A mechanism involving potassium channels in the brain that control brain cell activity could provide a new and fundamentally different way of treating depression symptoms in adults with major depressive disorder, according to two complementary papers published recently by researchers at the Icahn School of Medicine at Mount Sinai.
In two new research articles, published in Biological Psychiatry and Molecular Psychiatry, the researchers provide new insights into how a drug called ezogabine may impact the brain to improve depression.
"Depression is a devastating public health problem, and our understanding of what changes in the brain to cause the illness is still very limited," says James Murrough, MD, PhD, 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."
Ezogabine was approved by the U.S. Food and Drug Administration in 2011 as an anticonvulsant medication for partial-onset seizures in adults with epilepsy. Previous neuroscience research in mice, conducted by researchers at The Friedman Brain Institute at Mount Sinai, suggested that increasing KCNQ channel activity could also represent a new approach to treating depression.
Building on these findings, Dr. Murrough's research team became the first to test the hypothesis in humans with depression. That study, published in the American Journal of Psychiatry in 2021, revealed ezogabine was associated with significant improvements in depression symptoms and the ability to experience pleasure (anhedonia) in patients who were treated with the drug compared to patients who received placebo. The two new papers provide details from new analyses of the human brain imaging data collected from that initial clinical trial.
The first of the two papers, published in Molecular Psychiatry , sheds light on the effects of ezogabine on a specific brain pathway. This study examined the impact of ezogabine on the ventral tegmental area (VTA) of the brain, which is involved in the release of dopamine, a neurotransmitter essential for motivation, pleasure, and reinforcement of behaviors. The results, based on functional magnetic resonance imaging, showed an important role for KCNQ channel openers like ezogabine in normalizing hyperactivity of the VTA in people with both depression and anhedonia.
"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," says Laurel S. Morris, PhD, 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."
In a second paper, published in Biological Psychiatry, research revealed that ezogabine was able to normalize connectivity between the brain's key reward regions and larger-scale brain networks including the posterior cingulate cortex, which plays a key role in internally directed thought and negative emotions. Patients who experienced greater improvement in their depression and anhedonia when treated with ezogabine showed decreased connectivity between brain reward regions and the cingulate cortex.
Together, these two complementary studies suggest that KCNQ channel openers can potentially alleviate the specific known neurobiological changes that occur in animal models of depression as well as change the function of larger brain networks that might be uniquely used in humans to regulate thought processes such as rumination.
"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 explains. "This hypothesis will require confirmation in larger clinical trials."
Dr. Murrough is a named inventor on a pending patent application for the use of ezogabine and other KCNQ channel openers to treat depression and related disorders.
