A growing mound of scientific evidence has shown that ketamine — the painkiller, party drug, and veterinary anesthetic — can radically reduce symptoms of depression in some people. In a quest to find out how ketamine acts on depression so quickly and effectively, scientists have now scanned the brains of people who have taken ketamine and managed to identify how the drug acts on specific serotonin receptors in the brain.

In short, ketamine acts on the serotonin 1B receptors of the brain, which aids the increase of dopamine, another “feel good” neurotransmitter often associated with the brain’s reward system. 

Reported in the Nature journal Translational Psychiatry, scientists at Karolinska Institutet in Sweden carried out a randomized double-blind study on 30 people who suffer from depression that had not responded to the conventional treatment with SSRI antidepressants. For the first part of the research, 20 of the patients took a dose of ketamine while 10 were given a placebo. All the participants underwent a PET (positron emission tomography) neuroimaging before receiving the dose and then 24 to 72 hours afterward.

“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," Mikael Tiger, study first author and researcher at the Karolinska Institutet’s Department of Clinical Neuroscience, explained in a statement.

“We and another research team were previously able to show a low density of serotonin 1B receptors in the brains of people with depression.”

Off the back of this previous research, the team used a radioactive marker that binds specifically to serotonin 1B receptors and found that ketamine acts on these receptors using a mechanism never before seen. By binding to the serotonin 1B receptors, ketamine halts the release of serotonin but increases the release of dopamine. This, it's thought, could be the key to understanding ketamine's ability to enhance and maintain positive feelings in some people with depression, a condition often linked to dopamine and the role it plays with mood, motivation, and much more. 

"We show for the first time that ketamine treatment increases the number of serotonin 1B receptors," says the study's last author Johan Lundberg, research group leader at the Department of Clinical Neuroscience, Karolinska Institutet.

In the second phase of the study, 29 of the individuals received ketamine twice a week for two weeks. They concluded that over 70 percent of the treated people experienced an easing of depression symptoms and suicidal thoughts, which is in line with other clinical studies into the matter.

Now the researchers have got to grips with how ketamine targets these specific serotonin receptors, they hope to use this knowledge to refine and help further pave the way towards making ketamine a next-generation antidepressant. 

 "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,” said Lundberg. “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."