Depression: FDA Checks Out Ketamine

25. October 2016
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The FDA is currently reviewing a fast-track procedure for whether ketamine can be approved for the treatment of depression. Several studies demonstrate effectiveness – especially in patients who do not respond to conventional therapies.

As Janssen Pharmaceutical announced in August, the US-American Food and Drug Administration is currently through an expedited process reviewing whether ketamine can be officially approved for the treatment of depressions. In studies ketamine was able to relieve depression within a few hours with some patients – among these therapy-resistant cases. With its approval there would be available to psychiatrists an entirely new therapeutic option for the treatment of major depression.

Ketamine – evaluated and disreputable

As far as drug use goes ketamine is actually old hat: synthesised for the first time in 1962, in 1970 it obtained approval in the US for use in humans. US Army doctors valued the agent particularly during the Vietnam War period because of its good analgesic and sedative effects. Since then it has all over the world belonged to the set of standard medications in emergency medicine and in veterinary medicine as well; it is here to stay as part of injection-based anaesthesia. Due to its dissociative properties and hallucinogenic side effects, ketamine has however also come into disrepute as an intoxicant, sometimes also being referred to as a “date rape drug”.

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People with depression need quick help

For several years, international researchers have been examining the question of whether ketamine might also be suited to use in treating depression. Such a possibility was shown by a small, randomised 2006 US study of treatment-refractory depression patients where a mood-lifting effect was demonstrated within a few hours after a single injection of the drug, and caused quite a stir at the time. Since then, numerous other studies of the effect of ketamine on depression sufferers followed.

In particular, the rapid relief of symptoms makes this narcotic so attractive for potential use against depression, because most of the antidepressant drugs available exert their effect only after weeks – too long, says Roland Duman, psychiatrist at Yale School of Medicine. “Ketamine has great potential here – it could revolutionise the treatment of depression, especially in suicidal patients who cannot wait all that long”, is Dumans assessment. The risk of suicide, especially during the first nine days of therapy, is considered high.

Key to success: mechanism of action of ketamine

Before ketamine is to be employed as a possible alternative treatment for depression, researchers still however need to find out more about its mode of action in the brain. “We do not know exactly how it works”, says Dr. Julie Coffman from the Department of Internal and palliative Medicine of the OHIO Health Riverside Methodist Hospital. With a deeper knowledge of the mechanism of action, modified molecules could however eventually be synthesised whereby side effects such as hallucinations and addiction would be absent.

Previously, researchers believed that ketamine blocked the NMDA receptors in the brain, but what precisely triggers the antidepressant effect they did not know. Now things have moved one step further, because in May this year a study from the School of Medicine University in Baltimore, Maryland, published in Nature, delivers new insights. The scientists discovered in experiments done on mice that it’s not ketamine itself, but its metabolite (2R, 6R)-hydroxynorketamine which brings about the antidepressant effect. They also found that blocking the AMPA receptor – and not the NDMA receptors as previously assumed – was responsible for this. The very promising element in the investigation was that the animals seemed neither to be impaired in their sensory perception, nor showed evidence of addictive behaviour.

Scientists from the Charité in Berlin are also currently looking for a way in which ketamine could be used without having to accept major side effects. Study leader Prof. Dr. Malek Bajbouj for instance is investing efforts in a new route of administration: “From June we hope to start a Germany-wide study, in which for the first time a ketamine nasal spray will be used to treat depression”, says the head of the Centre for Neurology, Neurosurgery and Psychiatry at the Charité.

USA wants to act quickly

In the USA they want to get things done quickly. Janssen is presently working in clinical studies on two indications for ketamine: one being in treatment-resistant depression, another being depression involving suicidal thoughts. The company intends to present results of the phase III trials by 2018 and file them with the FDA. Most significant first and foremost is the rapid onset of action of ketamine in contrast to other antidepressants.

The medical director for ketamine research carried out at Janssen, psychiatrist Dr. David Hough, emphasises the need for the active agent by way of numbers: “About 41,000 people die each year through suicide in the United States”, which is more than die annually from breast cancer, says Hough. And the suicide rate is climbing, he adds.

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