The drug ketamine has been used for medical purposes since it was developed in the 1960s, but it is perhaps more widely known for its illicit use as a hallucinogenic tranquiliser. Now we’re beginning to realise the drug may have a future life as an alternative treatment for depression.
Ketamine is an approved anaesthetic drug, which can be used on its own, or in smaller doses in combination with other anaesthetics. Given under medical supervision, ketamine has powerful pain-killing properties and can also be used for mild sedation – for instance, for children who need to undergo multiple sessions of radiotherapy.
Under medical supervision, ketamine is very safe but in high doses, it can induce unwanted side effects such as hallucinations.
A better antidepressant?
Ketamine has powerful effects on the brain receptors for glutamate, the main chemical in the brain responsible for the activation of nerve cells.
This differs to current antidepressant medications, which mainly work on the serotonin and noradrenaline systems. Traditional antidepressants often take days to weeks for the effects to be seen. And only half of depressed people will respond to a trial of antidepressant medication.
This led Dr Robert Berman and his colleagues at Yale University to investigate the antidepressant properties of ketamine. In 2000, he published a small proof-of-concept study of seven depressed patients. They were all given a single, relatively small dose of ketamine (less than an anaesthetic dose), which was administered intravenously over 40 minutes.
The results were impressive, with rapid antidepressant effects that were obvious after 24 hours and increased further up to three days after treatment.
On the down side, the drug caused some psychiatric side effects such as altered perception or hallucinations, though these resolved within the first two hours.
These very promising early results have been replicated in subsequent trials, which have shown that 70% of depressed participants responded to a single treatment with ketamine.
Some overseas studies even reported that depressed patients who had failed to respond to electroconvulsive therapy, currently the strongest physical treatment we have for depression, may yet respond to ketamine treatment.
Next steps
My colleagues and I at the University of New South Wales and Black Dog Institute recently commenced the first Australian clinical trial testing the use of ketamine to treat depression, based at the Wesley Hospital in Kogarah. We’re trialling the effects of different doses of ketamine on volunteers who are clinically depressed and have failed to get better with other antidepressant treatments.
Results in the first eight volunteers have been encouraging, with all but one showing an improvement in mood. As found in the US trials, the response occurred rapidly, within a day of treatment.
But the trials so far have found that some people may relapse after a few days. So our research is also examining ways of making the response more lasting.
At this stage, it’s unclear whether ketamine may emerge as a useful stand-alone treatment, or as an adjunct to other treatments.
But we’re hoping that in future, ketamine may be useful to induce a rapid antidepressant response in urgent situations – where the patient is seriously depressed and acutely suicidal – and where other antidepressant treatments have failed.
To get involved in the study or find out more, click here.
Sue Ieraci
Public hospital clinician
Interesting article - thank you.
Ketamine is being re-discovered in lots of areas of medicine. It has been the mainstay of developing-world anaesthesia for many years, and now is back in use in Australia for sedation of children undergoing painful medical procedures (stitches, burns dressings), and in small doses to supplement pain relief in the severely injured. It's big advantages in these settings is that it doesn't cause low blood pressure or suppress breathing, as many other sedative drugs do.
The real disadvantage in adults of full doses has been that it does cause hallucinations - often quite disturbing ones.
Can the author tell us how the proposed dose in depression would compare with a sedative dose, and whether hallucinations are still a risk in that setting?
Dianna Arthur
Dianna Arthur is a Friend of The Conversation.
Environmentalist
Looks like I'll just continue taking my old antidepressant for the foreseeable.
At least I can take something that works.
Comment removed by moderator.
Peter Fox
Peter Fox is a Friend of The Conversation.
Medical doctor
Ketamine has also been widely used in the palliative care setting for severe cancer pain. A recent well designed, placebo-controlled, double-blind Australian study showed it causes more toxicity than benefit, with relatively weak analgesic effects that were outweighed by toxicities.
The number needed to treat to derive benefit was 25, whilst number needed to harm was 6.
http://www.ncbi.nlm.nih.gov/pubmed/22965960
Sue Ieraci
Public hospital clinician
On the other hand, this recent Australian trial showed that low-dose Ketamine added to morphine improved pain-control in trauma patients:
Annals of Emergency Medicine
Volume 59, Issue 6, June 2012, Pages 497–503
Morphine and Ketamine Is Superior to Morphine Alone for Out-of-Hospital Trauma Analgesia: A Randomized Controlled Trial
http://www.sciencedirect.com/science/article/pii/S0196064411017975
Ketamine is mainly a dissociative drug, with some analgesic effect. What was the nature of the adverse events in the cancer patients?
Peter Fox
Peter Fox is a Friend of The Conversation.
Medical doctor
Thanks Sue, the relative lack of efficacy of ketamine in this setting is a little surprising. The authors noted a strong placebo effect with the placebo subcutaneous saline injection, which perhaps explains the widespread anecdotal evidence of this treatment.
"Mean pain scores in this study improved over time for all participants irrespective of allo- cation, with no difference between arms. Although there was a greater improvement per day in the ketamine group in worst and average pain scores…
Read moreSue Ieraci
Public hospital clinician
I suspect you're right about the one-off vs repeated use, Peter. It's curious, though, that (in the study you cited) eight of the placebo arm got cognitive disturbance.
Maybe the answer in palliative care is to reserve a one-off or occasional dose for someone in distress who is unable to be kept comfortable in any other way.
I wonder what the proposed dose is for treating depression is, and whether there is a risk of hallucinations at that dose.
Peter Fox
Peter Fox is a Friend of The Conversation.
Medical doctor
Yes, Sue - the nocebo effect is a pretty strange thing.
Even on day 1, there was no difference in the pain response between placebo and ketamine. I suspect it just doesn't work as an analgesic in this setting. Or the dose is wrong:
In terms of dosing, the Black Dog Institute study give up to 0.1-0.5mg/kg intravenously weekly for 6 weeks - clinicaltrials.gov/ct2/show/NCT01441505 - while the pall care study allowed escalating doses from 100-500mg/24 hours daily for a week.
So the doses in the pall care setting are MUCH higher (up to ~3000mg over the week, and minimum of 700mg), compared with the depression study (<50mg per week). No wonder the pall care patients get so much cognitive toxicity.
Sue Ieraci
Public hospital clinician
The depression trial gives single IV doses weekly? How can that work with such a short half-life?
Tim Benham
Student
<i>Under medical supervision, ketamine is very safe but in high doses, it can induce unwanted side effects such as hallucinations.</i>
That's wrong. Ketamine is a general anesthetic. The anesthetic dose is higher than the recreational dose. That's not surprising because being unconscious is not very recreational.
Susan Ruthenbeck
Luftmensch
I endorse research into new treatments for depression and other clinical applications.
However, the article does not mention the side-effect which many street users of K have experienced - a transformation from a usually happy-go-lucky disposition to feelings of aggression which are very hard to control.
Colleen Loo
Professor of Psychiatry, University of NSW, Sydney at University of New South Wales
In our depression research trial, ketamine is given at a subanaesthetic dose so there is no loss of consciousness. The dose is also carefully calculated, mg/kg of body weight. Under these conditions, we have seen transient psychomimetic effects, but not aggression and anger. Recreational drug use varies in the drug obtained, route of administration etc, so it is often difficult to know what dose is actually received and the range of possible side effects is, I suspect, considerably wider than in our research trial.
To answer earlier comments, the initial part of the trial gives single treatments at a range of doses, a week apart, to test response and side effects for each individual, at each dose. We then plan to offer a series of treatments at the optimal dose, to achieve a more lasting response