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 neural correlates of this cytokine-induced depression as it relates to depression in the medically ill. As a model system, we plan to study patients receiving the cytokine, interferon (IFN) alpha, for the treatment of hepatitis C. 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. Preliminary data from our lab indicate that IFN alpha treatment is associated with reduced evoked activity in the striatum and medial prefrontal cortex as determined by functional magnetic resonance imaging (fMRI). These findings, in conjunction with clinical evidence of impaired functioning of the basal ganglia (e.g. reduced reaction time, psychomotor slowing, akathesia and anhedonia) in IFN alpha-treated patients, suggest that dysfunction of fronto-striatal neurocircuitry may underlie IFN alpha-induced depressive symptoms and may represent a critical pathway by which cytokines induce depression. The fundamental hypothesis of the proposed work is that IFN alpha-induced depression begins with reduced activation of striatal neurons that is associated with psychomotor slowing and anhedonia and in turn contributes to reduced activity in the prefrontal cortex. Reduced activity in the prefrontal cortex is then associated with the development of depressive symptoms and cognitive dysfunction. Thus, we hypothesize that reduced evoked activity in the striatum will 1) be predictive of the development of depressive symptoms during IFN alpha therapy, 2) will precede the development of reduced activity in the prefrontal cortex, and 3) will be a predominent feature of IFN alpha-induced depression compared to depression in medically healthy individuals. To test these hypotheses, we plan to conduct fMRIs and neuropsychiatric assessments in 40 patients with hepatitis C at various time points during IFN alpha therapy. Results will be compared to control populations of hepatitis C patients awaiting IFN alpha treatment (N=20) and medically healthy subjects with and without major depression (N=20 per group). 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH067990-02
Application #
6830304
Study Section
Brain Disorders and Clinical Neuroscience 5 (BDCN)
Program Officer
Meinecke, Douglas L
Project Start
2003-12-01
Project End
2008-11-30
Budget Start
2004-12-01
Budget End
2005-11-30
Support Year
2
Fiscal Year
2005
Total Cost
$240,975
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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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
Capuron, Lucile; Pagnoni, Giuseppe; Drake, Daniel F et al. (2012) Dopaminergic mechanisms of reduced basal ganglia responses to hedonic reward during interferon alfa administration. Arch Gen Psychiatry 69:1044-53
Raison, Charles L; Rye, David B; Woolwine, Bobbi J et al. (2010) Chronic interferon-alpha administration disrupts sleep continuity and depth in patients with hepatitis C: association with fatigue, motor slowing, and increased evening cortisol. Biol Psychiatry 68:942-9
Miller, Andrew H (2009) Norman Cousins Lecture. Mechanisms of cytokine-induced behavioral changes: psychoneuroimmunology at the translational interface. Brain Behav Immun 23:149-58
Capuron, Lucile; Fornwalt, Fiona B; Knight, Bettina T et al. (2009) Does cytokine-induced depression differ from idiopathic major depression in medically healthy individuals? J Affect Disord 119:181-5
Majer, Matthias; Welberg, Leonie A M; Capuron, Lucile et al. (2008) IFN-alpha-induced motor slowing is associated with increased depression and fatigue in patients with chronic hepatitis C. Brain Behav Immun 22:870-80
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Capuron, Lucile; Pagnoni, Giuseppe; Demetrashvili, Marina et al. (2005) Anterior cingulate activation and error processing during interferon-alpha treatment. Biol Psychiatry 58:190-6