Language

English

Publication Date

10-1-2025

Journal

Biological Psychiatry

DOI

10.1016/j.biopsych.2025.02.897

PMID

40049579

PMCID

PMC12353514

PubMedCentral® Posted Date

3-4-2026

PubMedCentral® Full Text Version

Author MSS

Abstract

Background: Major depressive disorder (MDD) is a leading cause of disability worldwide, with available treatments often showing limited efficacy. Recent research suggests that 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 with MDD ages 18 to 65 years compared daily dosing with ezogabine (n= 19) with placebo (n = 21) for 5 weeks. Functional magnetic resonance imaging assessed RSFC of the brain's key reward regions (ventral caudate, nucleus accumbens) at baseline and posttreatment. 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 with placebo, which was associated with a reduction in depression severity. Improvements in anhedonia (SHAPS) and depressive symptoms (MADRS) with ezogabine compared with placebo were also associated with decreased connectivity between the reward seeds and mid/posterior cingulate regions (midcingulate cortex, 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.

Keywords

Adolescent, Adult, Aged, Female, Humans, Male, Middle Aged, Young Adult, Anhedonia, Antidepressive Agents, Carbamates, Major Depressive Disorder, Double-Blind Method, KCNQ Potassium Channels, Magnetic Resonance Imaging, Phenylenediamines, Reward, Depression, Major Depressive Disorder, Reward, Anhedonia, Neuroimaging, Resting State Functional Connectivity, Ezogabine, KCNQ (Kv7) potassium channel opener

Comments

ClinicalTrials.gov identifier: NCT03043560.

Published Open-Access

yes

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