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.
Avijit Chowdhury, Sarah Boukezzi, Sara Costi, Sara Hameed, Yael Jacob, Ramiro Salas, Dan V Iosifescu, Ming-Hu Han, Alan Swann, Sanjay J Mathew, Laurel Morris, James W Murrough
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引用次数: 0
Abstract
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.
期刊介绍：
Biological Psychiatry is an official journal of the Society of Biological Psychiatry and was established in 1969. It is the first journal in the Biological Psychiatry family, which also includes Biological Psychiatry: Cognitive Neuroscience and Neuroimaging and Biological Psychiatry: Global Open Science. The Society's main goal is to promote excellence in scientific research and education in the fields related to the nature, causes, mechanisms, and treatments of disorders pertaining to thought, emotion, and behavior. To fulfill this mission, Biological Psychiatry publishes peer-reviewed, rapid-publication articles that present new findings from original basic, translational, and clinical mechanistic research, ultimately advancing our understanding of psychiatric disorders and their treatment. The journal also encourages the submission of reviews and commentaries on current research and topics of interest.
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