James Murrough, MD, PhD, from the Icahn School of Medicine at Mount Sinai.

James Murrough, MD, PhD

 Kv7 Channel Modulator Shows Promise for Anhedonia in MDD, With James Murrough, MD

A phase 2 randomized trial evaluating the Kv7 potassium channel opener azetukalner in 

 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 

 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

Fremont R, Neukam P, Govindarajulu U, et al. A Randomized, Controlled Trial Of The Novel Kv7 Channel Opener Azetukalner In Individuals With Major Depressive Disorder And Anhedonia. Poster presented at the 2026 Anxiety and Depression Association of America (ADAA) 2026 meeting in Chicago from April 9 – 11.

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Murrough discusses ADAA 2026 findings evaluating azetukalner in MDD with anhedonia; exploratory outcomes suggest potential benefit despite nonsignificant primary endpoints.

Kv7 Channel Modulator Shows Promise for Anhedonia in MDD, With James Murrough, MD

A phase 2 trial evaluating the Kv7 potassium channel opener azetukalner in individuals with 

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.

 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.”

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.

James Murrough, MD, PhD

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