A prospective evaluation of the directionality of the depression–inflammation relationship

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Abstract

Cross-sectional studies have found that individuals with depressive disorders or symptoms have elevated levels of inflammatory markers predictive of coronary artery disease, including interleukin-6 (IL-6) and C-reactive protein (CRP). Due to the paucity of prospective studies, however, the directionality of the depression–inflammation relationship is unclear. We evaluated the longitudinal associations between depressive symptoms and both IL-6 and CRP among 263 healthy, older men and women enrolled in the Pittsburgh Healthy Heart Project, a 6-year prospective cohort study. During the baseline and follow-up visits, participants completed the Beck Depression Inventory-II (BDI-II) to assess depressive symptoms and underwent blood draws to quantify serum IL-6 and CRP. Path analyses revealed that baseline BDI-II (β = 0.18, p = 0.01, ΔR2 = 0.02) was a predictor of 6-year change in IL-6, even after adjustment for demographic, biomedical, and behavioral factors as well as other negative emotions. Of all the factors examined, only body-mass index was a stronger predictor of IL-6 change than depressive symptoms. In contrast to these results, baseline IL-6 did not predict 6-year change in BDI-II. Evidence of a weak bidirectional relationship between BDI-II and CRP was also observed; however, neither of these longitudinal associations was significant. The present findings indicate that depressive symptoms may precede and augment some inflammatory processes relevant to coronary artery disease among healthy, older adults. Therefore, our results imply that depression may lead to inflammation and that inflammation may be one of the mechanisms through which depression contributes to cardiovascular risk.

Section snippets

Participants

Participants were 263 men and women enrolled in the Pittsburgh Healthy Heart Project (PHHP), a prospective study of healthy, community-dwelling adults aged 50–70 years. This study was approved by the University of Pittsburgh institutional review board. Participants provided written informed consent and were paid $700 for attending the baseline and 6-year visits. Details regarding recruitment and inclusion/exclusion criteria are provided elsewhere (Kamarck et al., 2007, Stewart et al., 2007).

Preliminary analyses

Bivariate correlations performed to examine the cross-sectional relationships among the factors of interest revealed that BDI-II was not associated with IL-6 (r = -0.01, p = 0.87) or CRP (r = -0.06, p = 0.36) at baseline. Similarly, 6-year BDI-II was not related to 6-year IL-6 (r = 0.03, p = 0.66) or CRP (r = 0.05, p = 0.41). Consistent with previous findings (Cesari et al., 2003, Luc et al., 2003), we observed moderate positive correlations between baseline IL-6 and CRP (r = 0.29, p < 0.01) and between 6-year

Discussion

The findings we report in this sample of healthy, older adults are most consistent with the notion that depression may lead to, rather than result from, augmented inflammation. Path analytic models revealed that greater depressive symptom severity at baseline was associated with larger 6-year increases in serum IL-6, even after adjustment for demographic, biomedical, and behavioral factors. Importantly, the magnitude of this relationship is not trivial; only one of the control variables, BMI,

Conflict of interest statement

All authors declare that there are no conflicts of interest.

Acknowledgments

This research was supported by the National Heart, Lung, and Blood Institute Grant HL056346 (TK, PI), Program Project Grant HL040962, and the Pittsburgh Mind-Body Center Grants HL076852 and HL076858. For their assistance with data collection, we thank the entire project staff of the Pittsburgh Healthy Heart Project.

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