IFN-α administration has been associated with elevated systemic IL-6 in a subset of individuals (Bonacccorso 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 study of 16 patients (Wichers et al., 2006
), we found that circulating IL-6 levels prior to IFN-α treatment predicted MDD incidence, an association that remained after adjustment for age, gender, weight, and baseline depressive symptoms.
Not only did baseline IL-6 levels predict MDD, but time-lagged hierarchical analyses revealed that circulating IL-6 was associated with following month’s BDI scores. Importantly, this relationship held even after controlling for BDI scores in the prior month. Conversely, BDI scores predicted the following month’s IL-6 levels, leading to the conclusion that a bi-directional relationship exists. This conclusion is consistent with the emergence of a positive feedback system during IFN-α treatment. That is, when exogenous IFN-α is given, the emergent positive feedback loop between depressive symptoms and IL-6 may escalate into the development of MDD in a vulnerable set of individuals. In the absence of IFN-α injections, there must be an interruption or brake in this positive feedback system.
Interestingly, IL-6 was associated with the next month’s self-report of poor sleep quality but not vice versa, suggesting more of a unidirectional relationship between these two variables during IFN-α treatment. There also appeared to be a unidirectional association between poor sleep quality and subsequent depression. Other studies have reported that subjective sleep disturbance can account for the association between depression and nocturnal IL-6 levels (Motivala et al., 2005
). Similarly, we found that poor sleep partially accounted for the relationship between elevated IL-6 and incidence of MDD, supporting the possibility that good sleep quality may interrupt the dynamics between elevated IL-6 and depression. However, to truly conclude that sleep is a mediator between IL-6 and depression, it would be necessary to experimentally improve sleep in patients with elevated IL-6 and examine whether this mitigates the development of MDD. At this point, because we did not find a correlation between sleep and IL-6 at pre-treatment baseline, we cannot definitively conclude that poor sleep mediates the relationship between elevated IL-6 and MDD.
There are several potential physiologic mechanisms that may moderate the relationship between inflammation and depressive symptoms. Impaired hypothamalic-pituitary-adrenal axis feedback and hyper-reactivity are some of the biological hallmarks of MDD (Pace et al., 2007
; Pariante and Miller, 2001
), including MDD secondary to IFN-α (Capuron et al., 2003
). Patients treated with IFN-α show flattened diurnal cortisol slopes and increased evening cortisol, which is correlated with depressive symptoms (Raison et al., 2008
). It is possible that failure of cortisol to regulate inflammatory processes, in those vulnerable to depression, may contribute to unleashing the bi-directional feedback loop observed in the present study. Consistent with this possibility, growing evidence supports glucocorticoid receptor (GR) dysfunction among depressives including disrupted GR expression, translocation, and concomitant resistance to cortisol (Pace et al., 2007
The parasympathetic arm of the autonomic nervous system can also regulate inflammation via the vagus nerve (Pavlov and Tracey, 2005
; Tracey, 2002
). In this regard, cross-sectional evidence shows that heart rate variability (HRV), an index of sympatho-vagal balance, is inversely related to systemic IL-6 (Sloan et al., 2007
). Heart rate variability has been shown to be reduced in depressed patients (Krittayaphong et al., 1997
; Rottenberg et al., 2007
). Whether this source of regulation is lost in vulnerable patients undergoing IFN-α therapy remains unknown. Thus far, the research exploring the effects of IFN-α treatment on HRV has been equivocal (Kadayifci et al., 1997; Takase et al., 2005
The relationship between IL-6 and depression may also be influenced by the serotonergic system. Indeed, reduced serotonin metabolites (e.g. 5-HIAA) have been observed in CSF of patients treated with IFN-α (Raison et al., 2009
), which correlated both with CSF IL-6 and depression. Similarly, converging evidence in animals and humans demonstrate that antidepressant medications reduce systemic inflammation in some contexts (Castanon et al., 2002
; Kenis and Maes, 2002
). With the aim of identifying genetic vulnerability, we reported previously that individuals with the L/L genotype for the serotonin transporter polymorphism (5-HTTLPR) are resilient to developing MDD during IFN-a treatment (Lotrich et al., 2009
). 5-HTTLPR may interact with IL-6 polymorphisms to influence MDD risk (Bull et al., 2008
). That is, the G/G genotype in the promoter region of the IL-6 gene (rs1800795), which has been previously associated with higher levels of IL-6 (Di Renzo et al., 2008
), was also associated with increased risk of MDD during IFN-α treatment (Bull et al., 2008
The current findings should be interpreted in the context of several limitations. First, while IFN-α treatment provides a distinct advantage for prospective investigations, our findings may not generalize to medically healthy populations and other instances of MDD. Indeed, not all cross-sectional studies have found elevations of circulating IL-6 in MDD patients compared to controls (Brambilla and Maggioni, 1998
; Haack et al., 1999
; Mikova et al., 2001
; O’Connor et al., 2007
). Whether our findings in patients receiving IFN-α can be extended to MDD more generally, or only a subtype of MDD requires determination. Increased systemic inflammatory activity may be present in a specific group of depressed patients, associated with antidepressant response (Lanquillon et al., 2000
; Maes et al., 1997
). That said, emerging evidence suggests that there is considerable overlap in symptom profiles of those with cytokine-induced depression and depression observed in medically healthy individuals, including on sleep measures (Capuron et al., 2009
). This study excluded subjects who currently were experiencing an MDD episode, which may impact the generalizability of our findings. It also did not include a non-IFN-α treated control group, and thus we cannot definitively state that MDD during treatment was the result if IFN-α. Second, there were likely unobserved variables (i.e. third factors) that may independently or interactively influence depressive symptoms, sleep quality, and/or systemic IL-6. Statistical associations, even when temporal, are not proof of causation. Also, several factors, including HCV severity, genetic variation in IL-6, and psychological stress may have contributed to IL-6 levels, sleep quality, and depressive symptoms at baseline and across time. Third, potential influences on poor sleep quality, such as obstructive sleep apnea (OSA) or pain, were not assessed. That said, evidence suggests the PSQI scores may not be associated with apnea status. For instance, in a study of 435 individuals, nearly 60% of whom had OSA, PSQI scores failed to distinguish those with OSA from non-sleep disordered individuals (Gliklich et al., 2000
Finally, the source of IL-6 elevations could not be determined. While we adjusted for weight in these analyses, given that adipose tissue can produce IL-6 (Mohamed-Ali et al., 1997
), we did not directly measure CSF IL-6. In this regard, Raison et al (2009)
found elevated CSF IL-6 without an increase in systemic IL-6.
Despite these limitations, we were nonetheless able to examine the temporal dynamics between depressive symptoms and evidence of systemic inflammation. In sum, we found that IFN-α treatment is associated with time-related increases in depressive symptoms, poor sleep quality, and systemic IL-6 in a subset of patients. Moreover, pre-treatment levels of circulating IL-6 predicted the subsequent development of MDD, a relationship that may have been partially accounted for by pre-treatment PSQI scores. Although this prospective design did not allow for causal inference, it did inform our understanding of temporal relations. Uni-directional associations indicated that IL-6 could predict next month’s PSQI, and PSQI could predict next month’s depressive symptoms. Moreover, time-lagged analyses supported a bi-directional positive feedback loop between depressive symptoms and circulating IL-6, plausibly contributing to emergence of MDD in those patients for whom this feedback dynamic was undeterred. Further prospective research is warranted to examine this possibility, and to further identify the mechanistic paths relating systemic cytokines to sleep, mood, and MDD.