title: Interferon-alpha-induced inflammation is associated with reduced glucocorticoid negative feedback sensitivity and depression in patients with hepatitis C virus.
abstract: Major medical illnesses are associated with increased risk for depression and alterations in hypothalamic-pituitary-adrenal (HPA) axis function. Pathophysiological processes such as inflammation that occur as a part of medical illnesses and their treatments have been shown to cause depressive symptoms, and may also affect the HPA axis. We previously reported that patients with hepatitis C virus chronically administered interferon (IFN)-alpha develop increased evening plasma cortisol concentrations and a flattened diurnal cortisol slope, which correlated with increased tumor necrosis factor (TNF) and its soluble receptor 2 (sTNFR2). Increased TNF and sTNFR2 were further correlated with depression and fatigue scores. The current study examined whether flattened cortisol slope might be secondary to reduced glucocorticoid receptor (GR) sensitivity, by measuring glucocorticoid negative feedback to dexamethasone (DEX) administration followed by corticotropin releasing hormone (CRH) challenge. In an exploratory analysis, 28 male and female patients with hepatitis C virus were studied at baseline (Visit 1) and after 12weeks (Visit 2) of either IFN-alpha plus ribavirin (n=17) or no treatment (n=11). Patients underwent dexamethasone DEX-CRH challenge, neuropsychiatric assessments, and measurement of plasma TNF and sTNFR2 during each visit. IFN-alpha did not affect neuroendocrine responses following CRH but did increase post-DEX cortisol, which was correlated with flattening of the diurnal cortisol slope (r=0.57, p=0.002) and with increased depression scores (r=0.38, p=0.047). Furthermore, the change in post-DEX cortisol was associated with IFN-alpha-induced increase in sTNFR2 (r=0.51, p=006), which was in turn correlated with depression (r=0.63, p<0.001) and fatigue (r=0.51, p=0.005) scores. Whereas the relationship between sTNFR2 and depression scores were independent of the change in post-DEX cortisol, the correlation between post-DEX cortisol and depression scores was not significant when controlling for sTNFR2. These findings suggest that inflammation induced in patients with hepatitis C virus during IFN-alpha therapy precipitates decreased GR sensitivity to lead to a flattened diurnal cortisol slope. Decreased GR sensitivity may in turn further increase inflammation and its ultimate effects on behavior. Treatments that target inflammation and/or GR sensitivity may reduce depressive symptoms associated with medical illnesses.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA 30322, United States; The Winship Cancer Institute, Emory University, Atlanta, GA 30322, United States. Electronic address: jfelger@gmail.com.
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Felger
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA 30322, United States; The Winship Cancer Institute, Emory University, Atlanta, GA 30322, United States.
authors.forename: Ebrahim
authors.initials: E
authors.lastname: Haroon
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA 30322, United States.
authors.forename: Bobbi J
authors.initials: BJ
authors.lastname: Woolwine
authors.affiliation: School of Human Ecology, University of Wisconsin-Madison, Madison, WI 53706, United States; Department of Psychiatry, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53706, United States.
authors.forename: Charles L
authors.initials: CL
authors.lastname: Raison
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA 30322, United States; The Winship Cancer Institute, Emory University, Atlanta, GA 30322, United States.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Miller
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000097:blood; D000328:Adult; D000998:Antiviral Agents / Q000009:adverse effects*; D019540:Area Under Curve; D003346:Corticotropin-Releasing Hormone / Q000008:administration & dosage; D003863:Depression / Q000209:etiology*; D003907:Dexamethasone / Q000008:administration & dosage; D005221:Fatigue / Q000139:chemically induced / Q000503:physiopathology; D005260:Female; D005938:Glucocorticoids / Q000378:metabolism; D006526:Hepatitis C / Q000097:blood / Q000150:complications* / Q000188:drug therapy; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007249:Inflammation / Q000139:chemically induced*; D016898:Interferon-alpha / Q000009:adverse effects*; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D011569:Psychiatric Status Rating Scales; D011863:Radioimmunoassay; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism; D012254:Ribavirin / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D005938:Glucocorticoids; D016898:Interferon-alpha; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D012254:Ribavirin; D003907:Dexamethasone; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D006854:Hydrocortisone
keywords: Depression; Dexamethasone; Fatigue; HPA-axis; Hepatitis C virus; Inflammation