Source: Radio New Zealand
Ketamine was first approved for use as an anaesthetic in the 1970s. AFP / Thom Leach / Science Photo Library
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Anaesthetic, horse tranquilizer, illicit party drug; and now one of the most promising medicines for those with treatment-resistant depression, according to some New Zealand psychiatrists.
First synthesised in 1962, ketamine is by no means a new drug, but research across the last three decades has revealed its potential to help some people with stubborn mental health disorders.
Now a team are hoping that their New Zealand-developed tablet will meet regulatory approval in the US, to help this treatment become more widely available.
The kick-starter Yale study
Ketamine was first approved for use as an anaesthetic in the 1970s, but it wasn’t until the late 1990s that Yale psychiatrist Dr John Krystal led a study investigating its effects on people with major depression.
The work was published in 2000 and showed that even single doses of ketamine could result in rapid improvements for some of these patients.
“It was an absolute revelation” says Professor Paul Glue of the University of Otago. “It’s having an effect on the glutamate system in your brain. That is the most common type of neurotransmitter in the brain. But up till that point nobody had even thought about there being something abnormal with glutamate transmission in the brain.”
Because it was so new and unexpected, psychiatrists and researchers in the field were sceptical, but then five years later another, larger study showed the same effects. “So it wasn’t a fluke,” says Paul.
Having researched antidepressants in the UK and worked on them in the pharamceutical industry, Paul returned to New Zealand in 2008 and began investigating ketamine himself.
One of the first projects he ran in Dunedin involved injecting ketamine in patients with terminal cancer who were also depressed. Some of the results astounded him, “the first patient that we admitted had been depressed on and off for probably 15 years… and within an hour of dosing she was well. And if we continued dosing every week, she stayed well.”
Further studies across Dunedin and Christchurch followed, revealing a potential for ketamine to help patients with treatment-resistent OCD, PTSD and anxiety.
But while 60-70 percent of patients seemed to be responding positively to the ketamine in terms of their symptoms, there was a major downside to the ketamine injections – the considerable side effects.
The game-changer metabolites study
“People are very spaced out for a half hour after the injection” says Paul.
“They have to sit in a big lazy boy… often they’re very sleepy as well. And having those sort of side effects means it has to be given in a clinic where you’ve got medical and nursing supervision.”
This means treatment that is potentially offputting and unpleasant for patients, and time-consuming and expensive for health professionals to administer.
But some research in mice was about to show up that would change the game.
A 2016 University of Maryland study demonstrated that it wasn’t ketamine that was doing the heavy lifting when it came to improving depressive symptoms, but its metabolites – the products released when ketamine is broken down in the liver.
Researchers, such as Paul, switched to trialling oral doses of ketamine instead of injections. They found that although the response was slower, the oral dosing did work for a similar number of patients.
This prompted Paul to begin discussions with New Zealand healthcare company Douglas Pharmaceuticals about developing a ketamine tablet.
And the early results were positive, says Paul “really from the first time we dosed it in healthy volunteers and then in a small group of patients, it performed brilliantly.”
WLADIMIR BULGAR/SCIENCE PHOTO LI
The regulatory hurdles
Named R-107, the idea is that this slow-release tablet could be taken by patients at home, once or twice a week, to keep patient’s ketamine metabolites levels high for as long as possible.
To give it the best chance to get to market a San Francisco-based company, Tasman Therapeutics, was spun out. It’s tasked with raising funds for and running the next batch of clinical trials, to gather the evidence needed to get Food and Drug Administration (FDA) approval. The FDA approves drugs for use in the United States, explains Paul, and in terms of economic return that’s the best market to be in.
But they want to be assured of the efficacy and safety of the tablets first. Ketamine is also illicitly used in many countries as a party drug, including here in New Zealand.
Repeated high doses can lead to bladder damage, and addiction.
With their study design now approved by the FDA, Paul is hopeful they can find the investment to get the trials underway. If they go well and the drug proven safe and effective, Paul estimates it could be approved in the US in about two and a half years, with New Zealand approval likely following a few months after.
Treatment-resistant depression is defined as depression that has not responded to two or more treatments.
Over one in four of us will experience moderate to high anxiety or depression in our lives. About a third of people with depression, and about half of people with anxiety, will not respond to treatment, says Paul. It adds up to an estimated 300,000 New Zealanders, 60-70 percent of which would likely respond to ketamine treatment.
This, Paul says, is what motivates him.
“These people often, when they’ve failed a couple of treatments or a course of psychotherapy, will get discharged back to the GP and will sit at home… not be able to function.”
“And the options for them are pretty grim. So being able to help this group of patients would be massive.”
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– Published by EveningReport.nz and AsiaPacificReport.nz, see: MIL OSI in partnership with Radio New Zealand
