Acta Psychiatr Scand 2009: 119: 137142 All rights reserved DOI: 10.1111/j.1600-0447.2008.01283.

Copyright 2008 The Authors Journal Compilation 2008 Blackwell Munksgaard

ACTA PSYCHIATRICA SCANDINAVICA

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

Vanhala M, Jokelainen J, Keinanen-Kiukaanniemi S, Kumpusalo E, Koponen H. Depressive symptoms predispose females to metabolic syndrome: a 7-year follow-up study. Objective: To evaluate the risk for developing metabolic syndrome when having depressive symptoms. Method: The prevalence of depressive symptoms and metabolic syndrome at baseline, and after a 7-year follow-up as measured with Beck depression inventory (BDI), and using the modied National Cholesterol Education Program Adult Treatment Panel III criteria for metabolic syndrome (MetS) were studied in a middle-aged population-based sample (n = 1294). Results: The logistic regression analysis showed a 2.5-fold risk (95% CI: 1.25.2) for the females with depressive symptoms (BDI 10) at baseline to have MetS at the end of the follow-up. The risk was highest in the subgroup with more melancholic symptoms evaluated with a summary score of the melancholic items in BDI (OR 6.81, 95% CI: 2.0922.20). In men, there was no risk dierence. Conclusion: The higher risks for MetS in females with depressive symptoms at baseline suggest that depression may be an important predisposing factor for the development of MetS.

M. Vanhala1, J. Jokelainen2, S. Keinnen-Kiukaanniemi2,3, E. Kumpusalo4, H. Koponen5

1 Unit of Family Practice, Central Hospital of Middle Finland, Jyvskyl, Finland, 2Institute of Health Sciences, University of Oulu, and Unit of General Practice, Oulu University Hospital, Oulu, Finland, 3Oulu Health Center, City of Oulu, Finland, 4School of Public Health and Clinical Nutrition, Department of Family Medicine, University of Kuopio, and Unit of Family Practice, Kuopio University Hospital, Kuopio, Finland and 5Academy of Finland, Department of Psychiatry, Kuopio University, and Kuopio University Hospital, Kuopio, Finland

Key words: Beck depression inventory; cholesterol; depression; metabolic syndrome; triglycerides Prof. Hannu Koponen, Department of Psychiatry, Kuopio University Hospital, PO Box 1777, FIN-70211 Kuopio, Finland. E-mail: hannujuhani.koponen@uku.fi Accepted for publication September 16, 2008

Significant outcomes

Females with depressive symptoms at baseline showed to have a 2.5-fold risk to have metabolic syndrome at the end of the 7-year follow-up. The risk was highest in the subgroup with more melancholic symptoms.

Limitations

The identication of depressive symptoms was based on a self-report scale, not a diagnostic interview. Our genetically homogenous study population may hamper the generalizability of the results. The effect of age and subtype of depressive symptoms should be interpreted with caution because the small sample size in these subgroups.

Introduction

The metabolic syndrome (MetS) is a multifactorial disorder encompassing abdominal obesity, altered glucose and lipid metabolism, and elevated blood pressure (14). In previous cross-sectional studies, MetS has been observed with a higher prevalence

in depressed than in non-depressed subgroups, and the observed prevalence rates have ranged from 8% to 38% (58). The only previous long-term study focusing on the interaction between depression and MetS has shown that more severe depressive symptoms and stressful life events at baseline increased the risk to develop MetS during 137

Vanhala et al. the 15-year follow-up in an exclusively female study population (7). Previous studies have also shown that MetS increases its prevalence after menopause, and that the postmenopausal hormone replacement therapy may reduce abdominal obesity, insulin resistance, lipid levels and blood pressure (9). Previous studies also suggest that depression may be a risk factor for several components of MetS. Depression is associated with a tendency to dyslipidaemias and visceral fat accumulation (10). The results are not, however, equivocal as, in the Alameda County Study, depression did not increase the risk for future obesity (11). Depressed patients also frequently have insulin resistance (12), which may resolve after recovery from depression (13). A recent meta-analysis has also shown that the presence of depression increases the risk for diabetes (14). Besides the study of Raikkonen et al. (7), previous estima tions of the risk to develop MetS when having depression are based on cross-sectional clinical evaluation linked with previous history of depressive episode.
Aims of the study

of the 1998 participants took part in the 7-year follow-up visit.

Procedures

The aim of this study was to evaluate the putative risk to develop MetS until the end of 7-year followup when having depressive symptoms at baseline in a large population-based study sample. In addition, the sex dierences in risk levels were scrutinized.

Material and methods Subjects

The study was conducted in Pieksamaki area, South-Savo, Finland in order to determine the prevalence of risk factors and long-term course of MetS between 1998 and 2005. All inhabitants born in the years 1942, 1947, 1952, 1957 and 1962 in Pieksamaki (n = 1294) were invited for a compre hensive health check-up during 1998 at the study baseline. The addition of the last group, those born in 1962, extends the age spectrum of the sample when compared with the previously reported 1993 sampling (15). The study was carried out in accordance with the latest version of the Declaration of Helsinki. All participants gave a written informed consent, and the study protocol was approved by the Ethics Committee of the Kuopio University Hospital and the University of Kuopio. The participation rate at baseline in 1998 was 923 1294, i.e. 71.3%. In 2004 2005, 688 (74.5%) 138

At the 1998 and 2004 2005 study visits, all participants lled out a standard questionnaire containing questions about the use of medications including antidepressants and hormone replacement therapy in females. In addition, data were collected on both visits of smoking habits, use of alcohol (number of drinks per week) and physical activity (number of over 30 min exercise sessions per week). At baseline and at 7-year follow-up visit, the depressive symptoms were evaluated with the Beck depression inventory (BDI) (16), in which a score of 10 points was used as a cut-o point for depressive symptoms. In order to examine the eect of the subtype of depressive symptomatology, we used a summary score of the melancholic items in BDI (sadness, past failure, loss of pleasure, guilty feelings, punishment feelings, loss of interest, irritability, change in sleeping and appetite) in dividing the cases with depressive symptoms into subgroups with more frequent melancholic symptoms and non-melancholic symptoms subgroups (17, 18). At baseline and at 7-year follow-up, fasting blood samples including the glucose and lipid levels were drawn between 8 and 11 Oclock after 12 h of fasting. The physical examination included weight, height, waist circumference and blood pressure taken on the same study visit. Height and weight were measured in light clothing to the nearest 0.5 cm and 0.1 kg respectively. The waist circumference was measured to the nearest 1.0 cm at the midpoint between the lateral iliac crest and lowest rib. The blood pressure was measured twice with a mercury sphygmomanometer with subjects in sitting position after a 15-min rest. All measurements were carried out by two nurses who were specifically trained to the procedures during 1-day course at the Unit of General Practice of the Kuopio University. In the evaluation of MetS, we used the modied National Cholesterol Education Program Adult Treatment Panel III criteria (NCEPATPIII criteria) with the 100 mg dL blood glucose cut-o point (1). Originally, NCEP denes MetS as having three or more of the following criteria: i) fasting serum glucose of 110 mg dl or higher, ii) serum triglycerides of 150 mg dl or higher, iii) serum high-density lipoprotein (HDL) cholesterol <40 mg dl in men or <50 mg dl in women, iv) blood pressure of 130 85 mmHg or higher and v) waist circumference >102 cm in men or >88 cm in women (4).

Depression predisposes females to MetS

Statistical methods

Logistic regression models were used to examine the relationship between the MetS and depressive symptoms by gender. In multivariate analyses, the following possible confounding factors were used: age, education, marital status, smoking, physical activity, alcohol consumptions and use of antidepressive and hormone replacement therapy. All statistical testing were performed at a 5% level of signicance using sas for Windows version 9.2 (SAS Institute Inc., Cary, NC, USA).
Results

The key variables for the 488 members (294 women and 194 men) of the study population, who at baseline visit did not have MetS and who also participated in the 7-year follow-up, are shown in Table 1. The prevalence of MetS at 1998 baseline was 33% (n = 96) for males and 26.5% (n = 106) in females. These 202 excluded participants who had MetS at baseline did dier from the study group with regards to their age (the excluded were on average 2 years older) and degree of basic education (cases with MetS at baseline had lower basic education). No other dierences between demographic factors or life habits were observed.

At baseline, 48 women (16.3% of the baseline study population) and 16 men (8.2%) had depressive symptoms. At the 7-year follow-up, 55 initially non-depressed females (22.4%) had developed MetS; in females, with depressive symptoms at baseline the corresponding gure was 20 (or 41.7%; P = 0.01). After adjusting for age, education, physical activity, smoking, alcohol use, marital status and the use of antidepressive and hormone replacement therapy, the logistic regression analysis showed a 2.5-fold risk for the female cohort members with depressive symptoms at baseline to have MetS at the end of the follow-up (OR 2.5, 95% CI: 1.25.2). In men, two out of 16 males (12.5%) with depressive symptoms at baseline developed MetS during the follow-up; in nondepressed males the corresponding gures were 45 178 (25.3%; P = 0.25). As the risk to develop MetS when having depressive symptoms at the baseline was signicant only in women, we studied this subgroup in greater detail. At baseline, the depressed females had more severe symptoms than depressed males (v2 = 6.7, d.f. = 1, P = 0.001). We also observed a higher prevalence of low HDL-cholesterol levels in women with depressive symptoms than nondepressed females. The frequencies of individual criteria for MetS in women are presented in

Table 1. Study population characteristics at 20042005 follow-up Women MetS (n = 75) 49.5 (5.4) 4 (110) 28.6 61.3 16.0 22.7 10.7 77.3 12.0 22.7 30.7 14.7 84.1 25.9 69.8 135.3 81.9 60.0 1.1 1.6 5.6 No MetS (n = 219) 44.7 (6.2) 2 (16) 13.9 38.5 33.5 28.0 8.3 80.3 11.4 22.5 28.4 5.5 77.1 23.3 64.3 126.0 76.0 35.2 1.0 1.6 5.4 MetS (n = 47) 47.3 (5.8) 2 (05) 4.2 66.0 21.2 12.8 10.6 85.1 4.3 34.0 36.2 27.7 93.0 26.7 80.6 130.9 81.0 42.6 1.5 1.4 5.8 Men No MetS (n = 147) 45.6 (5.9) 2 (05) 9.5 54.4 32.7 12.9 8.2 86.4 5.4 26.5 33.3 27.2 88.8 24.9 78.2 134.4 80.9 61.9 1.2 1.4 5.7

Characteristic, 1998 Age, mean (SD) Beck depression inventory (BDI) score BDI 10 (%) Basic education (%) Elementary school Middle school Matriculation Marital status (%) Single Married cohabit Divorced widowed Current smokers (%) Physically active (%) Alcohol use (%) Waist circumference, mean (SD) BMI, mean (SD) Weight (kg), mean (SD) Systolic BP, mean (SD) Diastolic BP, mean (SD) Hypertension (sys 135 and or dia 85) (%) Triglycerides, mean (SD) HDL cholesterol, mean (SD) Glucose, mean (SD)

(8.5) (3.7) (10.0) (17.6) (8.9) (0.5) (0.3) (0.5)

(7.6) (2.8) (8.9) (16.4) (9.0) (0.4) (0.3) (0.4)

(7.3) (2.5) (8.7) (14.6) (8.3) (0.7) (0.2) (0.6)

(7.0) (2.6) (8.5) (15.2) (9.0) (0.6) (0.3) (0.5)

MetS, metabolic syndrome; SD, standard deviation; BMI, body mass index; HDL, high-density lipoprotein; sys, systolic blood pressure; dia, diastolic blood pressure.

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Table 2. Prevalence of modified NCEPATPIII MetS criteria in women (2004 2005 data) With more frequent melancholic symptoms (n = 20) (%) 30.0 35.0 50.0 55.0 55.6 Other depression (n = 28) (%) 28.6 22.2 32.1 75.0 48.2 With depressive symptoms, total (n = 48) (%) 29.2 27.7 39.6 66.7 51.1 P-value (cases with depressive symptoms vs. non-depressed) 0.3159 0.1243 <0.0001 0.7727 0.2405

Criteria Abdominal obesity Triglycerides HDL cholesterol Blood pressure Blood glucose HDL, high-density lipoprotein.

Non-depressed (n = 224) (%) 22.5 18.0 14.2 64.5 41.7

Table 2. When the subtype of depressive symptoms was scrutinized, the risk to develop MetS was higher in females with more frequent melancholic symptoms at baseline (n = 28; OR 4.2, 95% CI: 1.412.3) when compared to females with non-melancholic depression (n = 20; OR 1.8, 95% CI: 0.74.5). The eect of age and menopause were explored using the categorization by Luoto et al. (19): subjects in 3637 and 4142 years of age were considered premenopausal; subjects in 4647 and 5152 years of age were considered perimenopausal; and subjects in 5657 years of age postmenopausal. As the risk may be more clear-cut in menopausal transition, we took into the analyses peri- and postmenopausal females at baseline (n = 114). In this subgroup when compared with premenopausal females, it was more common to develop MetS as 14 out of the 24 females with depressive symptoms developed MetS during the follow-up (v2 = 3.7, d.f. = 1, P = 0.055). We also examined the eect of hormone replacement therapy. At 1998, 49 women used hormone replacement therapy, and 13 of them were depressed. At the 7-year follow-up, six of them had developed MetS. Women with depressive symptoms at baseline not using hormone replacement therapy developed MetS in 14 cases out of 34 (41% vs. 46%, NS).
Discussion

The key ndings in our population-based study containing both sexes and dierent age groups are the observation of 2.5-fold prevalence of MetS after the 7-year follow-up in middle-aged females with depressive symptoms at baseline and a higher risk in females with more frequent melancholic symptoms. In men there was no dierence, and males had less-severe depressive symptoms when compared with females suggesting that the severity of depressive symptoms may also play a role. The increased risk for MetS in depressed females is in line with the results of Raikkonen et al. (7), who found that more-severe depressive symptoms and 140

life stress at baseline were associated with 1.2- to 2.1-fold risk to develop MetS over the 15-year follow-up. We also observed that the risk to develop MetS was higher in peri- and postmenopausal women. This is in accordance with the results of Everson-Rose et al. (20) showing that depressive symptoms were signicantly related to excess risk of diabetes and insulin resistance in a female population at menopausal transition. The connection between depression and MetS is probably reciprocal as we have recently demonstrated an increased risk to develop depression when having MetS at study baseline (21). Our nding of increased liability in females to develop MetS when initially depressed is also in accordance with previous results from cross-sectional studies. Kinder et al. (5) using the Third National Health and Nutrition Examination Survey data noted that history of depressive episode was associated with MetS in women; in men the association was not statistically signicant. Onyike et al. (22) using the same database observed that obesity was associated with pastmonth depression in females; in males the association was non-signicant. Carpenter et al. (23) using the National Longitudinal Alcohol Epidemiological Survey data observed an association between increased body mass index and past-year major depression in females; in males the relationship was inverse. In the study of Carnethon et al. (24), association of depressive symptoms and incident diabetes was strongest in women. Thus there may be gender dierences in the connection between depression and MetS or its components, and the health risks linked to depression may be more critical to women. The psychological factors may also be important for the development of MetS as depression is associated with sedentary lifestyle and negative perception of oneself (23), and they may also dier between males and females (7, 25). Multiple factors appear to predispose to MetS, e.g. genetic decits in insulin signalling pathways, adipose tissue disorders, physical inactivity, mito-

Depression predisposes females to MetS chondrial dysfunction, individual genetic variability, advancing age and certain drugs. The MetS is a useful clinical concept as it identies patients who have twice the risk for atherosclerotic cardiovascular disease and ve times the risk for diabetes (26). In previous years, several dierent diagnostic criteria sets have been suggested for MetS (2, 3). The US NCEPATPIII criteria proposed easily applicable cut-o limits for waist circumference; lipid levels, blood glucose and blood pressure (4), and they have been widely used in both clinical practice and epidemiological studies. The recent modication of the criteria (1) uses a lower cut-o point for glucose and takes the antihypertensive, antidiabetic or antidyslipidaemic medication into account in the criteria. In addition, insulin resistance, the key feature in MetS, has been suggested to be a metabolic link between depressive disorder and atherosclerotic vascular diseases (27). Biological mechanisms that may explain the association between depression and MetS include cytokine-mediated inammation (28, 29), dysregulation of the hypothalamicpituitary adrenal (HPA) axis, and the eects of physiological or psychological stress related to depression. Cortisol excess may antagonize the actions of insulin-mediated glucose disposal or cause deposition of fat to abdomen resulting in visceral adiposity (24, 30). Depression has also previously linked with low total cholesterol levels (31); in this study, we observed a higher prevalence of low HDL-cholesterol levels in women with depressive symptoms. Low levels of HDL cholesterol may be related to high total cholesterol and the presence of MetS, but according to the study of Komulainen et al. (32) it may also predispose to memory impairment as high HDL-cholesterol levels may protect against hippocampal atrophy and promote synaptogenesis. More profound association between melancholic subtype of depression and disturbances in the HPA-axis or cytokine functioning may explain the higher risk for MetS associated with more frequent melancholic symptoms in females. There are several limitations in this study. The identication of depressive symptoms was based on a self-report scale, not a diagnostic interview, which is a limitation. Although not initially constructed for a diagnostic scale, the BDI with a cutof score of 10 points has been shown to be a useful instrument for detecting depressive disorders in follow-ups in various adult populations (see Ref. 7, 17, 33). Secondly, our genetically homogenous study population may hamper the generalizability of the results. Thirdly, the eect of age and subtype of depressive symptoms should be interpreted with caution because of the small sample size in these subgroups. Our results suggest that depressive symptoms, and in particular more frequent symptoms of melancholic depression, may be important predisposing factors for the development of MetS in females. Thus, eective treatment of depression could also be important for the prevention of MetS. In addition, insights into the pathophysiological links between depression and MetS would help to develop new treatments for depression.
Acknowledgements
This work was supported by grant from the Central Finland Hospital District (MV), and grant number 113 760 from the Academy of Finland (HK).

Declaration of interest
None.

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