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Is ketamine ready to be used clinically for the treatment of depression?

Colleen Loo
Med J Aust 2015; 203 (11): 425. || doi: 10.5694/mja15.00966
Published online: 14 December 2015

A single dose of ketamine produces rapid antidepressant effects, but attaining lasting remission remains a challenge

Some clinics in Australia and overseas have begun offering a course of ketamine treatments to patients with depression. However, this practice is premature, given that the efficacy and safety of this treatment approach has yet to be tested in controlled trials. Further, whether such a treatment approach leads to lasting response — that is, clinically meaningful effects — is as yet unknown. Ketamine differs from current antidepressant medications in that it acts primarily on the glutamate signalling system, rather than on the monoaminergic (eg, serotonin, noradrenalin) system. To date, eight randomised, placebo-controlled trials involving almost 200 participants with depression have shown robust antidepressant effects after a single, subanaesthetic dose of ketamine.1,2 These impressive clinical results have generated intense interest among researchers, clinicians and patients.

First, the onset of effects is much more rapid for ketamine than for other antidepressant treatments, with peak effects seen 24 hours after receiving a single treatment, in contrast with the several weeks required for most other treatments. Second, ketamine has a very high efficacy, as demonstrated by high overall remission rates,1 efficacy even in patients who are highly treatment resistant,3 and one preliminary report of superior efficacy to electroconvulsive therapy, typically considered the most effective proven biological treatment for depression.4 These observations have driven public demand for ketamine to be immediately made available as a clinical treatment for depression.5

However, a major drawback of this otherwise impressive treatment is that antidepressant effects typically last for only several days after a single treatment.6 The occasional patient may attain a lasting remission after a single dose;7 but, as yet, there is no way of identifying which patients will gain lasting benefit from a single treatment. Several strategies have been trialled in attempts to prolong the antidepressant effects of ketamine, but none have resulted in lasting improvement. The main strategy has been to give repeated doses of ketamine. Preliminary trials suggest this may prolong the antidepressant effects from a few days to a few weeks.8 So far, the efficacy and safety of repeated dosing has not been tested in placebo-controlled trials.

Risks of acute treatment with ketamine include induction of psychotomimetic effects and elevation of blood pressure. These are transient, occurring mainly in the first hour after treatment. Ketamine has been given safely to patients in clinical trials, in which patients were first carefully assessed in terms of hypertension, cardiac function, hepatic function and psychiatric illness, and with careful monitoring and constant supervision in the immediate hours after treatment. Longer-term use is associated with different risks, and the safety of ketamine with repeated treatments is unclear. Data on chronic use come largely from recreational users; that is, the data are unsystematic and uncontrolled. What evidence there is suggests a risk of hepatic impairment, bladder dysfunction and, possibly, cognitive impairment. 9 Until there are clear data on these risks, repeated treatment doses should be given within a framework of systematic evaluation of these adverse effects. Another important consideration is the risk of inducing craving for further ketamine in patients treated with the drug. Although research participants evaluated 6 months after participation in strictly controlled treatment trials for depression have not shown increased craving for ketamine, there is a cautionary report of ketamine tolerance and addiction developing after its use to treat depression.10 In this report, increasing doses of ketamine were used in an attempt to obtain lasting antidepressant effects, resulting in considerable adverse effects and eventual requirement for detoxification from ketamine, with resultant lapse into severe depression.

Other considerations in the use of ketamine as a treatment for depression include the optimal route of administration and dosage. Most clinical trials to date have administered 0.5 mg/kg ketamine over a 40-minute intravenous infusion. Ketamine has also been given by simpler methods: orally or sublingually, by intramuscular or subcutaneous injection, and by intranasal spray, with some studies reporting similar results to studies using an intravenous route.7,11-13 It is also unclear whether 0.5 mg/kg, the dose selected for initial trials and used in most subsequent trials, is the optimal dose level. To date, there have been minimal investigations of the important pharmacodynamic considerations of treatment route and dosage, and how these may determine the magnitude and persistence of the antidepressant response.

Given the current evidence and risk of potential harm, it is not surprising that recent actions have been taken by health authorities in Australia to curtail medical practitioners offering a course of ketamine treatments to patients with depression.14 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.


Provenance: <p>Commissioned; externally peer reviewed.</p>

  • Colleen Loo

  • University of New South Wales, Sydney, NSW

Correspondence: colleen.loo@unsw.edu.au

Competing interests:

No relevant disclosures.

  • 1. McGirr A, Berlim MT, Bond DJ, et al. A systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials of ketamine in the rapid treatment of major depressive episodes. Psychol Med 2015; 45: 693-704.
  • 2. Lai R, Katalinic N, Glue P, et al. Pilot dose-response trial of I.V. ketamine in treatment-resistant depression. World J Biol Psychiatry 2014; 15: 579-584.
  • 3. Ibrahim L, Diazgranados N, Luckenbaugh DA, et al. Rapid decrease in depressive symptoms with an N-methyl-d-aspartate antagonist in ECT-resistant major depression. Prog Neuropsychopharmacol Biol Psychiatry 2011; 35: 1155-1159.
  • 4. Ghasemi M, Kazemi MH, Yoosefi A, et al. Rapid antidepressant effects of repeated doses of ketamine compared with electroconvulsive therapy in hospitalized patients with major depressive disorder. Psychiatry Res 2014; 215: 355-361.
  • 5. Arbusson K. Alarm over experimental ketamine treatment. Australian Doctor 2015; 16 Feb. http://www.australiandoctor.com.au/News/Latest-News/Alarm-over-experimental-ketamine-treatment (accessed Oct 2015).
  • 6. Zarate CA Jr, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 2006; 63: 856-864.
  • 7. Galvez V, O’Keefe E, Cotiga L, et al. Long-lasting effects of a single subcutaneous dose of ketamine for treating melancholic depression: a case report. Biol Psychiatry 2014; 76: e1-e2.
  • 8. Murrough JW, Perez AM, Pillermer S, et al. Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biol Psychiatry 2013; 74: 250-256.
  • 9. Katalinic N, Lai R, Somogyi A, et al. Ketamine as a new treatment for depression: a review of its efficacy and adverse effects. Aust N Z J Psychiatry 2013; 47: 710-727.
  • 10. Bonnet U. Long-term ketamine self-injections in major depressive disorder: focus on tolerance in ketamine’s antidepressant response and the development of ketamine addiction. J Psychoactive Drugs 2015; 47: 276-285.
  • 11. Lapidus KA, Levitch CF, Perez AM, et al. A randomized controlled trial of intranasal ketamine in major depressive disorder. Biol Psychiatry 2014; 76: 970-976.
  • 12. Chilukuri H, Reddy NP, Pathapati RM, et al. Acute antidepressant effects of intramuscular versus intravenous ketamine. Indian J Psychol Med 2014; 36: 71-76.
  • 13. Lara DR, Bisol LW, Munari LR. Antidepressant, mood stabilizing and procognitive effects of very low dose sublingual ketamine in refractory unipolar and bipolar depression. Int J Neuropsychopharmacol 2013; 16: 2111-2117.
  • 14. Worthington E. Ketamine injections: AHPRA bans former Aura Medical director Graham Barrett from prescribing drug amid investigation. ABC News. 16 Jun 2015. http://www.abc.net.au/news/2015-06-16/ketamine-injections-graham-barrett-banned-from-prescribing-drug/6550804 (accessed Oct 2015).

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access_time 06:48, 14 December 2015
Minh Le Cong

Dear MJA
I thank you and Professor Loo for this timely editorial on ketamine for depression treatment. I support research into this indication and am glad to hear the Professor is planning a ketamine study in 2016.
I wish to comment on two aspects of the editorial piece.
Firstly Professor Loo states that long term ketamine use is only reported from recreational drug use research. That is not true as pain medicine research describes long term prescribed medical use of up to 15 years. Secondly the case report of ketamine addiction that she cites as a cautionary tale was one of unsupervised abuse, essentially recreational use. I am not aware of any case of addiction when ketamine is medically prescribed and supervised.
I agree that a careful approach is reasonable and good research is vital but I disagree that we need to fear a drug that has been extensively studied for over 40 years.

Competing Interests: No relevant disclosures

Dr Minh Le Cong
Royal Flying Doctor Service

access_time 07:46, 14 December 2015
Stephen James Hyde


It is correct that to date placebo-controlled trials on the use of repeated doses of ketamine to help those with treatment resistant depression are yet to be done.

The main reason for this is that ketamine is long off-patent so there is no incentive for pharmaceutical companies to invest the time and money required to do full scale, multicenter, double blind, placebo-controlled trials. It is pleasing to know that Professor Colleen Loo et al at the Black Dog Institute have recently been given a grant to extend their research in Australia but this will take several years to be completed and reported.

In the meantime people are suffering and dying prematurely from treatment-resistant depression – on average those suffering from chronic psychiatric illness die 20 years before their peers, some by suicide but most through the illnesses that will kill us all in time, cardiovascular disorders and cancer.

350 million people worldwide experience major depression.
With our current treatments one third have good responses, a third partially respond and a third do not respond at all to counseling and medication approaches, even ECT.

The use of ketamine in this treatment-resistant population leads on average to a 70% response rate and around a 30% remission rate in this very hard to treat group. Ketamine has helped people whether given orally, sublingually, subcutaneously, intranasally, intramuscularly and intravenously.

Short-term side effects are well described and easily managed.
Longer-term side effects are also known from the experiences of recreational users around 5% of whom can develop tolerance, dependence and addiction with the associated urinary and hepatic problems appearing in those who take very large doses [3-5 grams] on a daily basis for years on end.

Ketamine has been used over the past 50 years by millions as an anaesthetic, [it is currently the most widely used anaesthetic in the world] by hundreds of thousands for pain relief including those who have had repeated continuous infusions for the treatment of burns and CRPS, and now for thousands of people with severe depression [Dr. Angelo De Gioannis and colleagues in Brisbane have now treated over 600 patients with oral ketamine over the past 3 years with a 70% response rate – results of his trial will be published shortly].

It is noteworthy that with the extensive use of medically prescribed and monitored ketamine over the past 50 years that there have been no reports of dependence or addiction as a consequence.

So a psychiatrist faced with a patient with a severe life-threatening illness has the option of discussing with them the risks and benefits of trialing ketamine. The RANZCP has just released a clinical memorandum describing ketamine as a novel, innovative treatment to be used with caution and appropriate safeguards in patients with treatment-resistant depression. I believe this is a considered and humane response to the suffering our patients endure.

Competing Interests: I am the author of the recently published book "Ketamine for Depression."

Dr Stephen James Hyde
Franzcp

access_time 09:52, 16 December 2015
Varun K Jaitly

As an outside observer - I am anaesthetist with an interest in chronic pain who lives on the other side of the planet - the only thing that qualifies me to make some sort of comment on Loo' s editorial (1) is the fact that I have some clinical experience in dealing with patients who have been taking regular low dose Ketamine for a long time to manage their chronic pain problems. Several years ago I was encouraged to publish my observations and readers can access the fruits of this labour in the open access article I wrote, where I describe my more than 200 patient years of experience with this drug (2).

Readers with the stamina to read the whole paper can then judge for themselve the risks of whether regular low dose sublingual Ketamine is likely to cause significant hepatic impairment, bladder dysfunction and cognitive impairment. Alternatively they can accept my summary statement that in my series the patient who had been taking it for the longest time has been taking it for 15 years - and generally speaking in my small group of patients, there was no easily observable harm. Compared to the daily doses of abuse described in the literature which can amount to more than several grammes per day(3), most of my patients are prescribed doses well below this - often of the order of 90-120 mg per day. Furthermore, in my series, no patient reported an easily observable abstinence syndrome when they stopped their Ketamine, even if they discontinued their Ketamine after several years of treatment.

1.Colleen Loo, Med J Aust 2015; 203 (11): 425

2. Jaitly V.K. Sublingual Ketamine in chronic pain : Service evaluation by examining over 200 patient years of data
Journal of Observational Pain Medicine – Volume 1, Number 2 (2013) ISSN 2047-0800 (open access)
http://www.joopm.com/index.php?journal=joopm&page=article&op=view&path[]=26 (last accessed 15 12 15)

3. http://www.bbc.co.uk/news/resources/idt-bc7d54e7-88f6-4026-9faa-2a36d3359bb0

Competing Interests: Over the years I have attended meetings and had lunches/dinners sponsored by a range of pharmaceutical firms and equipment manufacturers.

Dr Varun K Jaitly
Wrightington Wigan and Leigh NHS Foundation Trust

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