Are there bi-directional associations between depressive symptoms and C-reactive protein in mid-life women?

Depression is associated with an increased risk of mortality and recurrent morbidity in patients with coronary heart disease (CHD) and depression may increase the risk of the initial onset of CHD in healthy populations (Rozanski et al., 1999; Suls and Bunde, 2005; Wulsin and Singal, 2003). In reporting the findings from these studies, the standard risk factors for CHD are statistically controlled for, and therefore do not preclude alternative risk factors or other intermediate pathways as explanatory factors or mediators in the associations between depression and CHD. Among the potential pathways that may be relevant to understanding depression's risk for CHD morbidity and mortality is chronic inflammation (Carney et al., 1995), which is thought to be important throughout the natural history of coronary atherosclerosis from the initial defect in endothelial function through plaque rupture (Ross, 1999). A marker of chronic inflammation that is a strong predictor of clinical coronary events is C-reactive protein (CRP) (Pearson et al., 2003). A recent meta-analysis of 51 cross-sectional studies, published between 1967 and 2008, found that depression was associated concurrently with CRP levels (Howren et al., 2009). Subanalyses showed that (a) the relationship was significant in men but not in women in those studies that stratified by gender; (b) the effect was larger in clinic-based as opposed to community-based samples; and (c) the studies that did not adjust for body mass index (BMI) reported associations three times larger than those studies that did adjust for BMI. That obesity might also moderate the association between depression and some inflammatory markers was not examined in the meta-analysis. However, in men enrolled in MONICA (Ladwig et al., 2003), depression and anxiety were related to CRP but only among those who were obese, suggesting stratification by obesity status may be informative. In summary, depression is a reliable correlate of CRP levels, with weaker associations apparent in women, in community samples, and in analyses that consider BMI. Recently it has been suggested that inflammation can produce symptoms resembling those of depression, including anhedonia, vegetative symptoms, and sleeping difficulties (Dantzer et al., 2009; Raison et al., 2006). Patients treated with interferon, which induces inflammation, develop depressive symptoms that can be ameliorated by antidepressants (Capuron et al., 2002). In experimental studies of healthy participants, endotoxin administration leads to short-term increases in anxiety, depressed mood, and poor memory performance (Reichenberg et al., 2001). These findings suggest that inflammation may not only be a consequence of depressive symptoms but also contribute to its presentation. In the present report, we addressed the bi-directional and temporal relation of depressive symptoms and CRP levels across 7 years among women enrolled in the Study of Women's Health Across the Nation (SWAN). Specifically, we addressed two questions: Are women with higher depressive symptoms likely to have higher CRP levels at the next annual visit, adjusted for the CRP levels at the prior visit? And, are women with higher CRP levels likely to have higher depressive symptoms at the next annual visit, adjusted for depressive symptom levels at the prior visit? Secondarily, we explore the role of obesity in understanding any observed relationships because obesity is a strong correlate of CRP.