Can ketamine lift treatment-resistant depression?

‘Ketamine is a tremendous new development in treatment for severe and treatment-resistant depression. But it is a tricky drug to use. It can work incredibly quickly – but it can wear off incredibly quickly too.’
 
That is UNSW Professor of Psychiatry Colleen Loo, based at the Black Dog Institute, who has been studying the potential of the drug in a clinical trial.  
 
At present, off-label prescribing of ketamine for major depression is possible, but uncommon, given regulatory hurdles and uncertainty around efficacy and safety.
 
The Royal Australian and New Zealand College of Psychiatrists (RANZCP) has called on medical practitioners to proceed with caution when treating patients with ketamine.
 
Professor Loo believes GPs will soon be fielding many requests for information on the drug, given that a nasal spray using the related compound esketamine is now being used in the US and EU to treat treatment-resistant depression.
 
Professor Loo told newsGP she expects the new esketamine-based antidepressant – Janssen’s Spravarto – to be approved here within a year.
 
‘Most people are expecting it will be approved – it’s hard to imagine it won’t,’ she said.
 
‘I think we are going to see a number of ketamine clinics set up in the country. That will be good for patients, to have another treatment option that can be incredibly effective. But we don’t want to present this as a miracle cure.’
 
At present, ketamine is listed as a Schedule 8 poison, meaning off-label prescribing requires regular approvals from relevant health authorities. 
 
In recent years, there has been great excitement about the potential for the drug to lift the fog of major depression in a matter of hours or days.
 
Long used recreationally as a party drug for its dissociative and hallucinogenic effects, ketamine has seen a spike in clinical interest after the first study was published 20 years ago.
 
Between 15–30% of people with depression are not helped with the first two attempts at treatment using standard SSRI antidepressants.
 
But with ketamine, a minority of users can see this treatment-resistant depression lift for months after a single dose.
 
‘We’ve had people in our trials go into remission [from depression] for months. It’s astounding,’ Professor Loo said.
 
‘But these are the super-responders, and what makes someone a super-responder, we don’t know.’
 
The problem for many people is that the effect simply doesn’t last, plunging the person back into the depths of depression.
 
‘It’s more typical that you get well and then relapse in days or weeks. That’s the reason we’re not using it up front,’ Professor Loo said.
 
But that may change.
 
In Janssen’s clinical trials, experiments with medication tapering showed that reducing treatment from twice a week to once every fortnight could keep many people over the longer term.
 
Professor Loo said that generic off-patent ketamine also works ‘extremely well’; however, she suggests that tapering could potentially be used here too.
 
Even if the new medication is approved, ketamine still needs to be approached with caution.
 
‘You need a full psychiatric evaluation and a thorough review into why you would use this, rather than something else,’ Professor Loo said.
 
‘In the literature, there are case reports of people who respond really well initially – but then see less and less effect. That puts pressure on the practitioner, who ends up prescribing it more and more frequently.
 
‘If you take someone who is depressed but stable and put them on the rollercoaster they can go up, but they can also crash in a day. I know this has happened, because I’ve had practitioners call me in this situation.
 
‘Practitioners need to be familiar with how the drug works and the pitfalls before starting. That’s really important. It can be very safe with adequate medical monitoring.’
 
In addition, ketamine is not risk-free, with potentially severe side effects such as inflammation of the liver and bladder linked to repeated high doses.
 
Melbourne University professor of psychiatry Malcolm Hopwood told newsGP that for some patients, it seemed likely that ketamine could be ‘a very significant step forward’.
 
‘We need clinical experience to define for whom and when. Depression is an enormous public health burden, so improvements are valuable,’ Professor Hopwood said.
 
Professor Hopwood added that for people with treatment resistant depression, between 40–50% of trial participants showed improvement – depending on study methodologies – which he described as ‘very promising’.
 
Like Professor Loo, Professor Hopwood believes it is likely the nasal spray will be available within the next 12 months.
 
‘Were that to happen, we would need a good education program about when, where and for whom this might be applicable,’ he said.
 
Professor Hopwood said that the most common side effect is that a small percentage of people can have elevated blood pressure, necessitating monitoring after dosing.
 
‘In countries where this is available, it has to be administered in a day patient setting where they can be observed for two to three hours after the dose,’ he said.
 
‘That limits its utility, but it’s a good safeguard to start with as we develop experience with this drug and helps alleviate concerns around drug diversion.’
 
For Professor Hopwood, a key clinical question is whether single dose or repeated doses provide better outcomes.
 
‘In many people who get the rapid boost [from a single dose], the effect is gone in around a week,’ he said.
 
‘That may offer a window to intervene with other treatments. Or is this a drug we should be giving repeatedly?
 
‘Repeated dose acute trials and maintenance trials demonstrate that the drug has efficacy and tolerability with repeated dosing. But there’s still a lot for us to learn.’
 
The way the drug actually produces its effects has been the subject of much research.
 
Swedish researchers recently found that the drug specifically targets serotonin 1B receptors in the brain, potentially opening the door to new antidepressants.
 
Binding to this receptor reduces the release of serotonin but increases dopamine release. Dopamine – part of the brain’s reward circuitry – helps produce positive emotions about life, which can often be lacking in depression, which is characterised by a lack of pleasure or positive feelings.
 
‘Without proper understanding of the mode of action, we may fail to utilise the rapid antidepressant actions of ketamine in the development of new drugs for [major depressive disorder],’ the researchers write in Translational Psychiatry.  
 
‘Compounds that could combine the striking antidepressant effects of ketamine with longer duration of effect, and hopefully without the inherent risk of abuse well known for ketamine, could further revolutionise the field.’
 
Johan Lundberg, research group leader at the institute’s Department of Clinical Neuroscience, said their work shows ‘for the first time’ that ketamine treatment increases the number of serotonin 1b receptors.
 
‘Ketamine has the advantage of being very rapid-acting, but at the same time it is a narcotic-classed drug that can lead to addiction,’ he said.
 
‘So it’ll be interesting to examine in future studies if this receptor can be a target for new, effective drugs that don’t have the adverse effects of ketamine.’
 
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