STAR*D Study Examines Effect Of Genetic Variation In Treatment Resistant Depression

Researchers are now better able to predict which patients will respond to treatment for depression through the presence of genetic markers, according to results from a major NIH study on treatment resistant depression released at the annual meeting of the American College of Neuropsychopharmacology.



"Medications to treat depression are widely available, but no one treatment works for everyone. Additionally, it can be difficult to predict which patients will experience harmful or unpleasant side effects," said Francis McMahon, MD, Chief of Genetic Basis of Mood & Anxiety Disorders, National Institute of Mental Health. "We are seeking to better understand why this is the case, and, using genetic markers, develop personalized treatments that give patients the best chance at remission."



The research is part of a landmark clinical trial known as Sequenced Treatment Alternatives to Relieve Depression, or STAR*D. The STAR*D is the only large sample of patients who suffer from major depression, and who are treatment resistant with the same drug for a significant period of time.



McMahon examined the effects of polymorphisms (common differences in DNA sequences) of 68 genes on treatment effectiveness and incidence of side effects. Analysis of the data showed that polymorphisms in a gene that regulates serotonin was positively associated with treatment outcome. McMahon concluded that individuals who carried two copies of the polymorphism associated with response were 18% more likely to respond to treatment than those who did not.



Polymorphisms in 2 other genes - a receptor for the brain chemical glutamate and a protein involved in neurogenesis - were also associated with treatment effectiveness. Neurogenesis is a dynamic process in the brain through which neural connections are formed and lost. Patients who carried all 3 response-associated polymorphisms were 40% more likely to respond to treatment than those who carried none of them.



Other investigators have knocked down genes involved with neurogenesis or blocked neurogenesis directly in rodents, which eliminated the animals' ability to respond to anti-depressants. This supports the hypothesis that neurogenesis is involved in the response to antidepressant treatment in humans.



McMahon and colleagues studied over 1900 study participants with major depression who donated a blood sample and received the antidepressant citalopram over a period of at least 6 weeks.



In addition to providing valuable information that may be ultimately useful in a clinical treatment setting, the study is part of a larger movement in depression research.



"This is the beginning of a new generation of studies to help clinicians personalize treatment." noted Dr. Thomas Insel, Director of the National Institute of Mental Health (NIMH). "I predict that genomics will be an important tool for future psychiatrists treating people with depression just as it is being used today by oncologists selecting treatments for breast cancer or lymphoma."



McMahon noted that this success is just the beginning. "Ultimately, our goal is to put together a panel of genetic markers that can guide treatment decisions and help doctors choose an antidepressant that will work best for an individual patient."







ACNP held its Annual Meeting December 3 - 7, 2006, in Hollywood, FL.



ACNP, founded in 1961, is a professional organization of more than 700 leading scientists, including three Nobel Laureates. The mission of ACNP is to further research and education in neuropsychopharmacology and related fields in the following ways: promoting the interaction of a broad range of scientific disciplines of brain and behavior in order to advance the understanding of prevention and treatment of disease of the nervous system including psychiatric, neurological, behavioral and addictive disorders; encouraging scientists to enter research careers in fields related to these disorders and their treatment; and ensuring the dissemination of relevant scientific advances. A non-profit organization, ACNP receives revenues from a variety of sources including membership dues, publication sales, registration fees, and pharmaceutical industry grants.



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