Ezogabine Modulates Brain Circuits To Reduce Depression Symptoms
Ezogabine, a potassium channel opener, may ease depression by normalizing brain reward circuit activity.
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Researchers at the Icahn School of Medicine at Mount Sinai have identified a potential mechanism involving potassium channels in the brain that could represent a novel way to alleviate symptoms of major depressive disorder in adults.
Insights from two complementary studies
Two recent papers, published in Biological Psychiatry and Molecular Psychiatry, explore how the drug ezogabine influences brain activity related to depression. Ezogabine, approved by the U.S. Food and Drug Administration in 2011 for treating partial-onset seizures in epilepsy, targets KCNQ potassium channels that regulate neuronal excitability.
KCNQ potassium channels
KCNQ channels are a family of potassium ion channels found in neurons that help control electrical activity by regulating the flow of potassium ions across cell membranes. They influence neuronal excitability and firing rates, making them important for brain function and potential targets for neurological and psychiatric disorders.
Previous animal research suggested that activating KCNQ channels might provide antidepressant effects. Building on this, the Mount Sinai team conducted a clinical trial, first reported in 2021, demonstrating that ezogabine improved depression symptoms and reduced anhedonia, the diminished ability to experience pleasure, in people with major depressive disorder compared with placebo. The new studies provide further analysis of brain imaging data from that trial.
Effects on the brain’s reward system
The study published in Molecular Psychiatry examined the impact of ezogabine on the ventral tegmental area (VTA), a brain region critical for dopamine release. Dopamine is a neurotransmitter involved in motivation and reward. Using functional magnetic resonance imaging, researchers observed that ezogabine normalized hyperactivity in the VTA of individuals with depression and anhedonia. This suggests KCNQ channel openers may help correct dysfunctional reward processing associated with these symptoms.
Connectivity changes in brain networks
The second paper, published in Biological Psychiatry, investigated how ezogabine affects connectivity between brain regions involved in reward and larger brain networks, including the posterior cingulate cortex. This area plays a role in self-referential thought and negative emotions. The analysis showed that patients who experienced greater improvements in depression and anhedonia after ezogabine treatment had decreased connectivity between reward regions and the cingulate cortex. These findings indicate that ezogabine may modulate communication between brain networks involved in negative thinking and emotion regulation.
Implications for depression treatment
Together, the studies suggest that targeting KCNQ potassium channels could modify brain circuits implicated in depression and anhedonia. The researchers propose that reducing interactions between reward centers and regions involved in negative emotion might underlie the antidepressant effects of ezogabine. Further clinical trials with larger patient groups will be needed to confirm these findings.
Reference: Morris LS, Costi S, Hameed S, et al. Effects of KCNQ potassium channel modulation on ventral tegmental area activity and connectivity in individuals with depression and anhedonia. Mol Psychiatry. 2025. doi: 10.1038/s41380-025-02957-7
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