Non-melancholic depressive symptoms increase risk for incident cardiovascular disease: A prospective study in a primary care population at risk for cardiovascular disease and type 2 diabetes

Journal Pre-proof Non-melancholic depressive symptoms increase risk for incident cardiovascular disease: A prospective study in a primary care population at risk for cardiovascular disease and type 2 diabetes

Ansa Talvikki Rantanen, Jyrki Jaakko Antero Korkeila, Hannu Kautiainen, Päivi Elina Korhonen PII:

S0022-3999(19)30550-1

DOI:

https://doi.org/10.1016/j.jpsychores.2019.109887

Reference:

PSR 109887

To appear in:

Journal of Psychosomatic Research

Received date:

8 June 2019

Revised date:

28 November 2019

Accepted date:

29 November 2019

Please cite this article as: A.T. Rantanen, J.J.A. Korkeila, H. Kautiainen, et al., Nonmelancholic depressive symptoms increase risk for incident cardiovascular disease: A prospective study in a primary care population at risk for cardiovascular disease and type 2 diabetes, Journal of Psychosomatic Research(2019), https://doi.org/10.1016/ j.jpsychores.2019.109887

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© 2019 Published by Elsevier.

Journal Pre-proof

Non-melancholic depressive symptoms increase risk for incident cardiovascular disease: A prospective study in a primary care population at risk for cardiovascular disease and type 2 diabetes

Running title: Depressive symptoms and incident cardiovascular disease Ansa Talvikki Rantanena,b, Jyrki Jaakko Antero Korkeilac,d, Hannu Kautiainene,f, Päivi Elina Korhonena,g

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a) Department of General Practice, University of Turku and Turku University Hospital, Turku, Finland

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b) Salo Health Center, Salo, Finland

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c) Department of Psychiatry, University of Turku and Turku University Hospital, Turku, Finland

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d) Department of Psychiatry, Hospital District of Satakunta, Pori, Finland e) Folkhälsan Research Center, Helsinki, Finland

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f) Unit of Primary Health Care, Kuopio University Hospital, Kuopio, Finland

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g) Central Satakunta Health Federation of Municipalities, Harjavalta, Finland

Corresponding author: Ansa Rantanen, ICT-City, General Practice, Joukahaisenkatu 35A, 20520 Turku, Finland. Tel: +358 40 8474369; fax: +358 2 9450 5040; e-mail: [email protected].

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Non-melancholic depressive symptoms increase risk for incident cardiovascular disease: A prospective study in a primary care population at risk for cardiovascular disease and type 2 diabetes ABSTRACT Objective: To assess subtypes of depressive symptoms and their relationship with cardiovascular disease (CVD) morbidity among CVD risk persons.

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Methods: A prospective study of 2522 CVD risk persons was conducted. Non-

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melancholic and melancholic depressive symptoms were assessed by Beck’s Depression Inventory. Data on incident CVD was gathered from a national register,

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after 8 years of follow-up.

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Results: At baseline, the prevalence of non-melancholic and melancholic depressive

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symptoms was 14.9% and 5.2%, respectively. A total of 18413 person-years was followed up, and the incidence of CVD was 9.6% in non-depressive, 14.1% in non-

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melancholically depressive, and 13.0% in melancholically depressive subjects. When adjusted for age, gender, education, smoking, alcohol use, and leisure-time physical

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activity, hypertension, and dyslipidemia, the incidence rate ratios (IRR) for CVD in subjects with non-melancholic and melancholic depressive symptoms compared to non-depressiveness were IRR 1.69 (95% CI: 1.23-2.31) and IRR 1.31 (95% CI: 0.75-2.26).

Conclusion: Non-melancholic depressive symptoms seem to increase risk for incident CVD among CVD risk subjects. Considering non-melancholic depressive symptoms might be useful when treating subjects with other CVD risk factors.

KEYWORDS Beck’s Depression Inventory; cardiovascular disease; depressive symptom subtypes; melancholic; non-melancholic; risk

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INTRODUCTION Reducing cardiovascular (CV) morbidity is a one of the key targets in global healthcare. Psychosocial risk factors, including depressiveness, modify risk for cardiovascular disease (CVD), and according to the European Guidelines on cardiovascular risk prevention[1], they should be assessed among CVD risk subjects. In addition to

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contributing to traditional CVD risk factors[2–7], depression also independently

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predicts incident CVD[8–10]. However, depressive symptomatology is

associated with CVD than others.

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multifaceted[11], and some subtypes of depressive symptoms might be more strongly

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Subtyping depression has been suggested to be useful in clinical practise[12]

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and in research[11], also specifically when studying the association of depression and

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CVD[13–15] . The most straightforward classification of depressed populations is division into melancholic, i.e. typical, and non-melancholic, i.e. atypical subtypes[16].

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In a study conducted among Finnish middle-aged population, non-melancholic depressive symptoms have been found to be twice as prevalent as melancholic symptoms[17]. The non-melancholic subtype is characterized by mood reactivity, interpersonal rejection sensitivity, hypersomnia, fatigue, increased appetite, and weight gain[18], and it is suggested to be associated with a cluster of metabolic CVD risk factors[17,19–24]. Hence, namely non-melancholic depressiveness might be associated with an increased risk for CVD morbidity having important clinical implications. First, physicians might not recognize atypical depressive symptoms[25], and thus underestimate a subject’s CVD risk, and barriers to engage to preventive lifestyle activities. Second, when treating non-melancholically depressive subjects,

Journal Pre-proof attention should be drawn also to CVD risk factors and metabolic side effects of antidepressants. To the best of our knowledge, only one study has previously studied the association of different depression subtypes and incident CVD among subjects without established CVD in a prospective setting. This study of Case et al.[26] among 28 000 U.S. adults indeed suggests that those with atypical depression might be at particular

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CVD morbidity risk. However, in their study, incident CVD was assessed by self-report

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during the past 12 months, after at most three years of follow-up. We had the opportunity to study the association of different subtypes of depressive symptoms and

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their relationship with incident CVD among CVD risk persons without manifested CVD

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or type 2 diabetes (T2D) after 8 years of follow-up, and with register-based data on

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CVD morbidity. The aim of our study was to find out if depressive symptoms affects

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CVD morbidity risk, and specifically, if either melancholic or non-melancholic depressive symptoms warrant specific attention when treating CVD risk persons. We

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also studied if the different subtypes of depressive symptoms associate more strongly with specific CVD categories (ischemic heart disease (IHD), cerebrovascular disease (CeVD), or peripheral artery disease (PAD)). We hypothesized that non-melancholic depressive symptoms are more strongly predicting incident CVD than melancholic depressive symptoms, compared to non-depressiveness.

METHODS Study population The study sample was drawn from a population survey, the Harjavalta Risk Monitoring for Cardiovascular Disease (Harmonica) Project. From August 2005 to September 2007,

Journal Pre-proof all home-dwelling inhabitants aged 45 to 70 years (n=6 013) of two rural towns, Harjavalta and Kokemäki, were mailed a CVD risk factor survey, a tape for waist circumference measurement, and a T2D risk assessment form (FINDRISC, Finnish Diabetes Risk Score, available from www.diabetes.fi/english, Supplemental Table 1). Of those invited, 74% returned the survey. Persons with at least one CVD risk factor (n=3 072) were invited for an enrolment examination performed by a trained nurse.

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CVD risk factors considered were the latest blood pressure measurement ≥ 140/90

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mmHg, use of antihypertensive medication, history of gestational diabetes or hypertension, family history of premature CVD, waist circumference at the level of the

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navel ≥ 80 cm in women and ≥ 94 cm in men in Harjavalta, and FINDRISC-score ≥ 12 in

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Harjavalta (estimated 1 in 6 will develop T2D within 10 years) or ≥ 15 in Kokemäki

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(estimated 1 in 3 will develop T2D within 10 years). A stricter criterion had to be used

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in Kokemäki due to limited financial resources and surprisingly high response rate with FINDRISC score ≥ 12. Those having an established CVD or renal disease, or T2D were

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excluded, as T2D has been found to be an IHD equivalent[27]. For this study, only subjects with completed Beck’s Depression Inventory (BDI)[28] were included (n=2522).

Questionnaires and measurements Before the enrolment examination, the subjects completed self-administered questionnaires: education, cohabiting (yes/no), current smoking (yes/no), alcohol use (Alcohol Use Disorders Identification Test, AUDIT[29]), leisure-time physical activity (LTPA) level, and depressive symptoms (BDI, version BDI-1A)[28].

Journal Pre-proof Definition for increased depressive symptoms was a BDI-score ≥ 10[30]. Subjects were divided into melancholic and non-melancholic subgroups by comparing means of summary scores of melancholic and non-melancholic items in the BDI[17,31– 33] . Items considered melancholic based on DSM-V-defined criteria were sadness, past failure, loss of pleasure, guilty feelings, punishment feelings, irritability, loss of interest, change in sleeping, and change in appetite. Other items were considered non-

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melancholic. A subject was classified into melancholic subtype if the mean of the

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summary score of the melancholic items was higher than that of the non-melancholic items, and vice versa. If the means were equal, depressiveness was considered

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melancholic. A summary score of melancholic symptoms in the BDI (sadness, past

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failure, loss of pleasure, guilty feelings, punishment feelings, loss of interest, irritability,

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change of sleep and appetite) was used to divide the subjects into melancholic and

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non-melancholic depressive symptom subgroups[31].The level of LTPA was classified to three categories: low: LTPA for ≥ 30 minutes at a time for maximum of three times a

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week; moderate: LTPA for ≥ 30 minutes at a time for four to five times a week; high: LTPA ≥ 30 minutes at a time for six or more times a week. At the enrolment examination performed by a trained nurse, height and weight were measured with subjects in a standing position without shoes and outer garments. Body mass index (BMI) was calculated as weight (kg) divided by the square of height (m2). Waist circumference was measured at the level midway between the lower rib margin and the iliac crest. Blood pressure was measured with a mercury sphygmomanometer with subjects in a sitting posture, after resting for at least five minutes. The mean of two readings taken at intervals of at least two minutes was used in the study.

Journal Pre-proof Laboratory tests were determined in blood samples obtained after at least 12 hours of fasting. An oral glucose tolerance test was also performed. Glucose values were measured from capillary whole blood with HemoCue Glucose 201+ system (Angelholm, Sweden), which converts the result into plasma glucose values. Total cholesterol, high-density lipoprotein cholesterol (HDL-c) and triglycerides were measured from venous plasma enzymatically (Olympus® AU640). Low-density

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lipoprotein (LDL-c) was calculated according to Friedewald’s formula. Glucose

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metabolism disorders were categorized into T2D (fasting glucose ≥ 7.0 mmol/l or 2hour postload plasma glucose ≥ 12.2 mmol/l), impaired glucose tolerance (IGT, 2-hour

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postload plasma glucose 8.9-12.2 mmol/l), and impaired fasting glucose (IFG, fasting

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glucose 6.1-6.9 mmol/l)[34]. Those with both IGT and IFG were classified to IGT.

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medical records.

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Data on regularly used medication was gathered from the questionnaire and

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Interventions on CV risk factors

The study nurse gave lifestyle counselling to all subjects attending the enrolment examination. Subjects were further invited to a physician’s appointment, if hypertension, diabetes, impaired glucose tolerance, metabolic syndrome, obesity (BMI ≥30.0 kg/m2), or ≥ 5 % ten year risk for CVD death estimated by the SCORE (Systematic Coronary Risk Evaluation) [35] was detected at the nurse’s appointment (n=1928). Preventive medication (an antihypertensive drug, a lipid lowering agent, or low dose aspirin) was started if the ten year risk for developing a fatal CVD event was ≥ 5% estimated by the SCORE [35] . Antihypertensive medication was prescribed according

Journal Pre-proof to the national care guidelines if systolic BP was ≥ 160 mmHg or diastolic BP ≥ 100 mmHg, or target organ damage was diagnosed.

Incident cardiovascular disease Data on incident CVD was obtained from the Care Register for Health Care of the National Institute of Health and Welfare. Endpoints of interest were incident CVD

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diagnosed according to the International Statistical Classification of Diseases and

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Related Health Problems (ICD-10, Finnish language), specifically: I20 angina pectoris, I21 acute myocardial infarction, I25 chronic ischemic heart disease, I60 subarachnoid

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haemorrhage, I61 intracerebral haemorrhage, I62 other nontraumatic intracranial

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haemorrhage, I63 cerebral infarction, I65 occlusion and stenosis of precerebral

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arteries, not resulting in cerebral infarction, I66 occlusion and stenosis of cerebral

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arteries, not resulting in cerebral infarction, I70 atherosclerosis, I71 aortic aneurysm and dissection, and I74 arterial embolism and thrombosis. We categorised CVD

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diagnoses to ischaemic heart disease (IHD, ICD-10 codes I20, I21, I25), cerebrovascular disease (CeVD, ICD-10 codes I60, I61, I62, I63, I65, I66), and peripheral artery disease (PAD, ICD-10 codes I70, I71, I74).

Follow-up time started at the time of the enrolment examination, and ended on 31st December 2013, or on the date of the first occurrence of incident CVD, or death.

Statistical analysis The characteristics are presented as means with standard deviation (SD) for continuous variables and as frequencies with percentages for categorical variables.

Journal Pre-proof Statistical comparisons between the groups were made by using chi-square test or analysis of variance (ANOVA). The bootstrap method was used when the theoretical distribution of the test statistics was unknown or in the case of violation of the assumptions (e.g. non-normality). Hommel’s adjustment was applied to correct levels of significance for multiple testing, if appropriate. Age- and gender-adjusted KaplanMeier cumulative CVD morbidity rates were estimated using two propensity score-

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based techniques, stratification and weighting (MMWS, marginal mean weighting

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through stratification)[36]. MMWS is an extension of propensity score matching that combines propensity score stratification and inverse probability of treatment

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weighting. Cox regression model could not be used because proportional-hazards

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assumption was violated. Adjusted incidence rate and incidence rate ratio (IRR) were

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calculated using Poisson regression models. Poisson regression is a generalized linear

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model (GLM) used to model count data with Poisson distribution and log link function. Poisson models goodness-of-fit were assessed using deviance and Pearson chi-squared

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tests, which showed a good fit in all models. No interactions were found between BDI groups and covariates. The normality of variables was evaluated graphically and using the Shapiro–Wilk W test. Stata 15.1 (StataCorp LP; College Station, Texas, USA) statistical package was used for the analysis.

Ethical approval The ethics committee of Satakunta Hospital District reviewed and approved the study protocol and consent forms. All participants provided written informed consent for the project and subsequent research.

Journal Pre-proof RESULTS Characteristics of the subjects We evaluated 2522 subjects with a mean age of 58 years (SD 7), 55.7% being females. Of the study population, 506 (20.1%) had increased depressive symptoms (BDI ≥ 10): 14.9% with non-melancholic and 5.2% with melancholic depressive features. Increased depressive symptoms were more prevalent among women than in men (23.3% vs.

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16.0%, p < 0.001, χ2 = 32.18, df = 1). The prevalence of increased non-melancholic

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depressive symptoms was higher in women (18.3%) than in men (10.6%) (p < 0.001, χ 2 = 29.36, df = 1), whereas the prevalence of increased melancholic depressive

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symptoms was similar in both genders (5.0% and 5.5% in women and men,

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respectively, p = 0.59, χ2 = 0.29, df = 1). The BDI mean score was 3.8 (SD 2.7), 15.1 (SD

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5.5) and 14.8 (SD 5.5) among non-depressive, non-melancholically depressive and

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melancholically depressive subjects, respectively. The distribution of the BDI score

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according to depressive symptoms is presented in Figure 1.

Journal Pre-proof B

A 15

30

BDI<10 NMeD MeD

14 13

Women Men 25

12 11

20

9

Percentage

Percentage

10 8 7 6 5

15

10

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4 3

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2 1 0

5

10

15

25

30+

0

p<0.001

p=0.59

NMeD

MeD

Type

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BDI

20

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0

5

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Figure 1 The distribution of the Beck´s Depression Inventory score in subjects without depressive symptoms (BDI <10), with non-melancholic and melancholic depressiveness (BDI ≥ 10).

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Abbreviations: BDI, Beck’s Depression Inventory; NMeD, non-melancholic depressive symptoms; MeD, melancholic depressive symptoms.

The characteristics of the subjects according to depressive symptoms are presented in Table 1. Subjects with non-melancholic depressive symptoms were older than non-depressive subjects, and a little less educated than all the others. Women and men with increased non-melancholic depressive symptoms had higher BMI, and women also larger waist circumference compared to the other groups, and men compared to non-depressive subjects. Those with increased non-melancholic depressive symptoms had more often glucose disorders and higher triglyceride level compared to those without depressive symptoms. The mean of the AUDIT score was higher in those with increased melancholic depressive symptoms compared to the two

Journal Pre-proof other groups. Persons with increased non-melancholic depressive symptoms performed less LTPA than subjects without depressiveness. At baseline before the physician’s appointment, persons with either type of increased depressive symptoms used more often medication for depression/anxiety compared to non-depressive subjects, whereas antihypertensive medication was more often used by subjects with increased non-melancholic depressive symptoms

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compared to non-depressive subjects.

Journal Pre-proof Table 1 Baseline characteristics of the study population according to the categories of depressive symptoms. BDI < 10 I n= 2016

BDI ≥ 10 II NMeD n=375 59 (7) 257 (69) 10.1 (2.7) 279 (74) 30.0(5.9)

III MeD n=131 58 (7) 70 (53) 10.8 (3.1) 102 (78) 28.9(5.6)

P-value* [multiple comparison] <0.001 [I/II] <0.001 [I/II, II/III] 0.013 [I/II, II/III] 0.18 <0.001 [I/II, II/III]

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Age, mean, years (SD) 58 (7) Females, n (%) 1078 (53) Education years, mean (SD) 10.4 (2.7) Cohabiting, n (%) 1587 (79) 2 Body mass index, kg/m , mean (SD) 28.6 (4.7) Waist circumference, cm, mean (SD) women 91 (12) 96 (15) 92 (15) <0.001 [I/II, II/III] men 101 (11) 104 (13) 101 (13) 0.046 [I/II] Current smoking, n (%) 343 (17) 74 (20) 30 (23) 0.12 AUDIT-score, mean (SD) 4.5 (4.6) 4.8 (5.2) 6.9 (7.1) <0.001 [I/III, II/III] Leisure-time physical activity level, n (%) <0.001 [I/II] low 333 (17) 95(25) 29(22) moderate 1020 (51) 182(49) 59(46) high 653 (33) 97(26) 41(32) Blood pressure, mmHg, mean (SD) systolic 141(19) 140(18) 139(17) 0.57 diastolic 84(10) 84(10) 86(10) 0.29 Plasma lipids, mmol/l, mean (SD) total cholesterol 5.4 (1.0) 5.5 (1.1) 5.5 (1.0) 0.068 HDL cholesterol 1.6 (0.4) 1.6 (0.5) 1.5 (0.4) 0.84 LDL cholesterol 3.2 (0.9) 3.3 (1.0) 3.3 (0.9) 0.30 triglycerides 1.4 (0.7) 1.6 (0.9) 1.5 (0.7) <0.001 [I/II] Plasma glucose, mmol/l, mean (SD) fasting 5.6 (1.1) 5.7 (1.3) 5.6 (1.7) 0.14 2h glucose 7.3 (2.2) 7.7 (2.7 ) 7.5 (2.2) 0.040 [I/II] Glucose disorder, n (%) 0.040 [I/II] impaired fasting glucose 202 (10) 40 (11) 14 (11) impaired glucose tolerance 265 (13) 50 (13) 16 (12) type 2 diabetes 153 (8) 50 (13) 13 (10) Medication, n (%) Hypertension 623(31) 165 (44) 47 (36) <0.001 [I/II] Lipid disorders 242 (12) 47 (13) 16 (12) 0.96 Depression/anxiety 39 (2) 50 (13) 15 (11) <0.001 [I/II, I/III] *Hommel’s multiple comparison procedure was used to correct significance levels for post hoc testing (p < 0.05) Abbreviations: AUDIT, Alcohol Use Disorders Identification Test; BDI, Beck’s Depression Inventory; HDL, high-density lipoprotein; LDL, low-density lipoprotein; MeD, increased (BDI ≥ 10) melancholic depressive symptoms; NMeD, increased non-melancholic depressive symptoms

Incident cardiovascular disease In the whole cohort, a total of 18413 person-years was followed up, and 263 subjects (10.4%) were diagnosed with incident CVD. The amount of person-years followed was

Journal Pre-proof 14790 in non-depressive, 2262 in non-melancholically depressive, and 961 in melancholically depressive subjects. A diagnosis of CVD was made for 193 (9.6%) of those without depressive symptoms, for 53 (14.1%) of those with increased nonmelancholic depressive symptoms, and for 17 (13.0%) of those with increased melancholic depressive symptoms (p = 0.018, χ2 = 8.00, df = 2). Age- and gender-adjusted cumulative CVD morbidity rates (p = 0.003, χ2 =

15 13

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BDI<10 NMeD MeD

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12 11

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10 9

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8 7 6 5

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Adjusted cumulative CVD, %

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11.05, df = 2) are presented in Figure 2.

4 3 2

1936 353 126

1 0 0

1

2

3

1851 320 117

4

5

6

7

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Time since health check, years Figure 2 Age- and gender-adjusted cumulative cardiovascular morbidity rates according to depressive symptoms. The numbers of individuals at 3 and 6 years still at risk (BDI<10, NMeD, MeD). Abbreviations: BDI, Beck’s Depression Inventory; CVD, cardiovascular disease; MeD, increased (BDI ≥10) melancholic depressive symptoms; NMeD, increased non-melancholic depressive symptoms

Journal Pre-proof The incidence rate ratios (IRR), adjusted for the commonly known CVD risk factors (age, gender, education, smoking, alcohol use, LTPA, hypertension, dyslipidemia) for all and different subtypes of CVD are summarized in Table 2. Compared to non-depressive subjects, those with non-melancholic depressive symptoms had an increased risk for all CVD and different subtypes of CVD.

All CVD N

IHD

IRR (95% CI)

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Table 2 Number of* and adjusted** incidence rate ratios (IRR) for cardiovascular disease according to depressive subtypes compared to non-depressiveness. CeVD

IRR (95% CI)

PAD

N

IRR (95% CI)

N

IRR (95% CI)

60

1.00

30

1.00

193

1.00

121

1.00

NMeD

53

1.69 (1.23 to 2.31)

32

1.71 (1.14 to 2.55)

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1.79 (1.05 to 3.05)

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2.39 (1.21 to 4.70)

MeD

17

1.31 (0.75 to 2.26)

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1.40 (0.71 to 2.78)

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1.74 (0.74 to 4.08)

4

1.11 (0.26 to 4.73)

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BDI<10

DISCUSSION

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* The sum of the events in the three categories exceeds the number of all CVD events because some of the subjects were diagnosed with more than one CVD at the same time. **Adjusted for age, gender, education, smoking, alcohol use, leisure time physical activity, hypertension (systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg, or antihypertensive medication), dyslipidemia (total cholesterol ≥ 5.0 mmol/l or medication for lipid disorders) Abbreviations: CeVD, cerebrovascular disease; CVD, cardiovascular disease; IHD, ischemic heart disease; MeD increased (BDI ≥10) melancholic depressive symptoms; NMeD, increased non-melancholic depressive symptoms; PAD, peripheral artery disease

We analysed 2522 apparently healthy CVD risk subjects and found non-melancholic depressive symptoms increasing the risk for CVD morbidity compared to those without depressive symptoms. Our results imply that the presence of depressive symptoms is associated with increased risk for CVD events beyond what could be expected from traditional CVD risk factors. In clinical settings this is important since non-melancholic depressive symptoms might be easily undetected by physicians, yet contributing to

Journal Pre-proof increased CVD morbidity risk. To the best of our knowledge, this was one of the first studies to investigate the association of subtypes of depressive symptoms and incident CVD. The main finding of our study is in line with a longitudinal study of Case et al.[26]. In their analysis of more than 28 000 U.S. adults, atypical depression was more strongly associated with incident CVD than typical depression, when compared to non-depressive subjects.

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They found also typical depression significantly predicting incident CVD. After adjusting

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for CVD risk factors, both atypical and typical depression still predicted incident CVD (OR 1.78 and OR 1.42, respectively), but comparisons between depression groups were

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not significant. Case at al. determined depression with a fully structural diagnostic

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after at most three years of follow-up.

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interview, but they assessed incident CVD by self-report during the past 12 months,

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Depression has previously been evenly associated with different subtypes of incident CVD in a large register-based study[37]. Similarly, we found no statistically

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significant difference in the association with depressive symptoms and different subtypes of CVD, although non-melancholic depressive symptoms seemed to associate more strongly with incident PAD than other subtypes. On contrary, probably because of few incident cases, melancholic depressiveness seemed to associate weakest with PAD. There are several possible mechanisms connecting depression and CVD[15]. Behavioural factors associated with depression such as unhealthy lifestyle[2,4,5] and poor adherence to medical treatment[38,39] are plausible mediators of depressive symptomology increasing CVD risk. Depression or depressive symptoms are associated for example with smoking[2], probability of not meeting recommended levels of

Journal Pre-proof physical activity[4], and unhealthy food choices[5]. However, depression has been suggested to predict incident CVD even after adjustment for lifestyle factors[8], and also our results also suggest that the association of non-melancholic depressive symptoms and incident CVD is not mediated only by unhealthy lifestyle. The associations remained significant even after adjusting for smoking, alcohol use, and LTPA.

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Depression is also associated with many traditional CVD risk factors such as

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obesity[3,6], dyslipidemia[6], and hypertension[7]. Considering metabolic syndrome, namely its obesity-related components have been associated with depression[40].

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Moreover, precisely atypical depression and non-melancholic depressive symptoms

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have been associated with an increased risk for metabolic disturbances[17,19–24]. In a

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study among 2800 Finnish middle-aged and elderly subjects sampled from the general

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population, non-melancholic depressive symptoms (categorized according to BDI melancholic summary score) were associated with a significantly higher risk for

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metabolic syndrome when compared to non-depressed subjects (OR 1.68) and to melancholically depressed subjects (OR 1.87) [17]. Similar to our results, subjects with non-melancholic depressive symptoms had higher BMI, larger waist circumference (in women), higher triglyceride level, and they performed less LTPA. Recently, in a large community-based sample of over 150 000 middle-aged UK adults[22], atypical depression was associated with higher odds for metabolic syndrome and all its components, compared to non-atypical depression. Considering lifestyle, subjects with atypical depression were more likely to be smokers and less likely to report moderate physical activity. Even more, atypical depression has been associated with an increased risk for incident metabolic syndrome[19]. However, our results suggest that non-

Journal Pre-proof melancholic depressive symptoms increase the risk for CVD events independently of main CVD risk factors, hypertension and dyslipidemia. In addition to metabolic dysregulation, there are several other biological mechanisms that may link depression and CVD: dysregulation of autonomic nervous system, hypothalamic-pituitary-adrenal (HPA) axis, and immune-inflammatory system[15,16]. There is growing evidence that different biological dysregulations might

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be responsible for the depression-CVD association in different subtypes of

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depression[14], which might contribute to the different CVD incidence risk according to depressive subtype. HPA axis hyperactivity has been associated with melancholic

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depression[20,41], whereas there is some evidence that atypical depression is

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associated with greater inflammation[20,42,43]. As inflammation is a core factor in

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atherosclerosis[44], and strongly associated with fat-mass associated metabolic

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regulation[16], the increased CVD morbidity risk in non-melancholically depressed subjects might at least partly be inflammation driven.

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Strengths of our study include a presentative community-based sample of apparently healthy middle-aged subjects and register-based data on incident CVD. Clinical measurements were performed by trained nurses. The population survey was conducted in 2005-2007, and our follow-up ended 2013, but as the prevalence of depressive symptoms and many CVD risk factors has only increased since in Finland[45], it is likely that the results of our study are still clinically relevant. As a limitation, the subjective nature of BDI must be noted: we assessed only subjective depressive symptoms, not definite diagnosis of depression. BDI was also assessed only at the baseline, thus it is possible that some subjects without depressive symptoms at the baseline have developed them during the follow-up, and vice versa. In addition,

Journal Pre-proof the classification of depressive symptoms might have changed, although it has suggested to be quite stable[46]. Furthermore, it is possible that the subjects most at risk of CVD are also those who develop most depressive symptoms. We did not have data on treatment of depression and adherence to preventive medication, both of which might significantly affect CVD morbidity. Despite we adjusted for several sociodemographic and lifestyle-associated factors, bias caused by remaining

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confounding factors is possible, such as the time a participant has had a certain risk

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factor. We adjusted for education years, but did not have data on household income or occupational status, which have been found to affect the association of depressive

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symptoms and CVD[47–49], especially in men[48]. In addition, the number of

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melancholically depressive subjects was small, although comparable to Finnish general

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middle-aged population[17]. As our study population consisted of CV risk subjects, the

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higher prevalence of non-melancholic depressive symptoms is rational. However, nonmelancholic depressive symptoms have been found to be more prevalent than

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melancholic symptoms in Finland also before [17]. Hence non-melancholic depressiveness might be a cultural phenomenon. Importantly, there were only 17 incident CVD cases among those with melancholic depressive symptoms, which leads to a lack of statistical power to confirm the non-significant association of melancholic depressive symptoms and incident CVD. The IRRs for CVD in non-melancholic and melancholic depressiveness were quite similar, confidence intervals being wider in melancholic depressiveness. Finally, we studied only Finnish middle-aged CVD risk subjects, and the generalizability of our results to general populations and CVD risk populations in other countries must be carefully considered.

Journal Pre-proof To conclude, non-melancholic depressive symptoms seem to be associated with an increased risk for incident CVD. Thus, it could be useful in clinical settings to carefully consider for non-melancholic depressive symptoms as increased appetite, fatigue and mood reactivity when treating subjects with other CVD risk factors. These results should be replicated outside of Finland, and moreover with more rigorous definitions of depressive subtypes based on structured interviews and course of illness.

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An essential implication for future research is to study if treatment of depression could

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prevent CVD morbidity.

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DECLARATIONS OF INTEREST

ACKNOWLEDGEMENTS

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None.

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This study was supported by the Central Satakunta Health Federation of Municipalities.

REFERENCES [1]

Jo ur

The study funder played no role in the study.

Piepoli MF, Hoes AW, Agewall S, Albus C, Brotons C, Catapano AL, et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J 2016;37:2315–81. doi:10.1093/eurheartj/ehw106.

[2]

Luger TM, Suls J, Vander Weg MW. How robust is the association between smoking and depression in adults? A meta-analysis using linear mixed-effects models. Addict Behav 2014;39:1418–29. doi:10.1016/j.addbeh.2014.05.011.

[3]

Luppino FS, de Wit LM, Bouvy PF, Stijnen T, Cuijpers P, Penninx BWJH, et al. Overweight, Obesity, and Depression. Arch Gen Psychiatry 2010;67:220.

Journal Pre-proof doi:10.1001/archgenpsychiatry.2010.2. [4]

Azevedo Da Silva M, Singh-Manoux A, Brunner EJ, Kaffashian S, Shipley MJ, Kivimäki M, et al. Bidirectional association between physical activity and symptoms of anxiety and depression: the Whitehall II study. Eur J Epidemiol 2012;27:537–46. doi:10.1007/s10654-012-9692-8.

[5]

Konttinen H, Männistö S, Sarlio-Lähteenkorva S, Silventoinen K, Haukkala A. Emotional eating, depressive symptoms and self-reported food consumption. A population-based study. Appetite 2010;54:473–9.

Demakakos P, Zaninotto P, Nouwen A. Is the Association Between Depressive

ro

[6]

of

doi:10.1016/j.appet.2010.01.014.

-p

Symptoms and Glucose Metabolism Bidirectional? Evidence From the English Longitudinal Study of Ageing. Psychosom Med 2014;76:555–61.

Meng L, Chen D, Yang Y, Zheng Y, Hui R. Depression increases the risk of

lP

[7]

re

doi:10.1097/PSY.0000000000000082.

hypertension incidence. J Hypertens 2012;30:842–51.

Gan Y, Gong Y, Tong X, Sun H, Cong Y, Dong X, et al. Depression and the risk of

Jo ur

[8]

na

doi:10.1097/HJH.0b013e32835080b7.

coronary heart disease: A meta-analysis of prospective cohort studies. BMC Psychiatry 2014;14:1–11. doi:10.1186/s12888-014-0371-z. [9]

Wu Q, Kling JM. Depression and the Risk of Myocardial Infarction and Coronary Death. Medicine (Baltimore) 2016;95:e2815. doi:10.1097/MD.0000000000002815.

[10]

Pan A, Sun Q, Okereke OI, Rexrode KM, Hu FB. Depression and risk of stroke morbidity and mortality : a meta-analysis and systematic review. Jama 2011;306:2011–2. doi:10.1001/jama.2011.1282.Depression.

[11]

Fried EI, Nesse RM. Depression is not a consistent syndrome: An investigation of unique symptom patterns in the STAR*D study. J Affect Disord 2015;172:96– 102. doi:10.1016/j.jad.2014.10.010.

Journal Pre-proof [12]

Malhi GS, Mann JJ. Depression. Lancet 2018;392:2299–312. doi:10.1016/S01406736(18)31948-2.

[13]

Carney RM, Freedland KE. Depression and coronary heart disease. Nat Rev Cardiol 2017;14:145–55. doi:10.1038/nrcardio.2016.181.

[14]

Baune BT, Stuart M, Gilmour A, Wersching H, Heindel W, Arolt V, et al. The relationship between subtypes of depression and cardiovascular disease: A systematic review of biological models. Transl Psychiatry 2012;2:e92-19.

[15]

of

doi:10.1038/tp.2012.18. Penninx BWJH. Depression and cardiovascular disease: Epidemiological evidence

Penninx BWJH, Milaneschi Y, Lamers F, Vogelzangs N. Understanding the

re

[16]

-p

doi:10.1016/J.NEUBIOREV.2016.07.003.

ro

on their linking mechanisms. Neurosci Biobehav Rev 2017;74:277–86.

somatic consequences of depression: biological mechanisms and the role of

[17]

na

11-129.

lP

depression symptom profile. BMC Med 2013;11:129. doi:10.1186/1741-7015-

Seppälä J, Vanhala M, Kautiainen H, Eriksson J, Kampman O, Mäntyselkä P, et al.

Jo ur

Prevalence of metabolic syndrome in subjects with melancholic and nonmelancholic depressive symptoms. A Finnish population-based study. J Affect Disord 2012;136:543–9. doi:10.1016/j.jad.2011.10.032. [18]

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Fifth. Arlington, VA: American Psychiatric Association; 2013. doi:10.1176/appi.books.9780890425596.

[19]

Lasserre AM, Strippoli M-PF, Glaus J, Gholam-Rezaee M, Vandeleur CL, Castelao E, et al. Prospective associations of depression subtypes with cardio-metabolic risk factors in the general population. Mol Psychiatry 2017;22:1026–34. doi:10.1038/mp.2016.178.

[20]

Lamers F, Vogelzangs N, Merikangas KR, De Jonge P, Beekman ATF, Penninx BWJH. Evidence for a differential role of HPA-axis function, inflammation and

Journal Pre-proof metabolic syndrome in melancholic versus atypical depression. Mol Psychiatry 2013;18:692–9. doi:10.1038/mp.2012.144. [21]

Glaus J, Vandeleur C, Gholam-Rezaee M, Castelao E, Perrin M, Rothen S, et al. Atypical depression and alcohol misuse are related to the cardiovascular risk in the general population. Acta Psychiatr Scand 2013;128:282–93. doi:10.1111/acps.12057.

[22]

Brailean A, Curtis J, Davis K, Dregan A, Hotopf M. Characteristics, comorbidities, and correlates of atypical depression: Evidence from the UK Biobank Mental

Takeuchi T, Nakao M, Kachi Y, Yano E. Association of metabolic syndrome with

ro

[23]

of

Health Survey. Psychol Med 2019:1–10. doi:10.1017/S0033291719001004.

-p

atypical features of depression in Japanese people. Psychiatry Clin Neurosci

[24]

re

2013;67:532–9. doi:10.1111/pcn.12104.

Lamers F, De Jonge P, Nolen WA, Smit JH, Zitman FG, Beekman ATF, et al.

lP

Identifying depressive subtypes in a large cohort study: Results from the Netherlands Study of Depression and Anxiety (NESDA). J Clin Psychiatry

Piek E, Nolen WA, van der Meer K, Joling KJ, Kollen BJ, Penninx BWJH, et al.

Jo ur

[25]

na

2010;71:1582–9. doi:10.4088/JCP.09m05398blu.

Determinants of (non-)recognition of depression by general practitioners: results of the Netherlands Study of Depression and Anxiety. J Affect Disord 2012;138:397–404. doi:10.1016/j.jad.2012.01.006. [26]

Case SM, Sawhney M, Stewart JC. Atypical depression and double depression predict new‐onset cardiovascular disease in U.S. adults. Depress Anxiety 2018;35:10–7. doi:10.1002/da.22666.

[27]

Juutilainen A, Lehto S, Rönnemaa T, Pyörälä K, Laakso M. Type 2 diabetes as a “coronary heart disease equivalent”: An 18-year prospective population-based study in Finnish subjects. Diabetes Care 2005;28:2901–7. doi:10.2337/diacare.28.12.2901.

[28]

Beck AT, Rush AJ, Shaw BF, Emery G. Cognitive therapy of depression. New York:

Journal Pre-proof Guilford Press; 1979. [29]

Babor TF, de la Fuente JR, Saunders J, Grant M. AUDIT: the alcohol use disorders identification test: guidelines for use in primary healthcare. Geneva: World Health Organization; 1989.

[30]

Koponen H, Jokelainen J, Keinänen-Kiukaanniemi S, Vanhala M. Depressive symptoms and 10-year risk for cardiovascular morbidity and mortality. World J Biol Psychiatry 2010;11:834–9. doi:10.3109/15622975.2010.486842. Steer RA, Ball R, Ranieri WF, Beck AT. Dimensions of the Beck depression

of

[31]

inventory-II in clinically depressed outpatients. J Clin Psychol 1999;55:117–28.

Vanhala M, Jokelainen J, Keinänen-Kiukaanniemi S, Kumpusalo E, Koponen H.

-p

[32]

ro

doi:10.1002/(SICI)1097-4679(199901)55:1<117::AID-JCLP12>3.0.CO;2-A.

re

Depressive symptoms predispose females to metabolic syndrome: a 7-year

0447.2008.01283.x.

Ovaskainen Y, Koponen H, Jokelainen J, Keinänen-Kiukaanniemi S, Kumpusalo E,

na

[33]

lP

follow-up study. Acta Psychiatr Scand 2009;119:137–42. doi:10.1111/j.1600-

Vanhala M. Depressive symptomatology is associated with decreased

Jo ur

interleukin-1 beta and increased interleukin-1 receptor antagonist levels in males. Psychiatry Res 2009;167:73–9. doi:10.1016/j.psychres.2007.12.004. [34]

World Health Organization, International Diabetes Federation. Definition and diagnosis of diabetes mellitus and intermediate hyperglycaemia : report of a WHO/IDF consultation. Geneva: World Health Organization; 2006.

[35]

Conroy RM, Pyörälä K, Fitzgerald AP, Sans S, Menotti A, De Backer G, et al. Estimation of ten-year risk of fatal cardiovascular disease in Europe: the SCORE project. Eur Heart J 2003;24:987–1003. doi:10.1016/S0195-668X(03)00114-3.

[36]

Linden A. Combining propensity score-based stratification and weighting to improve causal inference in the evaluation of health care interventions. J Eval Clin Pract 2014;20:1065–71. doi:10.1111/jep.12254.

[37]

Daskalopoulou M, George J, Walters K, Osborn DP, Batty GD, Stogiannis D, et al.

Journal Pre-proof Depression as a risk factor for the initial presentation of twelve cardiac, cerebrovascular, and peripheral arterial diseases: Data linkage study of 1.9 million women and men. PLoS One 2016;11:1–16. doi:10.1371/journal.pone.0153838. [38]

Berntson J, Stewart KR, Vrany E, Khambaty T, Stewart JC. Depressive symptoms and self-reported adherence to medical recommendations to prevent cardiovascular disease: NHANES 2005–2010. Soc Sci Med 2015;138:74–81. doi:10.1016/j.socscimed.2015.05.041. Ziegelstein RC, Fauerbach JA, Stevens SS, Romanelli J, Richter DP, Bush DE.

of

[39]

ro

Patients with depression are less likely to follow recommendations to reduce cardiac risk during recovery from a myocardial infarction. Arch Intern Med

Pan A, Keum N, Okereke OI, Sun Q, Kivimaki M, Rubin RR, et al. Bidirectional

re

[40]

-p

2000;160:1818–23.

lP

association between depression and metabolic syndrome: a systematic review and meta-analysis of epidemiological studies. Diabetes Care 2012;35:1171–80.

[41]

na

doi:10.2337/dc11-2055.

Juruena MF, Bocharova M, Agustini B, Young AH. Atypical depression and non-

Jo ur

atypical depression: Is HPA axis function a biomarker? A systematic review. J Affect Disord 2018;233:45–67. doi:10.1016/j.jad.2017.09.052. [42]

Woelfer M, Kasties V, Kahlfuss S, Walter M. The Role of Depressive Subtypes within the Neuroinflammation Hypothesis of Major Depressive Disorder. Neuroscience 2019;403:93–110. doi:10.1016/j.neuroscience.2018.03.034.

[43]

Yang C, Tiemessen KM, Bosker FJ, Wardenaar KJ, Lie J, Schoevers RA. Interleukin, tumor necrosis factor-α and C-reactive protein profiles in melancholic and nonmelancholic depression: A systematic review. J Psychosom Res 2018;111:58–68. doi:10.1016/j.jpsychores.2018.05.008.

[44]

Libby P, Ridker PM, Maseri A. Inflammation and Atherosclerosis. Circulation 2002;105:1135–43. doi:10.1161/hc0902.104353.

Journal Pre-proof [45]

Koponen P, Borodulin K, Lundqvist A, Sääksjärvi K, Koskinen S. Terveys, toimintakyky ja hyvinvointi Suomessa FinTerveys 2017-tutkimus RAPORTTI 4 | 2018. THL; 2018.

[46]

Lamers F, Rhebergen D, Merikangas KR, De Jonge P, Beekman ATFF, Penninx BWJHJH. Stability and transitions of depressive subtypes over a 2-year followup. Psychol Med 2012;42:2083–93. doi:10.1017/S0033291712000141.

[47]

Cho Y, Lim TH, Kang H, Lee Y, Lee H, Kim H. Socioeconomic status and depression as combined risk factors for acute myocardial infarction and stroke:

of

A population-based study of 2.7 million Korean adults. J Psychosom Res

Wiernik E, Meneton P, Empana JP, Siemiatycki J, Hoertel N, Vulser H, et al.

-p

[48]

ro

2019;121:14–23. doi:10.1016/j.jpsychores.2019.01.016.

Cardiovascular risk goes up as your mood goes down: Interaction of depression

re

and socioeconomic status in determination of cardiovascular risk in the

lP

CONSTANCES cohort. Int J Cardiol 2018;262:99–105. doi:10.1016/j.ijcard.2018.02.033.

na

Lemogne C, Meneton P, Wiernik E, Quesnot A, Consoli SM, Ducimetière P, et al. When blue-collars feel blue. Circ Cardiovasc Qual Outcomes 2017;10:1–10. doi:10.1161/CIRCOUTCOMES.116.002767.

Jo ur

[49]

Journal Pre-proof HIGHLIGHTS

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

Non-melancholic depressiveness is common in cardiovascular risk persons Cardiovascular morbidity is increased in persons with non-melancholic depressiveness In clinical practice, non-melancholic depressive symptoms should be noted

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 