Summary: Ezogabine, an FDA approved anti-convulsant, appears to significantly reduce symptoms in those with major depressive disorder.
Source: Mount Sinai Hospital.
Researchers from the Icahn School of Medicine at Mount Sinai found that patients with Major Depressive Disorder (MDD) exhibited a significant reduction of depressive symptoms after being treated with ezogabine, an FDA approved drug used to treat seizures.
After treatment, patients showed a 45 percent reduction in depression, a significant reduction in anhedonia, the inability to feel pleasure; and a significant increase in resilience.
This is the first study to suggest that ezogabine, part of a class of drugs known as potassium channel openers, may have an antidepressant affect in humans.
The review will be published online on Thursday November 1st at 9AM EST , in Molecular Psychiatry.
Major depressive disorder (MDD) impacts 15 million Americans and is the leading cause of disability, yet current treatments possess limited efficacy. A new therapeutic direction is emerging from the increased understanding of natural resilience as an active stress-coping process. It is known that potassium channels in the brain’s reward system are an active mediator of resilience.
In a previous study, the Mount Sinai research team tested ezogabine, also known as retigabine, a potassium channel opener, in mice. They found that that ezogabine had significant antidepressant effects in the mice, expressed by two common measures in rodents: increased social interactions and preferences for natural rewards.
In this study, 18 medication free individuals with MDD experiencing a major depressive episode received up to 900 mg of ezogabine daily during 10 weeks in an open label study to determine if the drug significantly engaged their reward system. Resting state functional magnetic resonance imaging data revealing the connectivity of the reward system were collected at baseline and post-treatment to reexamine brain reward circuitry. After treatment with ezogabine, subjects exhibited a significant reduction of depressive symptoms measured by the the change in connectivity of their reward system.
“The results of this study are exciting because we haven’t had a new medicine to treat depression in decades,” said the study’s senior author, James Murrough, MD, PhD, Director of the Mood and Anxiety Disorders Program at the Icahn School of Medicine at Mount Sinai. “Most antidepressants are in the same class of drugs and work by increasing serotonin. Our research suggests a different molecular target that works through other brain mechanisms and could be helpful for patents.”
The research team at Mount Sinai is currently conducting a larger multi-site double blind trial of ezogabine in patients with depression funded by the National Institute of Mental Health to further determine its efficacy in treating depression.
“We know that patients with depression become depressed for different reasons, and we’ve been stuck in a one size fits all treatment for a long time,” said Dr. Murrough. “A new class of medicines could give us an opportunity to treat patients based on the specific underlying cause of their disease.”
Source: Rachel Zuckerman – Mount Sinai Hospital
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Original Research: Abstract for “Effects of the KCNQ channel opener ezogabine on functional connectivity of the ventral striatum and clinical symptoms in patients with major depressive disorder” by Aaron Tan, Sara Costi, Laurel S. Morris, Nicholas T. Van Dam, Marin Kautz, Alexis E. Whitton, Allyson K. Friedman, Katherine A. Collins, Gabriella Ahle, Nisha Chadha, Brian Do, Diego A. Pizzagalli, Dan V. Iosifescu, Eric J. Nestler, Ming-Hu Han & James W. Murrough in Molecular Psychiatry. Published November 1 2018.
Effects of the KCNQ channel opener ezogabine on functional connectivity of the ventral striatum and clinical symptoms in patients with major depressive disorder
Major depressive disorder (MDD) is a leading cause of disability worldwide, yet current treatment strategies remain limited in their mechanistic diversity. Recent evidence has highlighted a promising novel pharmaceutical target—the KCNQ-type potassium channel—for the treatment of depressive disorders, which may exert a therapeutic effect via functional changes within the brain reward system, including the ventral striatum. The current study assessed the effects of the KCNQ channel opener ezogabine (also known as retigabine) on reward circuitry and clinical symptoms in patients with MDD. Eighteen medication-free individuals with MDD currently in a major depressive episode were enrolled in an open-label study and received ezogabine up to 900 mg/day orally over the course of 10 weeks. Resting-state functional magnetic resonance imaging data were collected at baseline and posttreatment to examine brain reward circuitry. Reward learning was measured using a computerized probabilistic reward task. After treatment with ezogabine, subjects exhibited a significant reduction of depressive symptoms (Montgomery–Asberg Depression Rating Scale score change: −13.7 ± 9.7, p < 0.001, d = 2.08) and anhedonic symptoms (Snaith–Hamilton Pleasure Scale score change: −6.1 ± 5.3, p < 0.001, d = 1.00), which remained significant even after controlling for overall depression severity. Improvement in depression was associated with decreased functional connectivity between the ventral caudate and clusters within the mid-cingulate cortex and posterior cingulate cortex (n = 14, voxel-wise p < 0.005). In addition, a subgroup of patients tested with a probabilistic reward task (n = 9) showed increased reward learning following treatment. These findings highlight the KCNQ-type potassium channel as a promising target for future drug discovery efforts in mood disorders.