In a sample of 984 outpatients with stable CHD, we found no evidence that depression is associated with increased inflammation. Specifically, we found that depression was not associated with increased WBC, CD40 ligand, CRP, fibrinogen, or IL-6. To the contrary, mean levels of CRP, fibrinogen, and IL-6 appeared lower in depressed as compared with nondepressed participants. Our results suggest that inflammation is unlikely to be responsible for the adverse cardiovascular outcomes associated with depression in patients with established CHD.
We were surprised to find that depression was associated with lower CRP, IL-6, and fibrinogen. This unexpected inverse association should be considered only as hypothesis-generating, unless confirmed by future studies. However, there is some prior evidence that monocytes are decreased in depressed patients (McAdams and Leonard 1993
; Rothermundt et al. 2001
). Because monocytes secrete IL-6 as one of their byproducts, a decreased level of monocytes might result in lower levels of IL-6. Margaglione et al.
(1996) showed that IL-6 affects the production of plasma fibrinogen via a mechanism involving protein kinase C. Thus, it is possible that decreased levels of IL-6 in depressed individuals lead to lower levels of plasma fibrinogen via this mechanism. Depression is associated with elevated levels of cortisol in patients with CHD (Otte et al. 2004
), and cortisol is known to have anti-inflammatory properties. It is possible that the increased cortisol in depressed CHD patients contributes to lower levels of inflammation.
Prior work has suggested that the association of depression with inflammation might vary by gender (Danner et al. 2003
; Ford and Erlinger 2004
), statin use (Lesperance et al. 2004
), and obesity (Ladwig et al. 2005
). Two studies of young adults without known CHD have reported an association of depression with increased CRP in men but not in women (Danner et al. 2003
; Ford and Erlinger 2004
). In contrast, we found that depression was associated with lower inflammation in men. However, the lack of association we observed between depression and CRP in women is similar to the findings of these two studies. One group of authors suggested that menstrual fluctuations in CRP might render the relationship between depression and CRP more difficult to detect in women (Ford and Erlinger 2004
), but the vast majority of women in our sample were post-menopausal, making a menstrual effect unlikely.
A study of patients hospitalized for acute coronary syndrome found that depression was associated with increased CRP in nonusers but not in users of statins (Lesperance et al. 2004
), suggesting that the absence of association in users might have been due to the anti-inflammatory properties of statins (Albert et al. 2001
). We found no evidence for an association of depression with greater inflammation in users or nonusers of statins. Conversely, we found that depression was associated with decreased fibrinogen and IL-6 in statin users and no evidence of an association in statin nonusers.
A study of middle-age healthy men demonstrated that depression was associated with elevated CRP in obese but not in non-obese patients (Ladwig et al. 2005
). We found no evidence of elevated CRP in obese patients. In contrast, we found that depression was associated with lower CRP, fibrinogen, and IL-6 in non-obese patients. These inconsistencies across studies increase the likelihood that the inverse association we observed between depression and inflammation might be due to chance. However, the absolute lack of association we observed between depression and increased inflammation remains a robust finding.
Strengths of our study include its large sample of outpatients with stable CHD, comprehensive measurement of potential confounding variables, and standardized measurement of inflammatory markers after fasting for 12 hours, abstaining from smoking for 5 hours, and not taking aspirin for a week. However, several limitations must be considered in interpreting our results. First, because our study population consisted of mostly older men, our results might not generalize to all populations. Second, it is possible that the CDIS resulted in some misclassification of depression, because use of a standardized instrument cannot replace the diagnosis of depression by a clinician. Finally, owing to the cross-sectional study design, we are not able to determine the causal direction of any relation (or lack of relation) between depression and inflammatory markers.
In summary, we found no evidence that depression is associated with elevated levels of inflammation in patients with stable CHD. We observed an inverse association of depression with CRP, fibrinogen, and IL-6 that needs confirmation in future studies. In the meantime, our results indicate that greater inflammation is unlikely to explain the adverse cardiovascular outcomes associated with depression in patients with CHD.