Effects of the KCNQ (Kv7) Channel Opener Ezogabine on Resting-State Functional Connectivity of Striatal Brain Reward Regions, Depression and Anhedonia in Major Depressive Disorder: Results from a Randomized Controlled Trial.

BACKGROUND: Major depressive disorder (MDD) is a leading cause of disability worldwide, with available treatments often showing limited efficacy. Recent research suggests targeting specific subtypes of depression and understanding the underlying brain mechanisms can improve treatment outcomes. This study investigates the potential of the potassium KCNQ (Kv7) channel opener ezogabine to modulate the resting-state functional connectivity (RSFC) of the brain's reward circuitry and alleviate depressive symptoms, including anhedonia, a core feature of MDD. METHODS: A double-blind, randomized, placebo-controlled clinical trial in individuals aged 18 to 65 with MDD compared daily dosing with ezogabine (n=19) to placebo (n=21) for five weeks. Functional magnetic resonance imaging (fMRI) assessed RSFC of the brain's key reward regions (ventral caudate, nucleus accumbens) at baseline and post-treatment. Clinical symptoms were measured using the Snaith-Hamilton Pleasure Scale (SHAPS), Montgomery-Åsberg Depression Rating Scale (MADRS), and other clinical symptom scales. RESULTS: Ezogabine significantly reduced RSFC between the reward seeds and the posterior cingulate cortex (PCC)/precuneus compared to placebo, which was associated with a reduction in depression severity. Improvements in anhedonia (SHAPS) and depressive symptoms (MADRS) with ezogabine compared to placebo were also associated with decreased connectivity between the reward seeds and mid/posterior cingulate regions (MCC, PCC, precuneus). CONCLUSIONS: The findings suggest that ezogabine's antidepressant effects are mediated through modulation of striatal-mid/posterior cingulate connectivity, indicating a potential therapeutic mechanism for KCNQ-targeted drugs for MDD and anhedonia. Future studies should validate these results in larger trials. CLINICALTRIALS: gov identifier: NCT03043560.