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Ezogabine’s Antidepressant Effect Points to Novel Treatment Target
The anticonvulsant ezogabine, also known as retigabine, may offer a new approach to the treatment of depression and anhedonia, suggests a proof-of-concept trial published online ahead of print in The American Journal of Psychiatry.
The drug, which opens KCNQ2/3 potassium channels in the brain, was previously identified as a novel depression target in animal studies. In particular, researchers noticed that mice that appeared resistant to developing depression in a stress model showed increased KCNQ2/3 channel activity. When mice that had developed depressive behaviors under stress were subsequently given a drug to increase KCNQ2/3 channel activity, their depressive and anhedonic behaviors ceased.
“Our study is the first randomized, placebo-controlled trial to show that a drug affecting this type of ion channel in the brain can improve depression and anhedonia in patients. Targeting this channel represents a completely different mechanism of action than any currently available antidepressant treatment,” said study senior author James Murrough, MD, PhD, an associate professor and the director of the Depression and Anxiety Center for Discovery and Treatment at the Icahn School of Medicine at Mount Sinai, New York, New York.
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To test the effect of ezogabine in humans, researchers randomized 45 adults with depression and elevated levels of anhedonia to 5 weeks of daily ezogabine or placebo in a double-blind trial. Participants underwent clinical evaluations weekly and, at baseline and following treatment, underwent functional magnetic resonance imaging (fMRI) scans during a reward task.
At the end of the trial, participants treated with ezogabine showed significant reductions in measures of depression severity, anhedonia, and overall illness severity compared with those who received placebo, researchers reported. Improvements were observed on the Montgomery-Åsberg Depression Rating Scale, the Quick Inventory of Depressive Symptomatology-Self Report, the Snaith-Hamilton Pleasure Scale, and the Temporal Experience of Pleasure Scale –Anticipatory Subscale.
Patients in the ezogabine group showed a trend toward an increase in response to reward anticipation in the brain on fMRI, compared with those in the placebo group, but the effect did not reach statistical significance.
Nevertheless, researchers believe the findings support future studies of the KCNQ2/3 channel as a novel treatment target for depression and anhedonia.
“I think it’s fair to say that most of us on the study team were quite surprised at the large size of the beneficial effect of ezogabine on clinical symptoms across multiple measures related to depression,” Dr. Murrough said. “We are greatly encouraged by these findings and the hope they offer for the prospect of developing novel, effective treatments for depression and related disorders.”
—Jolynn Tumolo
References
Costi S, Morris LS, Kirkwood KA, et al. Impact of the KCNQ2/3 channel opener ezogabine on reward circuit activity and clinical symptoms in depression: results from a randomized controlled trial. The American Journal of Psychiatry. 2021 March 3;[Epub ahead of print].
