A randomized, controlled experimental medicine study of the novel Kv7 channel opener azetukalner in individuals with major depressive disorder and anhedonia
Abstract
Major Depressive Disorder (MDD) is a common and debilitating disease. Kv7 potassium channels are relevant to reward processing and represent a novel target for depression and anhedonia. Azetukalner is a positive allosteric modulator of Kv7 channels. This phase II, randomized, double-blind, placebo-controlled trial assessed changes in brain reward function, clinical outcomes, and safety following treatment with azetukalner or placebo in individuals with MDD and anhedonia. The study included 60 participants with MDD and anhedonia in a current major depressive episode. Participants were randomized 1:1 to receive azetukalner (20 mg orally once daily with food) or placebo for 8 weeks. The primary endpoint was change in bilateral ventral striatum (VS) activity assessed by functional MRI (fMRI) during a reward task from baseline to week 8. Secondary endpoints included changes in depression severity and anhedonia measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) and Snaith-Hamilton Pleasure Scale (SHAPS). Of 60 participants, 29 were randomized to azetukalner and 31 to placebo. There was no significant difference in VS response to reward anticipation between groups. Compared to placebo, azetukalner was associated with numerical benefit on the MADRS and SHAPS that did not reach statistical significance. Most exploratory endpoints numerically favored azetukalner over placebo. Discontinuation rates due to adverse events were low and did not differ across groups. Despite not meeting the primary neuroimaging endpoint, secondary and exploratory outcomes suggested potential improvement in depressive symptoms and anhedonia. Trial Registration: Clinicaltrials.gov ID NCT04827901.
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BibTeX
@article{fremont2026randomized,
title = {{A randomized, controlled experimental medicine study of the novel Kv7 channel opener azetukalner in individuals with major depressive disorder and anhedonia}},
author = {Rachel Fremont and Philipp T. Neukam and Usha S. Govindarajulu and Jessica L. Ables and Sara Hameed and Marcella Corwin and Mackenzie B. Hargrove and Helena L. Chang and Sarah Boukezzi and Chris A. Kelly and Alan Swann and Ramiro Salas and Dania Amarneh and Julia Engelhardt and Andreas Weyland and Emilia Bagiella and Laurel Morris and Sanjay J. Mathew and James W. Murrough},
journal = {Translational Psychiatry},
year = {2026},
month = oct,
doi = {10.1038/s41398-026-04431-6},
url = {https://www.nature.com/articles/s41398-026-04431-6},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - A randomized, controlled experimental medicine study of the novel Kv7 channel opener azetukalner in individuals with major depressive disorder and anhedonia
AU - Rachel Fremont
AU - Philipp T. Neukam
AU - Usha S. Govindarajulu
AU - Jessica L. Ables
AU - Sara Hameed
AU - Marcella Corwin
AU - Mackenzie B. Hargrove
AU - Helena L. Chang
AU - Sarah Boukezzi
AU - Chris A. Kelly
AU - Alan Swann
AU - Ramiro Salas
AU - Dania Amarneh
AU - Julia Engelhardt
AU - Andreas Weyland
AU - Emilia Bagiella
AU - Laurel Morris
AU - Sanjay J. Mathew
AU - James W. Murrough
PY - 2026
DA - 2026/10/07
JO - Translational Psychiatry
DO - 10.1038/s41398-026-04431-6
UR - https://www.nature.com/articles/s41398-026-04431-6
AB - Major Depressive Disorder (MDD) is a common and debilitating disease. Kv7 potassium channels are relevant to reward processing and represent a novel target for depression and anhedonia. Azetukalner is a positive allosteric modulator of Kv7 channels. This phase II, randomized, double-blind, placebo-controlled trial assessed changes in brain reward function, clinical outcomes, and safety following treatment with azetukalner or placebo in individuals with MDD and anhedonia. The study included 60 participants with MDD and anhedonia in a current major depressive episode. Participants were randomized 1:1 to receive azetukalner (20 mg orally once daily with food) or placebo for 8 weeks. The primary endpoint was change in bilateral ventral striatum (VS) activity assessed by functional MRI (fMRI) during a reward task from baseline to week 8. Secondary endpoints included changes in depression severity and anhedonia measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) and Snaith-Hamilton Pleasure Scale (SHAPS). Of 60 participants, 29 were randomized to azetukalner and 31 to placebo. There was no significant difference in VS response to reward anticipation between groups. Compared to placebo, azetukalner was associated with numerical benefit on the MADRS and SHAPS that did not reach statistical significance. Most exploratory endpoints numerically favored azetukalner over placebo. Discontinuation rates due to adverse events were low and did not differ across groups. Despite not meeting the primary neuroimaging endpoint, secondary and exploratory outcomes suggested potential improvement in depressive symptoms and anhedonia. Trial Registration: Clinicaltrials.gov ID NCT04827901.
SN - 2158-3188
ER -