Cytokine-induced depression during IFN-α treatment: The role of IL-6 and sleep quality
Introduction
Major Depressive Disorder (MDD) is associated with the onset and progression of several medical conditions (Eaton et al., 1996, Everson-Rose and Lewis, 2005, Frasure-Smith et al., 1993, Zautra et al., 1994). One link between MDD and illness is inflammation, which plays an essential role in the pathogenesis of a number of chronic diseases, including cardiovascular disease, diabetes, and cancer (Antoni et al., 2006, Black, 2003, Papanicolaou et al., 1998, Pradhan et al., 2001, Pradhan and Ridker, 2002, Ridker et al., 2000). Relatedly, elevations in systemic inflammation have been observed in patients with MDD (Howren et al., 2009, Raison et al., 2006, Zorrilla et al., 2001), as evinced by increases in circulating levels of interleukin (IL)-6, when compared to non-depressives (Frommberger et al., 1997, Maes et al., 1995, Musselman et al., 2001b, Pike and Irwin, 2006, Sluzewska et al., 1996).
An emerging literature suggests that proinflammatory cytokines may contribute to the development of depressive symptoms including depressed mood, anhedonia, fatigue, and impaired sleep (Dantzer et al., 2008, Irwin and Miller, 2007, Raison et al., 2006). IL-6 and its receptor are synthesized in the brain (Schobitz et al., 1994), with high densities in the hippocampus and hypothalamus (Hopkins and Rothwell, 1995). Healthy humans treated with an acute inflammatory stimulus (e.g., Salmonella abortis equi endotoxin or typhoid vaccination) exhibit significant increases in depressive symptoms, decreases in cognitive functioning, and alterations in sleep electrophysiology (Haack et al., 2001, Mullington et al., 2000, Reichenberg et al., 2001, Wright et al., 2005). Furthermore, there is growing evidence that cytokine antagonists mitigate these behavioral changes in rodents and have been shown to reduce depressive symptoms among patients with inflammatory conditions (Cohen et al., 2006, Dantzer et al., 2008, Tyring et al., 2006). Nevertheless, it is also plausible that the converse may be true. In other words, depression may lead to changes in inflammatory cytokine levels. For instance, there is laboratory evidence that people with depression display exaggerated stress-related increases in inflammatory responses (Miller et al., 2005, Pace et al., 2006). In addition, perturbations in depressed mood have been associated with subsequent increases of circulating IL-6 (Rohleder and Miller, 2008), raising the possibility that changes in negative mood may contribute to elevations in inflammatory activity.
To prospectively explore the bi-directional relations between depression and proinflammatory cytokines in humans, patients undergoing interferon (IFN)-α therapy offer a unique opportunity. IFN-α is a cytokine of the early innate immune system released in response to viral infection and induces cellular release of other proinflammatory mediators, namely IL-1β and IL-6, into systemic circulation (Dantzer et al., 2008, Shimizu et al., 1995). In combination with ribavirin, IFN-α is the primary treatment for patients with chronic hepatitis C viral (HCV) infection. But while efficacious, a substantial portion of patients (10–40%) develop major depression during treatment (Capuron et al., 2002, Capuron and Miller, 2004, Musselman et al., 2001a). Several studies have demonstrated elevations in peripheral levels of IL-6 among patients undergoing IFN-α therapy (Bonaccorso et al., 2001, Wichers et al., 2007). Recent findings indicate that levels of IL-6 in the CSF of patients receiving IFN-α may negatively correlate with serotonin metabolite levels, which in turn may negatively correlate with depression symptoms (Raison et al., 2009). To date, however, whether increased IL-6 precedes, follows, or simply co-occurs with depression remains unresolved.
Sleep disturbance may be another variable that is related to both MDD and inflammation (Motivala et al., 2005, Opp et al., 2007). Controlling for co-existing depressive symptoms, poor sleep quality increases risk for subsequent IFN-α induced depression (Franzen et al., in press), and poor sleep has been cross-sectionally associated with inflammation (Bryant et al., 2004, Suarez, 2008). But again, the direction of causation between sleep and inflammation is not definitively known. In experimental settings, sleep architecture is readily modulated with cytokines or cytokine inducers (e.g., endotoxin) (Haack et al., 2001, Spath-Schwalbe et al., 1998, Spath-Schwalbe et al., 2000). Thus changes in inflammation may plausibly contribute to sleep abnormalities, and thereby increase depression risk. Conversely, full and partial sleep deprivation results in increased circulating levels of IL-6, TNF-α, and C-reactive protein when compared to periods of undisturbed sleep (Meier-Ewert et al., 2004, Vgontzas et al., 1999, Vgontzas et al., 2004). For instance, Vgontzas and colleagues (2004) demonstrated that 1 week of a 2 h sleep reduction (from 8 to 6 h/night) in normal non-depressed sleepers results in deeper sleep (i.e., increased slow wave sleep), increased daytime sleepiness, and elevated circulating levels of IL-6 and TNF-α. Thus sleep disturbances could plausibly contribute to increased systemic inflammation.
There is a need to delineate the temporal relationships among systemic inflammation, sleep, and depression. Towards this end, we prospectively measured depression, global sleep quality, and circulating levels of IL-6 for four consecutive months in 95 HCV patients undergoing IFN-α therapy. This design enabled us to test whether depressive symptoms preceded elevated systemic inflammation or vice versa, and whether poor sleep quality preceded or followed inflammatory activity. Using time-lagged analyses, we examined the temporal relationships of sleep quality, depressive symptoms, and the inflammatory cytokine IL-6 with the goal of disentangling these dynamic associations.
Section snippets
Participants
Ninety-five non-depressed patients were started on pegylated (PEG) IFN-α2 (PEG-IFN-α2a: 135 μg/week or PEG-IFN-α2b: 120 or 150 μg/week) and oral ribavirin for treatment of HCV and followed for 4 months of treatment. We used this time frame because depression incidence during IFN-α treatment most typically occurs by week 8 (Dieperink et al., 2003, Reichenberg et al., 2005) or 12 (Castera et al., 2006, Hauser et al., 2002, Schaefer et al., 2004). Using the Structured Clinical Interview for DSM-IV
Results
Demographic characteristics of the sample and correlations to baseline levels of circulating IL-6 are displayed in Table 1. Baseline IL-6 levels were higher among older and heavier patients; however, basal pre-treatment levels of IL-6 were unrelated to gender, race, and nicotine usage. In addition, pre-treatment IL-6 levels were not correlated with pre-treatment BDI or PSQI scores. Baseline IL-6 levels were also not correlated with initial viral load (r = 0.02; p = 0.85), gamma-glutamyl
Discussion
IFN-α administration has been associated with elevated systemic IL-6 in a subset of individuals (Bonaccorso et al., 2001, Wichers et al., 2007). In 17 patients, the increased IL-6 was only statistically elevated at week 8 (Wichers et al., 2007). We also found that IFN-α treatment resulted in both modulation of circulating daytime IL-6 levels and concomitant changes in depression scores. Notably, IL-6 levels were only higher in those who ultimately developed MDD. Moreover, replicating an earlier
Acknowledgement
Funding for this study was provided by NIMH Grant K23 MH074012 (FEL); the NIMH had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.
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