Summary: Two new studies reveal that ezogabine, a drug originally approved for epilepsy, may alleviate depression symptoms by targeting potassium channels in the brain. Researchers found that the drug improves function in reward-related brain regions like the ventral tegmental area (VTA), which is key to motivation and pleasure.
Ezogabine also reduced abnormal connectivity between reward centers and regions associated with negative thoughts, such as the posterior cingulate cortex. These findings suggest that potassium channel openers could offer a new, biology-based treatment strategy for depression and anhedonia.
Key Facts:
- New Mechanism: Ezogabine targets KCNQ potassium channels to modulate brain activity.
- Reward Circuitry: It normalizes overactive dopamine-related brain areas in depressed patients.
- Cognitive Shift: Reduces connectivity between reward and negative emotion networks, easing symptoms.
Source: Mount Sinai Hospital
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.
About this psychopharmacology and depression research news
Author: Elizabeth Dowling
Source: Mount Sinai Hospital
Contact: Elizabeth Dowling – Mount Sinai Hospital
Image: The image is credited to Neuroscience News
Original Research: Closed access.
“Effects of KCNQ potassium channel modulation on ventral tegmental area activity and connectivity in individuals with depression and anhedonia” by James Murrough et al. Molecular Psychiatry
Closed access.
“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” by James Murrough et al. Biological Psychiatry
Abstract
Effects of KCNQ potassium channel modulation on ventral tegmental area activity and connectivity in individuals with depression and anhedonia
Up to half of individuals with depression do not respond to first-line treatments, possibly due to a lack of treatment interventions informed by neurobiology.
A novel therapeutic approach for depression has recently emerged from translational work targeting aberrant activity of ventral tegmental area (VTA) dopamine neurons via modulation of the KCNQ voltage-gated potassium channels.
In this study, individuals with major depressive disorder (MDD) with elevated anhedonia were randomized to five weeks of the KCNQ channel opener, ezogabine (up to 900 mg/day) or placebo. Participants completed functional MRI during a monetary anticipation task and resting-state at baseline and at end-of-treatment.
The clinical results were reported previously.
Here, we examined VTA activity during monetary anticipation and resting-state functional connectivity between the VTA and the ventromedial prefrontal cortex (mesocortical pathway) and ventral striatum (mesolimbic pathway) at baseline and end-of-treatment.
Results indicated a significant drug-by-time interaction in VTA activation during anticipation (F(1,34) = 4.36, p = 0.044), where VTA activation was reduced from pre-to-post ezogabine, compared to placebo.
Mesocortical functional connectivity was also higher in depressed participants at baseline compared to a healthy control group (t(56) = 2.68, p = 0.01) and associated with VTA hyper-activity during task-based functional MRI at baseline (R = 0.352, p = 0.033). Mesocortical connectivity was also reduced from pre-to-post ezogabine, compared to placebo (significant drug-by-time interaction, F(1,33) = 4.317, p = 0.046).
Together this translational work is consistent with preclinical findings highlighting VTA hyper-activity in depression, and suggesting a mechanism of action for KCNQ channel openers in normalizing this hyper-activity in individuals with both depression and anhedonia.
Abstract
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 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.
