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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: commentary, author response

Published online by Cambridge University Press:  27 May 2025

Colleen Loo Open the ORCID record for Colleen Loo [Opens in a new window] ,
Angelo Alonzo ,
David Barton ,
Michael Berk ,
Mary Lou Chatterton Open the ORCID record for Mary Lou Chatterton [Opens in a new window] ,
Vanessa Dong ,
Veronica Gálvez ,
Natalie T. Mills Open the ORCID record for Natalie T. Mills [Opens in a new window] ,
Philip B. Mitchell Open the ORCID record for Philip B. Mitchell [Opens in a new window]  and
Shanthi Sarma
...Show all authors
Colleen Loo*
Affiliation:
Discipline of Psychiatry and Mental Health, University of New South Wales, Sydney, New South Wales, Australia; Black Dog Institute, Randwick, New South Wales, Australia; and George Institute for Global Health, Newtown, New South Wales, Australia
Angelo Alonzo
Affiliation:
Discipline of Psychiatry and Mental Health, University of New South Wales, Sydney, New South Wales, Australia; Black Dog Institute, Randwick, New South Wales, Australia; and The George Institute for Global Health, Barangaroo, New South Wales, Australia
David Barton
Affiliation:
Neurocentrix, South Carlton, Victoria, Australia
Michael Berk
Affiliation:
Institute for Mental and Physical Health and Clinical Translation (IMPACT), School of Medicine, Barwon Health, Deakin University, Geelong, Australia
Mary Lou Chatterton
Affiliation:
School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
Vanessa Dong
Affiliation:
Discipline of Psychiatry and Mental Health, University of New South Wales, Sydney, New South Wales, Australia; and Black Dog Institute, Randwick, New South Wales, Australia
Veronica Gálvez
Affiliation:
Department of Psychiatry and Mental Health, Hospital Universitari Parc Tauli, Sabadell, Spain; and Institut Investigacio I Innovacio Parc Tauli, Sabadell, Spain
Natalie T. Mills
Affiliation:
Discipline of Psychiatry, University of Adelaide, Adelaide, South Australia, Australia
Philip B. Mitchell
Affiliation:
Discipline of Psychiatry and Mental Health, University of New South Wales, Sydney, New South Wales, Australia
Shanthi Sarma
Affiliation:
Mental Health and Specialist Services, Gold Coast Health, Bond University, Robina, Queensland, Australia
Andrew A. Somogyi
Affiliation:
Discipline of Pharmacology, School of Biomedicine, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, Australia
Anthony Rodgers
Affiliation:
George Institute for Global Health, Barangaroo, New South Wales, Australia
*
Correspondence: Colleen Loo. Email: colleen.loo@unsw.edu.au
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Abstract

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Keywords

Ketamine/esketaminemajor depressive disorderclinical drug studiesneuroscienceaffective disorders

Information

Type
Commentary
Information
The British Journal of Psychiatry , Volume 226 , Issue 5 , May 2025 , pp. 317 - 318
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Copyright
© The Author(s), 2025. Published by Cambridge University Press on behalf of Royal College of Psychiatrists

Response

We thank Dr Joks et al for their commentsReference Joks, Su and King1 on our paper.Reference Loo, Glozier, Barton, Baune, Mills and Fitzgerald2

The degree of treatment resistance has several dimensions, not just severity of mood score on a particular day. Failure to respond to electroconvulsive therapy (ECT) in the current episode is widely recognised as the highest indicator of treatment resistance, given the superiority of ECT over antidepressant medications.3 Individuals with this level of treatment resistance comprised 1 in 4 of the KADS trial participants but were excluded from the TRANSFORM-2 and TRANSFORM-3 studies testing intranasal esketamine. This higher level of treatment resistance in the KADS study likely contributed to the lower absolute response and remission rates compared with the TRANSFORM studies, although the difference between active treatment and placebo in absolute terms was similar.

The larger before/after change in Montgomery-Åsberg Depression Rating Scale (MADRS) scores in TRANSFORM is unlikely to be due to concurrent antidepressant medication, since much of it occurred on the first day after initiation of treatment. This pattern is characteristic of regression to the mean following a high threshold for randomisation and not in keeping with the expected time course of benefits from a newly started selective serotonin reuptake inhibitor or serotonin–noradrenaline reuptake inhibitor. The requirement for only a moderately elevated MADRS score (≥20) at both screening and randomisation in KADS minimised the regression to the mean – with a far smaller change in the comparator group scores 2 days after randomisation.

Since the KADS population had higher levels of treatment resistance than, for example, the TRANSFORM-2 trial population, absolute response and remission rates cannot be compared. However, in both trials the number needed to treat for one person remitting was about five. We fully agree, though, that indirect comparisons are suboptimal and head-to-head comparisons of racemic ketamine and esketamine within a single trial are required, and it is unfortunate these have not yet been conducted.Reference Rodgers, Bahceci, Davey, Chatterton, Glozier and Hopwood4

Data availability

Data availability is not applicable to this commentary as no new data were created or analysed in its writing.

Author contributions

C.L. and A.R. were involved in writing the original draft. A.A., D.B., M.B., M.L.C., V.D., V.G., N.T.M., P.B.M, S.S. and A.A.S revised the content. All authors reviewed and approved the final manuscript.

Funding

The original study to which this commentary pertains was funded by a competitive research grant from the Australian National Health and Medical Research Council (APP1105089).

Declaration of interest

C.L. is supported by a National Health and Medical Research Council (NHMRC) Investigator Grant (1195651), 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, speaker fees from the Australian Private Hospitals Association, Wesley Hospital ECT course, Royal Australian and New Zealand College of Psychiatrists Congress, Spanish Psychiatric Hospitalisation Units Conference, Japanese Society of Psychiatry and Neurology conference. 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. M.B. is supported by an NHMRC Senior Principal Research Fellowship (1156072); in the past 3 years he received grant/research support from NHMRC, Wellcome Trust, Medical Research Future Fund, Victorian Medical Research Acceleration Fund, Centre for Research Excellence CRE, Victorian Government Department of Jobs, Precincts and Regions and Victorian COVID-19 Research Fund; he received honoraria from EPA Warsaw, Lundbeck, Controversias Barcelona, Servier, Medisquire, HealthEd, ANZJP, European Psychiatric Association, Janssen, Medplan, Milken Institute, RANZCP, Abbott India, ASCP, Headspace, Allori for Eisai, Otsuka, Global Congress of Biological Psychiatry India, St Bio Pharma and Sandoz. P.B.M. is supported by an Investigator Grant from the NHMRC; within the past 3 years he has received remuneration from Janssen (Australia) and Sanofi (Hangzhou) for lectures or advisory board membership. 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.

References

Joks, G, Su, S, King, J. Efficacy and safety of a 4-week course of repeated subcutaneous ketamine injections for treatment-resistant depression (KADS study): commentary, joks et al.. Br J Psychiatry 2024 (https://resolve.cambridge.org/core/journals/the-british-journal-of-psychiatry/article/abs/efficacy-and-safety-of-a-4week-course-of-repeated-subcutaneous-ketamine-injections-for-treatmentresistant-depression-kads-study-commentary-joks-et-al/ECA661E0DB69EA284F9776A794244726).CrossRefGoogle ScholarPubMed
Loo, C, Glozier, N, Barton, D, Baune, BT, Mills, NT, Fitzgerald, P, et al. 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; 223: 533–41.CrossRefGoogle ScholarPubMed
UK ECT Review Group. Efficacy and safety of electroconvulsive therapy in depressive disorders: a systematic review and meta-analysis. Lancet 2003; 361: 799–808.CrossRefGoogle Scholar
Rodgers, A, Bahceci, D, Davey, CG, Chatterton, ML, Glozier, N, Hopwood, M, et al. Ensuring the affordable becomes accessible-lessons from ketamine, a new treatment for severe depression. Aust N Z J Psychiatry 2024; 58: 109–16.CrossRefGoogle ScholarPubMed

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