Administration of high doses of cytokines such as interferon a (IFNa) to humans has been shown to induce a depression-like syndrome, also referred to as """"""""sickness behavior,"""""""" that includes symptoms of depressed mood, anhedonia, anorexia, fatigue, and disrupted sleep. This syndrome occurs in a high percentage of patients receiving high dose IFNa therapy for selected cancers (e.g. malignant melanoma) or viral illnesses (e.g. hepatitis C) and is a significant limiting factor to therapeutic success. The mechanism(s) by which IFNa causes depression, and the optimal ways to treat this syndrome have not been fully elucidated. Recent studies conducted by our group and others suggest that IFNa, induces factors known to contribute to the expression of depressive symptoms including corticotropin releasing hormone (CRH) and the proinflammatory cytokines, tumor necrosis factor a (TNFa) and IL-10. In addition, IFNa may induce cytokines [e.g. interleukin (IL)-la] which inhibit the ability of glucocorticoids (via their receptors) to mediate feedback inhibition on these factors. Pretreatment with antidepressants, which have been shown to facilitate feedback inhibition and regulation of the hypothalamic-pituitary-adrenal (HPA) axis, appears to block the development of the syndrome. The long term objectives of the proposed research are to determine the mechanism of cytokine-induced depression and establish strategies for its treatment. In this application, investigators propose to test the hypothesis that IFNa therapy induces proinflammatory cytokines, including IL-la, which in turn induce glucocorticoid resistance [as manifested by an abnormal dexamethasone suppression test (DST)], thereby releasing CRH and proinflammatory cytokines, such as TNFa and IL-1,B, from glucocorticoid-mediated feedback inhibition. In addition, investigators hypothesize that pretreatment with antidepressants, by facilitating glucocorticoid receptor function, will prevent glucocorticoid resistance and thereby prevent the development of cytokine-induced depression. To test these hypotheses, the investigators plan to systematically examine proinflammatory cytokines, neuroendocrine function, and behavior in 140 patients receiving IFNa (3 million units sc, 3 times/week) for the treatment of chronic hepatitis C (CHC). CHC afflicts over 4 million individuals in the U.S., and IFNa (plus ribavirin) is the only FDA-approved treatment. Using a double blind, placebo-controlled design, the investigators also plan to pretreat patients receiving high dose IFNa therapy with the antidepressant, paroxetine, and thus prevent the associated sickness behavior. Given the millions of CHC patients who are candidates for IFNa therapy, further understanding of IFNa-induced behavioral toxicity not only is relevant for defining the neuroendocrine-immune mechanisms of cytokine induced depression but also may provide timely treatment strategies for the clinical management of this and related toxicities.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH060723-04
Application #
6618130
Study Section
Special Emphasis Panel (ZRG1-BDCN-6 (01))
Program Officer
Babcock, Debra J
Project Start
2000-07-15
Project End
2005-06-30
Budget Start
2003-07-01
Budget End
2005-06-30
Support Year
4
Fiscal Year
2003
Total Cost
$342,000
Indirect Cost
Name
Emory University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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Raison, Charles L; Demetrashvili, Marina; Capuron, Lucile et al. (2005) Neuropsychiatric adverse effects of interferon-alpha: recognition and management. CNS Drugs 19:105-23

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