Ketamine Mechanism of Action in Depression Observed in New Study

June 30, 2020
Grace Halsey
Grace Halsey

Ketamine used in patients with treatment-resistant depression operates via serotonin 1B receptors by way of a previously unknown mechanism of action, according to a new study from Sweden.

Researchers at the Karolinksa Institutet, in Sweden, have identified a key brain target for the anesthetic ketamine’s effect on treatment-resistant major depressive disorder (MDD). Using positron emission tomography (PET), scientists were able to demonstrate that ketamine increases the number of serotonin 1B receptors in critical brain structures.

The findings were published in the journal Translational Psychiatry.

In their study the authors state that most approved and characterized antidepressants increase serotonin concentrations at the synapse, either by inhibiting reuptake or degradation of serotonin, and that low levels of the peptide are associated with more serious disease. Ketamine may share a serotonergic effect.

“We and another research team were previously able to show a low density of serotonin 1B receptors in the brains of people with depression,” said first author Mikael Tiger, researcher at the Department of Clinical Neuroscience at the Karolinska Institutet, in the news release. Noting that this is the largest PET study of its kind to date, Tiger continued, “…we wanted to look at not only the magnitude of the [ketamine] effect but also if ketamine acts via serotonin 1B receptors.”

Before/After PET

Thirty patients with MDD resistant to treatment with selective serotonin reuptake inhibitor agents were randomized to double-blind monotherapy with 0.5 mg/kg ketamine or placebo (saline) infusion. The patients were examined with the 5-HT1B receptor selective radioligand and PET before infusion and 24–72 hours after treatment.

In the open-label phase of the study, 29 individuals who elected to continue received ketamine twice a week for 2 weeks. More than 70% of treated patients were found to have responded to the ketamine therapy, based on responses to the Montgomery-Åsberg Depression Rating Scale and Patient Health Questionnaire.

“Altogether 72% of the patients in the study responded to the full ketamine treatment, while remission was obtained for 48% of the patients.”

The authors report no statistically significant difference in overall 5-HT1B receptor binding changes between ketamine-treated patients and those treated with saline but there was an increase in 5-HT1B receptor binding in the hippocampus after ketamine treatment.

The results showed that for these patients with treatment-resistant MDD, 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,” the authors concluded. The results “corroborate the 5-HT1B receptor as a biomarker for the depressive state and puts forward 5-HT1B receptor binding as a ketamine treatment response marker.”