Vascular risk factors for depression and apathy | Part II 144 Scope and objectives The first three studies (Part I) of this dissertation aimed at exploring and describing associations between cardio- and cerebrovascular disease and depression, and whether and how vascular risk and neuroticism affect this relationship. In the subsequent three studies (Part II) we looked at associations between cerebrovascular disease, specifically cerebral small vessel disease (CSVD), and apathy. We focused on the relationship between CSVD and apathy in remitted depression and also the concept of vascular apathy was thoroughly evaluated. Since this thesis includes more than a decade of research, in this chapter we will not only summarize and discuss the results of the studies reported on but also add recent relevant findings and consider our findings in the light of this new knowledge. The studies were mostly presented in chronological order to emphasize the development of knowledge and insights derived, which influenced the designs of the subsequent studies and our point of view when evaluating and interpreting the results. For reasons of clarity and legibility, we will discuss the findings of each study immediately after its summary (printed in italics). Does late-life depression raise the risk of cerebrovascular disease? In the Longitudinal Aging Study Amsterdam, we tested the hypotheses that (1) clinically relevant depressive symptoms are an independent risk factor for incident stroke in cardiac and noncardiac patients and that (2) more chronic and severe depressive symptoms are associated with a higher incidence of stroke (Chapter 2). Between 1992 and 2002 a random-sampled community-based cohort of older Dutch people (aged ≥55 years) without a history of stroke (N=2965) was followed for 9 years. The study end point was a first (nonfatal or fatal) stroke, at which point we determined associations with depression, as measured at baseline with the National Institute of Mental Health Diagnostic Interview Schedule and the Center for Epidemiological Studies-Depression Scale (CES-D) by means of multivariate Cox proportional hazards regression analyses of stroke incidence. We also investigated associations between the chronicity and severity of the depressive symptoms and stroke incidence using time-dependent variables. We found that in participants with pre-existent cardiac disease (not in those without such a history) clinically relevant depressive symptoms at baseline (hazard ratio [HR], 2.18; 95% confidence interval [CI], 1.17-4.09) and the severity (range, 0-60; HR, 1.08; 95% CI, 1.02-1.13) and chronicity (HR, 3.51; 95% CI, 1.13-10.93) of depressive symptoms during follow-up were associated with stroke. Based on these results, we concluded that pre-existent cardiac disease moderates the association between depressive symptoms and incident stroke and that in cardiac patients, baseline depressive symptoms and both the severity and chronicity of symptoms during follow-up are associated with incident stroke. This study was published in 2008 and since then, several replication studies have found more and consistent support for a association between depression and stroke, where a meta-analysis calculated the pooled adjusted HR a 1.45 (95% CI, 1.29-1.63) for total
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