Ezogabine treatment for depression did not meet primary neuroimaging endpoint

Treatment with the potassium channel opener ezogabine among individuals with depression did not meet the primary neuroimaging endpoint of a randomized controlled trial published in American Journal of Psychiatry.

However, it did meet several secondary clinical endpoints.

“As an initial proof-of-concept translational study, our group conducted a 10-week open-label pilot study of the effects of ezogabine, up to 900 mg/day, on clinical symptoms and brain connectivity in patients with major depressive disorder,” Sara Costi, MD, of the Depression and Anxiety Center for Discovery and Treatment at Icahn School of Medicine at Mount Sinai, and colleagues wrote. “In that study, ezogabine showed good tolerability, and participants exhibited a significant improvement in clinical and behavioral measures of depression and anhedonia.”

In the current study, the researchers evaluated the effect of the KCNQ2/3 potassium channel modulator ezogabine on reward circuit activity and clinical outcomes among 45 individuals with depression who had elevated levels of anhedonia. A total of 21 participants received 5 weeks of 900 mg/day of ezogabine treatment and 24 received placebo. The researchers obtained participants’ functional MRI data during a reward flanker task at baseline and after treatment. They also collected depression and anhedonia clinical measures during weekly visits. Change from baseline to week 5 in ventral striatum activation during reward anticipation served as the primary endpoint. Depression and anhedonia severity measured via the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Snaith-Hamilton Pleasure Scale (SHAPS), respectively, served as secondary endpoints.

Although the study did not meet the primary neuroimaging endpoint, those who received ezogabine exhibited a numerical increase in ventral striatum response to reward anticipation after treatment vs. those in the placebo group from baseline to week 5. Ezogabine vs. placebo was linked to a significantly larger improvement in MADRS and SHAPS scores, as well as in other clinical endpoints. Participants tolerated ezogabine well, and the researchers reported no serious adverse events.

“Given the study findings, larger randomized controlled trials of KCNQ2/3 channel openers in mood disorders are warranted to explore their potential as viable treatments for depression and anhedonia,” Costi and colleagues wrote.