Anti-Seizure Drug Also Reduces Depressive Symptoms

James Murrough, MD, PhD

The anti-seizure drug ezogabine reduced the symptoms of major depressive disorder (MDD), according to the results of a new repurposing strategy study.

Researchers from the Icahn School of Medicine at Mount Sinai studied 18 adult patients with MDD in order to see how their depressive symptoms changed while taking ezogabine. The patients were otherwise healthy and did not have any seizure disorders. The patients received up to 900 mg ezogabine daily for 10 weeks.

Senior study author James Murrough, MD, PhD told MD Magazine® that the researchers identified a specific protein that resilient mice increased in their brains. When mice increased this protein, they didn’t become depressed when exposed to chronic stress. Then, they searched out drugs on the market that increased that protein in human’s brains. They found ezogabine, which happened to be an anti-seizure drug, and repurposed it for their study. There was an abundance of research about ezogabine, as it was approved by the FDA to treat seizures in 2011. However, it was not marketed as an antidepressant.

“There was no evidence this drug was antidepressant,” Murrough explained. “There’s no other antidepressant as far as we know that do anything with this protein. So, in that way, it was certainly not well-charted territory.”

The patients underwent fMRI brain scans at baseline and after the treatment period so the researchers could track any progress. After the intervention, the researchers found that the patients showed a significant reduction of MDD symptoms based on the changes in the connectivity of their reward circuit. The patients showed a 45% reduction in depression, plus a significant reduction in anhedonia (the inability to feel pleasure), as well as a significant increase in resilience, according to the study authors.

“We’re getting away from this idea of ‘give drug, increase serotonin, now you’re better,’” Murrough said. “That model never really held up. Now it’s, ‘I give drug which changes the chemical, but what circuit in the brain is that affecting?’”

Being able to link the clinical improvement back to what changed in the brain of the patients taking the drug, Murrough said, “closed the loop” for the team.

Because of this research, the team was granted an NIH grant to continue their work. A larger, placebo-controlled, two-site study is underway, and they expect to have the results within about a year.

“It’s definitely too soon for clinical recommendation,” Murrough said. “We’re very much still in a basic research mode. This is an initial hint that drugs or medicines of the future might affect the specific protein or system in the brain, this KCN2 channel, and could represent a new class of antidepressants.”

The paper, “Effects of the KCNQ channel opener ezogabine on functional connectivity of the ventral striatum and clinical symptoms in patients with major depressive disorder,” was published in Molecular Psychiatry.