Researchers at the Icahn School of Medicine at Mount Sinai have discovered that ezogabine, a drug originally approved for epilepsy, could provide a novel approach to treating depression by targeting potassium channels in the brain.
Two complementary studies published in Biological Psychiatry and Molecular Psychiatry reveal how ezogabine affects brain function in patients with major depressive disorder (MDD), particularly those experiencing anhedonia—the inability to feel pleasure or joy.
"Depression is a devastating public health problem, and our understanding of what changes in the brain to cause the illness is still very limited," said Dr. James Murrough, Director of the Depression and Anxiety Center for Discovery and Treatment at Mount Sinai and senior author of both studies. "Our work represents a major step in unraveling the potential role of a specific protein complex in the brain—the KCNQ channel—and how targeting it could eventually offer a significant new modality for treating depression."
A New Mechanism for Depression Treatment
Ezogabine (also known as retigabine) was approved by the FDA in 2011 as an anticonvulsant for partial-onset seizures in adults with epilepsy. The drug works by opening KCNQ potassium channels, which regulate neuronal excitability.
Previous research in mice at Mount Sinai's Friedman Brain Institute suggested that increasing KCNQ channel activity could represent a new approach to treating depression. Dr. Murrough's team was the first to test this hypothesis in humans with depression.
Their initial clinical trial, published in the American Journal of Psychiatry in 2021, showed that ezogabine was associated with significant improvements in depression symptoms and anhedonia compared to placebo. The two new studies provide detailed analyses of brain imaging data from that trial.
Normalizing Brain Reward Circuitry
The first study, published in Molecular Psychiatry, examined ezogabine's effects on the ventral tegmental area (VTA), a brain region involved in dopamine release that is essential for motivation, pleasure, and behavior reinforcement.
Using functional magnetic resonance imaging (fMRI), researchers found that ezogabine normalized hyperactivity in the VTA in people with depression and anhedonia. The drug also reduced connectivity between the VTA and the ventromedial prefrontal cortex (mesocortical pathway).
"Up to half of people with depression do not respond to first-line treatment, which may be due to the lack of interventions that directly affect the neurobiology underlying symptoms like anhedonia," explained Dr. Laurel S. Morris, Adjunct Professor of Psychiatry at the Icahn School of Medicine and first author of the paper. "By specifically targeting VTA activity and connectivity, ezogabine could open the door to decidedly improved outcomes for people who struggle daily with depression and anhedonia."
Reducing Negative Thought Patterns
The second study, published in Biological Psychiatry, revealed that ezogabine normalized connectivity between the brain's key reward regions and larger-scale brain networks, including the posterior cingulate cortex, which plays a role in internally directed thought and negative emotions.
Patients who experienced greater improvement in depression and anhedonia when treated with ezogabine showed decreased connectivity between brain reward regions and the cingulate cortex.
"These findings suggested to us that drugs targeting the KCNQ channel may trigger antidepressant effects by reducing interactions between the reward centers in the brain and those related to negative thinking and emotion," Dr. Murrough explained. "This hypothesis will require confirmation in larger clinical trials."
Clinical Implications and Future Directions
The research represents a significant advancement in understanding depression's neurobiological basis and developing targeted treatments. By focusing on KCNQ potassium channels, ezogabine offers a fundamentally different approach from current antidepressants, which primarily target monoamine neurotransmitters like serotonin and norepinephrine.
This novel mechanism could be particularly beneficial for patients with anhedonia, a symptom that often persists even when other depression symptoms improve with conventional treatments.
Sara Costi, an honorary consultant at Oxford Health NHS Foundation Trust and senior clinical researcher at the University of Oxford's Department of Psychiatry, who co-led related research, confirmed that after five weeks of treatment, ezogabine reduced brain activity related to anticipation and decreased connections between specific brain areas.
While these results are promising, larger clinical trials are needed to confirm ezogabine's efficacy and safety profile for depression treatment. Dr. Murrough is named as an inventor on a pending patent application for using ezogabine and other KCNQ channel openers to treat depression and related disorders.
For the millions of people with treatment-resistant depression, this research offers hope that a new class of medications targeting brain potassium channels could eventually provide relief where other treatments have failed.
