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Pitt Researchers Find Men And Women Have Different Genes Behind Depression

PITTSBURGH, March 28, 2002 — Researchers at the University of Pittsburgh have found evidence that men and women have different genes that anchor the roots of depression, a revelation that could have a major impact on the way doctors treat patients in the future.

The researchers are the first to report the results of a systematic search for chromosomal regions that harbor genes that affect susceptibility to severe depression, the second leading cause of disability worldwide. Their results will be published in the April American Journal of Medical Genetics, but were posted today on the journal’s website.

"We suspected there were at least a few different genes involved in making women and men susceptible to major depression," said lead author George S. Zubenko, M.D., Ph.D., professor of psychiatry at the University of Pittsburgh School of Medicine and adjunct professor of biological sciences at Carnegie Mellon University. "The results of this study suggest that sex-specific genes for recurrent major depression may actually be the rule rather than the exception."

For the study, funded by the National Institute of Mental Health, Dr. Zubenko and his colleagues compared genetic markers from 100 men and women with recurrent, early-onset major depressive disorder (RE-MDD) and 100 people with no history of this disorder, to find out which chromosomal regions were associated with the illness. RE-MDD is a severe form of clinical depression that runs in families and impairs the health and life span of family members.

Out of 19 chromosomal regions that were associated with the development of RE-MDD, 16 were significantly associated with the disorder in either men or women – but not both. According to Dr. Zubenko, these findings suggest important differences in the molecular basis of clinical depression in men and women, or sex-specific differences that determine resistance to stressful events. These genetic factors may also contribute to differences in the symptoms of clinical depression in men and women, differential treatment responses, and the development of additional psychiatric disorders such as anxiety disorders, alcoholism, and other substance use disorders that frequently accompany major depression and run in the same families.

According to Dr. Zubenko, this research may provide an important step toward changing the way doctors diagnose and treat major depression – a disease that affects nearly 10 percent of the population.

"Studies such as this one are providing us with a better understanding of the biology of complicated disorders such as major depression, which is unlikely to represent a single disease with a unitary cause," said Dr. Zubenko. "Instead, clinical depression is probably more like anemia. Both of these disorders are defined by a collection of clinical features that result from different causes in different people. Treatment or prevention efforts are usually most successful when they are aimed at the specific causes of a disorder."

Further progress in diagnosis and treatment of clinical depression that result from these findings will likely proceed along several avenues, according to Dr. Zubenko. "It will be important for us and others to confirm our findings using complementary genetic methods and independent populations. This will be followed by intense efforts by many investigators to identify the susceptibility genes in the chromosomal regions that are confirmed. The identification and characterization of these genes and their products will provide new opportunities for drug development and disease prevention, and new information about the biology of mood and its regulation," said Dr. Zubenko.

Dr. Zubenko explained that these developments are time and resource intensive, and that it would be unlikely for the results of this avenue of research to affect clinical care in less than a decade. However, other applications may have important implications in the nearer future.

"Genotyping markers in chromosomal regions that harbor susceptibility genes may provide more immediate advances in the treatment of major depression. For example, individuals with particular genetic markers in these regions may respond better to particular current treatments than others. This strategy may enable clinicians to use genetic markers to better match individual patients to treatments to which they will optimally respond, while minimizing side effects," Dr. Zubenko said. "In current practice, the choice of a particular antidepressant for a patient is largely a hit or miss proposition that often leads to multiple medication trials before the depression remits. Side effects are common and can be debilitating."

Other researchers include Hugh B. Hughes III, M.S.; J. Scott Stiffler, B.S.; Wendy N. Zubenko, Ed.D., R.N., C.S., all of the University of Pittsburgh, and Barry B. Kaplan, Ph.D., University of Pittsburgh and Laboratory of Molecular Biology, National Institute of Mental Health.

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