Vascular Risk Status as a Predictor of Later-Life Depressive Symptoms: A Cohort Study

Background Common etiology of vascular diseases and later-life depression may provide important synergies for prevention. We examined whether standard clinical risk profiles developed for vascular diseases also predict depressive symptoms in older adults. Methods Data were drawn from the Whitehall II study with baseline examination in 1991; follow-up screenings in 1997, 2003, and 2008; and additional disease ascertainment from hospital data and registry linkage on 5318 participants (mean age 54.8 years, 31% women) without depressive symptoms at baseline. Vascular risk was assessed with the Framingham Cardiovascular, Coronary Heart Disease, and Stroke Risk Scores. New depressive symptoms at each follow-up screening were identified by General Health Questionnaire caseness, a Center for Epidemiologic Studies Depression Scale score ≥16, and use of antidepressant medication. Results Diagnosed vascular disease (that is, coronary heart disease or stroke) was associated with an increased risk for depressive symptoms, age- and sex-adjusted odds ratios from 1.5 (95% confidence interval 1.0–2.2) to 2.0 (1.4–3.0), depending on the indicator of depressive symptoms. Among participants without manifest vascular disease, the Stroke Risk Score was associated with Center for Epidemiologic Studies Depression Scale depressive symptoms before age 65 (age- and sex-adjusted odds ratio per 10% absolute change in the score = 3.1 [1.5–6.5]), but none of the risk scores predicted new-onset depressive symptoms in those aged ≥65 (odds ratios from .8 to 1.2). Conclusions These data suggest that public health measures to improve vascular risk status will influence the incidence of later-life depressive symptoms via reduced rates of manifest vascular disease.


Supplement Sample Selection for Analysis 1
Participants were eligible for these analyses if they completed the health questionnaire at any two consecutive phases between Phase 3 and Phase 9 and had no missing data on disease status at the corresponding baseline phases. At each of the 3 data collection cycles, we successively excluded participants who had missing data on General Health Questionnaire (GHQ) symptoms at baseline (n = 188, 383 and 102 at phases 3, 5 and 7); those who had GHQ symptoms at baseline (n = 1624, 2187 and 2522); or had missing data on GHQ symptoms at follow-up (n = 486, 85 and 73). Conversely, participants who did not have missing data or depressive symptoms in one data cycle were eligible to the next data cycle. The analysis was therefore based on 5230, 4029, and 3571 participants in the 1st, 2nd and 3rd data cycles, a total of 12,830 person-observations (Table S1). The corresponding figures for the analysis of antidepressant use were 7326, 6405 and 5890 respectively (a total of 19,621 person-observations). In the analysis on Center for Epidemiologic Studies Depression scale (CES-D) depressive symptoms (measured only at Phases 7 and 9), we excluded prevalent CES-D cases by restricting the analysis to 4509 participants in the last data cycle (4509 person-observations).

Sample Selection for Analysis 2
Participants were eligible for these analyses if they completed the health questionnaire and attended the screening at any two consecutive phases between Phase 3 and Phase 9.
At the baseline of each of the 3 screening cycles, we successively excluded participants who had missing data on GHQ symptoms at baseline (n = 7, 141 and 66 at phases 3, 5 and 7); those with prevalent coronary heart disease or stroke (n = 217, 370 and 518 at Phases 3, 5 and 7, respectively), prevalent or previous GHQ symptoms (n = 1485, 1792 and 2163), missing data on risk factors for the Framingham scores at baseline (n = 258, 547 and 126); and missing data on GHQ symptoms at follow-up (n = 404, 57, and 48), leaving 4687, 2956, and 3013 participants for the analytic samples (a total of 10,656 person-observations) ( Table   S1). In the analysis of antidepressant use, the corresponding numbers of participants were 6339, 4474 and 4889 after the corresponding exclusions (15,702 person-observations). In the analyses for CES-D depressive symptoms, we excluded prevalent CES-D depressive symptoms by restricting the analysis to the 2786 participants in the last data cycle (a total of Table S2 shows characteristics of the participants included in Analysis 1 (test of prevalence disease-depressive symptoms association) and Analysis 2 (test of risk scoredepressive symptoms associations among participants with no vascular disease at baseline) and those excluded from these analyses. Any differences between the groups were relatively small.

Analysis of Sample Retention and Unadjusted Relationships
Tables S3 and S4 present unadjusted odds ratios for associations of Framingham risk scores and incident depressive symptoms. We found higher scores to be associated with a reduced likelihood of early-onset GHQ symptoms but, as shown in Table S4, these negative associations disappeared after adjustment for age and sex. Irrespective of adjustments, there were no associations between the vascular risk scores and late-life GHQ symptoms.
This apparently paradoxical finding is likely to be due to confounding by age, as Framingham risk scores increase with increasing age, corresponding to the higher risk of vascular disease in elderly individuals, but the prevalence of GHQ symptoms decreased between the ages of 40 and 60 and subsequently remained relatively stable at older ages. These contrasting age-related trends explain the unadjusted inverse association of vascular risk with incidence of depression which disappeared after adjustment for age and sex.
Unadjusted associations of risk scores with CES-D depressive symptoms and antidepressant use were all null.

Sensitivity Analysis
Sensitivity analysis was based on a subgroup of Phase 5 participants with no current or  a Eligible participants are those who attended both the baseline and follow-up examination (see methods section). b Number of participants after exclusion of participants with GHQ-symptoms or missing data (Analysis 1) or with prevalent CHD or stroke (Analysis 2). For analyses of CES-D depressive symptoms and antidepressant medication use, the figures are not exactly the same.  CES-D-depressive symptoms, n (%) ----CES-D, Center for Epidemiologic Studies Depression Scale; GHQ, General Health Questionnaire; HDL, high-density lipoprotein; MI, myocardial infarction. a Of the 5763 participants contributing to analysis 1, 533 participants did not contribute to the first cycle of data from Phase 3 to Phase 5. b Of the 5318 participants contributing to analysis 2, 631 participants did not contribute to the first cycle of data from Phase 3 to Phase 5. c Data available only for a subsample (n = 696 excluded from Analysis 2, 1003 included in Analysis 2)).