The anaesthetic drug ketamine has been shown, in low doses, to have a rapid effect on difficult-to-treat depression. Researchers at Karolinska Institutet in Sweden now report that they have identified a key target for the drug: specific serotonin receptors in the brain. Their findings give hope of new, effective antidepressants.
Depression is the most common psychiatric diagnosis in Sweden, affecting one in 10 men and one in five women at some point during their lives. Between 15% and 30% of patients are not helped by the first two attempts at therapy, in which case the depression is designated difficult to treat. Studies have shown that low doses of the anesthetic drug ketamine are rapid acting on certain sufferers, but exactly how it works is unknown. A nasal spray containing ketamine has recently been approved in the United States and European Union for patients with treatment-resistant depression.
Researchers in Sweden have now used PET scans to study the effects of ketamine treatment on the brains of study participants.
The largest PET study of its kind
“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,” says Mikael Tiger, MD, PhD, researcher in the Department of Clinical Neuroscience, Karolinska Institutet. “We and another research team were previously able to show a low density of serotonin 1B receptors in the brains of people with depression.”
In the first phase of the study, 30 people with difficult-to-treat depression were randomly assigned to either a ketamine-infusion group (20 individuals) or a placebo (saline) group. It was a randomized double-blind study, so neither patient nor doctor initially knew who received the active substance. The participants’ brains were imaged with a PET camera before the infusion and 24 to 72 hours afterward.
In the next phase, those who so wished (29 individuals) received ketamine twice a week for 2 weeks. The result was that over 70% of those treated with ketamine responded to the drug according to a rating scale for depression.
Increases the number of receptors
Serotonin plays a key role in depression and low levels are thought to be linked to more serious disease. There are 14 different kinds of receptor for this neurotransmitter on the surface of neurons. For their PET imaging, the researchers used a radioactive marker that binds specifically to serotonin 1B receptors. They found that the ketamine operated via these receptors in a formerly unknown mechanism of action. Binding to this receptor reduces the release of serotonin but increases that of another neurotransmitter called dopamine. Dopamine is part of the brain’s reward system and helps people to experience positive feelings about life, something that is often lacking in depression.
“We show for the first time that ketamine treatment increases the number of serotonin 1B receptors,” says Johan Lundberg, MD, PhD, research group leader at the Department of Clinical Neuroscience, Karolinska Institutet. “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 examine in future studies if this receptor can be a target for new, effective drugs that don’t have the adverse effects of ketamine.”
Featured image: PET images of the brain where the region hippocampus has been magnified. As shown in the images, there has been a more extensive binding to the serotonin 1B receptor (more yellow color) after treatment with ketamine (above), compared to before the treatment. For the placebo treatment (below), no difference was seen before and after treatment. Source: Mikael Tiger & Emma Veldman.