Issue 48 / 14 December 2015

KETAMINE can be considered a novel therapy for treatment-resistant depression, according to the Royal Australian and New Zealand College of Psychiatrists, although some experts say the recommendation is premature.
 
Last month, the college published a clinical memorandum on its website regarding ketamine for depression, saying despite its short-term efficacy, there was “limited evidence” to recommend ketamine as a viable treatment for treatment-resistant depression. It advised the therapy be used under research trial conditions. (1)
 
The college has acknowledged that some patients wanted access to the therapy outside of trials and that some psychiatrists were keen to provide it off-label. In these cases, the college recommended the treating psychiatrist “consider such treatment as novel or innovative treatment” and clearly explain this to the patient, providing detailed information on the risks. 
 
The clinical memorandum said prescribing psychiatrists should discuss its use with peers, “preferably including a second opinion”, and recommended they seek institutional review and ethics committee consideration.
 
Dr Stephen Hyde, a Tasmanian psychiatrist and author of the book Ketamine for depression published earlier this year, welcomed the college’s new position. (2)
 
“I believe this is a considered and humane response to the suffering our patients endure”, he told MJA InSight.
 
Dr Hyde said while he supported research into the field, many patients could not wait several years for trials to be completed. “In the meantime, people are suffering and dying prematurely from treatment-resistant depression.”
 
He said he had been treating 18 patients with treatment-resistant depression for the past year with low-dose sublingual ketamine, saying 70% had responded and 35% remitted with no problems with dependence or addiction.
 
However, not all psychiatrists have welcomed the college’s new stance. 
 
Professor Philip Mitchell, of the school of psychiatry at the University of NSW, who is involved in ketamine research, said the college’s statement was “too liberal” and gave a licence for ketamine’s inappropriate use. 
 
“There is insufficient evidence to support ketamine going into the clinical armamentarium yet, although it’s potentially a very exciting treatment”, he told MJA InSight
 
“We have seen very dramatic results reported in various studies, but the results wear off very quickly, and we don’t yet have evidence for the safety and efficacy of giving repeated administrations.” 
 
Professor Mitchell said there had already been “excessive uptake and commercial exploitation” of ketamine for depression.
 
A chain of clinics known as the Aura Medical Corporation was reportedly charging more than $1000 for a course of eight ketamine injections for patients with depression. The company was forced to close in July this year amid negative publicity after it was linked to the controversial erectile dysfunction company Advanced Medical Institute. (3)
 
Associate Professor Graham Barrett, a GP and neurophysiologist at the University of Melbourne, was the medical director of Aura for one month before resigning in March. He told MJA InSight he was disillusioned that the company was “profit oriented and not giving enough time to follow up patients”.
 
Professor Barrett now has a voluntary agreement with the Australian Health Practitioner Regulation Agency not to prescribe ketamine. However, he told MJA InSight he still believed the drug should be legitimised for off-label use in the 40% of patients with depression who did not respond to existing antidepressants.
 
“There is now abundant evidence that ketamine will relieve depression in three-quarters of patients who don’t respond to existing antidepressants”, he said. “The alternative, favoured by many practitioners because it usually works, initially at least, is ECT [electroconvulsive therapy]. Unfortunately, it is now shown beyond doubt that ECT causes irreversible brain damage, amnesia and dementia.” (4)
 
Professor Colleen Loo, of the Black Dog Institute who is leading a major study into ketamine for treatment-resistant depression, said the clampdown by health authorities on clinical use of the drug was “not surprising”.
 
In an editorial in this week’s MJA, Professor Loo wrote that the risks of acute treatment with ketamine included induction of psychotomimetic effects and elevation of blood pressure, although these were typically transient. (5)
 
“If ketamine is prematurely applied clinically to treat depression, before research has determined how (and if) it can be effectively and safely used to achieve lasting remission of depression, the end result may be disillusionment and even abandonment of this otherwise promising therapy”, she wrote.
 
 
 
(Photo: funnyangel / shutterstock)

12 thoughts on “Ketamine decision “premature”

  1. Ajeet Singh says:

    What’s the NNT? What’s the NNH? What’s the level of evidence currently?

  2. Jules Black says:

    What about malignant hyperthermia? Has that side-effect of Ketamine been conquered nowadays?

  3. Linda Partridge says:

    Ketamine does not cause malignant hyperthermia

  4. Mick Vagg says:

    Having done hundreds of low-moderate dose ketamine infusions in chronic pain patients over the last decade, I’d have thought I should have seen something which would convince me of the plausibility of this as a treatment modality. But I haven’t and I’m not. Perhaps before wasting too much effort on it, psychiatrists could collaborate with those who use ketamine a lot in mood-disordered patients already?

  5. Guy Hibbins says:

    If ketamine is such a good treatment for depression, why is this not an approved indication in Australia?  Why is it not an approved indication in the US, Europe, Japan or Canada either?  If the evidence for its safety and effectiveness in depression is so strong, why have the manufacturers not been able to to convince regulators to approve it?  Maybe the lack of regulatory approval does not mean much to some people.  Maybe it should. 

  6. Saul Geffen says:

    Could the author please check the reference provided for the claim that ECT causes dementia? I note a meta analysis in the Lancet stating its more effective than medication. Does that article show “beyond doubt” that ECT causes dementia and permanent brain damage’ if not maybe the author should check.

  7. Dr Korede Stephen Jude Ayeni says:

    I have not yet read Dr Hyde’s book regarding his experience with the use of Ketamine for treatment resistant depression. I am surely keen to know more about the clinical features of the 18 patients that he has treated. The presumption here is that all these patients have treatment resistant depression. At the diagnostic level, are they all having depression as a disorder without any comorbid conditions such as generalised anxiety, psychoactive substances use problems and personality disorders. Some of my patients with GAD describe their symptoms as ” depression ” until the longitudinal course and symptoms profile are clarified. If course, we know that severe cases of GAD can be complicated by depression as a disorder. It also sometimes difficult to identify the primary mood problem when both coexist.Some of my patients with amphetamines dependence do complain of depression without disclosing the primary problem in terms of depressive symptoms while coming down. Besides this, some of my patients with Borderline PD will talk of depression when they are in crisis until the crisis resolve. In these cases changing anti-depressant to another seems a furtile efforts. As depression means different things to different people,we cannot therefore over emphasise the need for a robust methodological design that include a rigorous patients’ sample selection to objectively evaluate the significance of Dr Hyde’s observation. There are some psychiatrists who share Dr Hyde’s view about Ketamine although I do not at present. This view cannot however be ignored. My understanding of the College memoradum is to encourage further research in this area. This of course is one of the RANZCP’s pivotal function. It will be interesting to know what the future research outcome will be.

  8. Jeffrey Looi says:
    • Reference 4 is incorrectly cited and does not scientifically support the quotation preceding it.
    • The correct reference is: Lancet 2003; 361:799-808.
    • There is no material in the Lancet paper supporting any conclusion that ECT causes any long term irreversible brain damage or dementia.
    • Currently, while specific episodic (autobiographical) amnesia is known as a potential long-term cognitive side effect of ECT,  there remains no substantive evidence to date that ECT causes any long term irreversible brain damage or dementia

     

  9. Minh Le Cong says:

    Thanks for the editorial from Prof Loo and this Insight article. I find the level of mythology and misinformation about ketamine for medical use to be baffling. Ketamine certainly does not trigger malignant hyperthermia. It is one of the most extensively studied analgesics and anaesthetic agents in world history. It is one of only two anaesthetic agents on the WHO Essential drug list for ALL hospitals. The research into its use for depression is not recent and began over 10 years ago! Admittedly it is a recreationally abused drug and has a dirty street drug reputation. But thats separate from its medical use..just like morphine!. Dr Hyde has consulted pain medicine specialists like Dr Varun Jaitly in UK on chronic ketamine prescription in writing his book. Cochrane Evidence based reviews all come up with same conclusion : Ketamine is an antidepressant. Read here: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD011612.pub2/abstra

    The challenge is how to use it safely and effectively in long term and patient selection. These are all things being worked out right now and Australia will play its part with a study from Black Dog Institute starting next year.

    The demonisation of ketamine for depression treatment is unfortunately not aided by commercial interest clinics here in recent past in Sydney and overseas. Please separate this issue from the medical prescription of ketamine to consenting patients as a novel option for refractory depression as per the latest RANZCP clinical memorandum.

    Recall that ECT for a long time had no controlled studies to support its use. At least ketamine is well studied already for analgesia/anaesthesia

  10. Steve Hyde says:

    In reponse to MV I would suggest you look at the work of Correll and Futter in MacKay Queensland [2006] who, after noting that patients with chronic severe pain conditions given ketamine infusions reported improvement in depressive symptoms, then gave patients with treatment-resistant depression similar infusions over 5 days with positive results. My own interest in the use of ketamine was sparked by the improvement in depression seen in one of my patients who had a 10 day subcutaneous infusion for severe chronic pain. Varun Jaitly in England [2013] has 15 years of experience in the use of sublingual ketamine for chronic pain and importantly has not noted problems with long term side effects, nor dependence or addiction over that time – one of his patients has been on daily ketamine for 15 years.

    To GDH – the prime reason that ketamine is not an approved indication in any juridiction is that ketamine is long out of patent so pharmaceutical companies have no financial incentive to do the very expensive studies required. Instead they are workingon derivatieves or analogues of ketamine which will be patentable and doubtless very costly to patients and governments alike when they are eventually released.

    To KSJ – my patients have Major Depression as per DSM, all have physical and psychological comorbities and have trialled a range of psychological and medication therapies, for many inclusing ECT and for one psychosurgery, with limited or no relief – they are the typical “difficut” patients that all psychiatrists see, not those who get selected for clinical trials on the basis of exclusion criteria.

    My book “Ketamine for Depression” covers all these topics in greater detail and all profits go to further research.

     

  11. Josh Geffen says:

    Cannot let throw away alarmist comments about ECT from a non-psychiatrist with a vested interest go unchecked. The reference is from th UK ECT review group’s 2093 meta analysis (not 2013). It does not support his assertions (no convincing research does) and it concludes as follows

    Interpretation

    ECT is an effective short-term treatment for depression, and is probably more effective than drug therapy. Bilateral ECT is moderately more effective than unilateral ECT, and high dose ECT is more effective than low dose.

     

  12. Dr Gary Reynolds says:

    The concept of  “a licence for inappropriate use”  is nonsense. People who use drugs, both licit and illicit, inappropriately have no need of the “cover” of a “licence”.  Substance misuse and dependence simply does not work that way.  For what it’s worth, in my the patient population of my dependence service, ketamine is vanishingly rarely reported as a current or previous recreational or dependence drug. Nor is it mentioned by them as something that’s around among users who are not presenting to such services.

     

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