This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.OBJECTIVE: The objectives of this study are to improve the understanding of major depression and its pathophysiology, improve the ability to predict future episodes, and identify susceptibility genes predisposing subjects to major mood disorders.RESEARCH PLAN: A candidate gene approach will be utilized to study the association of several monoamine related genotypic markers and the depressive response to Tryptophan (TRP) depletion as a newly defined phenotype. The TRP depletion paradigm is a broadly utilized research methodology that safely and effectively has contributed to an improved understanding of the physiological effects of serotonin neurotransmission in a variety of research models and subject populations. Specifically, the neurotransmitter depletion paradigms have been proposed as phenotypes for major affective disorders based on their ability to induce brief and reversible depressive responses in subjects considered at risk for depression - such as remitted depressives, and subjects with multigenerational family history of affective disorders - but not in healthy controls. We propose to study a new phenotypic definition because 'depression' is a highly heterogeneous condition. This, along with the lack of objective biological measurements of the disease, has limited progress in the field.METHODS: This multi-site study will include three sites: Departments of Psychiatry at University of Texas Health Science Center at San Antonio, The University of Arizona, and Case Western Reserve University. The present study will conduct TRP depletion testing in 100 subjects (40 at UTHSCSA) with history of major depression but who are currently in remission and medication-free for at least three months. TRP depletion involves two 3-day sessions (active depletion and control) in a double blind, controlled, crossover design. Day one involves the ingestion of a TRP-free 15 amino acid drink or a TRP-supplemented 16 amino acid drink. Clinician and self-rated behavioral measurements of depression, anxiety, and somatic symptoms, as well as blood samples for measurement of plasma TRP and large neutral amino acids will be obtained prior to, during, and after testing. Subjects will be monitored prospectively for major depressive recurrences during the follow-up year. In addition, 200 healthy controls (80 at UTHSCSA) will be recruited for genotyping purposes and will be matched to history positive subjects in age, ethnicity/race, and socioeconomic status. Polymerase chain reaction based genotyping will be performed in order to study several candidate gene polymorphisms relevant to monoamine function.CLINICAL
Most psychiatric practice is dictated by behavioral observations. In other areas of medicine, laboratory tests are used representing a much greater advantage. If effective tests of brain neurotransmitter system function can be developed and if they relate clearly to the prognosis, treatment response, and course of illness, easily applied clinical versions of these tests could be utilized by practicing clinicians for more effective management of patients. Possibly the most important benefit to society would be the improved understanding of the pathophysiology of depression and genetic basis for vulnerability and symptom expression, so that more rapid, safe, and effective diagnostic, preventive, and treatment strategies could be designed.
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