An excess of one type of serotonin receptor in the center of the brain may explain why antidepressants fail to relieve symptoms of depression for 50 percent of patients, a new study from researchers at Columbia University Medical Center shows.

The study in a mouse model is the first to find a causal link between receptor number and antidepressant treatment and may lead to more personalized treatment for depression, including treatments for patients who do not respond to antidepressants and ways to identify these patients before they undergo costly, and ultimately, futile therapies.

The research, led by Rene Hen, PhD, professor of pharmacology in the Departments of Psychiatry and Neuroscience at Columbia University, and a researcher the New York State Psychiatric Institute, appears in the January 15 issue of the journal Neuron.

Most antidepressants – including the popular SSRIs – work by increasing the amount of serotonin made by cells - called raphe neurons - deep in the middle of the brain. Serotonin relieves symptoms of depression when it is shipped to other brain regions.

But too many serotonin receptors of the 1A type on the raphe neurons sets up a negative feedback loop that reduces the production of serotonin, Dr. Hen and his colleagues discovered

“The more antidepressants try to increase serotonin production, the less serotonin the neurons actually produce, and behavior in mice does not change,” Dr. Hen says.

Dr. Hen and his colleagues measured the effect of antidepressants with a commonly used behavioral test that measures the boldness in mice when retrieving food from bright open areas. Mice on antidepressants usually become more daring, but the drugs had no such effect on mice with surplus serotonin receptors.

Recent genetic and imaging studies of depressed patients have suggested that high receptor numbers of the 1A type in the raphe neurons are associated with treatment failure. Until now, no direct test of the association could be performed because the number of receptors in the raphe neurons could not be altered without changing the number of receptors in other parts of the brain.

Using new techniques in genetic engineering, Dr. Hen created a strain of mouse that can be programmed to produce high or low levels of serotonin receptors of the 1A type only in the raphe neuron. The levels present in the mice mimicked the levels found in people who are resistant to antidepressant treatment.

“By simply tweaking the number of receptors down, we were able to transform a non-responder into a responder,” Dr. Hen adds.

That strategy also may work for patients resistant to antidepressant treatment, Dr. Hen says, if drugs can be found to reduce the number of receptors or impede their activity.

But first the role of surplus serotonin receptors in people must be confirmed. Dr. Hen’s lab is now looking at patients enrolled in clinical trials to see if receptor levels predict response to antidepressants.

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Authors of the Neuron study are Jesse W. Richardson-Jones, Caryne P. Craige, Bruno P. Guiard, Alisson Stephen, Kayla L. Metzger, Hank F. Kung, Alain M. Gardier, Alex Dranovsky, Denis J. David, Sheryl G. Beck, Rene Hen and E. David Leonardo.

This study was supported in part by NIMH, NARSAD and AstraZeneca.

Columbia Psychiatry is ranked among the best departments and psychiatric research facilities in the Nation and has contributed greatly to the understanding of and current treatment for psychiatric disorders. Located at the New York State Psychiatric Institute on the NewYork-Presbyterian Hospital/Columbia University Medical Center campus in the Washington Heights community of Upper Manhattan, the department enjoys a rich and productive collaborative relationship with physicians in various disciplines at Columbia University’s College of Physicians and Surgeons. Columbia Psychiatry is home to distinguished clinicians and researchers noted for their clinical and research advances in the diagnosis and treatment of depression, suicide, schizophrenia, bipolar and anxiety disorders, and childhood psychiatric disorders.

Columbia University Medical Center provides international leadership in basic, pre-clinical and clinical research, in medical and health sciences education, and in patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the College of Physicians and Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Established in 1767, Columbia’s College of Physicians and Surgeons was the first institution in the country to grant the M.D. degree and is among the most selective medical schools in the country. Columbia University Medical Center is home to the largest medical research enterprise in New York City and state and one of the largest in the United States.

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