Researchers at the Icahn School of Medicine at Mount Sinai have uncovered a novel mechanism involving potassium (KCNQ) channels in the brain that may offer a fundamentally different approach to treating major depressive disorder (MDD) in adults. In two new studies published in Molecular Psychiatry and Biological Psychiatry, the team explored how ezogabine a drug originally approved to treat epilepsy may improve depression by modulating brain activity.

Dr. James Murrough, senior author and Director of the Depression and Anxiety Center at Mount Sinai, emphasized that this research highlights the KCNQ channel complex as a promising target for depression treatment, especially given the limited understanding of its underlying neurobiology. Earlier studies in mice suggested enhancing KCNQ channel activity could help treat depression. Building on this, Dr. Murrough’s team was the first to evaluate the hypothesis in humans, with a 2021 clinical trial showing ezogabine significantly improved symptoms of depression and anhedonia.

The new papers delve into the brain imaging data from that trial. The Molecular Psychiatry study found ezogabine reduced hyperactivity in the ventral tegmental area (VTA) a dopamine-producing region tied to motivation and pleasure. First author Dr. Laurel S. Morris noted this could help improve treatment outcomes, especially for those unresponsive to standard therapies.

The second study, in Biological Psychiatry, showed that ezogabine normalized connectivity between reward centers in the brain and the posterior cingulate cortex, which is involved in self-reflection and negative emotions. Improvements in symptoms correlated with reduced connectivity between these regions.

Together, the studies suggest KCNQ channel openers may correct specific neurobiological dysfunctions tied to depression and modulate broader brain networks that regulate thought patterns like rumination. Dr. Murrough emphasized the need for larger clinical trials to confirm these promising findings.

Source: https://www.mountsinai.org/about/newsroom/2025/mount-sinai-researchers-uncover-a-promising-new-way-to-modulate-brain-cell-activity-to-potentially-treat-major-depressive-disorder-in-adults