Association of Symptoms of Depression With Cardiovascular Disease and Mortality in Low-, Middle-, and High-Income Countries | Cardiology | JAMA Psychiatry | JAMA Network
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Figure 1.  Associations Between Number of Depressive Symptoms and Primary Outcomes
Associations Between Number of Depressive Symptoms and Primary Outcomes

Relative risks of incident cardiovascular disease (CVD), mortality, and the combined outcome (the first of either incident CVD or death) increased with the number of symptoms of depression. Participants who were either asymptomatic or only reported feeling sad, blue, or depressed received a Short-Form Composite International Diagnostic Interview (CIDI-SF) score of 0. We report hazard ratios (HRs) for each CIDI-SF score from 1 to 7 relative to those with a score of 0, using Cox proportional hazards models adjusted for age, sex, educational attainment, urban/rural residence, use of statins, 1 or 2 or more disabilities, former and current smoking and alcohol use, hypertension, diabetes, social isolation (an index from 0-5), and including random intercepts for study center (model 2). P for trend was modeled using the CIDI-SF score as a continuous variable.

Figure 2.  Associations Between ≥4 Symptoms of Depression and Mortality and Incident CVD, in Subgroups Determined by Traditional NCD Risk Factors and Social Determinants of Health
Associations Between ≥4 Symptoms of Depression and Mortality and Incident CVD, in Subgroups Determined by Traditional NCD Risk Factors and Social Determinants of Health

Associations between depression and incident cardiovascular death (CVD), mortality, and the combined outcome (the first of either incident CVD or death) were stronger in men compared with women but were otherwise independent of traditional risk factors after adjustments for age, sex, educational attainment, urban/rural residence, use of statins, 1 or 2 or more disabilities, current smoking, alcohol use, hypertension, diabetes, and social isolation index and including random intercepts for center (model 2). HR indicates hazard ratio; NCD, noncommunicable diseases; WHR, waist-to-hip ratio.

Table 1.  Baseline Prevalence of ≥4 Depressive Symptoms and Sample Characteristics
Baseline Prevalence of ≥4 Depressive Symptoms and Sample Characteristics
Table 2.  Event Rates and Survival Analyses Showing Associations Between ≥4 Depressive Symptoms and Adverse Clinical Outcomesa
Event Rates and Survival Analyses Showing Associations Between ≥4 Depressive Symptoms and Adverse Clinical Outcomesa
Table 3.  Associations Between ≥4 Depressive Symptoms and the Combined Outcome by Geographical Regions, Country Income Status, and Urban/Rural Communitiesa
Associations Between ≥4 Depressive Symptoms and the Combined Outcome by Geographical Regions, Country Income Status, and Urban/Rural Communitiesa
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    Depression, incident cardiovascular disease, and all-cause mortality
    Tomoyuki Kawada, MD | Nippon Medical School
    Rajan et al. conducted a prospective study to investigate the association between depression and incident cardiovascular disease (CVD) and all-cause mortality in countries with different levels of economic developments (1). Adults with depressive symptoms were significantly associated with the increased risk of incident CVD and mortality, especially in urban areas and in men. I have some comments about their study.

    First, Many factors can be considered as risk factors of CVD incidence, and depression is one of the psychological risk factors. Furthermore, there exist many mortality risks in patients with depression, including suicide and physical commodities. Epidemiological risk assessment
    of CVD incidence and all-cause mortality should be conducted comprehensively by considering sociodemographic and socioeconomic status. Causal mechanism regarding urbanization and increased risk of CVD or mortality should be specified by further studies.

    Second, Harshfield et al. conducted a pooled prospective analysis to investigate the association between depressive symptoms and CVD incidence (2). Baseline depressive symptoms were significantly associated with subsequent CVD incidence, even symptoms lower than the threshold of clinical depressive disorder. This study presented minimum risk of depressive symptom on subsequent CVD incidence. As the type of CVD and causality of depressive symptoms might be various, stratified analysis by classifying clinical outcomes and cause of depression might be needed.

    Finally, Kabutoya et al. reported that CVD incidence in men was higher in the depression group than in the non-depression group, although there was no difference in women (3). The frequency and severity of depression differ in women and men, and the association between depression and CVD incidence should be considered in each sex. I speculate that difference in working environment and hormonal factors in women and men might influence the association. In any case, further studies are needed.

    References
    1. Rajan S, McKee M, Rangarajan S, et al. Association of Symptoms of Depression With Cardiovascular Disease and Mortality in Low-, Middle-, and High-Income Countries. JAMA Psychiatry 2020;77(10):1052-1063.
    2. Harshfield EL, Pennells L, Schwartz JE, et al. Association Between Depressive Symptoms and Incident Cardiovascular Diseases. JAMA 2020;324(23):2396-2405.
    3. Kabutoya T, Hoshide S, Davidson KW, Kario K. Sex differences and the prognosis of depressive and nondepressive patients with cardiovascular risk factors: the Japan Morning Surge-Home Blood Pressure (J-HOP) study. Hypertens Res 2018;41(11):965-972.
    CONFLICT OF INTEREST: None Reported
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    Original Investigation
    June 10, 2020

    Association of Symptoms of Depression With Cardiovascular Disease and Mortality in Low-, Middle-, and High-Income Countries

    Author Affiliations
    • 1Department of Health Services Research and Policy, London School of Hygiene & Tropical Medicine, Tavistock Place, London, United Kingdom
    • 2Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Ontario, Canada
    • 3Department of Molecular and Clinical Medicine, Sahlgrenska Academy, Sahlgrenska University Hospital, University of Gothenburg, Sweden
    • 4Eternal Heart Care Centre & Research Institute, Jaipur, India
    • 5Health Action by People, Trivandrum, India
    • 6Department of Medicine, University of Ottawa, Ontario, Canada
    • 7Faculty of Health Sciences, Simon Fraser University, Burnaby, Division of Cardiology, Providence Health Care, Vancouver, British Columbia, Canada
    • 8Department of Cardiac Sciences, King Fahad Cardiac Center, College of Medicine, King Saud University, Riyadh, Saudi Arabia
    • 9University of the Philippines College of Medicine, Manila, Philippines
    • 10Masira Research Institute, Medical School, Universidad de Santander (UDES), FOSCAL, Bucaramanga, Colombia
    • 11Department of Medicine, Universidade de Santo Amaro, Hospital Alemão Oswaldo Cruz, São Paulo, Brazil
    • 12Universidad de La Frontera, Temuco, Chile
    • 13Istanbul Medeniyet University, Faculty of Medicine, Department of Internal Medicine, Istanbul, Turkey
    • 14Africa Unit for Transdisciplinary Health Research, North-West University, Potchefstroom, South Africa
    • 15Estudios Clínicos Latinoamérica (ECLA), Rosario, Santa Fe, Argentina
    • 16Faculty of Medicine, UiTM, Malaysia
    • 17University of Zimbabwe College of Health Sciences, Department of Physiology, Harare, Zimbabwe
    • 18Department of Medicine, Queen's University, Kingston, Ontario, Canada
    • 19Isfahan Cardiovascular Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
    • 20Department of Medicine, Dubai Medical University, Hatta Hospital, Dubai Health Authority, Dubai, United Arab Emirates
    • 21Department of Angiology, Wroclaw Medical University, Poland
    • 22Advocate Research Institute, Advocate Health Care, Downers Grove, Illinois
    • 23Institute for Community and Public Health, Birzeit University, Birzeit, Palestine
    • 24Department of Community Health Sciences, Aga Khan University, Karachi, Pakistan
    • 25Independent University, Bangladesh, Dhaka, Bangladesh
    • 26National Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences, Beijing, China
    JAMA Psychiatry. 2020;77(10):1052-1063. doi:10.1001/jamapsychiatry.2020.1351
    Key Points

    Question  Does the increased risk of incident cardiovascular disease and mortality in middle-aged adults with depressive symptoms vary across and within countries?

    Findings  In this cohort study from 21 countries and 145 862 participants, cardiovascular events and death increased by 20% in people with 4 or more depressive symptoms compared with people without. The relative risk increased in countries at all economic levels but was more than twice as high in urban than rural areas.

    Meaning  Adults with depressive symptoms experience poor physical health outcomes and increased risk of mortality across the world and in different settings, especially in urban areas.

    Abstract

    Importance  Depression is associated with incidence of and premature death from cardiovascular disease (CVD) and cancer in high-income countries, but it is not known whether this is true in low- and middle-income countries and in urban areas, where most people with depression now live.

    Objective  To identify any associations between depressive symptoms and incident CVD and all-cause mortality in countries at different levels of economic development and in urban and rural areas.

    Design, Setting, and Participants  This multicenter, population-based cohort study was conducted between January 2005 and June 2019 (median follow-up, 9.3 years) and included 370 urban and 314 rural communities from 21 economically diverse countries on 5 continents. Eligible participants aged 35 to 70 years were enrolled. Analysis began February 2018 and ended September 2019.

    Exposures  Four or more self-reported depressive symptoms from the Short-Form Composite International Diagnostic Interview.

    Main Outcomes and Measures  Incident CVD, all-cause mortality, and a combined measure of either incident CVD or all-cause mortality.

    Results  Of 145 862 participants, 61 235 (58%) were male and the mean (SD) age was 50.05 (9.7) years. Of those, 15 983 (11%) reported 4 or more depressive symptoms at baseline. Depression was associated with incident CVD (hazard ratio [HR], 1.14; 95% CI, 1.05-1.24), all-cause mortality (HR, 1.17; 95% CI, 1.11-1.25), the combined CVD/mortality outcome (HR, 1.18; 95% CI, 1.11-1.24), myocardial infarction (HR, 1.23; 95% CI, 1.10-1.37), and noncardiovascular death (HR, 1.21; 95% CI, 1.13-1.31) in multivariable models. The risk of the combined outcome increased progressively with number of symptoms, being highest in those with 7 symptoms (HR, 1.24; 95% CI, 1.12-1.37) and lowest with 1 symptom (HR, 1.05; 95% CI, 0.92 -1.19; P for trend < .001). The associations between having 4 or more depressive symptoms and the combined outcome were similar in 7 different geographical regions and in countries at all economic levels but were stronger in urban (HR, 1.23; 95% CI, 1.13-1.34) compared with rural (HR, 1.10; 95% CI, 1.02-1.19) communities (P for interaction = .001) and in men (HR, 1.27; 95% CI, 1.13-1.38) compared with women (HR, 1.14; 95% CI, 1.06-1.23; P for interaction < .001).

    Conclusions and Relevance  In this large, population-based cohort study, adults with depressive symptoms were associated with having increased risk of incident CVD and mortality in economically diverse settings, especially in urban areas. Improving understanding and awareness of these physical health risks should be prioritized as part of a comprehensive strategy to reduce the burden of noncommunicable diseases worldwide.

    Introduction

    The Sustainable Development Goals aim to reduce premature mortality from noncommunicable diseases (NCDs) by 30% and improve mental well-being worldwide by 2030.1 These goals are inextricably linked, and otherwise healthy people with depression have been shown to experience increased risks of incident cardiovascular disease (CVD),2 cancers,3,4 and mortality5 (eTable in the Supplement). Yet, these relationships have been studied almost exclusively in high-income countries5,6 and in China,7,8 with a recent multicountry meta-analysis2 reporting no prospective studies for depression from elsewhere. Even if the associations with CVD and mortality are real in high-income countries, they cannot necessarily be generalized to low- and middle-income countries, where most of the global burden of NCDs and mental disorders exists.9,10 First, any underlying mechanisms are likely to involve complex behavioral and metabolic pathways11 (associated with increased smoking behaviors, diabetes, and hypertension for example) that may vary by setting. Second, few people receive treatment that might modify any association in these countries.12 Despite initiatives to scale-up mental health services worldwide,13-16 the physical health outcomes of people with depression in resource-poor settings remain a neglected area, and it is therefore crucial for health service planning that we research CVD incidence and mortality in people with depression in these settings. Another especially important question is whether these associations vary between urban and rural settings, given that rapid urbanization is associated with erosion of protective factors for depression such as traditional social support17 and healthy behaviors.18,19

    Using data from the Prospective Urban Rural Epidemiological (PURE) study, with standardized information on baseline depression and subsequent physical health outcomes from 21 countries, we ask whether associations reported previously from high-income countries can be found in low- and middle-income countries and in urban and rural areas.

    Methods
    Study Design and Participants

    The design and methods of PURE are described elsewhere20,21 and in the eMethods in the Supplement. Briefly, PURE is a prospective cohort study in 51 centers in 21 high-, middle-, and low-income countries. When countries joined PURE, we categorized them according to World Bank income groupings, which included 5 low- (Bangladesh, India, Pakistan, Zimbabwe, and Tanzania), 5 lower-middle– (China, the Philippines, Colombia, Iran, and Occupied Palestinian Territory), 7 upper-middle– (Argentina, Brazil, Chile, Malaysia, Poland, South Africa, and Turkey), and 4 high-income countries (Canada, Sweden, United Arab Emirates, and Saudi Arabia) (eMethods in the Supplement). Countries and communities were selected to reflect socioeconomically diverse populations, with broadly representative samples of each community. The final samples were also broadly representative of populations in each country (eMethods in the Supplement). Individuals aged 35 to 70 years with no intention to change address for 4 years were eligible to enroll in the first 2 phases of the PURE core study, which involved detailed baseline data collection and follow-up for subsequent health outcomes. We approached 506 087 individuals from 132 977 households in 997 urban and rural communities, of whom 458 434 (91%) consented to a family census. Of 235 180 who were eligible, 166 762 (71%) enrolled (eMethods in the Supplement). The study was coordinated by the Population Health Research Institute (Hamilton, ON, Canada) and approved by ethics committees at each participating center. Patients provided written informed consent.

    Baseline Procedures

    Trained field researchers administered standardized, locally translated questionnaires to participants at baseline, recorded anthropometrics, and collected fasting blood samples. The questionnaires included an adapted Short-Form Composite International Diagnostic Interview (CIDI-SF) for major depressive disorders.22 This has been used previously in large multicountry epidemiologic trials,23 including in China,7 and is based on the Composite International Diagnostic Interview (CIDI),24 which has been validated in low- and middle-income countries.12 Participants were asked whether they had felt sad, blue, or depressed for 2 weeks or longer in the previous year and if so, whether they experienced loss of interest in pleasurable activities, tiredness, unintentional weight changes, difficulty sleeping or concentrating, feeling worthless, or thoughts about death during the same period. Validation studies from the United States and Canada25,26 show that 4 or more of these 7 symptoms are predictive of major depressive disorder, and we therefore used this threshold to classify depressive symptoms. We also recorded antidepressant use at baseline and during follow-up.

    Follow-up and Outcomes

    Three yearly follow-up visits took place between January 2008 and June 2019. At each visit, standardized forms were used to record incident diseases and intervening mortality, using information from household interviews, medical records, death certificates, and other sources. Events were adjudicated centrally in each country (eMethods in the Supplement). Primary outcomes included incidence of major CVD (including cardiovascular death, myocardial infarction, stroke, or heart failure), all-cause mortality, and a combined outcome, defined as either the incidence of major CVD or all-cause mortality. In secondary analyses, we divided the first 2 categories into incident myocardial infarction, stroke, heart failure and mortality from cardiovascular and noncardiovascular causes, and included incidence of any cancer.

    Statistical Analysis

    We compared event rates for all outcomes in people with 4 or more and less than 4 depressive symptoms, standardizing directly for the age and sex of the PURE population. Using 2 Cox proportional hazards shared frailty models, we modeled associations between 4 or more depressive symptoms and each outcome, incorporating random intercepts for study center as most clustering was within center or country. In model 1, we adjusted for baseline age, sex, urban/rural residence, educational attainment, use of statins, and self-reported disabilities (0, 1, or ≥2 physical impairments). In model 2, we also included baseline characteristics that were indistinguishable as confounders or mediators including former or current smoking or alcohol use, hypertension, diabetes, and a social isolation index based on the Modified Social Network Index.27 More detailed descriptions of covariate classifications are in the eMethods in the Supplement. In sensitivity analyses, we adjusted separately for a further 7 variables in addition to those in model 2, including physical inactivity, unhealthy diet,28 and obesity (where this data was available); relative wealth29 and adverse life experiences; and antidepressant use. To address concerns about reverse causation, we excluded participants who reported an outcome within 2 years of enrollment, as well as participants who reported chest pain, persistent cough, or jaundice in the 6 months before enrollment, and repeated the analyses for that outcome. We also excluded participants who had been bereaved within the previous year. To determine whether associations with the primary outcomes were dose dependent, we modeled hazard ratios (HRs) for each CIDI-SF score from 1 to 7 (relative to a score of 0), using model 2 and report the P value for linear trend.

    To study the consistency of the associations between 4 or more depressive symptoms and the combined outcome in different geographical regions; in high-/upper-middle–income countries and lower-middle–/low-income countries; and in urban and rural residents, we compared HRs derived from models 1 and 2, examining coefficients for modifiable risk factors and performing tests for interactions between depression and each setting. To account for potential crosscountry differences in symptom reporting,30 we also modeled associations between both CIDI-SF score (as a continuous variable) and the presence of 4 or more depressive symptoms (as a binary variable) with the combined outcome in each country, adjusting minimally for age and sex.

    Finally, we examined the consistency of the associations between depressive symptoms and CVD, mortality, and the combined outcome in subgroups determined by age, sex, traditional NCD risk factors, and social determinants, again performing tests for interaction in each case. Because of multiple comparisons in this analysis, only 2-sided P values over .001 were interpreted as showing significant associations. All analyses were conducted using Stata version 15.0 (StataCorp). Analysis began February 2018 and ended September 2019.

    Results

    Of 166 762 participants, 164 007 (98%) completed at least 1 round of follow-up, while 2553 (2%) were lost before completing any follow-up visits (displayed by country and by visit number in the eMethods in the Supplement). We included 145 862 participants in the final analysis after excluding 1441 (0.9%) without depression data, 13 846 (9.5%) with baseline CVD or cancer, and 1530 (0.9%) without event data (eMethods in the Supplement).

    The age-sex standardized prevalence of depressive symptoms in PURE was 11% (n = 15 983) overall, 15% (n = 8213) in high-/upper-middle–income countries, and 8% (n = 7770) in lower-middle–/low-income countries (Table 1). As shown in eResults 1 in the Supplement, prevalence ranged from 2% (n = 645) in China to 40% (n = 527) in Occupied Palestinian Territory (although this was an outlier, with all other countries below 30%). eResults 1 in the Supplement also shows that the CIDI-SF demonstrated reasonable internal consistency, with a Cronbach α of .71 and similar symptom ranking between countries. Prevalence was also higher in urban areas (9601 [13%] vs 6382 [9%] in rural areas), in women (11 409 [13%] vs 4574 [7%] in men), in people with 2 or more disabilities (5475 [22%] vs 10 508 [9%] without), and in people with diabetes (1785 [12%] vs 14 198 [11%] without). People with depressive symptoms were also more likely to smoke (2378 [15%] vs 13 277 [10%]), consume alcohol (4610 [30%] vs 31 514 [24%]), eat unhealthily (5608 [38%] vs 38 175 [32%]),28 be socially isolated (2140 [13%] vs 8650 [7%]),27 and were more likely to mistrust others (3230 [25%] vs 16 340 [15%]). Of the people who reported depressive symptoms at baseline, 97 (0.6%) reported using antidepressants at the time, while 1359 (9%) used antidepressants during follow-up.

    Over a median (interquartile range) follow-up of 9.3 (7.4-10.7) years, there were 9721 deaths and 7258 major cardiovascular events comprising 11 860 occurrences of the combined outcome. Deaths were mostly cardiovascular (2618 [29%]) and cancer related (1844 [20%]), with fewer due to respiratory diseases (627 [7%]), infections (558 [6%]), and injury or suicide (664 [7%]). After direct standardization for age and sex, event rates for all conditions were higher in people with depressive symptoms compared with people without, except for stroke, for which event rates were similar between groups (Table 2).

     Table 2 also shows that the HRs for all primary outcomes increased between 17% and 20% in people with 4 or more depressive symptoms, after adjustments for demographics, education, use of statins, and disability and including random intercepts for center (model 1). These risks were not markedly attenuated by further adjustments for traditional risk factors and social isolation (model 2) and remained strong and significant for all-cause mortality (HR, 1.17; 95% CI, 1.11-1.25; P < .001), major CVD (HR, 1.14; 95% CI, 1.05-1.24; P = .001), and the combined outcome (HR, 1.18; 95% CI, 1.11-1.24; P < .001) (Table 2). In secondary analyses, depressive symptoms were also associated with incident myocardial infarction (HR, 1.23; 95% CI, 1.10-1.37) and noncardiovascular death (HR, 1.21; 95% CI, 1.13-1.31). In sensitivity analyses, these estimates were materially unchanged after further adjustments and removal of recently bereaved participants, and we did not find evidence of reverse causation (eResults 2 in the Supplement). Associations with incident heart failure (HR, 1.09; 95% CI, 0.86-1.31), stroke (HR, 1.05; 95% CI, 0.91-1.21), cardiovascular death (HR, 1.07; 95% CI, 0.94-1.22), and cancer (HR, 1.04; 95% CI, 0.94-1.14) were directionally similar but nonsignificant (Table 2).

    The relative risks of all primary outcomes increased progressively with the number of depressive symptoms. Accordingly, risks of the combined outcome increased from HR of 1.05 (95% CI, −0.92 to 1.19) in those with 1 symptom to HR of 1.24 (95% CI, 1.12-1.37) in those with 7 symptoms (P for trend < .001) (Figure 1).

    Table 3 shows the event rates for the combined outcome and HRs associated with depression in each geographical setting for models 1 and 2. It also shows interaction effects for depression × setting and includes the coefficients for each of the key covariates in the model to show their relative contributions in each setting. These results show that context is important and that in certain settings, adjustments (in model 2) for smoking, alcohol use, hypertension, diabetes, and social isolation led to a 25% to 30% attenuation in the strength of the associations between depression and the combined outcome in specific areas. These settings included the Middle East; North America and Europe; South America; and high-/upper-middle–income countries as well as urban areas. This was mostly attributable to diabetes but not tobacco or alcohol use. Conversely, in other geographical regions, in low-/lower-middle–income countries, and in rural areas, where these risk factors were less common (eResults 3 and 4 in the Supplement), the same adjustments did not attenuate the strength of these associations. Despite these differences, the HRs for depression were similar in all geographical regions (P for interaction = .56) and in both country income groups (P for interaction = .52) but increased by 2 times in urban (HR, 1.23; 95% CI, 1.13-1.34) compared with rural communities (HR, 1.10; 95% CI, 1.02-1.19; P for interaction = .001). The relative contributions of other covariates were fairly similar in different settings.

    In age- and sex-adjusted models, both the CIDI-SF score and having 4 or more symptoms were associated with the combined outcome in most individual countries. Precision of these estimates was greater in countries with more than 3000 participants (eResults 5 in the Supplement). The associations between depression and all primary outcomes were also twice as strong in men compared with women (combined outcome: HR, 1.27; 95% CI, 1.17-1.38 vs HR, 1.14; 95% CI, 1.06-1.23) (P for interaction < .001) but were otherwise independent of traditional NCD risk factors and social determinants of health, including education and relative wealth (Figure 2).

    Discussion

    In this prospective study of 145 862 people from urban and rural communities in 21 economically diverse countries, middle-aged adults with 4 or more depressive symptoms are at 14% and 17% increased risks of incident CVD and all-cause mortality, respectively. Our initial question was whether previous research identifying similar patterns of association in mostly Western countries7,31-33 could be generalized to other parts of the world. Our findings suggest that they can, and we obtained similar results in countries at all economic levels. However, these associations are not the same within countries. After accounting for traditional NCD risk factors and disability, the relative risks of death and CVD were more than twice as high in urban than in rural areas. Men (in whom depressive symptoms were less common) were also at more than double the risk of women. Our analyses of secondary outcomes supports previous research showing that the relative risks of incident CVD are highest for myocardial infarction (23%) when compared with heart failure (9%) and stroke (5%),7,8,34-36 while the relative risks of all-cause mortality are highest from noncardiovascular (21%) compared with cardiovascular (7%) causes.31

    These findings are consistent with previous, geographically limited research. For example, the 43% increased risk of death or CVD in China is comparable with the 32% increased risk of ischemic heart disease found in another large study undertaken in China, in which urban residents also experienced greater risks.7 The elevated urban risk may be partly attributable to the increased prevalence of traditional risk factors, although our results showed that these accounted for only 20% to 30% of the increased risk. It is also possible that consequences of urbanization such as overcrowded housing, lack of green space, widened inequalities,37,38 and low social cohesion18 might affect the association between mental health and disease, but this requires further study. Similarly, the stronger associations between depressive symptoms and incident CVD and mortality in men have been reported previously (for both CVD39,40 and all-cause mortality41,42). There are a number of factors that could be responsible for this difference. First, women younger than age 70 years have a longer life expectancy than men, and as the PURE population ages and the mean age increases from 50 years old, we may see these differences attenuate as we do in studies of depression in older populations.43,44 Second, for a given level of psychological morbidity, men report fewer depressive symptoms than women40,45 and are also less likely to seek treatment,46 which could also contribute to the apparent increase in risk.

    Direct comparisons within the PURE study show that associations between depressive symptoms and death and CVD are similar to those with smoking, unhealthy eating, and abdominal obesity.21 Although our aim was not to understand the underlying causal mechanisms, we found that the influence of modifiable risk factors and social isolation on the estimated risks of death and CVD in people with depressive symptoms was limited to the Middle East, North America and Europe, South America, high-/upper-middle–income countries, and urban areas, suggesting that these individual risks may be less critical than previously presumed47 in any causal pathway.

    While it is not possible to determine whether the associations between depression and mortality are causal, the temporality, dose response, consistency, and coherence with other research do support such an interpretation. The wide range of cardiovascular and noncardiovascular outcomes associated with depression could point to some common pathways, which previous literature suggests may involve biological mechanisms, including inflammation and autonomic dysregulation.11,48

    Our findings have several implications for the global NCD agenda. First, they lend credibility to existing World Health Organization (WHO) policies to integrate treatment and prevention of mental disorders into primary care14 by demonstrating this need in resource-poor parts of the world where the physical health outcomes of depression are poorly understood. Although the evidence to support the use of biopsychosocial treatments for secondary prevention of CVD is weak,49 collaborative care models that combine treatment for depression with the support to live healthier lives can reduce mortality in older adults with depression by 25%50 and reduce metabolic risk.51 Future studies must now examine the potential role for these approaches in primary prevention. Finally, our results support the position taken by several international organizations52,53 that depression should be considered a risk factor for ischemic heart disease and provide support for the view articulated by others54 that it should also be included in future estimates of the burden of disease study, enabling these relationships to be documented globally and over time.

    Strengths and Limitations

    This is the first study to our knowledge to use standardized methods to collect data on depression, covariates, and health outcomes in 5 continents and to show that longitudinal associations between depressive symptoms and adverse health outcomes exist worldwide. However, there are some limitations. In the absence of a single globally validated screening instrument for depression, we assumed that a CIDI-SF score of 4 or more was predictive of major depressive disorder in each country. However, symptom reporting varied between countries and did not include somatic symptoms, commonly observed in some Asian countries,55 which could explain the low prevalence in Asia. Nonetheless, while the estimated prevalence of depressive symptoms in PURE was similar to WHO estimates for major depressive disorder56 in China (2%), Bangladesh (4%), and the Philippines (3%), it may have been less sensitive in some countries (eg, India [5%], Saudi Arabia [5%], Sweden [5%], and Canada [5%]).30 The risks of incident CVD in people with major depressive disorder may therefore be higher as shown in a recent meta-analysis2 of mostly high-income countries data, showing risks as high as 72%.

    Despite these well-recognized crossnational differences in symptom reporting,30 we also found that both CIDI-SF score and the presence of 4 or more symptoms consistently predicted mortality or incident CVD in most countries, suggesting that the underlying constructs measured by the instrument are valid crossnationally. Second, we cannot rule out residual confounding, particularly where effect sizes are modest, although by adjusting for potential mediators, we may have underestimated true associations between depression and outcomes. Third, while this is the largest study that we are aware of to examine associations between depression and incident cancer, there were insufficient events to analyze each cancer type separately, which is important because we would expect the mechanisms to vary.57,58 Finally, we report depressive symptoms at baseline only and cannot therefore evaluate its time-varying effects until these assessments have been repeated.

    Conclusions

    We confirmed that associations between depressive symptoms and incident CVD and mortality exist in countries at all levels of development. However, the strength of the association varies within countries, being higher in urban areas. This is important because by 2050,59 most of the global population is expected to live in urban areas, where we found depression was also more common. If governments are to achieve the health-related Sustainable Development Goals, especially in resource-poor settings, they should raise awareness of the physical health risks associated with depression and prioritize an integrated and comprehensive approach to tackling NCDs and mental disorders. Meanwhile, broader public policies should promote mental well-being and healthy behaviors as part of a comprehensive strategy to control NCDs.

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    Article Information

    Corresponding Author: Selina Rajan, MSc, London School of Hygiene & Tropical Medicine, Bldg 15-17, Tavistock Place, London WC1H 9SH, United Kingdom (selina.rajan@lshtm.ac.uk).

    Accepted for Publication: April 12, 2020.

    Published Online: June 10, 2020. doi:10.1001/jamapsychiatry.2020.1351

    Author Contributions: Drs Rajan and Yusuf had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Rajan, Rangarajan, Rosengren, Gupta, Lopez-Jaramillo, Oguz, Kruger, Mat Nasir, Chifamba, Iqbal, Bo, Yibing, Wei, Yusuf.

    Acquisition, analysis, or interpretation of data: Rajan, McKee, Bangdiwala, Rosengren, Gupta, Kutty, Wielgosz, Lear, AlHabib, Co, Lopez-Jaramillo, Avezum, Seron, Oguz, Kruger, Diaz, Chifamba, Yeates, Kelishadi, Sharief, Szuba, Khatib, Rahman, Yusuf.

    Drafting of the manuscript: Rajan, Lopez-Jaramillo, Avezum, Kruger.

    Critical revision of the manuscript for important intellectual content: All authors.

    Statistical analysis: Rajan, Bangdiwala, Lopez-Jaramillo, Khatib, Yusuf.

    Obtained funding: Rangarajan, Rosengren, AlHabib, Oguz, Kruger.

    Administrative, technical, or material support: Rajan, Rangarajan, Wielgosz, Co, Lopez-Jaramillo, Seron, Oguz, Kruger, Diaz, Yeates, Kelishadi, Sharief, Rahman.

    Supervision: McKee, Rangarajan, Rosengren, Gupta, AlHabib, Lopez-Jaramillo, Seron, Kruger, Mat Nasir, Chifamba, Kelishadi, Szuba, Iqbal, Yusuf.

    Conflict of Interest Disclosures: Dr Kruger reported grants from National Research Foundation–South Africa and grants from Population Health Research Institute–Canada during the conduct of the study. Dr Diaz reported grants from Population Health Research Institute during the conduct of the study. No other disclosures were reported.

    Funding/Support: Dr Yusuf is supported by the Mary W. Burke endowed chair of the Heart and Stroke Foundation of Ontario. The PURE study is an investigator-initiated study that is funded by the Population Health Research Institute, Hamilton Health Sciences Research Institute (HHSRI), the Canadian Institutes of Health Research, Heart and Stroke Foundation of Ontario, support from Canadian Institutes of Health Research’s Strategy for Patient Oriented Research, through the Ontario SPOR Support Unit and the Ontario Ministry of Health and Long-Term Care and through unrestricted grants from several pharmaceutical companies with major contributions from AstraZeneca (Canada), Sanofi-Aventis (France and Canada), Boehringer Ingelheim (Germany and Canada), Servier, and GlaxoSmithKline and additional contributions from Novartis and King Pharma and from various national or local organizations in participating countries. These include: Argentina: Fundacion ECLA (Estudios Clínicos Latino America); Bangladesh: Independent University, Bangladesh and Mitra and Associates; Brazil: Unilever Health Institute; Chile: Universidad de La Frontera (grant DI13-PE11); China: National Center for Cardiovascular Diseases and ThinkTank Research Center for Health Development; Colombia: Colciencias (grants 6566-04-18062 and 6517-777-58228); India: Indian Council of Medical Research; Malaysia: Ministry of Science, Technology and Innovation of Malaysia (grant 100-IRDC/BIOTEK 16/6/21 [13/2007] and 07-05-IFN-BPH 010), Ministry of Higher Education of Malaysia (grant 600-RMI/LRGS/5/3 [2/2011]), Universiti Teknologi MARA, and Universiti Kebangsaan Malaysia (UKM-Hejim-Komuniti-15-2010); Occupied Palestinian Territory: the United Nations Relief and Works Agency for Palestine Refugees in the Near East, and International Development Research Centre (Canada); Philippines: Philippine Council for Health Research and Development; Poland: Polish Ministry of Science and Higher Education (grant 290/W-PURE/2008/0), Wroclaw Medical University; Saudi Arabia: Saudi Heart Association, Saudi Gastroenterology Association, Dr Mohammad Alfagih Hospital, The Deanship of Scientific Research at King Saud University, and Riyadh, Saudi Arabia (research group RG -1436-013); South Africa: The North-West University, SA and Netherlands Programme for Alternative Development, National Research Foundation, Medical Research Council of South Africa, The South Africa Sugar Association, and Faculty of Community and Health Sciences; Sweden: grants from the Swedish state under the agreement concerning research and education of doctors; the Swedish Heart and Lung Foundation; the Swedish Research Council; the Swedish Council for Health, Working Life and Welfare, King Gustaf V and Queen Victoria Freemason’s Foundation, and AFA Insurance; Turkey: Metabolic Syndrome Society, AstraZeneca, and Sanofi Aventis; United Arab Emirates: Sheikh Hamdan Bin Rashid Al Maktoum Award For Medical Sciences and Dubai Health Authority, Dubai. This study was also supported by an unrestricted grant from Dairy Farmers of Canada and the National Dairy Council (US), Public Health Agency of Canada, and Champlain Cardiovascular Disease Prevention Network.

    Role of the Funder/Sponsor: The external funders and sponsors had no role in the design and conduct of the study; in the collection, analysis, and interpretation of the data; in the preparation, review, or approval of the manuscript; or in the decision to submit the manuscript for publication.

    Group Information: The Prospective Urban Rural Epidemiology (PURE) Study Group members are: Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Canada: S. Yusuf, S. Rangarajan, K. K. Teo, S. S. Anand, C. K. Chow, M. O’Donnell, A. Mente, D. Leong, P. Joseph, M. Duong, O. Kurmi, R. D’Souza, M. Walli-Attaei, S. Islam, W. Hu, C. Ramasundarahettige, P. Sheridan, S. Bangdiwala, L. Dyal, M. Dehghan, A. Aliberti, A. Zaki, B. Connolly, D. Agapay, D. Krol, F. Shifaly, G. McAlpine, J. Rimac, M. Di Marino, M. Jakymyshyn, M(a). Mushtaha, M(o). Mushtaha, N. Aoucheva, N. Kandy, P. Mackie, R. Buthool, R. Patel, R. Solano, S. Ramacham, S. Trottier, G. Pare, M. McQueen, S. Lamers, J. Keys; Estudios Clinicos Latinoamerica (ECLA), Rosario, Santa Fe, Argentina: R. Diaz, A. Orlandini, P. Lamelas, M. L. Diaz, A. Pascual, M. Salvador, C. Chacon; Independent University, Bangladesh, Dhaka, Bangladesh: O. Rahman, R. Yusuf, S. A. K. S. Ahmed, T. Choudhury, M. Sintaha, A. Khan, O. Alam, N. Nayeem, S. N. Mitra, S. Islam, F. Pasha; Dante Pazzanese Institute of Cardiology; Hospital Alemao Oswaldo Cruz, Sao Paulo, SP Brazil: A. Avezum, C. S. Marcilio, A. C. Mattos, G. B. Oliveira; Université Laval Institut Universitaire de Cardiologie et de Pneumologie de Québec, Quebec, Canada: G. Dagenais, P. Poirier, G. Turbide, A. S. Bourlaud, A. LeBlanc De Bluts, M. Cayer, I. Tardif, M. Pettigrew; Simon Fraser University, Deptartment of Biomedical Physiology & Kinesiology, British Columbia, Canada: S. Lear, V. de Jong, A. N. Saidy, V. Kandola, E. Corber, I. Vukmirovich, D. Gasevic; Department of Medicine, University of Ottawa, Ottawa, Canada: A. Wielgosz, A. Pipe, A. Lefebvre, A. Pepe, A. Auclair, A. Prémont, A. S. Bourlaud; Universidad de La Frontera, Temuco, Chile: F. Lanas, P. Serón, M. J. Oliveros, F. Cazor, Y. Palacios; National Centre for Cardiovascular Diseases, Cardiovascular Institute & Fuwai Hospital Chinese Academy of Medical Sciences, Beijing, China: Liu Lisheng, Li Wei, Chen Chunming, Zhao Wenhua, Hu Bo, Yin Lu, Zhu Jun, Liang Yan, Sun Yi, Wang Yang, Deng Qing, Jia Xuan, He Xinye, Zhang Hongye, Bo Jian, Wang Xingyu, Liu Xu, Gao Nan, Bai Xiulin, Yao Chenrui, Cheng Xiaoru, Wang Chuangshi, Li Sidong, Liu Weida, Lang Xinyue, Liu Xiaoyun, Zhu Yibing, Xie Liya, Liu Zhiguang, Ren Yingjuan, Dai Xi, Gao Liuning, Wang Liping, Su yuxuan, Han Guoliang, Song Rui, Cao Zhuangni, Sun Yaya, Li Xiangrong, Wang Jing, Wang Li, Peng Ya, Li Xiaoqing, Li Ling, Wang Jia, Zou Jianmei, Gao Fan, Tian Shaofang, Liu Lifu, Li Yongmei, Bi Yanhui, Li Xin, Zhang Anran, Wu Dandan, Cheng ying, Xiao Yize, Lu Fanghong, Li Yindong, Hou Yan, Zhang Liangqing, Guo Baoxia, Liao Xiaoyang, Chen Di, Zhang Peng, Li Ning, Ma Xiaolan, Lei Rensheng, Fu Minfan, Liu Yu, Xing Xiaojie, Yang Youzhu, Zhao Shenghu, Xiang Quanyong, Tang Jinhua, Liu Zhengrong, Qiang Deren, Li Xiaoxia, Xu Zhengting, Aideeraili.Ayoupu, Zhao Qian; Facultad de Ciencias de la Salud, Universidad de Santander (UDES), Bucaramanga, Santander, Fundacion Oftalmologica de Santander (FOSCAL) Floridablanca-Santander, Colombia: P. Lopez-Jaramillo, P. A. Camacho-Lopez, M. Perez, J. Otero-Wandurraga, D. I. Molina, C. Cure-Cure, J. L. Accini, E. Hernandez, E. Arcos, C. Narvaez, A. Sotomayor, F. Manzur, H. Garcia, G. Sanchez, F. Cotes, A. Rico, M. Duran, C. Torres; St John's Medical College and Research Institute, Bangalore, India: P. Mony, M. Vaz, S. Swaminathan, A. V. Bharathi, K. Shankar, A. V. Kurpad, K. G. Jayachitra, H. A. L. Hospital, A. R. Raju, S. Niramala, V. Hemalatha, K. Murali, C. Balaji, A. Janaki, K. Amaranadh, P. Vijayalakshmi, A. Devanath; Madras Diabetes Research Foundation & Dr. Mohan’s Diabetes Specialities Centre, Chennai: V. Mohan, R. M. Anjana, M. Deepa, K. Parthiban, L. Dhanasekaran, S. K. Sundaram, M. Rajalakshmi, P. Rajaneesh, K. Munusamy, M. Anitha, S. Hemavathy, T. Rahulashankiruthiyayan, D. Anitha, R. Dhanasekar, S. Sureshkumar, D. Anitha, K. Sridevi; Eternal Heart Care Centre and Research Institute, Jaipur, India: R. Gupta, R. B. Panwar, I. Mohan, P. Rastogi, S. Rastogi, R. Bhargava, M. Sharma, D. Sharma; Health Action by People, Thiruvananthapuram, Kerala, India: V. Raman Kutty, K. Vijayakumar, S. Nair, R. Kamala, M. S. Manu, A. R. Arunlal, A. Veena, Sandeep P. Kumar, Leena Kumari, R. Tessi, S. Jith, K. Ajayan, G. Rajasree, A. R. Renjini, A. Deepu, B. Sandhya, S. Asha, H. S. Soumya; School of Public Health, Post Graduate Institute of Medical Education & Research, Chandigarh, India: R. Kumar, M. Kaur, P. V. M. Lakshmi, V. Sagar, J. S. Thakur, B. Patro, R. Mahajan, A. Josh, G. Singh, K. Sharma, P. Chaudary; Isfahan Cardiovascular Research Center, Isfahan Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran: R. Kelishadi, A. Bahonar, N. Mohammadifard, H. Heidari; Research Institute of Cardiology & Internal Diseases, Almaty, Kazakhstan: K. Davletov, B. Assembekov, B. Amirov; Kyrgyz Society of Cardiology, National Center of Cardiology and Internal Disease, Bishkek, Kyrgyzstan: E. Mirrakhimov, S. Abilova, U. Zakirov, U. Toktomamatov; Universiti Teknologi MARA, Sungai Buloh, Selangor, Malaysia and UCSI University, Cheras, Selangor, Malaysia: K. Yusoff, T. S. Ismail, K. Ng, A. Devi, N. Mat-Nasir, A. S. Ramli, M. N. K. Nor-Ashikin, R. Dasiman, M. Y. Mazaouspavina, F. Ariffin, M. Miskan, H. Abul-Hamid, S. Abdul-Razak, N. Baharudin, N. M. N. Mohd-Nasir, S. F. Badlishah-Sham, M. Kaur, M. Koshy, F. A. Majid, N. A. Bakar, N. Zainon, R. Salleh, S. R. Norlizan, N. M. Ghazali, M. Baharom, H. Zulkifli, R. Razali, S. Ali, C. W. J. C. W. Hafar, F. Basir; Department of Community Health, Faculty of Medicine, University Kebangsaan Malaysia, Kuala Lumpur, Malaysia: Noorhassim Ismail, M. J. Hasni, M. T. Azmi, M. I. Zaleha, R. Ismail, K. Y. Hazdi, N. Saian, A. Jusoh, N. Nasir, A. Ayub, N. Mohamed, A. Jamaludin, Z. Rahim; Institute of Community and Public Health, Birzeit University, Ramallah, Occupied Palestinian Territory: R. Khatib, U. Khammash, R. Giacaman; Department of Community Health Sciences and Medicine, Aga Khan University, Karachi Pakistan: R. Iqbal, R. Khawaja, I. Azam, K. Kazmi; CRONICAS Centro de Excelencia en Enfermedades Crónicas, Universidad Peruana Cayetano Heredia, Lima, Peru: J. Miranda, A. Bernabe Ortiz, W. Checkley, R. H. Gilman, L. Smeeth, R. M. Carrillo, M. de los Angeles, C. Tarazona Meza; University of Philippines, Section of Adult Medicine & Medical Research Unit, Manila, Philippines: A. Dans, H. U. Co, J. T. Sanchez, L. Pudol, C. Zamora-Pudol, L. A. M. Palileo-Villanueva, M. R. Aquino, C. Abaquin, S. L. Pudol, K. Manguiat, S. Malayang; Wroclaw Medical University, Department of Internal Medicine; Department of Social Medicine, Wroclaw, Poland: W. Zatonski, A. Szuba, K. Zatonska, R. Ilow, M. Ferus, B. Regulska-Ilow, D. Różańska, M. Wolyniec; Department of Epidemiology, The Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland: Joanna Didkowska, Marta Manczuk, Pawel Koczkodaj, Agata Ciuba; Department of Cardiac Sciences, King Fahad Cardiac Center, College of Medicine, King Saud University, Riyadh, Saudi Arabia: K. F. AlHabib, M. Alshamiri, H. B. Altaradi, O. Alnobani, N. Alkamel, M. Ali, M. Abdulrahman, R. Nouri; Faculty of Health Science, North-West University, Potchefstroom Campus, Potchefstroom, South Africa: L. Kruger, A. Kruger, P. Bestra, H. Voster, A. E. Schutte, E. Wentzel-Viljoen, F. C. Eloff, H. de Ridder, H. Moss, J. Potgieter, A. Roux, M. Watson, G. de Wet, A. Olckers, J. C. Jerling, M. Pieters, T. Hoekstra; University of the Western Cape, Department of Dietetics and Nutrition, Bellville, South Africa: T. Puoane, R. Swart, E. Igumbor, L. Tsolekile, K. Ndayi, D. Sanders, P. Naidoo, N. Steyn, N. Peer, B. Mayosi, B. Rayner, V. Lambert, N. Levitt, T. Kolbe-Alexander, L. Ntyintyane, G. Hughes, J. Fourie, M. Muzigaba, S. Xapa, N. Gobile, K. Ndayi, B. Jwili, K. Ndibaza, B. Egbujie; Sahlgrenska Academy, University of Gothenburg, Sweden: A. Rosengren, K. Bengtsson Boström, A. Rawshani, A. Gustavsson, M. Andreasson, L. Wirdemann; Pamoja Tunaweza Health Research Centre, Moshi, Tanzania; Division of Nephrology, Department of Medicine, Queen’s University: K. Yeates, M. Oresto, N. West; Istanbul Medeniyet University, Istanbul, Turkey: A. Oguz, N. Imeryuz, Y. Altuntas, S. Gulec, A. Temizhan, K. Karsidag, K. B. T. Calik, A. K. Akalin, O. T. Caklili, M. V. Keskinler, K. Yildiz; Dubai Medical University, Hatta Hospital, Dubai Health Authority, Dubai, United Arab Emirates: A. H. Yusufali, F. Hussain, M. H. S. Abdelmotagali, D. F. Youssef, O. Z. S. Ahmad, F. H. M. Hashem, T. M. Mamdouh, F. M. AbdRabbou, S. H. Ahmed, M. A. AlOmairi, H. M. Swidan, M. Omran, N. A. Monsef; University of Zimbabwe, College of Health Sciences, Physiology Department, Harare, Zimbabwe: J. Chifamba, T. Ncube, B. Ncube, C. Chimhete, G. K. Neya, T. Manenji, L. Gwaunza, V. Mapara, G. Terera, C. Mahachi, P. Murambiwa, R. Mapanga, A. Chinhara.

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