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A Randomized, Controlled Trial of the Novel, Potent Kv7 Channel Opener Azetukalner in Individuals with Major Depressive Disorder and Anhedonia: Neural Response to Reward, Clinical Outcomes, and Safety
Open accessAbstract
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. 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 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. Additional exploratory endpoints also 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 and anhedonia symptoms, consistent with recent studies. Trial Registration: Clinicaltrials.gov ID NCT04827901
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In major depressive disorder with prominent anhedonia, ezogabine produced meaningful reductions in depressive symptoms and improved reward sensitivity in randomized and open-label studies, with parallel changes in ventral striatal connectivity and reward learning.
“In major depressive disorder with prominent anhedonia, ezogabine produced meaningful reductions in depressive symptoms and improved reward sensitivity in randomized and open-label studies, with parallel changes in ventral striatal connectivity and reward learning [259,260,261].”
From Synaptic Plasticity—Intrinsic Excitability and Antidepressant Discovery (2026) · cites this paper as [260]
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Synaptic Plasticity—Intrinsic Excitability and Antidepressant Discovery
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From Retigabine to Azetukalner: Reviving Voltage‐Gated Potassium Channels for Epilepsy Therapy
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Metadata
- Authors
- Murrough, J., Fremont, R., Neukam, P., Govindarajulu, U., Ables, J., Hameed, S., Corwin, M., Hargrove, M., Chang, H., Boukezzi, S., Kelly, C., Swann, A., Salas, R., Amarneh, D., Engelhardt, J., Weyland, A., Bagiella, E., Morris, L., & Mathew, S.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Baylor College of Medicine (US)
- BCM
- ORCID
- Venue
- Research Square
- Published
- 2025-09-15
- PMC
- PMC12458563
- OpenAlex
- W4414205348
- Cited by
- 2
- References
- 25
- Citations by year
- 2026: 2
- Type
- posted content
- Language
- en
- Open access
- green
- doi.org
- Locations
- Research Square (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (submittedVersion, cc-by)
- Funders
- U.S. Department of Veterans Affairs
- Menninger Clinic
- Georgia Clinical and Translational Science Alliance
- National Institutes of Health (UL1TR001433)
- National Institute of Mental Health (R33MH111932)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Keywords
- Kv7 potassium channels, major depressive disorder, anhedonia, reward processing, ventral striatum, positive allosteric modulators, antidepressant drug development, drug safety
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