
²⁸ Department of Psychiatry, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USA; and Department of Surgery, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USA.
²⁹ Department of Behavioral Sciences and Social Medicine, Florida State University College of Medicine, Tallahassee, Florida, USA.

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.

Keywords: Ketamine/esketamine; affective disorders.; clinical drug studies; major depressive disorder; neuroscience.

Publication types

Randomized Controlled Trial
Multicenter Study
Clinical Trial, Phase III
Research Support, Non-U.S. Gov't

MeSH terms

Australia
Depression
Depressive Disorder, Treatment-Resistant* / drug therapy
Humans
Ketamine* / adverse effects
Midazolam / adverse effects

Substances

Ketamine
Midazolam

Grants and funding

APP1105089/National Health and Medical Research Council