March 27, 2019 | Joanne Morrison
Dr. Todd Gould’s Research Helps Uncover How Certain Receptors Play Role in the Mechanism of Fast-Acting Antidepressants
Effective treatment of clinical depression remains a major mental health issue, with roughly 30 percent of patients who do not respond to any of the available treatments. Researchers at the University of Maryland School of Medicine (UMSOM) have discovered a crucial receptor called mGlu2 that is critical to the mechanism of fast-acting antidepressants such as ketamine when used to treat depression.
This discovery into how this type of receptor in the brain works with fast-acting antidepressants is a critical discovery in treating depression, because existing treatments can take weeks before they are effective. A single dose of ketamine that is lower than the amount required to cause anesthesia within 24 hours can alleviates depression in some treatment-resistant patients.
Todd Gould, MD., Associate Professor in the Department of Psychiatry, together with researchers from the National Institutes of Health Intramural Research Program, discovered that this special type of glutamate receptor interacts with ketamine’s mechanism.
“Understanding the neurological response to antidepressants such as ketamine help us better understand depression and how to best treat this serious disease,” said Dr. Gould.
The effects of ketamine can last up to a few weeks. And while it is a fast-acting treatment for depression, it is not an ideal treatment because it can alter sensory perception and has a high potential for abuse. Thus, there is a tremendous need to identify the mechanisms through which ketamine mediates its antidepressant effects to help identify alternative drugs that more specifically enhance the pathway in the brain that is suppressed in depressed patients.
Necessary Receptors
Dr. Gould’s research, which was conducted in mice, showed that the mGlu2 receptor is necessary of the antidepressant activity of ketamine, and the ketamine metabolite. Researchers were able to uncover the important role this receptor plays in ketamine effectiveness by removing the gene for this receptor in mice, which in turn blocked the antidepressant effects of fast-acting treatment. Additionally, Dr. Gould’s research provided evidence that an increase in a particular form of brain activity, measured by quantitative EEG, can be used as an indicator of on-target activity of fast-acting antidepressants.
The researchers used mice to determine that (2R, 6R)-HNK’s mechanism of action involved mGlu2 receptors. Various experimental strategies were applied, including pharmacological manipulation of mGlu2 activity, genetic knockout of the mGlu2-encoding gene, behavioral tests, and cortical EEG measurements.
“Having a better understanding of how the brain reacts to Ketamine is a critical pathway toward advancing treatment of Depression,” said UMSOM Dean E. Albert Reece, MD, PhD, MBA, who is also the Executive Vice President for Medical Affairs, University of Maryland, and the John Z. and Akiko K. Bowers Distinguished Professor.
The research was funded by the National Institutes of Health, a Veterans Affairs Merit Award, a Harrington Discovery Institute Scholar-Innovator grant and the Kahlert Foundation.
About the University of Maryland School of Medicine
Now in its third century, the University of Maryland School of Medicine was chartered in 1807 as the first public medical school in the United States. It continues today as one of the fastest growing, top-tier biomedical research enterprises in the world -- with 43 academic departments, centers, institutes, and programs; and a faculty of more than 3,000 physicians, scientists, and allied health professionals, including members of the National Academy of Medicine and the National Academy of Sciences, and a distinguished recipient of the Albert E. Laser Award in Medical Research. With an operating budget of more than $1 billion, the School of Medicine works closely in partnership with the University of Maryland Medical Center and Medical System to provide research-intensive, academic and clinically-based care for more than 1.2 million patients each year. The School has over 2,500 students, residents, and fellows, and more than $530 million in extramural funding, with most of its academic departments highly ranked among all medical schools in the nation in research funding. As one of the seven professional schools that make up the University of Maryland, Baltimore campus, the School of Medicine has a total workforce of nearly 7,000 individuals. The combined School and Medical System (“University of Maryland Medicine”) has an annual budget of nearly $6 billion and an economic impact more than $15 billion on the state and local community. The School of Medicine faculty, which ranks as the 8th highest among public medical schools in research productivity, is an innovator in translational medicine, with 600 active patents and 24 start-up companies. The School works locally, nationally, and globally, with research and treatment facilities in 36 countries around the world. Visit medschool.umaryland.edu/
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