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Kv7 Channel Modulator Shows Promise for Anhedonia in MDD, With James Murrough, MD
Murrough discusses ADAA 2026 findings evaluating azetukalner in MDD with anhedonia; exploratory outcomes suggest potential benefit despite nonsignificant primary endpoints.
A phase 2 randomized trial evaluating the Kv7 potassium channel opener azetukalner in major depressive disorder (MDD) with anhedonia showed encouraging signals across secondary and exploratory measures, according to findings presented at ADAA 2026. James Murrough, MD, from the Icahn School of Medicine at Mount Sinai, discussed the results in an interview with HCPLive, highlighting preliminary antidepressant effects and a favorable tolerability profile.
The double-blind, placebo-controlled study enrolled 60 participants with MDD and anhedonia in a current depressive episode. Individuals were randomized 1:1 to receive azetukalner 20 mg once daily or placebo for 8 weeks. The primary endpoint evaluated changes in bilateral ventral striatum activity during a reward-processing task using functional MRI. Secondary outcomes included changes in depressive symptoms and anhedonia measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) and Snaith-Hamilton Pleasure Scale (SHAPS).
The trial did not demonstrate a significant difference between groups for the primary neuroimaging endpoint. However, Murrough noted that clinical symptom measures numerically favored azetukalner, and the magnitude of symptom improvement fell between a 2 – 4 difference on the MADRS.
“Although it didn't meet statistical significance, it's in the range that we would expect of drugs that have established antidepressant efficacy, so that was encouraging,” Murrough said.
Additional exploratory endpoints, including multiple assessments of anhedonia and clinician-rated global improvement, also trended in favor of azetukalner.
Safety and tolerability findings were favorable overall. Known class-related adverse effects associated with antiseizure medications were observed, including sedation, confusion, and occasional perceptual disturbances such as visual illusions. These events were generally transient, occurred primarily at night when dosing occurred, and did not typically lead to discontinuation. He noted that the cognitive or perceptual changes, although not severe enough to lead to discontinuation, need to be monitored in future trials.
Murrough emphasized that while the results remain preliminary, they contribute to growing interest in targeting reward circuitry and anhedonia in depression. Future research will focus on larger trials to clarify efficacy and further characterize safety.
“Our data from this trial encourages the further pursuit of this target, but we can't say a lot more beyond that,” Murough said. “We need more research.”
A relevant disclosure for Murrough includes Janssen Scientific Affairs, LLC.
Part 1 of the interview with Murrough can be watched here: Kv7 Channel Modulator Azetukalner May Improve Anhedonia, With James Murrough, MD, PhD
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