Serum SAA was increased significantly and, on average, by over 86% in the group of remitted, unmedicated MDD women versus BMI-matched control subjects. Serum CRPhs was increased significantly and by an average of almost three-fold in these patients. The proportion of women at high risk for future CAD, on the basis of established cut-off values for SAA and CRP, was 4 times higher in MDD women than in controls. These differences were based on two separate determinations showing high test-retest reliability, indicating their stability over time. Measurements were done with an automated system that minimizes human error, reducing intra- and interassay variability, and were done in a blinded fashion.
These findings are unlikely to represent artifacts of BMI or phase of the menstrual cycle, and cannot be attributed to a transient effect of a current depressive episode. Given that the patients had been off psychotropic medications for at least three months prior to study, it is also difficult to attribute these findings to an effect of antidepressant medications, although a long-term effect of such medications cannot be ruled out. The MDD patients were slightly, but not significantly older on average than the control subjects; moreover, there was no significant correlation between age and either SAA or CRPhs, analyzing either in the combined sample or by study group. Thus, these elevated levels of SAA and CRPhs are also unlikely to be secondary to an age effect. As expected given their clinically remitted status, hypercortisolism was not present in the patients compared with controls, and there was no evidence of a significant association between 24 hour urinary free cortisol and serum levels of either SAA or CRPhs.
Our findings indicate that elevation of CRP is not confined to the depressive state, and indicate that SAA is also increased during sustained remission of MDD. These data suggest the presence of a persistent pro-inflammatory state in women who have clinically recovered from depressive episodes and have discontinued antidepressant medications for several months or more.
Our results do not allow conclusions as to whether elevated SAA and CRP in unmedicated remitted patients is a consequence of prior depressive episodes, or represents a shared vulnerability to CAD and MDD. Studies of individuals at high risk for development of MDD, but who have not yet manifested the depressive phenotype, would help to address this question.
CRP and SAA are not simply surrogate biochemical markers of CAD risk, but play important roles during inflammatory responses Although both likely confer survival value by their roles in the response to acute infection or tissue injury, more sustained, low-grade elevations in these mediators are proposed to participate in the chronic inflammatory process leading to progression and/or rupture of atherosclerotic lesions (Kisilevsky and Tam 2002
; Pepys and Hirschfield 2003
) Both CRP and SAA are found in the walls of arterial plaques and inflamed endothelial linings. Moreover, SAA functions as an apolipoprotein for HDLs that modulates “reverse” cholesterol transport, with the net effect of reducing cholesterol retrieval by HDL from most tissue sites other than macrophages (Kisilevsky and Tam 2002
). Thus, these mediators may directly participate in the pathogenic process of CAD.
The elevation of both SAA and CRP reported here is of interest given possible differential tissue origins of these mediators. Thus, CRP derives mainly from liver, while recent data suggest a greater derivation of SAA in humans from visceral fat than from liver (Poitou et al 2005
; Sjoholm et al 2004
; Yang et al 2004
) Thus, secretion of inflammatory mediators by visceral fat may play a role in the CAD risk associated with MDD in addition to increased CRP production by the liver in response to pro-inflammatory signals. The relatively low concordance rate between elevated SAA and CRP in our study subjects may reflect their distinct origin and suggests the need for further studies of both of these mediators in MDD.
Our findings support the premise that MDD is associated with clinically significant systemic manifestations, even following remission of depressive symptoms. The presence of a persistent pro-inflammatory state may contribute to the increased CAD risk associated with MDD (Lett et al 2004
; Wulsin 2004
) We thus propose that further studies be conducted to: 1) confirm these findings in larger and more diverse samples of patients with MDD; 2) examine whether our observations extend to men as well as women with MDD; 3) explore their biological determinants and relationship to other known CAD risk factors; and 4) examine their clinical implications for CAD risk in both cross-sectional and longitudinal studies Should these findings be confirmed and found to have value in predicting increased CAD risk, MDD patients manifesting pro-inflammatory risk markers may be candidates for preventive therapies such as drugs with anti-inflammatory actions including aspirin statins or other agents (Jain and Ridker 2005
; Plutzky 2003
) to reduce their likelihood of developing clinically significant CAD.