This K05 Senior Scientist Award is designed to provide the applicant protected time in order to continue ongoing research on the pathology and treatment of cytokine-induced depression. Depression in the medically ill is a significant public health concern, occurring in up to 50% of patients and having a significant impact on treatment adherence, quality of life, and morbidity and mortality. New developments in the conceptualization of depression in the medically ill have focused on the potential role of immune activation/inflammation and the associated release of proinflammatory cytokines. Proinflammatory cytokines have been found to influence neurobiologic function including neurochemistry and behavior, and induce a depressive syndrome that has overlapping features with major depression. The long-term objective of the proposed work is to further understand the pathology and treatment of this cytokine-induced depression as it relates to depression in the medically ill, including patients with HIV/AIDS. As a model system, we plan to study patients receiving the cytokine, interferon (IFN) alpha, for the treatment of hepatitis C, which afflicts approximately 4 million individuals in the US and up to 25% of patients with HIV/AIDS. IFN alpha is a potent inducer of proinflammatory cytokines (especially interleukin 6) and leads to depressive symptoms in 30-50% of patients depending on the dose. In addition, IFN alpha activates corticotropin releasing hormone pathways and has been shown to lead to monoamine depletion in laboratory animals. IFN alpha also has been shown to alter fronto-striatal neurocircuitry in humans and induce REM sleep changes (decreased REM latency, increased REM percentage); changes consistent with the neurobiology of depression. Thus, IFN alpha treatment provides a unique model system to further understand the pathology and treatment of cytokine-induced mood disorders.
The specific aims of the proposed research plan are 1) To determine the neuroendocrine pathways involved in the vulnerability to and development of cytokine-induced depression, 2) To determine the neural circuitry of cytokine-induced depression using functional magnetic resonance imaging and positron emission tomography, and 3) a) To test the efficacy of antidepressants in patients receiving IFN alpha therapy for hepatitis C (including patients with HCV/HIV co-infection) and b) To test novel strategies for the treatment of cytokine-induced depressive symptoms including cytokine antagonists and dopamine agonists. Results from these studies will provide important new data on neural pathways by which cytokines induce depression and will establish a foundation for developing novel strategies to diagnose and treat depression in the medically ill. In addition to the proposed research, the applicant will develop his skills in the area of neuroimaging and will participate in training and education of pre- and postdoctoral fellows and junior faculty, as well as serving as Director of the HIV/AIDS Clinical Research Training Program.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Scientist Award (K05)
Project #
5K05MH069124-04
Application #
7149988
Study Section
AIDS and Related Research 8 (AARR)
Program Officer
Joseph, Jeymohan
Project Start
2003-12-01
Project End
2008-11-30
Budget Start
2006-12-01
Budget End
2007-11-30
Support Year
4
Fiscal Year
2007
Total Cost
$116,932
Indirect Cost
Name
Emory University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Felger, Jennifer C; Haroon, Ebrahim; Woolwine, Bobbi J et al. (2016) Interferon-alpha-induced inflammation is associated with reduced glucocorticoid negative feedback sensitivity and depression in patients with hepatitis C virus. Physiol Behav 166:14-21
Felger, Jennifer C; Hernandez, Carla R; Miller, Andrew H (2015) Levodopa reverses cytokine-induced reductions in striatal dopamine release. Int J Neuropsychopharmacol 18:
Miller, Andrew H; Haroon, Ebrahim; Raison, Charles L et al. (2013) Cytokine targets in the brain: impact on neurotransmitters and neurocircuits. Depress Anxiety 30:297-306
Felger, Jennifer C; Mun, Jiyoung; Kimmel, Heather L et al. (2013) Chronic interferon-? decreases dopamine 2 receptor binding and striatal dopamine release in association with anhedonia-like behavior in nonhuman primates. Neuropsychopharmacology 38:2179-87
Felger, Jennifer C; Li, Li; Marvar, Paul J et al. (2013) Tyrosine metabolism during interferon-alpha administration: association with fatigue and CSF dopamine concentrations. Brain Behav Immun 31:153-60
Smith, A K; Simon, J S; Gustafson, E L et al. (2012) Association of a polymorphism in the indoleamine- 2,3-dioxygenase gene and interferon-?-induced depression in patients with chronic hepatitis C. Mol Psychiatry 17:781-9
Felger, Jennifer C; Miller, Andrew H (2012) Cytokine effects on the basal ganglia and dopamine function: the subcortical source of inflammatory malaise. Front Neuroendocrinol 33:315-27
Felger, J C; Cole, S W; Pace, T W W et al. (2012) Molecular signatures of peripheral blood mononuclear cells during chronic interferon-? treatment: relationship with depression and fatigue. Psychol Med 42:1591-603
Felger, Jennifer C; Alagbe, Oyetunde; Pace, Thaddeus W W et al. (2011) Early activation of p38 mitogen activated protein kinase is associated with interferon-alpha-induced depression and fatigue. Brain Behav Immun 25:1094-8
Miller, Andrew H (2010) Depression and immunity: a role for T cells? Brain Behav Immun 24:1-8

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