Researchers are identifying the brain ion channel as a new way of treating depression

Researchers from the Icahn School of Medicine at Mount Sinai have identified a drug that works against depression with a completely different mechanism than existing treatments.

Their study showed that ezogabine (also known as retigabine), a drug that opens KCNQ2 / 3 potassium channels in the brain, is associated with significant improvements in symptoms of depression and anhedonia in patients with depression. . Anhedonia is the reduced ability to experience pleasure or lack of reactivity to pleasurable stimuli; it is a major symptom of depression and is associated with worse outcomes, a poor response to antidepressant medication, and an increased risk for suicide.

Ezogabine was approved by the U.S. Food and Drug Administration in 2011 as an anticonvulsant for the treatment of epilepsy but has not previously been studied in depression. The results of the research, published March 3 in the American Journal of Psychiatry, provide initial evidence in humans for the KCNQ2 / 3 channel as a new target for novel drug detection for depression and anhedonia.

“Our study is the first randomized, placebo-controlled trial to show that a drug that affects this type of ion channel in the brain can improve depression and anhedonia in The targeting of this channel represents a completely different mode of action than any currently available antidepressant treatment, “said James Murrough, MD, PhD, Associate Professor of Psychology. , and Ignorance, Director of the Center for Depression and Anxiety for Detection and Treatment at Icahn School of Medicine at Mount Sinai, and senior author of the paper.

The new drug target, the KCNQ2 / 3 channel, is a member of a large family of ion channels called the KCNQ (or Kv7) family that are important regulators of brain cell excitability and function in the central nervous system. These channels affect brain cell activity by controlling the flow of electrical charge over the cell membrane in the form of potassium ions (K +). Researchers at Mount Sinai, including study co-author Ming-Hu Han, PhD, Professor of Pharmacological Sciences, and Neuroscience, had previously conducted a series of studies in mice showing the role of changes in potassium channel KCNQ2 / 3 are important in determining whether the animals exhibit depression and anhedonic-like behavior after persistent stress in an experimental model of depression. In particular, mice that appear to be resistant to the development of depression against stress show an increase in KCNQ2 / 3 channels in the brain.

“We looked at the enhanced activity of the KCNQ channel as a molecular device that can be flexible in stress and depression,” said Dr. Han, who also found that if he took a drug that could activate this channel, such as ezogabine, elevated to mice that had developed depression in the weight model, the mice no longer showed the depression and anhedonic behavior; in other words, the drug acted as an antidepressant.

The current study was a two-site, double-blind, randomized, placebo-controlled clinical trial designed as a preliminary test on the notion that elevated KCNQ2 / 3 channel activity in the brain is a novel operative approach for treatment of depression. Forty-five adult patients diagnosed with depressive disorder were assigned to a five-week treatment period with daily doses of ezogabine or a placebo match. All participants underwent clinical evaluations and magnetic resonance imaging (fMRI) assessments during reward activity at baseline and at the end of the treatment period. Compared with placebo-treated patients, those treated with ezogabine showed a significant and significant reduction in several key stages of depression, anhedonia, and severity of the disease. For example, significant improvements after treatment with ezogabine compared with placebo were observed using the Montgomery-Asberg Low Evaluation Scale (MADRS), the Rapid Index of Symptomatology-Self Depressive (QIDS-SR), the Throat- Hamilton (SHAPS), and the Temporary Knowledge Scale (TEPS) – Strategic Subscale. The ezogabine group also showed a trend toward an increase in response to reward expectancy in the brain compared with placebo although this effect did not reach statistical significance.

“The basic vision of Dr. Han’s group that a drug that largely mimics a stress-inducing mechanism in the brain to represent a completely new approach to the treatment of depression was very inspiring to us,” he said. Dr. Murrough.

In collaboration with Dr. Han, Dr. Murrough conducted a series of studies in patients with depression to begin testing whether the observations in mice could be translated into humans. An initial open-label (or placebo) study in patients with depression led by Dr. Murrough provided initial evidence that ezogabine may improve symptoms of depression and anhedonia in a way that was related to changes in brain function.

“I think it’s fair to say that most of us on the study team were amazed at the sheer magnitude of the beneficial effect of ezogabine on clinical symptoms across a number of depression-related measures. We are very encouraged by these decisions and the hope they offer for developing new, effective treatments for depression and related disorders. as more than a third of people with depression are properly treated with currently approved medication. “

###

This research was supported by the National Institute of Mental Health. Additional funding was provided by the Friedman Brain Institute at Icahn School of Medicine at Mount Sinai and the Ehrenkranz Laboratory for Human Sustainability, part of the Center for Depression and Anxiety for Detection and Treatment at Icahn School of Medicine at Mount Sinai.

Study authors James Murrough, MD, PhD and Ming-Hu-Han, PhD, have named entrepreneurs on an upcoming patent application for the use of ezogabine and other KCNQ channel openings to treat depression and comorbid disorders related treatment.

About the Mount Sinai health system

Mount Sinai Health System is the largest academic medical system in New York City, comprising eight hospitals, a major medical school, and a large network of mobile practices throughout the New York area. Mount Sinai is a national and international source of unparalleled education, translational discovery and discovery, and collaborative clinical leadership ensuring we deliver the highest quality care – from prevention to treatment of the worst and most complex human diseases. The Health System comprises more than 7,200 physicians and features a strong and growing network of multidisciplinary services, including over 400 mobile use spaces across five urban areas. New York, Westchester, and Long Island. Mount Sinai Hospital is ranked 14th US News and World Reportthe “Honor Roll” of the Top 20 Hospitals in the Country and Icahn School of Medicine as one of the top 20 medical schools in the country. Mount Sinai Health System hospitals are consistently ranked regionally by specialty and our physicians are in the top 1% of physicians nationally by US News and World Report.

For more information, visit https: //www.mountsinai.org or find Mount Sinai on Facebook, Twitter and YouTube.