Brain imaging studies by scientists at the Karolinska Institutet in Sweden suggest that a particular serotonin receptor may be involved in the mechanism by which low a low dose of the anesthetic drug, ketamine, has antidepressant effects in patients with hard-to-treat major depressive disorder (MDD).

“We show for the first time that ketamine treatment increases the number of serotonin 1B receptors,” said Johan Lundberg, PhD, research group leader at the department of clinical neuroscience, Karolinska Institutet, who is co-author of the team’s published paper in Translational Psychiatry. “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.”

Lundberg and colleagues reported their findings in a paper titled, “A randomized placebo-controlled PET study of ketamine’s effect on serotonin 1B receptor binding in patients with SSRI-resistant depression.”

Depression is the most common psychiatric diagnosis in Sweden, affecting one in ten men and one in five women at some point during their lives. Between 15–30% of patients are not helped by the first two therapies tried, and their depression is then designated difficult-to-treat. Studies have shown that low doses of the anesthetic drug ketamine can have a rapid antidepressant effect for some patients. A nasal spray containing ketamine has recently been approved in the United States and EU for patients with treatment-resistant depression.

“Subanesthetic dosing of ketamine has brought about a paradigm shift in the treatment of MDD, with therapeutic effects within hours rather than weeks,” the authors wrote. However, they noted, what isn’t known is exactly how ketamine works as an antidepressant. “Despite large research efforts, ketamine’s mechanism of action in MDD has still not been determined.”

The Karolinska Institutet researchers took PET (positron emission tomography) images of the brains of MDD patients, before and after ketamine treatment, to look a little more closely at the effects of the drug. Serotonin plays a key role in depression and, low levels are thought to be linked to more serious disease, so the researchers were particularly interested in whether ketamine impacted serotonin 1B receptors. “The 5-HT1B receptor is a potential target for antidepressant treatment based on studies of knockout mice, animal models for depression, MDD case–control studies, antidepressive effects of 5-HT1B receptor ligands, and of the 5-HT1B receptor action of established treatments for depression,” they commented.

“We and another research team were previously able to show a low density of serotonin 1B receptors in the brains of people with depression,” explained first author Mikael Tiger, PhD, a researcher at the department of clinical neuroscience, Karolinska Institutet. “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.”

For the first phase of the randomized, double-blind study, 30 participants with difficult-to-treat depression were randomly assigned to either a ketamine-infusion group (20 individuals) or a placebo (saline) group. The participants’ brains, were examined by PET using a radiolabel that binds specifically to serotonin 1B receptors, both before the infusion and 24–72 hours after infusion of either ketamine or saline.

In the next, open-label phase of the study, 29 individuals who elected to continue received ketamine twice a week for two weeks. More than 70% of treated patients were found to have responded to the ketamine therapy, according to a rating scale for depression. “Altogether 72% of the patients in the study responded to the full ketamine treatment, while remission was obtained for 48% of the patients,” the investigators wrote.

The results showed that for these patients with treatment-resistant depression, a reduction of depressive symptoms after ketamine treatment correlated inversely with 5-HT1B receptor binding in the ventral striatum (VST) region of the brain at baseline.

“In this study, we suggest a role for the 5-HT1B receptor in the antidepressant mechanism of action of ketamine,” they concluded. “Even though we found no statistically significant differences in overall 5-HT1B receptor binding changes between ketamine-treated patients and the placebo group, there was an increased 5-HT1B receptor binding in the hippocampus after ketamine treatment.”

Binding to this receptor reduces the release of serotonin but increases that of the 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. “Further studies examining the role of 5-HT1B receptors in the antidepressant mechanism of action of ketamine should be conducted, homing in on the 5-HT1B receptor as an MDD treatment response marker,” the researchers concluded.

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