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. 2020 Dec 15;324(23):2396-2405.
doi: 10.1001/jama.2020.23068.

Association Between Depressive Symptoms and Incident Cardiovascular Diseases

Eric L Harshfield  1   2 , Lisa Pennells  1 , Joseph E Schwartz  3   4 , Peter Willeit  1   5 , Stephen Kaptoge  1 , Steven Bell  1   2 , Jonathan A Shaffer  6 , Thomas Bolton  1 , Sarah Spackman  1 , Sylvia Wassertheil-Smoller  7 , Frank Kee  8 , Philippe Amouyel  9 , Steven J Shea  10 , Lewis H Kuller  11 , Jussi Kauhanen  12 , E M van Zutphen  13   14   15 , Dan G Blazer  16 , Harlan Krumholz  17 , Paul J Nietert  18 , Daan Kromhout  19 , Gail Laughlin  20 , Lisa Berkman  21 , Robert B Wallace  22 , Leon A Simons  23 , Elaine M Dennison  24 , Elizabeth L M Barr  25 , Haakon E Meyer  26 , Angela M Wood  1 , John Danesh  1 , Emanuele Di Angelantonio  1 , Karina W Davidson  27 ; Emerging Risk Factors Collaboration
Affiliations

Association Between Depressive Symptoms and Incident Cardiovascular Diseases

Eric L Harshfield et al. JAMA. .

Abstract

Importance: It is uncertain whether depressive symptoms are independently associated with subsequent risk of cardiovascular diseases (CVDs).

Objective: To characterize the association between depressive symptoms and CVD incidence across the spectrum of lower mood.

Design, setting, and participants: A pooled analysis of individual-participant data from the Emerging Risk Factors Collaboration (ERFC; 162 036 participants; 21 cohorts; baseline surveys, 1960-2008; latest follow-up, March 2020) and the UK Biobank (401 219 participants; baseline surveys, 2006-2010; latest follow-up, March 2020). Eligible participants had information about self-reported depressive symptoms and no CVD history at baseline.

Exposures: Depressive symptoms were recorded using validated instruments. ERFC scores were harmonized across studies to a scale representative of the Center for Epidemiological Studies Depression (CES-D) scale (range, 0-60; ≥16 indicates possible depressive disorder). The UK Biobank recorded the 2-item Patient Health Questionnaire 2 (PHQ-2; range, 0-6; ≥3 indicates possible depressive disorder).

Main outcomes and measures: Primary outcomes were incident fatal or nonfatal coronary heart disease (CHD), stroke, and CVD (composite of the 2). Hazard ratios (HRs) per 1-SD higher log CES-D or PHQ-2 adjusted for age, sex, smoking, and diabetes were reported.

Results: Among 162 036 participants from the ERFC (73%, women; mean age at baseline, 63 years [SD, 9 years]), 5078 CHD and 3932 stroke events were recorded (median follow-up, 9.5 years). Associations with CHD, stroke, and CVD were log linear. The HR per 1-SD higher depression score for CHD was 1.07 (95% CI, 1.03-1.11); stroke, 1.05 (95% CI, 1.01-1.10); and CVD, 1.06 (95% CI, 1.04-1.08). The corresponding incidence rates per 10 000 person-years of follow-up in the highest vs the lowest quintile of CES-D score (geometric mean CES-D score, 19 vs 1) were 36.3 vs 29.0 for CHD events, 28.0 vs 24.7 for stroke events, and 62.8 vs 53.5 for CVD events. Among 401 219 participants from the UK Biobank (55% were women, mean age at baseline, 56 years [SD, 8 years]), 4607 CHD and 3253 stroke events were recorded (median follow-up, 8.1 years). The HR per 1-SD higher depression score for CHD was 1.11 (95% CI, 1.08-1.14); stroke, 1.10 (95% CI, 1.06-1.14); and CVD, 1.10 (95% CI, 1.08-1.13). The corresponding incidence rates per 10 000 person-years of follow-up among individuals with PHQ-2 scores of 4 or higher vs 0 were 20.9 vs 14.2 for CHD events, 15.3 vs 10.2 for stroke events, and 36.2 vs 24.5 for CVD events. The magnitude and statistical significance of the HRs were not materially changed after adjustment for additional risk factors.

Conclusions and relevance: In a pooled analysis of 563 255 participants in 22 cohorts, baseline depressive symptoms were associated with CVD incidence, including at symptom levels lower than the threshold indicative of a depressive disorder. However, the magnitude of associations was modest.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Pennells reported receiving grants from British Heart Foundation (BHF). Dr Schwartz reported receiving grants from the National Heart, Lung, and Blood Institute (NHLBI). Dr Kaptoge reported receiving grants from the BHF and the Medical Research Council. Dr Bell reported receiving grants from the National Institute for Health Research (NIHR) Blood and Transplant Research Unit in Donor Health and Genomics, the BHF, and the UK Medical Research Council. Ms Spackman reported receiving grants from BHF. Dr Wassertheil-Smoller reported receiving grants from the National Institutes of Health (NIH). Dr Kee reported receiving grants from the UK Clinical Research Collaborative. Dr Amouyel reported being the director of the Fondation Alzheimer, a nonprofit organization, and receiving personal fees from Genoscreen. Dr Shea reported receiving grants from the NHLBI. Dr Krumholz reported receiving personal fees from UnitedHealth, IBM Watson Health, Element Science, Aetna, Facebook, Siegfried & Jensen law firm, Arnold & Porter law firm, Martin/Baughman law firm, National Center for Cardiovascular Diseases, Beijing; support from HugoHealth, Refactor Health, Centers for Medicare & Medicaid Services; and grants from Medtronic and the US Food and Drug Administration, Medtronic and Johnson & Johnson, and Shenzhen Center for Health Information. Dr Nietert reported receiving grants from the NIH. Dr Davidson reported receiving grants from the NIH. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Selection of Eligible Studies and Participants From the Emerging Risk Factors Collaboration and the UK Biobank
Figure 2.
Figure 2.. Association of Depressive Symptoms With Coronary Heart Disease, Stroke, and Cardiovascular Disease
Hazard ratio (HR) reported is per 1-SD increase in depressive symptoms, adjusted for age, sex (stratified), smoking status, and history of diabetes. Values on the x-axis display the geometric mean Center for Epidemiological Studies Depression (CES-D) scale within quintiles across all studies (plotted on a log scale), or the 2-item Patient Health Questionnaire (PHQ-2) depression score. Floating absolute variances were used to derive 95% CIs (indicated by error bars) from the variances that corresponded to the amount of information underlying each group (including the reference group).
Figure 3.
Figure 3.. Adjusted Hazard Ratios for Cause-Specific Mortality and Major Cardiovascular Disease Per 1-SD Higher Depression Scorea
aAdjusted for age, sex (stratified), smoking status, and history of diabetes. Studies with fewer than 10 events were excluded from the analysis of each outcome. A 1-SD increase in depression score corresponds to a 2.7-fold increase in the CES-D and 1-unit increase in the PHQ-2 scores. bIncludes fatal and nonfatal events. CES-D indicates, Center for Epidemiological Studies Depression scale; CHD, coronary heart disease; CVD, cardiovascular disease; HR, hazard ratio; and PHQ-2, 2-item Patient Health Questionnaire.
Figure 4.
Figure 4.. Adjusted Hazard Ratios for Coronary Heart Disease, Stroke, and Cardiovascular Disease per 1-SD Higher Depressive Symptoms in Comparison With Established Cardiovascular Disease Risk Factors
Hazard ratios (HRs) for continuous variables are per 1-SD higher baseline values. Risk factors were adjusted for age, sex, smoking status, history of diabetes, and depression score. CES-D indicates Center for Epidemiological Studies Depression scale; CHD, coronary heart disease; CVD, cardiovascular disease; HDL, high-density lipoprotein; PHQ-2, 2-item Patient Health Questionnaire.
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Comment in

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