The purpose of the study was to ask whether higher depressive symptoms led subsequently to higher CRP levels, and whether higher CRP levels led subsequently to higher depressive symptoms in middle-aged women who were healthy at baseline We found evidence in our initial models for a bi-directional relationship between depressive symptoms and CRP levels over seven years of follow-up in an ethnically diverse sample of middle-aged women. In multivariate models adjusted for a substantial number of covariates known to influence CRP or depression or both, including health conditions, medications, ethnicity, age, menopausal status, and life style factors, we found that CRP remained a modest, albeit statistically significant, predictor of subsequent depressive symptoms, whereas the reverse association (CES-D→CRP) only approached conventional levels of significance. Adiposity is a strong correlate of CRP so any longitudinal influence of psychosocial factors in relation to CRP may be masked in obese women. However, formal tests for interactions with obesity were nonsignificant. We previously reported that among SWAN women followed for 5 years (with four observations of CRP, i.e. at years 0, 1, 3, and 5 and including women with health problems at baseline), CES-D scores did not predict concurrent CRP levels over time in a risk factor-adjusted model (Matthews et al., 2007
). Note that depression and CRP were unrelated in women in cross-sectional studies that stratified by gender (Howren et al., 2009
). Taken together, our lagged and concurrent analyses suggest that the temporal relationship and the direction of the influence are apparent from CRP levels to subsequent depressive symptoms.
To our knowledge, there are three longitudinal reports relevant to our study. In the Leiden 85-plus Study, CRP levels predicted increases in depressive symptoms over 5 years in those not initially depressed or cognitively impaired (van den Biggelaar et al., 2007
). The Whitehall II study of over 3,000 civil servants tested for bi-directionality between CRP and a 4-item measure of cognitive symptoms of depression that were measured twice, 12 years apart (Gimeno et al., 2008). The cognitive symptom measure included feelings of hopelessness, worthlessness, life not worth living, and not able to do anything because of nerves. In fully adjusted models, which included health conditions, lifestyle factors, obesity, and other covariates, baseline CRP levels predicted subsequent cognitive symptoms of depression, adjusted for initial levels of depressive symptoms, but cognitive symptoms of depression did not predict subsequent levels of CRP or IL-6. Tests for interactions with gender were nonsignificant. Finally, among 263 healthy men and women, depressive symptoms predicted IL-6 six years later, but not CRP in structural equation models. In that sample depressive symptoms were not correlated with CRP measured concurrently at either assessment, although baseline CRP tended to predict change in depressive symptoms, p = 0.06 (Stewart et al., 2009
). In sum, our results are consistent with most of the available literature suggesting that higher CRP levels lead to greater depressive symptoms.
The study also revealed several other interesting findings. Strong predictors of later depressive symptoms, adjusted for earlier symptoms, were sleep problems, osteoarthritis and pain medications, and ethnicity; strong predictors of later CRP levels, adjusted for earlier levels, were BMI, waist circumference (independent of BMI), current smoking, and ethnicity. Furthermore, women who were excluded from the primary analytic sample primarily because of health conditions present at baseline already had higher CRP and CES-D scores at baseline than had the women who did not have exclusionary health conditions; no directional effects of depressive symptoms to subsequent CRP or vice versa were observed in these women.
Our study has several limitations. The sampling frequency was driven by the overall study design as opposed to biological considerations of how long the duration of exposure to depression or elevated CRP would be required to have an influence. Second, we have not measured history of clinical depression in the full sample. Third, the findings are restricted to women around the time of the menopause. The study also has several strengths, including the multi-ethnic sample of women, thorough assessment of time-varying covariates, excellent retention of women across 7 years, and multiple measures of CRP and depressive symptoms.
In conclusion, our study shows that higher CRP levels are modestly related to higher subsequent depressive symptoms over a 7 year period, findings consistent with the Whitehall II study, Leiden 85-plus study, and experimental data. Given that our findings demonstrate that inflammation can influence depressive symptoms, which is a risk factor for CHD, efforts to evaluate the dynamic and bi-directional relationships between other psychosocial risk factors for CHD and putative pathways may also be worthwhile.