Anesthetic drug Ketamine uses serotonin receptors to relieve depression

By Dr. Liji Thomas, MDMay 31 2020

Ketamine is a drug used to induce general anesthesia. It has also been found to act rapidly to relieve depression that has failed to respond to two other rounds of medication. A new study published in the journal Translational Psychiatry in May 2020 reports the mechanism of action of the drug, which was hitherto unknown. This could help find new ways to treat this debilitating and sometimes fatal condition.

The study comes from Sweden, where depression affects 10% of men and 20% of women. This makes it the most frequently diagnosed mental disorder in this country. The treatment of this condition fails after two rounds or more in about 15-30% of patients. At this point, the depression is termed difficult-to-treat.

Study: A randomized placebo-controlled PET study of ketamine´s effect on serotonin1B receptor binding in patients with SSRI-resistant depression. Image Credit: MilletStudio / Shutterstock

Ketamine and Depression

Ketamine is a non-competitive N-methyl D-aspartate (NMDA) receptor antagonist. It is a dissociative drug, meaning it disrupts the user's relationship with sensory perceptions.

Higher doses can cause breathing to slow dangerously, produce muscle spasms, dizziness, loss of balance, and slurring, with severe confusion. Hallucinations described as "out of body" experiences occur when emerging from the drug, which can be very distressing.

Treatment-resistant depression that has been found to respond quickly to ketamine at low doses. This has led to the approval of a nasal ketamine-containing spray in the USA and EU for this condition. Despite this knowledge, little has been known about how it acts.

Another researcher, Johan Lundberg, says, "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."  

The Ketamine Study: What Was Done?

In the current study, researchers used positron emission tomography (PET) to image the brains of depression patients on ketamine treatment. Calling it "the largest PET study of its kind in the world," researcher Mikael Tiger says their focus was on finding how much of an effect ketamine has on depression, as well as trying to identify the role of serotonin 1B receptors.

Earlier research, in which Tiger and his team had collaborated, shows that the brains of people with depression presented low levels of these receptors.

In the first step, the researchers performed a randomized double-blinded controlled study on 30 patients with treatment-resistant depression. They divided them at random into two groups. One group of 20 received ketamine infusions. The other group of 10 received only saline infusions.

Neither the doctor treating them nor the patients knew who was getting what. Both before and after infusions, the patients underwent brain imaging using the PET cameras. This was repeated after 24-72 hours after the completion of the procedure.

The second part of the study involved voluntary participation. This phase included 29 individuals who got ketamine infusions twice weekly for two weeks.

Ketamine Acts by Boosting Serotonin 1B Receptors

When the results were assessed, the doctors found that more than 70% of the patients who had received ketamine experienced relief of depressive symptoms, as recorded using a rating scale for depression.

The researchers found that the therapeutic effects of ketamine were due to inhibition of serotonin action. Serotonin is a neurochemical which acts like a brain hormone, in part. It is best known for its significant contribution to triggering depression. Low levels of this hormone are thought to be associated with more severe depression.

Neurons have 14 serotonin receptor subtypes on their cell surfaces. However, in the current study, the researchers used a more specific molecule, a radioactive substance that binds only to serotonin 1B receptors. They thus discovered a novel mechanism of action for ketamine.

The binding of the serotonin 1B receptor causes serotonin levels to go down, while another neurochemical called dopamine, which also transmits nerve signals, is increased. Dopamine is a neurotransmitter related to the reward circuits of the brain, which means its levels cause more positive feelings or mood elevation. This feature is highly desirable in depression.

So how does ketamine do what it does? Apparently, it increases the number of serotonin 1B receptors. This is the first time this effect has been observed, and it explains the quick and favorable action of ketamine.

This discovery could trigger more research on whether the serotonin 1B receptor offers a target for newer drugs that may avoid ketamine's adverse effects even while maintaining its rapid mood-lifting capability.