We agree with Dr. Manev and colleagues that our study (1) does not rule out the possibility that inflammatory pathways alternative to those pertinent to the common biomarkers C-reactive protein (CRP) and interleukin (IL)-6 may be involved in the link between depression and cardiovascular disease (CVD). Depression is associated with a number of inflammatory markers in addition to CRP and IL-6, including, for example, IL-1 beta and tumor necrosis factor alpha (2). The list may well include 5-lipoxygenase (5-LOX), but unfortunately this has not yet been described, at least in humans. C-reactive protein and IL-6 are the 2 biomarkers most consistently associated with cardiovascular risk and therefore it makes sense to begin with these as we try to disentangle the complex link between depression, inflammation, and CVD. Because they are produced as part of the acute phase response, it is possible that these common biomarkers are not truly biologic markers for depression. On the other hand, inflammatory cytokines have well-characterized effects in the central nervous system that may influence depressive behavior, including effects on neurotransmitter function and stimulation of the hypothalamus-pituitary-adrenal axis (3). These actions suggest that inflammatory processes are central to the pathogenesis of depression similar to many other chronic conditions, such as CVD. It is also possible that inflammation contributes to some, but not all, cases of depression, as suggested by the wide range of inflammatory activity commonly found in samples of depressed individuals. Thus, subsets of individuals at the upper end of cytokine levels could drive most of the association (4).