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Genetic defect confers risk of major depression, resistance to SSRI drug therapy

DURHAM, N.C. A newly discovered genetic defect might represent an important risk factor for major depression, a condition which effects 20 million people in the U.S., according to Duke University Medical Center researchers. The mutation in the gene -- whose protein product plays a primary role in synthesizing the brain chemical serotonin -- could lead to the first diagnostic test for genetic predisposition to depression, the team said.

"Abnormalities in brain levels of serotonin have been widely suspected as a key contributor to major depression and other neuropsychiatric disorders," said James B. Duke professor Marc Caron, Ph.D., a researcher in the department of cell biology, the Duke Institute for Genome Sciences and Policy and senior author of the study. "Our findings provide a novel molecular mechanism underlying dysfunction in serotonin neurotransmission in some patients with depression."

The genetic defect is the first genetic variant of functional consequence in the production of serotonin identified in any psychiatric disorder, the researchers said.

Patients with depression who carry the abnormal gene also show resistance to treatment with selective serotonin reuptake inhibitors (SSRIs), a class of drugs that includes paroxetine (PaxilTM), sertraline (ZoloftTM), and fluoxetine (ProzacTM), the team found. In addition to its diagnostic use, the genetic marker might therefore also aid in identifying, in advance, those patients who will likely fail to respond well to SSRI therapy.

The researchers further suggest that this and other variants of the gene might also explain such paradoxical adverse reactions to SSRI treatment as suicidal behavior and SSRI-exacerbated mania and psychosis.

The Duke team reported its findings Dec. 9, 2004, in the early online edition of Neuron. The work was supported by the National Institutes of Health, the Human Frontiers Science Program and the C
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Contact: Kendall Morgan
kendall.morgan@duke.edu
919-660-1306
Duke University Medical Center
9-Dec-2004


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