Interferon-α effects on diurnal hypothalamic pituitary-adrenal axis activity: Relationship with proinflammatory cytokines and behavior

Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA 30322, USA.
Molecular Psychiatry (Impact Factor: 14.5). 05/2010; 15(5):535-47. DOI: 10.1038/mp.2008.58
Source: PubMed


Interferon (IFN)-alpha has been used to investigate pathways by which innate immune cytokines influence the brain and behavior. Accordingly, the impact of IFN-alpha on diurnal secretion of hypothalamic-pituitary-adrenal (HPA) axis hormones was assessed in 33 patients eligible for treatment with IFN-alpha plus ribavirin for hepatitis C. In addition, the relationship between IFN-alpha-induced HPA axis changes and proinflammatory cytokines and behavior was examined. Plasma ACTH and cortisol as well as tumor necrosis factor (TNF)-alpha, interleukin-6 and their soluble receptors, were measured hourly between 0900 and 2100 hours at baseline and following approximately 12 weeks of either no treatment (n=13) or treatment with IFN-alpha/ribavirin (n=20). Plasma IFN-alpha was also measured at each visit. Depression and fatigue were assessed using the Montgomery-Asberg depression rating scale and the multidimensional fatigue inventory. Compared to no treatment, IFN-alpha/ribavirin administration was associated with significant flattening of the diurnal ACTH and cortisol slope and increased evening plasma ACTH and cortisol concentrations. Flattening of the cortisol slope and increases in evening cortisol were correlated with increases in depression (r=0.38, P<0.05 and r=0.36, P<0.05, respectively) and fatigue (r=0.43, P<0.05 and r=0.49, P<0.01, respectively). No relationship was found between immune and HPA axis measures, although increases in plasma IFN-alpha, TNF-alpha and soluble TNF-alpha receptor2 were independently correlated with behavioral endpoints. These data indicate that chronic exposure to innate immune cytokines may contribute to the altered diurnal HPA axis activity and behavior found in medically ill individuals. However, given the lack of correlation between HPA axis and immune measures, the mechanism by which chronic cytokine exposure influences HPA axis function remains to be determined.


Available from: Charles L Raison, Jan 16, 2014
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    • "We therefore explored effects of aging on the glutamate response to IFN-alpha in patients with hepatitis C virus (HCV) and determined whether these effects were associated with alterations in inflammatory markers and behaviors previously shown to be altered in IFN-alpha-treated patients including tumor necrosis factor (TNF) and its soluble receptor sTNFR2, motivation, and motor activity (Capuron et al., 2012; Majer et al., 2008; Raison et al., 2010). "

    Brain Behavior and Immunity 10/2015; 49:e24. DOI:10.1016/j.bbi.2015.06.100 · 5.89 Impact Factor
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    • "Moreover, elevated plasma levels of TNF-í µí»¼ are associated with treatment resistance to conventional antidepressants [15]. In hepatitis C patients that are chronically treated with interferon-í µí»¼, increased blood levels of TNF-í µí»¼ correlate with the development of depressive symptoms [16]. Furthermore, peripheral administration of anti-TNF-í µí»¼ antibodies improves depressed mood in patients suffering from psoriasis [17], Crohn's disease [18], and rheumatoid arthritis [19]. "
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    08/2015; 2015(1):716920. DOI:10.1155/2015/716920
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    • "Another potential interaction between interferon treatment and social support may act through the control of the HPA axis activity. Proinflammatory cytokines, such as interferon, may cause HPA axis hyperactivity by disturbing negative feedback inhibition of circulating corticosteroids on the HPA axis, although the exact mechanism is not well understood [34] [35]. However, social support is able to downregulate the HPA axis stress response possibly by influencing the topdown control processes both in animal studies and in humans [36]. "
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    ABSTRACT: The most frequent serious psychological side effect of immune therapies is depression. In the present study, we tested whether social support, as a positive environmental effect, is able to moderate depression or anxiety symptoms in melanoma patients during adjuvant low-dose interferon treatment. Hundred and twenty-seven melanoma patients with negative psychiatric history were included in our longitudinal study and followed up for one year. Depression and anxiety symptoms were measured six times during treatment: at baseline, at 1st, 3rd, 6th, 9th and 12th month of the therapy. In addition, social support was investigated with the Social Dimension Scale. Depressive symptoms significantly increased during the 12-month follow-up period (p<0.001). However, social support significantly moderated the depressogenic effect of low-dose interferon treatment (p<0.001). Patients with better social support showed attenuated increase of depression. Anxiety showed no significant changes during the low-dose interferon treatment (p=0.230). Social support had no moderating effect on anxiety symptoms (p=0.745) during the follow up. Our data provide evidence that social support and interferon alpha treatment significantly interact in the development of depression. In addition, our study emphasises that enhancement of social support can reduce depressogenic side effects and increase compliance during adjuvant interferon treatment, and thus, psychological screening and psychooncological counselling should be incorporated in the treatment protocol. Copyright © 2015 Elsevier Inc. All rights reserved.
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