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Kv7 Channel Modulator Azetukalner May Improve Anhedonia, With James Murrough, MD, PhD
Phase 2 data presented at ADAA 2026 suggest azetukalner may improve anhedonia in MDD, even though the trial did not meet its primary neuroimaging endpoint.
A phase 2 trial evaluating the Kv7 potassium channel opener azetukalner in individuals with major depressive disorder (MDD) suggests potential clinical benefit despite failing to meet its primary neuroimaging endpoint. The findings, presented at the Anxiety and Depression Association of America (ADAA) 2026 meeting in Chicago, highlight both the potential advantages and ongoing hurdles in biomarker-based antidepressant development.
The phase 2, randomized, double-blind, placebo-controlled trial enrolled 60 adults with MDD and anhedonia who were randomized to receive either azetukalner 20 mg daily (n = 29) or placebo (n = 31) for 8 weeks. The primary endpoint was the change in ventral striatum activity during a reward task from baseline to week 8. Secondary outcomes included changes in depression severity and anhedonia using the Montgomery-Åsberg Depression Rating Scale (MADRS) and Snaith-Hamilton Pleasure Scale (SHAPS), respectively.
Ahead of the meeting, HCPLive spoke with investigator James Murrough, MD, PhD, from the Icahn School of Medicine at Mount Sinai, on the rationale for the trial. He said the research stemmed from preclinical work identifying Kv7 potassium channels, also known as KCNQ channels, as regulators of stress resilience and reward circuitry. In animal models, upregulation of these channels appeared to protect against depression-like behaviors, prompting interest in pharmacologic modulation as a novel therapeutic strategy.
“We [were] focused on anhedonia… [because it’s] a core symptom of depression,” Murrough said. “Most people with depression have this to some degree…it's thought that there are specific brain systems and behavioral tendencies that underlie anhedonia, which might be particularly amenable to targeting with specific treatments.”
Although the trial did not demonstrate a significant difference in ventral striatal activation between azetukalner and placebo, clinical measures showed a consistent pattern favoring active treatment. Improvements in both depression severity and anhedonia scales numerically favored azetukalner, and exploratory outcomes followed a similar trend. Adverse event-related discontinuation rates were low and comparable between groups.
Murrough noted that the negative neuroimaging result should be interpreted cautiously, particularly given the evolving role of biological endpoints in psychiatric trials. The use of functional imaging as a primary outcome was intended to test whether objective brain-based measures could serve as sensitive indicators of treatment response, potentially enabling faster “go/no-go” decisions in drug development.
“This is what's called the fast-fail approach,” Murrough said. “We'd like a biologically informed endpoint to quickly tell researchers that this target, although it may have been a good idea… [is] really not viable in humans for whatever reason. That was why it was the primary [endpoint], because we wanted to really stick to that…at the end of the day, in psychiatry, our best bet is looking for the pattern of clinical change. We had really no effect on the brain, but…this pattern of clinical changes was encouraging. What does this mean? To me, the use of brain imaging hasn't evolved to the point in terms of clinical trial utility, that if there's a null finding, then that tells us that there's no point in pursuing this.”
Murrough also pointed to ongoing analyses examining more complex measures of brain connectivity rather than single-region activation. Prior work with another Kv7 channel opener demonstrated that changes in functional connectivity between the ventral striatum and large-scale networks, including default mode regions, correlated with symptom improvement. Preliminary analyses from the current dataset appear to show similar patterns, though these findings are not yet published.
“Our specific questions about how it acted in the brain turned out not to be correct,” Murrough said. “Again, it was a small study, and some of the key outcomes didn't meet our statistical endpoint, so it's still considered preliminary. But when you looked at the totality of changes and the magnitude of some of the changes, particularly on this anhedonia metric, we were very encouraged that we [might] be onto something in terms of medicines that target this KCNQ channel. The study we're presenting at the poster at the meeting may be a small step on that journey.”
A relevant disclosure for Murrough includes Janssen Scientific Affairs, LLC.
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