DEPRESSION
June 4, 2020

How Ketamine Combats Depression

Ketamine is known to help many with treatment-resistant depression. Now we know more precisely why that is. It's a little surprising.

The anesthetic and club drug ketamine has shown promise as a treatment for hard-to-treat depression. Low doses of the drug produce rapid antidepressant effects, and a nasal spray containing ketamine has recently been approved in the United States and European Union for patients with treatment-resistant depression. How the drug works, however, has not been clear.

Now a Swedish study has identified specific serotonin receptors in the brain that are targeted by the drug and an unexpected additional mode of action, raising the prospect of a new class of antidepressants.

Using positron emission tomography, or PET, scans to take images of study participants' brains while being treated with ketamine, researchers at the Karolinska Institutet traced the effects of ketamine through a radioactive marker that binds specifically to serotonin 1B receptors. They discovered something unexpected.

“In this, the largest PET study of its kind in the world, we wanted to look at not only the magnitude of the effect but also if ketamine acts via serotonin 1B receptors,” said Mikael Tiger, researcher at the Department of Clinical Neuroscience, Karolinska Institutet. Previous research by the group and another team had already determined that the brains of people with depression had low densities of serotonin 1B receptors.

Serotonin is a neurotransmitter and one of the chemical messengers in the brain that plays a key role in depression. The surface of neurons in the brain contain 14 different kinds of receptors for it. Low levels of serotonin have long been associated with more serious depression, and SSRIs — serotonin reuptake inhibitors — which keep more of the neurotransmitter available, have been used to treat depression since the 1980s.

The study had two phases. In the first phase, 30 people with treatment-resistant depression were randomly assigned to receive either an infusion of ketamine (20 individuals) or a placebo of saline solution. Neither patients nor doctors knew who received the active substance in the randomized double-blind study until the first part of the study was over.

The researchers took an image of each participant's brain with a PET camera before the infusion with saline or ketamine and 24-72 hours afterwards.

In the second phase of the study, participants could choose to receive ketamine twice a week for two weeks or not, and 29 of the 30 participants chose to take the drug. The results of a rating scale for depression showed that over 70 per cent of those treated with ketamine responded to the drug.

The PET scans revealed that the ketamine bound to the 1B receptors and reduced the release of serotonin, it also increased the release of the dopamine, another neurotransmitter in the brain. Dopamine is connected to the brain's reward system and having more of it seems to make easier for people to experience positive feelings about life, something those with depression find hard to come by.

“We show for the first time that ketamine treatment increases the number of serotonin 1B receptors,” researcher Johan Lundberg, a research group leader in the institute's Department of Clinical Neuroscience, said. “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. So it'll be interesting to [see] if this receptor can be a target for new, effective drugs that don't have the adverse effects of ketamine.”

The study is published in Translational Psychiatry.

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