Efficacy and Safety of Repeated Subcutaneous Ketamine Injections for Treatment Resistant Depression - The KADS Study: A Randomised, Double-Blind, Comparator-Controlled Trial

Abstract

Background: Studies suggest efficacy for racemic ketamine and esketamine in treatment resistant depression (TRD), but Phase 3 trials assessing the safety and efficacy of racemic ketamine are lacking.

Methods: This double-blind, randomised controlled trial enrolled participants with TRD from seven Australasian centres. Randomised was by computer-generated, permuted block sequence to twice-weekly subcutaneous racemic ketamine or midazolam for 4 weeks. Cohort 1 tested ketamine 0·5 mg/kg vs midazolam 0·025 mg/kg, but was stopped after a Data Safety Monitoring Committee recommendation; Cohort 2 tested ketamine 0·5‒0·9 mg/kg or midazolam 0·025‒0·045 mg/kg, with response-guided dosing increments. The primary outcome was remission (MADRS score ≤ 10) at week 4. Participants and investigators were blinded. Separate investigators assessed mood and safety outcomes to facilitate blinding. Primary and safety analyses included participants who received at least one treatment.

Findings: Between August 2016 and April 2020, 1033 individuals were assessed for eligibility, with 181 randomised. The final analysis set comprised 73 in Cohort 1, 106 in Cohort 2. Ketamine was more efficacious than midazolam in Cohort 2 (remission rate 19·6% vs 2·0%; modelled (adjusted) OR 12·11, 95% CI = 2·12 to 69·17, p=0.005), but not Cohort 1 (remission rate 6·3% vs 8·8%; modelled (adjusted) OR 1·34, 95% CI = 0·22 to 8·21, p=0·76). Group differences in remission were no longer evident four weeks after treatment (Cohort 2). Acute adverse effects (psychotomimetic, blood pressure increases) resolved within 2 hours. No safety issues over the 4 weeks were identified.

Interpretation: Adequately dosed, subcutaneous racemic ketamine was efficacious and safe in treating TRD over a 4-week period. The subcutaneous route is clinically practical and feasible. These results support subcutaneous racemic ketamine as an acute treatment for TRD. Future research should examine longer treatment periods and strategies to prevent relapse.

Trial Registration Details: Trial registration on www.anzctr.org.au [ACTRN12616001096448].

Funding Information: The study was funded by a competitive research grant from the Australian National Health and Medical Research Council (APP 1105089).

Declaration of Interests: CL is supported by a NHMRC investigator Grant (1195651) and has served on an advisory board for Janssen Cilag. BTB has received grants and served as consultant, advisor or CME speaker for the following entities: AstraZeneca, Bristol-Myers Squibb, Janssen, Lundbeck, Otsuka, Servier, the National Health and Medical Research Council, the Fay Fuller Foundation, the James and Diana Ramsay Foundation. BTB is supported by research grants from European Union, DFG (Germany) and NHMRC (Australia). DB has received grants from the NHMRC, as well as honoraria for educational support from Janssen-Cilag. He is a provider of Spravato esketamine and is receiving payment from Douglas Pharmaceuticals to undertake a clinical trial of oral ketamine. MB is supported by a NHMRC Senior Principal Research Fellowship (1156072). MB has received Grant/Research Support from the NIH, Cooperative Research Centre, Simons Autism Foundation, Cancer Council of Victoria, Stanley Medical Research Foundation, Medical Benefits Fund, National Health and Medical Research Council, Medical Research Futures Fund, Beyond Blue, Rotary Health, A2 milk company, Meat and Livestock Board, Woolworths, Avant and the Harry Windsor Foundation, has been a speaker for Abbot, Astra Zeneca, Janssen and Janssen, Lundbeck and Merck and served as a consultant to Allergan, Astra Zeneca, Bioadvantex, Bionomics, Collaborative Medicinal Development, Eisai, Janssen and Janssen, Lundbeck Merck, Pfizer and Servier. PB has received research support from the National Health and Medical Research Council, speaker fees from Servier, Janssen and the Australian Medical Forum, educational support from Servier and Lundbeck, has been a consultant for Servier, served on an advisory board for Lundbeck and has served as DSMC Chair for Douglas Pharmaceuticals. GC has received educational and travel support from Servier, Astra Zeneca, Otsuka Australia, Merck Sharp & Dohme, and Janssen-Cilag in the past five years. He also served on an advisory board for the AFFINITY trial. PBF is supported by a NHMRC Investigator Grant (1193596). In the last 3 years PBF has received equipment for research from Nexstim and Brainsway Ltd. He is a founder and board member of TMS Clinics Australia and Resonance Therapeutics. PBF is also a board member of Neurosciences Victoria and The United project, and a committee member of the RANZCP Section for ECT and Neurostimulation. Within the last 36 months, PG has attended a Janssen New Zealand advisory board, and is named on a patent for a controlled release ketamine tablet developed by Douglas Pharmaceuticals. NG is supported by grants from the NHMRC (1105089 and 2014381) and ARC (CE20010025). In the last 36 months, he has received honoraria from Servier Laboratories and Lundbeck and served on Advisory Boards for Servier Laboratories, Esia, Seqirus and Lundbeck. PH has received grants/contracts from the Department of Veteran Affairs and the National Institute of Mental Health. He receives royalties from Oxford University Press and UpToDate. PH has also 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. MH is supported by an NHMRC project grant (APP1105089) and an NHMRC fellowship (APP1141328). SH has received speaker fees from Janssen, served on advisory boards for Janssen and Lundbeck, and is a board member of UWA Young Lives Matter Foundation, International Master in Affective Neuroscience, and Journal of Psychopharmacology. FAK is a board member of the Clinical TMS Society (CTMSS), Co-Chair of the CTMSS Clinical Standards Committee and a member of the CTMSS Research Committee (all unpaid). KL has received contracts for research involving ketamine and other antidepressants and equipment support from ALTO Neuroscience. He has received grants/contracts, as well as consulting and manuscript writing fees, from Fisher Wallace. KL has also received consulting fees from Janssen and Third Bridge. He owns stocks in Validose and has a patent issued a pending for a device developed by the company that could deliver ketamine. He also owns stocks in Journey Clinical and is a Medical Director for this company. KL owns Affective Care, which is a company providing antidepressant treatments including company. He also owns several companies involved in medical care, including depression treatment (Psychiatric Care, Anxiety Psychiatry, Marham, and Sol2rise). CM was a member of the economic subcommittee of the Pharmaceutical Benefits Advisory Committee in Australia from 2013-2022. In the last 36 months, DM has received consulting fees from Douglas Pharmaceuticals for another study involving ketamine. PBM is supported by an Investigator Grant from the NHMRC. Within the last 3 years, he has received remuneration from Janssen (Australia) and Sanofi (Hangzhou) for lectures or advisory board membership. WMM is a member of the American Psychiatric Association (APA) Council on Research representing ECT and Neuromodulation Therapies. WMM is compensated as the chair of the DSMB for an NIA sponsored multicenter study. He is on the Board of and has received travel support from Skyland Trail. He is also on the Board of 3Keys. He is a paid consultant for Signant Health and Sage Therapeutics. He has received past funding from the Stanley Foundation, Soterix, Neuronetics, NeoSync and Cervel Neurotherapeutics. He has endowed chair funded by the JB Fuqua Foundation. He is an employee of Emory University School of Medicine. WMM receives royalties from Oxford University Press to co-edit a book on the Clinical Guide to Transcranial Magnetic Stimulation in the Treatment of Depression. PR-P has received payments for serving on consulting boards for Janssen Pharmaceuticals. AAS is a director of the Australian Medicines Handbook Pty Ltd and has received funding support by the Australian and New Zealand College of Anaesthetists to investigate ketamine for chronic postsurgical pain. The following authors declared no conflicts of interest: AA, MLC, VD, CF, DG, KG, VG, DHP, EL, JL, NM, SN, SMN, KR, AS, AR, DR, ES, SS, and NT.

Ethics Approval Statement: Ethics approval was obtained from the Sydney Local Health District (RPAH Zone) Human Research Ethics Committee (Australia; X16-0146 & HREC/16/RPAH/168) and the Southern Health and Disability Ethics Committee (New Zealand; 16/STH/104). The protocol is available at http://doi.org/10.17605/OSF.IO/6FPGU.

Keywords: ketamine, depression, treatment resistance, clinical trial, mood disorders, psychiatry, neuroscience, mental disorders, treatment.