A low-cost version of ketamine to treat severe depression has performed strongly in a double-blind trial that compared it with placebo.
In research published today in the British Journal of Psychiatry, researchers led by UNSW Sydney and the affiliated Black Dog Institute found that more than one in five participants achieved total remission from their symptoms after a month of bi-weekly injections, while a third had their symptoms improve by at least 50 per cent. The study was a collaboration between six academic clinical mood disorder units in Australia and one in New Zealand and was funded by the Australian National Health and Medical Research Council (NHMRC).
“For people with treatment-resistant depression – so those who have not benefitted from different modes of talk-therapy, commonly prescribed antidepressants, or electroconvulsive therapy – 20 per cent remission is actually quite good,” lead researcher Professor Colleen Loo says.
“We found that in this trial, ketamine was clearly better than the placebo – with 20 per cent reporting they no longer had clinical depression compared with only 2 per cent in the placebo group. This is a huge and very obvious difference and brings definitive evidence to the field which only had past smaller trials that compared ketamine with placebo.”
How the trial worked
The researchers recruited 179 people with treatment-resistant depression. All were given an injection of either a generic form of ketamine that is already widely available in Australia as a drug for anaesthesia and sedation – or placebo. Participants received two injections a week in a clinic where they were monitored for around two hours while acute dissociative and sedative effects wore off – usually within the first hour. The treatment ran for a month and participants were asked to assess their mood at the end of the trial and one month later.
As a double-blind trial, neither participants nor researchers administering the drug were aware which patients received generic ketamine or placebo, to ensure psychological biases were minimised. Importantly, a placebo was chosen that also causes sedation, to improve treatment masking. Midazolam is a sedative normally administered before a general anaesthetic, while in many previous studies the placebo was saline.
“Because there are no subjective effects from the saline, in previous studies it became obvious which people were receiving the ketamine and which people received placebo,” Prof. Loo says.
“In using midazolam – which is not a treatment for depression, but does make you feel a bit woozy and out of it – you have much less chance of knowing whether you have received ketamine, which has similar acute effects.”
Other features of the recent trial that set it apart from past studies included accepting people into the trial who had previously received electroconvulsive therapy (ECT).
“People are recommended ECT treatment for their depression when all other treatments have been ineffective,” Prof. Loo says.
“Most studies exclude people who have had ECT because it is very hard for a new treatment to work where ECT has not.”
Another difference about this trial was that the drug was delivered subcutaneously (injected into the skin) rather than by drip, thus greatly reducing time and medical complexity. The study is also the largest in the world to date that compares generic ketamine with placebo in treating severe depression.
Much more affordable
Apart from the positive results, one of the standout benefits of using generic ketamine for treatment-resistant depression is that it is much cheaper than the patented S-ketamine nasal spray currently in use in Australia. Where S-ketamine costs about $800 per dose, the generic ketamine is a mere fraction of that, costing as little as $5, depending on the supplier and whether the hospital buys it wholesale. On top of the cost for the drug, patients need to pay for the medical care they receive to ensure their experience is safe – which at Black Dog Institute clinics, comes to $350 per session.
“With the S-ketamine nasal spray, you are out of pocket by about $1200 for every treatment by the time you pay for the drug and the procedure, whereas for generic ketamine, you're paying around $300-350 for the treatment including the drug cost,” Prof. Loo says.
She adds that for both S-ketamine and generic ketamine treatments, the positive effects often wear off after a few days to weeks, so ongoing treatment may be required, depending on someone’s clinical situation. But the prohibitive costs of the drug and procedure make this an unsustainable proposition for most Australians.
“This is why we're applying for a Medicare item number to fund this treatment now, because it’s such a powerful treatment.
“And if you consider that many of these people might spend many months in hospital, or be unable to work and are often quite suicidal, it’s quite cost effective when you see how incredibly quickly and powerfully it works. We’ve seen people go back to work, or study, or leave hospital because of this treatment in a matter of weeks.”
The researchers will next be looking at larger trials of generic ketamine over longer periods, and refining the safety monitoring of treatment.
Participating trial sites
- UNSW / Black Dog Institute
- Royal Prince Alfred Hospital / University of Sydney
- NeuroCentrix Research Institute
- Royal Adelaide Hospital / University of Adelaide
- Monash Alfred Psychiatry Research Centre / Monash University
- University of Otago
- Gold Coast University Hospital
Institutions of non-site collaborators
- Deakin University
- University of Newcastle
- The George Institute for Global Health
- University of Western Australia
The British Journal of Psychiatry
Method of Research
Randomized controlled/clinical trial
Subject of Research
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
Article Publication Date
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 educa- tional 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 pay- ments 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 antidepres- sant 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 tes- timony 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.