Hyperlipidemia, Statin Use, and the Risk of Developing Depression: A Nationwide Retrospective Cohort Study Chieh-Sen Chuang M.D., Tse-Yen Yang Ph.D., Chih-Hsin Muo MSc., Hong-Lin Su PhD, Fung-Chang Sung Ph.D., Chia-Hung Kao M.D. PII: DOI: Reference:
S0163-8343(14)00114-5 doi: 10.1016/j.genhosppsych.2014.05.008 GHP 6859
To appear in:
General Hospital Psychiatry
Received date: Revised date: Accepted date:
31 October 2013 17 April 2014 1 May 2014
Please cite this article as: Chuang Chieh-Sen, Yang Tse-Yen, Muo Chih-Hsin, Su HongLin, Sung Fung-Chang, Kao Chia-Hung, Hyperlipidemia, Statin Use, and the Risk of Developing Depression: A Nationwide Retrospective Cohort Study, General Hospital Psychiatry (2014), doi: 10.1016/j.genhosppsych.2014.05.008
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ACCEPTED MANUSCRIPT The 2nd Revised Manuscript: Ms. Ref. No.: GHP-13-522.R1 Title: Hyperlipidemia, Statin Use, and the Risk of Developing Depression: A
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Running title: Hyperlipidemia, Statin, and Depression
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Nationwide Retrospective Cohort Study
Chieh-Sen Chuang, MD; Tse-Yen Yang, PhD; Chih-Hsin Muo, MSc; Hong-Lin Su,
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PhD; Fung-Chang Sung, PhD; Chia-Hung Kao, MD
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Departments of Neurology, Changhua Christian Hospital, Changhua, Taiwan (C.S.C.);
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Life Sciences, National Chung-Hsing University, Taichung, Taiwan (C.S.C., H.L.S.); Department of Nuclear Medicine and PET Center, China Medical University
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Hospital, Taichung, Taiwan (T.Y.Y., C.H.K.); Graduate Institute of Clinical Medicine Science and School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan (T.Y.Y., C.H.K.); Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan (C.H.M.); Department of Public Health, China Medical University Hospital, Taichung, Taiwan (F.C.S.)
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ACCEPTED MANUSCRIPT Correspondence: Dr. Chia-Hung Kao, MD, Graduate Institute of Clinical Medical
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Science and School of Medicine, College of Medicine, China Medical University, No.
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2, Yuh-Der Road, Taichung 404, Taiwan. Tel.: +886 4 22052121x7412; Fax: +886 4
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22336174. E-mail: d10040 @mail.cmuh.org.tw
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These authors’ individual contributions were as follows.
Conception and design: Chieh-Sen Chuang, Chia-Hung Kao. Administrative support: Tse-Yen Yang, Chih-Hsin Muo, Hong-Lin Su, Fung-Chang
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Sung.
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Collection and assembly of data: All authors.
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Data analysis and interpretation: Chieh-Sen Chuang, Tse-Yen Yang, Chih-Hsin Muo,
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Chia-Hung Kao.
Manuscript writing: All authors. Final approval of manuscript: All authors
Funding This work was supported by the study projects (DMR-102-014, DMR-103-012) in China Medical University Hospital; Taiwan Ministry of Health and Welfare, Clinical Trial and Research Center for Excellence (DOH102-TD-B-111-004), Taiwan
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ACCEPTED MANUSCRIPT Ministry of Health and Welfare, Cancer Research Center for Excellence (MOHW103-
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TD-B-111-03); and International Research-Intensive Centers of Excellence in Taiwan
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(I-RiCE) (NSC101-2911-I-002-303). The funders had no role in study design, data
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collection and analysis, decision to publish, or preparation of the manuscript. No
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additional external funding received for this study.
Conflict of interest
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The authors declare that they have no conflicts of interest.
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ACCEPTED MANUSCRIPT Abstract
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Objective: Depression is a highly prevalent disorder that is associated with disability.
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The aim of this study was to determine the relationship between depression and
statins to patients with hyperlipidemia.
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hyperlipidemia, and whether the onset of depression is associated with administering
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Material and Methods: The data analyzed in this study were retrieved from the National Health Insurance Research Database (NHIRD) in Taiwan. We identified newly diagnosed hyperlipidemia in 26 852 patients without a history of depression as
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the exposure group in the period of 2000–2002, and a comparison group comprised
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107 408 patients. The differences between the exposure group and the comparison
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group were examined using a chi-square test to calculate categorical variables. The
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hazard ratio and the 95% confidence interval (CI) for depression were used in the logistic regression. Results: The hyperlipidemia patients demonstrated a high risk for depression and comorbidities, such as hypertension, diabetes, and sleep disorder, which indicated synergistic effects related to a high risk of depression in hyperlipidemia patients. Hyperlipidemia patients who had received statins exhibited a lower risk of depression than did those who had not received statins.
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ACCEPTED MANUSCRIPT Conclusion: Our results suggested that hyperlipidemia increases the risk of
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depression and that using statins is associated with a decreased risk of depression in
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patients with hyperlipidemia.
Keywords: depression; hyperlipidemia; statins; National Health Insurance Research
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Database (NHIRD)
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ACCEPTED MANUSCRIPT Abbreviations and Acronyms:
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CI = confidence interval; NHIRD = National Health Insurance Research Database
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ACCEPTED MANUSCRIPT Introduction
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Depression is a common disorder that affects people worldwide. Depression is
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projected to be the major cause of disability worldwide.1 Depression considerably
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reduce quality of life, and at least 30% of people worldwide experience a depressive disorder during their lives.2
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Inflammation and inflammatory mediators are strongly associated with depressive disorders.1, 2 Experimental evidence has suggested an association between depressive disorders and circulating levels of C-reactive protein, which is a marker of 4
Elevated levels of systemic inflammatory cytokines have been
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inflammation.3,
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implicated in the development of depressive symptoms in elderly people.5, 6
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Hyperlipidemia is defined by abnormally elevated levels of lipids or lipoproteins
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in the blood. It is the most common form of dyslipidemia in western countries. Dyslipidemia is a risk factor in the development and progression of atherosclerosis, and increases the risk of cardiovascular disease.7,
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Hyperlipidemia has been
associated with elevated levels of systemic inflammatory markers.9, 10 Inflammation plays a prominent role in the development of atherosclerosis.11 Studying inflammation might facilitate determination of a link between hyperlipidemia and atherogenesis.12 In addition, vascular disease has also been suggested as a major risk factor for depression in late life.13 These studies indicated a connection among hyperlipidemia,
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ACCEPTED MANUSCRIPT inflammation, and depression. However, information on the link between
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hyperlipidemia and depression is scant.
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Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) are
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effective drugs that reduce serum cholesterol levels and provide secondary prevention from cardiovascular events.14 An increasing number of in vitro and in vivo studies
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have indicated that statins exert antiinflammatory effects that contribute to their beneficial effects in patients with hyperlipidemia.15 Substantial evidence suggests that statins exert a pleiotropic effect that regulates cholesterol-lowering activity.16
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However, few studies have been conducted on the connection between depression and
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the statin use of hyperlipidemia patients.
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We used representative National Health Insurance (NHI) data sets from Taiwan
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to conduct a cohort study assessing the relationship between depression and hyperlipidemia.
Materials and Methods Data source We used the National Health Insurance Research Database (NHIRD) compiled by the Bureau of National Health Insurance and maintained by the National Health
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ACCEPTED MANUSCRIPT Research Institutes in Taiwan.17, 18 The database contained all reimbursement claims
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records from 1996 to 2008 for 1 million randomly selected insurants. All data were
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deidentified and analyzed anonymously. In addition, this study was approved by the
Study Participants We
identified
26 852
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Ethics Review Board of China Medical University (CMU-REC-101-012).
patients
newly
diagnosed
with
hyperlipidemia
(International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-
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9) code 272) without a history of depression (ICD-9 codes 296.2, 296.3, 300.4, and
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311) in the period of 2000–2002 as the exposure group. The index date for the
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hyperlipidemia patients was the date of their first medical visit. For the comparison
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group of 107 408 patients, we selected insurants from those without hyperlipidemia and depression history in the same period and frequency matched them with the hyperlipidemia group according to age (18–29, 30–39, 40–49, 50–59, 60–69 and ≥ 70 y) and sex at a ratio of 4 to 1. The classifications of the urbanization level were modified through stratification into 4 levels, with the highest level comprising all levels above the fourth. They conducted cluster analysis by using the squared Euclidean distance and Ward’s minimum variance method to identify 7 clusters according to the population density
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ACCEPTED MANUSCRIPT (people/km2) of the townships and the numbers of people with a college degree or
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higher, elderly people over 65 years of age, agricultural workers, and physicians per
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100 000 people.
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The baseline comorbidity histories of each patient included hypertension (ICD-9CM codes 401-405), diabetes mellitus (ICD-9-CM code 250), sleep disorder (ICD-9-
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CM codes 307.4 and 780.5), and anxiety (ICD-9-CM code 300.00). All study patients were followed up from the index date to the date an insurance claim for diagnosis and treatment of depression, the end of 2008, or withdrawal from
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the insurance program, whichever occurred first. In addition, the hyperlipidemia
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patients were separated into 2 groups: a group of patients who had used statins for
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treatment and a group of patients who had never used statins for treatment.
Statistical Analysis The demographic characteristics and the prevalence of comorbidities in the exposure group and the comparison group were compared. The differences were examined using a chi-square test to calculate categorical variables. The hazard ratio (HR) and the 95% confidence interval (CI) for depression were used in a Cox proportional hazard regression. The multivariate model was used to control for age, sex, and comorbidities, which differed significantly between the 2 groups. We also
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ACCEPTED MANUSCRIPT investigated the interaction between hyperlipidemia and comorbidities by using a
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likelihood ratio test after adjusting for multiple covariates. All analyses were
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performed using the SAS statistical package (Version 9.2; SAS Institute Inc., Cary,
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NC, USA). All reported P values were 2-tailed, and statistical significance was
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defined at the α = 0.05 level.
Results
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The hyperlipidemia group and the control group exhibited significant differences
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in urbanization levels and comorbidities such as hypertension, diabetes mellitus, and
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sleep disorder (Table 1).
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The incidence rates of depression in the hyperlipidemia and nonhyperlipidemia groups demonstrated that the hazard ratio of hyperlipidemia (1.64, 95% CI, 1.55–1.74, Table 2) increased compared with that of the nonhyperlipidemia group. In addition, female patients demonstrated a higher risk for depression compared with male patients (HR = 1.47, 95% CI, 1.40–1.55, data not shown). The hazard ratio for female patients was 1.60 (95% CI, 1.49–1.72), and the hazard ratio for male patients was 1.70 (95% CI, 1.55–1.86). When the patients were classified according to age (18–39, 40– 49, 50–59, 60 ≥ years), the age-specific hazard ratio of hyperlipidemia was
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ACCEPTED MANUSCRIPT significantly higher. The urbanization-level-specific risk for depression was also
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significantly higher than that of the nonhyperlipidemia group. Risk for depression
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differed significantly based on sex and presence of hyperlipidemia (women, HR =
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1.57 (CI: 46–1.70); men, HR = 1.68 (CI: 1.54–1.85); interaction, P = .02) (Table 2).
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Regarding the interaction between hyperlipidemia and comorbidities, HRs between 1.70 and 2.05 were calculated for the patients exhibiting hyperlipidemia and hypertension
(Table
3).
When
hyperlipidemia
and
hypertension
occurred
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concurrently, the HR for depression increased to 2.39 (95% CI, 2.21–2.59, P < .001)
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and the P value of interaction was less than .0001 (Table. 3). When hyperlipidemia
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and diabetes occurred concurrently, the HR for depression was 1.86 (95% CI, 1.65–
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2.10, P < .001). The patients with either hyperlipidemia or diabetes exhibited an increased HR for depression, and the P value for the interaction indicated borderline significance. Sleep disorder was also a crucial comorbidity associated with depression. When hyperlipidemia and sleep disorder occurred concurrently, the HR was as high as 5.65 (95% CI, 5.13–6.21), and the HR of patients with hyperlipidemia and sleep disorder increased from 1.92 to 4.28. The risk for depression was higher in patients with hyperlipidemia and anxiety than in patients without hyperlipidemia and anxiety, followed by patients with anxiety and hyperlipidemia (HR = 5.84, 4.38, and
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ACCEPTED MANUSCRIPT 1.92, 95% CI = 5.01–6.81, 3.84–5.01, and 1.81–2.03, respectively). Hyperlipidemia
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a synergistic effect on patients and their risk of depression.
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and comorbidities, namely hypertension, diabetes, sleep disorder, and anxiety, exerted
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Table 4 presents the risk for depression stratified by statin use. Compared with the nonhyperlipidemia group, the risk for depression was 9.27 and 10.4 in
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hyperlipidemia patients with and without statin use. Hyperlipidemia patients who received statins exhibited a significantly lower risk for depression than did those who
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did not receive statins (HR = 0.81, 95% CI, 0.69–0.96).
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Discussion
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The present study demonstrated that, compared with the control group,
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hyperlipidemia increased the risk of depression 1.64-fold after adjusting for age, sex, and medical comorbidities over a 6-year period. The risk of depression was elevated when hyperlipidemia and sleep disorder occurred concurrently. The results of this cohort study indicated that statin use is associated with a reduced risk of depression in hyperlipidemia patients. Systemic inflammation and inflammatory mediators have been associated with the development of depressive disorders.1, 5 Hypercholesterolemia is associated with increased circulating levels of activated immune cells and proinflammatory
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ACCEPTED MANUSCRIPT cytokines.19, 20 In a previous study, Rogowski et al analyzed 12 072 people between
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2002 and 2009 in a cross-sectional study. A significant correlation was noted between
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the components of the metabolic syndrome and 4 inflammatory markers, the high-
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sensitivity C-reactive protein, erythrocyte sedimentation rate, concentration of fibrinogen, and white blood cell count.21 Viscogliosi et al investigated 133 elderly
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people (age, 68.9 ± 4 y) and observed that 57 patients with the metabolic syndrome exhibited a higher prevalence of depressive symptoms, a decrease in cognitive function, and higher levels of inflammatory markers.22 In the present study, we
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determined that hyperlipidemia increased the risk of depression in patients of various
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ages. These results indicated that the connection between depression and
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hyperlipidemia might be similar at distinct ages.
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In the 1980s, statins were shown to reduce LDL-cholesterol.23 Previous statin trials of patients at risk of cardiovascular disease have revealed a 20%–25% reduction in coronary mortality, and a 10%–15% reduction in all-cause mortality.24 Previous studies have shown that statins are associated with reduced plasma markers of inflammation, reduced T-cell and monocyte activation in vessels, and improved peripheral endothelial function.25,
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In a cohort study of patients diagnosed with
coronary artery disease, 140 patients who were continuously treated with statins for 4–7 years exhibited a reduced risk of anxiety (odds ratio: 0.69, 95% CI: 0.47–0.99)
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ACCEPTED MANUSCRIPT and a reduced risk of depression (odds ratio: 0.63, 95% CI: 0.43–0.93) compared with
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231 patients who did not use statins.27 Stafford et al indicated that using statins to treat
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patients after cardiac intervention (angioplasty, or coronary artery bypass graft
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surgery) reduced the risk of subsequent depression at 3 months (69%, P = .045) and 6 months (79%, P = .032) after hospitalization.28 In the present study, using statins
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reduced the risk of depression according to a 4-year follow-up. This suggests that the long-term use of statins can reduce the incidence of depression in hyperlipidemia patients.
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Sleep disorder has been highlighted as a potential risk for depression. Previous
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longitudinal epidemiological studies have indicated that nondepressed people with
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insomnia have a 2-fold risk of developing depression, compared with people with no
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sleep difficulties.27, 28 Poor sleep quality is also associated with dyslipidemia. Animal and human data have revealed that obstructive sleep apnea might mediate pathological alterations in cholesterol and triglyceride metabolism. The mechanisms involved are increased lipolysis, decreased lipoprotein clearance, and enhanced lipid output from the liver.29, 30 In our study, nonhyperlipidemia patients with sleep disorder exhibited a risk of developing depression (HR = 4.28, 95% CI, 3.95–4.63). When hyperlipidemia and sleep disorder occurred concurrently, the HR was as high as 5.65.
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ACCEPTED MANUSCRIPT Anxiety disorders are an established risk factor for depression.31-33 Anxiety
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disorders have also been associated with hyperlipidemia. A 2010 study was conducted
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on the influence of long-term awareness of hyperlipidemia and of 3 years of dietary
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counselling on depression, anxiety, and quality of life.34 Compared with a general population of men between 70 and 79 years of age, patients with hyperlipidemia
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exhibited significantly higher Hospital Anxiety and Depression Scale anxiety scores (4.0 vs 3.3, P < .001). In our study, nonhyperlipidemia patients with anxiety exibited a risk of developing depression (HR = 4.38, 95% CI, 3.84–5.01). When
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hyperlipidemia and anxiety occurred concurrently, the HR was as high as 5.84.
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Hypertension and diabetes are established risk factors for cardiovascular
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diseases. Longitudinal studies have revealed that hypertension is associated with
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clinical depression.35,
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The risk of depression increases substantially in patients
diagnosed with hypertension. The relationship between DM and depression has been reported in previous studies.37,
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Depression increases the risk for diabetes, and,
conversely, people with diabetes are twice as likely to experience depression as the general population.38 In the present study, nonhyperlipidemia patients with hypertension or diabetes exhibited an increased risk of developing depression. When hyperlipidemia and hypertension occurred concurrently, the hazard ratio was as high
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ACCEPTED MANUSCRIPT as 2.39 (CI, 2.21–2.58). The risk of depression in patients diagnosed with
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hyperlipidemia and diabetes was 1.86 (CI, 1.65–2.10).
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Several studies have suggested that a low cholesterol concentration is associated
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with depression.39-41 An observational cohort study that included 315 statins users and 441 nonusers revealed that constant statin use slightly increased the CES-D (Center
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for Epidemiological Studies Depression) depression scores (+0.88 points; P = .10) of older statin users (> 80 y of age) with more than 3 comorbidities.42 A randomized, double-blind, placebo-controlled study showed that simvastatin resulted in a
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statistically significant increase in depression among elderly people. Eighty healthy
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volunteers (> 65 y of age) received simvastatin (titrated to 20 mg/d) or a placebo for
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15 weeks. During the study period, the Lawton Positive Affect and Negative Affect
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scale revealed a statistically significant decrease in positive affects (interests, happiness, energy, and contentment) in the simvastatin group compared with that of the placebo group. The change in positive affects was statistically significant only among patients whose final serum cholesterol was lower than 148 mg/dL.43 These results indicated that aggressive cholesterol reduction might cause subtle affective changes in older adults. Menopause is considered a risk factor for cardiovascular diseases and its occurrence results in an increased risk of coronary artery disease in women.44 This
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ACCEPTED MANUSCRIPT increased risk might be caused not only by estrogen loss, but also by its effect on lipid
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profile, which is likely to occur in the perimenopause period.45 In Taiwan, the mean
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menopausal age is 49.8 years (standard deviation, 3.28 y).46 The ICD-9 code of
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menopause was not all recorded in old women. To avoid this confounding factor, we evaluated the relationship between depression and hyperlipidemia in women over 50
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years of age. Women with hyperlipidemia exhibited an increased risk of depression at over 50 years of age (HR = 1.50, 95% CI, 1.37–1.65). Women diagnosed with hyperlipidemia who did not receive statins exhibited a significant risk of depression
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(HR = 1.54, 95% CI, 1.40–1.70) but those who received statins did not differ
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significantly (HR = 1.21, 95% CI, 0.96–1.53) at over 50 years of age (Table 5).
Study limitations Several limitations in our study should be addressed. First, the evidence derived from an observational study is generally lower in quality than that from a randomized trial. Despite our meticulous study design, which involved an adequate control of confounding factors, a key limitation is that bias might have remained if unmeasured or unknown confounders were present. Second, numerous potentially confounding variables, including smoking, alcohol consumption, socioeconomic status, diet,
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ACCEPTED MANUSCRIPT infection status, education, employment, and family history, are not provided in the
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NHIRD. These variables might have contributed to the development of depression.
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Third, we were unable to contact the patients directly to enquire about their use of
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statins because all beneficiaries listed in the NHIRD are protected by anonymity. However, the data regarding the prescription of statins and the depression diagnoses
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were reliable.
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Conclusion
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In summary, our results suggested that hyperlipidemia increased the risk of
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depression and that statin use was associated with a decreased risk of depression in
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hyperlipidemia patients over a 6-year period. Additional investigations are required to elucidate the relationship between the serum cholesterol level and the severity of depression symptoms. Future studies should examine the role of statins in depression syndromes to determine the effect and safety of long-term statin use in young and old people.
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study. Journal of affective disorders 2004;83:127-33. [36] Bogner HR, de Vries HF, Kaye EM and Morales KH. Pilot trial of a licensed practical nurse intervention for hypertension and depression. Family medicine 2013;45:323-9. [37] Detka J, Kurek A, Basta-Kaim A, Kubera M, Lason W and Budziszewska B. Neuroendocrine link between stress, depression and diabetes. Pharmacological reports : PR 2013;65:1591-600.
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ACCEPTED MANUSCRIPT [38] Sweileh WM, Abu-Hadeed HM, Al-Jabi SW and Zyoud SH. Prevalence of
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depression among people with type 2 diabetes mellitus: a cross sectional study in
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Palestine. BMC public health 2014;14:163.
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[39] Fang CY, Egleston BL, Gabriel KP, Stevens VJ, Kwiterovich PO, Jr., Snetselaar
Behav Med 2013;36:143-52.
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LG, et al. Depressive symptoms and serum lipid levels in young adult women. J
[40] Aijanseppa S, Kivinen P, Helkala EL, Kivela SL, Tuomilehto J and Nissinen A. Serum cholesterol and depressive symptoms in elderly Finnish men. Int J Geriatr
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Psychiatry 2002;17:629-34.
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[41] Ancelin ML, Carriere I, Boulenger JP, Malafosse A, Stewart R, Cristol JP, et al.
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Gender and genotype modulation of the association between lipid levels and
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depressive symptomatology in community-dwelling elderly (the ESPRIT study). Biol Psychiatry 2010;68:125-32. [42] Agostini JV, Tinetti ME, Han L, McAvay G, Foody JM and Concato J. Effects of statin use on muscle strength, cognition, and depressive symptoms in older adults. J Am Geriatr Soc 2007;55:420-5. [43] Morales K, Wittink M, Datto C, DiFilippo S, Cary M, TenHave T, et al. Simvastatin causes changes in affective processes in elderly volunteers. J Am Geriatr Soc 2006;54:70-6.
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ACCEPTED MANUSCRIPT [44] Gohlke-Barwolf C. Coronary artery disease--is menopause a risk factor? Basic
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research in cardiology 2000;95 Suppl 1:I77-83.
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[45] Agrinier N, Cournot M, Dallongeville J, Arveiler D, Ducimetiere P, Ruidavets
based study. Maturitas 2010;65:237-43.
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JB, et al. Menopause and modifiable coronary heart disease risk factors: a population
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[46] Chang C, Chow SN and Hu Y. Age of menopause of Chinese women in Taiwan. International journal of gynaecology and obstetrics: the official organ of the
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International Federation of Gynaecology and Obstetrics 1995;49:191-2.
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Table 1. Baseline characteristics between hyperlipidemia group and non- hyperlipidemia group in 2000-2002 Hyperlipidemia Total No Yes Variables N = 134,260 N = 107,408 N = 26,852 n (%) n (%) n (%) p-value† Sex > 0.99 Women 65,650 (48.9) 52,520 (48.9) 13,130 (48.9) Men 54,888 (51.1) 54,888 (51.1) 13,722 (51.1) Age, years > 0.99 18-39 26,100 (19.4) 20,880 (19.4) 5,220 (19.4) 40-49 35,955 (26.8) 28,764 (26.8) 7,191 (26.8) 50-59 32,190 (24.0) 25,752 (24.0) 6,438 (24.0) ≥ 60 40,015 (29.8) 32,012 (29.8) 8,003 (29.8) Mean (SD) 51.5 (14.0) 51.3 (14.1) 52.1 (13.9) Urbanization level
S0163-8343(14)00114-5 doi: 10.1016/j.genhosppsych.2014.05.008 GHP 6859
To appear in:
General Hospital Psychiatry
Received date: Revised date: Accepted date:
31 October 2013 17 April 2014 1 May 2014
Please cite this article as: Chuang Chieh-Sen, Yang Tse-Yen, Muo Chih-Hsin, Su HongLin, Sung Fung-Chang, Kao Chia-Hung, Hyperlipidemia, Statin Use, and the Risk of Developing Depression: A Nationwide Retrospective Cohort Study, General Hospital Psychiatry (2014), doi: 10.1016/j.genhosppsych.2014.05.008
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ACCEPTED MANUSCRIPT The 2nd Revised Manuscript: Ms. Ref. No.: GHP-13-522.R1 Title: Hyperlipidemia, Statin Use, and the Risk of Developing Depression: A
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Running title: Hyperlipidemia, Statin, and Depression
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Nationwide Retrospective Cohort Study
Chieh-Sen Chuang, MD; Tse-Yen Yang, PhD; Chih-Hsin Muo, MSc; Hong-Lin Su,
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PhD; Fung-Chang Sung, PhD; Chia-Hung Kao, MD
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Departments of Neurology, Changhua Christian Hospital, Changhua, Taiwan (C.S.C.);
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Life Sciences, National Chung-Hsing University, Taichung, Taiwan (C.S.C., H.L.S.); Department of Nuclear Medicine and PET Center, China Medical University
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Hospital, Taichung, Taiwan (T.Y.Y., C.H.K.); Graduate Institute of Clinical Medicine Science and School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan (T.Y.Y., C.H.K.); Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan (C.H.M.); Department of Public Health, China Medical University Hospital, Taichung, Taiwan (F.C.S.)
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ACCEPTED MANUSCRIPT Correspondence: Dr. Chia-Hung Kao, MD, Graduate Institute of Clinical Medical
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Science and School of Medicine, College of Medicine, China Medical University, No.
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2, Yuh-Der Road, Taichung 404, Taiwan. Tel.: +886 4 22052121x7412; Fax: +886 4
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22336174. E-mail: d10040 @mail.cmuh.org.tw
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These authors’ individual contributions were as follows.
Conception and design: Chieh-Sen Chuang, Chia-Hung Kao. Administrative support: Tse-Yen Yang, Chih-Hsin Muo, Hong-Lin Su, Fung-Chang
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Sung.
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Collection and assembly of data: All authors.
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Data analysis and interpretation: Chieh-Sen Chuang, Tse-Yen Yang, Chih-Hsin Muo,
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Chia-Hung Kao.
Manuscript writing: All authors. Final approval of manuscript: All authors
Funding This work was supported by the study projects (DMR-102-014, DMR-103-012) in China Medical University Hospital; Taiwan Ministry of Health and Welfare, Clinical Trial and Research Center for Excellence (DOH102-TD-B-111-004), Taiwan
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ACCEPTED MANUSCRIPT Ministry of Health and Welfare, Cancer Research Center for Excellence (MOHW103-
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TD-B-111-03); and International Research-Intensive Centers of Excellence in Taiwan
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(I-RiCE) (NSC101-2911-I-002-303). The funders had no role in study design, data
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collection and analysis, decision to publish, or preparation of the manuscript. No
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additional external funding received for this study.
Conflict of interest
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The authors declare that they have no conflicts of interest.
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ACCEPTED MANUSCRIPT Abstract
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Objective: Depression is a highly prevalent disorder that is associated with disability.
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The aim of this study was to determine the relationship between depression and
statins to patients with hyperlipidemia.
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hyperlipidemia, and whether the onset of depression is associated with administering
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Material and Methods: The data analyzed in this study were retrieved from the National Health Insurance Research Database (NHIRD) in Taiwan. We identified newly diagnosed hyperlipidemia in 26 852 patients without a history of depression as
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the exposure group in the period of 2000–2002, and a comparison group comprised
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107 408 patients. The differences between the exposure group and the comparison
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group were examined using a chi-square test to calculate categorical variables. The
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hazard ratio and the 95% confidence interval (CI) for depression were used in the logistic regression. Results: The hyperlipidemia patients demonstrated a high risk for depression and comorbidities, such as hypertension, diabetes, and sleep disorder, which indicated synergistic effects related to a high risk of depression in hyperlipidemia patients. Hyperlipidemia patients who had received statins exhibited a lower risk of depression than did those who had not received statins.
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ACCEPTED MANUSCRIPT Conclusion: Our results suggested that hyperlipidemia increases the risk of
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depression and that using statins is associated with a decreased risk of depression in
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patients with hyperlipidemia.
Keywords: depression; hyperlipidemia; statins; National Health Insurance Research
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Database (NHIRD)
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ACCEPTED MANUSCRIPT Abbreviations and Acronyms:
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CI = confidence interval; NHIRD = National Health Insurance Research Database
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ACCEPTED MANUSCRIPT Introduction
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Depression is a common disorder that affects people worldwide. Depression is
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projected to be the major cause of disability worldwide.1 Depression considerably
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reduce quality of life, and at least 30% of people worldwide experience a depressive disorder during their lives.2
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Inflammation and inflammatory mediators are strongly associated with depressive disorders.1, 2 Experimental evidence has suggested an association between depressive disorders and circulating levels of C-reactive protein, which is a marker of 4
Elevated levels of systemic inflammatory cytokines have been
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inflammation.3,
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implicated in the development of depressive symptoms in elderly people.5, 6
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Hyperlipidemia is defined by abnormally elevated levels of lipids or lipoproteins
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in the blood. It is the most common form of dyslipidemia in western countries. Dyslipidemia is a risk factor in the development and progression of atherosclerosis, and increases the risk of cardiovascular disease.7,
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Hyperlipidemia has been
associated with elevated levels of systemic inflammatory markers.9, 10 Inflammation plays a prominent role in the development of atherosclerosis.11 Studying inflammation might facilitate determination of a link between hyperlipidemia and atherogenesis.12 In addition, vascular disease has also been suggested as a major risk factor for depression in late life.13 These studies indicated a connection among hyperlipidemia,
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ACCEPTED MANUSCRIPT inflammation, and depression. However, information on the link between
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hyperlipidemia and depression is scant.
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Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) are
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effective drugs that reduce serum cholesterol levels and provide secondary prevention from cardiovascular events.14 An increasing number of in vitro and in vivo studies
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have indicated that statins exert antiinflammatory effects that contribute to their beneficial effects in patients with hyperlipidemia.15 Substantial evidence suggests that statins exert a pleiotropic effect that regulates cholesterol-lowering activity.16
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However, few studies have been conducted on the connection between depression and
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the statin use of hyperlipidemia patients.
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We used representative National Health Insurance (NHI) data sets from Taiwan
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to conduct a cohort study assessing the relationship between depression and hyperlipidemia.
Materials and Methods Data source We used the National Health Insurance Research Database (NHIRD) compiled by the Bureau of National Health Insurance and maintained by the National Health
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ACCEPTED MANUSCRIPT Research Institutes in Taiwan.17, 18 The database contained all reimbursement claims
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records from 1996 to 2008 for 1 million randomly selected insurants. All data were
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deidentified and analyzed anonymously. In addition, this study was approved by the
Study Participants We
identified
26 852
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Ethics Review Board of China Medical University (CMU-REC-101-012).
patients
newly
diagnosed
with
hyperlipidemia
(International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-
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9) code 272) without a history of depression (ICD-9 codes 296.2, 296.3, 300.4, and
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311) in the period of 2000–2002 as the exposure group. The index date for the
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hyperlipidemia patients was the date of their first medical visit. For the comparison
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group of 107 408 patients, we selected insurants from those without hyperlipidemia and depression history in the same period and frequency matched them with the hyperlipidemia group according to age (18–29, 30–39, 40–49, 50–59, 60–69 and ≥ 70 y) and sex at a ratio of 4 to 1. The classifications of the urbanization level were modified through stratification into 4 levels, with the highest level comprising all levels above the fourth. They conducted cluster analysis by using the squared Euclidean distance and Ward’s minimum variance method to identify 7 clusters according to the population density
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ACCEPTED MANUSCRIPT (people/km2) of the townships and the numbers of people with a college degree or
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higher, elderly people over 65 years of age, agricultural workers, and physicians per
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100 000 people.
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The baseline comorbidity histories of each patient included hypertension (ICD-9CM codes 401-405), diabetes mellitus (ICD-9-CM code 250), sleep disorder (ICD-9-
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CM codes 307.4 and 780.5), and anxiety (ICD-9-CM code 300.00). All study patients were followed up from the index date to the date an insurance claim for diagnosis and treatment of depression, the end of 2008, or withdrawal from
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the insurance program, whichever occurred first. In addition, the hyperlipidemia
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patients were separated into 2 groups: a group of patients who had used statins for
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treatment and a group of patients who had never used statins for treatment.
Statistical Analysis The demographic characteristics and the prevalence of comorbidities in the exposure group and the comparison group were compared. The differences were examined using a chi-square test to calculate categorical variables. The hazard ratio (HR) and the 95% confidence interval (CI) for depression were used in a Cox proportional hazard regression. The multivariate model was used to control for age, sex, and comorbidities, which differed significantly between the 2 groups. We also
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ACCEPTED MANUSCRIPT investigated the interaction between hyperlipidemia and comorbidities by using a
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likelihood ratio test after adjusting for multiple covariates. All analyses were
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performed using the SAS statistical package (Version 9.2; SAS Institute Inc., Cary,
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NC, USA). All reported P values were 2-tailed, and statistical significance was
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defined at the α = 0.05 level.
Results
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The hyperlipidemia group and the control group exhibited significant differences
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in urbanization levels and comorbidities such as hypertension, diabetes mellitus, and
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sleep disorder (Table 1).
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The incidence rates of depression in the hyperlipidemia and nonhyperlipidemia groups demonstrated that the hazard ratio of hyperlipidemia (1.64, 95% CI, 1.55–1.74, Table 2) increased compared with that of the nonhyperlipidemia group. In addition, female patients demonstrated a higher risk for depression compared with male patients (HR = 1.47, 95% CI, 1.40–1.55, data not shown). The hazard ratio for female patients was 1.60 (95% CI, 1.49–1.72), and the hazard ratio for male patients was 1.70 (95% CI, 1.55–1.86). When the patients were classified according to age (18–39, 40– 49, 50–59, 60 ≥ years), the age-specific hazard ratio of hyperlipidemia was
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ACCEPTED MANUSCRIPT significantly higher. The urbanization-level-specific risk for depression was also
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significantly higher than that of the nonhyperlipidemia group. Risk for depression
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differed significantly based on sex and presence of hyperlipidemia (women, HR =
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1.57 (CI: 46–1.70); men, HR = 1.68 (CI: 1.54–1.85); interaction, P = .02) (Table 2).
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Regarding the interaction between hyperlipidemia and comorbidities, HRs between 1.70 and 2.05 were calculated for the patients exhibiting hyperlipidemia and hypertension
(Table
3).
When
hyperlipidemia
and
hypertension
occurred
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concurrently, the HR for depression increased to 2.39 (95% CI, 2.21–2.59, P < .001)
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and the P value of interaction was less than .0001 (Table. 3). When hyperlipidemia
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and diabetes occurred concurrently, the HR for depression was 1.86 (95% CI, 1.65–
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2.10, P < .001). The patients with either hyperlipidemia or diabetes exhibited an increased HR for depression, and the P value for the interaction indicated borderline significance. Sleep disorder was also a crucial comorbidity associated with depression. When hyperlipidemia and sleep disorder occurred concurrently, the HR was as high as 5.65 (95% CI, 5.13–6.21), and the HR of patients with hyperlipidemia and sleep disorder increased from 1.92 to 4.28. The risk for depression was higher in patients with hyperlipidemia and anxiety than in patients without hyperlipidemia and anxiety, followed by patients with anxiety and hyperlipidemia (HR = 5.84, 4.38, and
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ACCEPTED MANUSCRIPT 1.92, 95% CI = 5.01–6.81, 3.84–5.01, and 1.81–2.03, respectively). Hyperlipidemia
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a synergistic effect on patients and their risk of depression.
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and comorbidities, namely hypertension, diabetes, sleep disorder, and anxiety, exerted
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Table 4 presents the risk for depression stratified by statin use. Compared with the nonhyperlipidemia group, the risk for depression was 9.27 and 10.4 in
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hyperlipidemia patients with and without statin use. Hyperlipidemia patients who received statins exhibited a significantly lower risk for depression than did those who
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did not receive statins (HR = 0.81, 95% CI, 0.69–0.96).
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Discussion
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The present study demonstrated that, compared with the control group,
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hyperlipidemia increased the risk of depression 1.64-fold after adjusting for age, sex, and medical comorbidities over a 6-year period. The risk of depression was elevated when hyperlipidemia and sleep disorder occurred concurrently. The results of this cohort study indicated that statin use is associated with a reduced risk of depression in hyperlipidemia patients. Systemic inflammation and inflammatory mediators have been associated with the development of depressive disorders.1, 5 Hypercholesterolemia is associated with increased circulating levels of activated immune cells and proinflammatory
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ACCEPTED MANUSCRIPT cytokines.19, 20 In a previous study, Rogowski et al analyzed 12 072 people between
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2002 and 2009 in a cross-sectional study. A significant correlation was noted between
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the components of the metabolic syndrome and 4 inflammatory markers, the high-
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sensitivity C-reactive protein, erythrocyte sedimentation rate, concentration of fibrinogen, and white blood cell count.21 Viscogliosi et al investigated 133 elderly
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people (age, 68.9 ± 4 y) and observed that 57 patients with the metabolic syndrome exhibited a higher prevalence of depressive symptoms, a decrease in cognitive function, and higher levels of inflammatory markers.22 In the present study, we
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determined that hyperlipidemia increased the risk of depression in patients of various
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ages. These results indicated that the connection between depression and
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hyperlipidemia might be similar at distinct ages.
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In the 1980s, statins were shown to reduce LDL-cholesterol.23 Previous statin trials of patients at risk of cardiovascular disease have revealed a 20%–25% reduction in coronary mortality, and a 10%–15% reduction in all-cause mortality.24 Previous studies have shown that statins are associated with reduced plasma markers of inflammation, reduced T-cell and monocyte activation in vessels, and improved peripheral endothelial function.25,
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In a cohort study of patients diagnosed with
coronary artery disease, 140 patients who were continuously treated with statins for 4–7 years exhibited a reduced risk of anxiety (odds ratio: 0.69, 95% CI: 0.47–0.99)
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ACCEPTED MANUSCRIPT and a reduced risk of depression (odds ratio: 0.63, 95% CI: 0.43–0.93) compared with
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231 patients who did not use statins.27 Stafford et al indicated that using statins to treat
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patients after cardiac intervention (angioplasty, or coronary artery bypass graft
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surgery) reduced the risk of subsequent depression at 3 months (69%, P = .045) and 6 months (79%, P = .032) after hospitalization.28 In the present study, using statins
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reduced the risk of depression according to a 4-year follow-up. This suggests that the long-term use of statins can reduce the incidence of depression in hyperlipidemia patients.
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Sleep disorder has been highlighted as a potential risk for depression. Previous
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longitudinal epidemiological studies have indicated that nondepressed people with
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insomnia have a 2-fold risk of developing depression, compared with people with no
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sleep difficulties.27, 28 Poor sleep quality is also associated with dyslipidemia. Animal and human data have revealed that obstructive sleep apnea might mediate pathological alterations in cholesterol and triglyceride metabolism. The mechanisms involved are increased lipolysis, decreased lipoprotein clearance, and enhanced lipid output from the liver.29, 30 In our study, nonhyperlipidemia patients with sleep disorder exhibited a risk of developing depression (HR = 4.28, 95% CI, 3.95–4.63). When hyperlipidemia and sleep disorder occurred concurrently, the HR was as high as 5.65.
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ACCEPTED MANUSCRIPT Anxiety disorders are an established risk factor for depression.31-33 Anxiety
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disorders have also been associated with hyperlipidemia. A 2010 study was conducted
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on the influence of long-term awareness of hyperlipidemia and of 3 years of dietary
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counselling on depression, anxiety, and quality of life.34 Compared with a general population of men between 70 and 79 years of age, patients with hyperlipidemia
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exhibited significantly higher Hospital Anxiety and Depression Scale anxiety scores (4.0 vs 3.3, P < .001). In our study, nonhyperlipidemia patients with anxiety exibited a risk of developing depression (HR = 4.38, 95% CI, 3.84–5.01). When
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hyperlipidemia and anxiety occurred concurrently, the HR was as high as 5.84.
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Hypertension and diabetes are established risk factors for cardiovascular
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diseases. Longitudinal studies have revealed that hypertension is associated with
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clinical depression.35,
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The risk of depression increases substantially in patients
diagnosed with hypertension. The relationship between DM and depression has been reported in previous studies.37,
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Depression increases the risk for diabetes, and,
conversely, people with diabetes are twice as likely to experience depression as the general population.38 In the present study, nonhyperlipidemia patients with hypertension or diabetes exhibited an increased risk of developing depression. When hyperlipidemia and hypertension occurred concurrently, the hazard ratio was as high
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ACCEPTED MANUSCRIPT as 2.39 (CI, 2.21–2.58). The risk of depression in patients diagnosed with
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hyperlipidemia and diabetes was 1.86 (CI, 1.65–2.10).
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Several studies have suggested that a low cholesterol concentration is associated
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with depression.39-41 An observational cohort study that included 315 statins users and 441 nonusers revealed that constant statin use slightly increased the CES-D (Center
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for Epidemiological Studies Depression) depression scores (+0.88 points; P = .10) of older statin users (> 80 y of age) with more than 3 comorbidities.42 A randomized, double-blind, placebo-controlled study showed that simvastatin resulted in a
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statistically significant increase in depression among elderly people. Eighty healthy
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volunteers (> 65 y of age) received simvastatin (titrated to 20 mg/d) or a placebo for
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15 weeks. During the study period, the Lawton Positive Affect and Negative Affect
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scale revealed a statistically significant decrease in positive affects (interests, happiness, energy, and contentment) in the simvastatin group compared with that of the placebo group. The change in positive affects was statistically significant only among patients whose final serum cholesterol was lower than 148 mg/dL.43 These results indicated that aggressive cholesterol reduction might cause subtle affective changes in older adults. Menopause is considered a risk factor for cardiovascular diseases and its occurrence results in an increased risk of coronary artery disease in women.44 This
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profile, which is likely to occur in the perimenopause period.45 In Taiwan, the mean
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menopausal age is 49.8 years (standard deviation, 3.28 y).46 The ICD-9 code of
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menopause was not all recorded in old women. To avoid this confounding factor, we evaluated the relationship between depression and hyperlipidemia in women over 50
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years of age. Women with hyperlipidemia exhibited an increased risk of depression at over 50 years of age (HR = 1.50, 95% CI, 1.37–1.65). Women diagnosed with hyperlipidemia who did not receive statins exhibited a significant risk of depression
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(HR = 1.54, 95% CI, 1.40–1.70) but those who received statins did not differ
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significantly (HR = 1.21, 95% CI, 0.96–1.53) at over 50 years of age (Table 5).
Study limitations Several limitations in our study should be addressed. First, the evidence derived from an observational study is generally lower in quality than that from a randomized trial. Despite our meticulous study design, which involved an adequate control of confounding factors, a key limitation is that bias might have remained if unmeasured or unknown confounders were present. Second, numerous potentially confounding variables, including smoking, alcohol consumption, socioeconomic status, diet,
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NHIRD. These variables might have contributed to the development of depression.
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Third, we were unable to contact the patients directly to enquire about their use of
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statins because all beneficiaries listed in the NHIRD are protected by anonymity. However, the data regarding the prescription of statins and the depression diagnoses
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were reliable.
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Conclusion
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In summary, our results suggested that hyperlipidemia increased the risk of
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depression and that statin use was associated with a decreased risk of depression in
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hyperlipidemia patients over a 6-year period. Additional investigations are required to elucidate the relationship between the serum cholesterol level and the severity of depression symptoms. Future studies should examine the role of statins in depression syndromes to determine the effect and safety of long-term statin use in young and old people.
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Table 1. Baseline characteristics between hyperlipidemia group and non- hyperlipidemia group in 2000-2002 Hyperlipidemia Total No Yes Variables N = 134,260 N = 107,408 N = 26,852 n (%) n (%) n (%) p-value† Sex > 0.99 Women 65,650 (48.9) 52,520 (48.9) 13,130 (48.9) Men 54,888 (51.1) 54,888 (51.1) 13,722 (51.1) Age, years > 0.99 18-39 26,100 (19.4) 20,880 (19.4) 5,220 (19.4) 40-49 35,955 (26.8) 28,764 (26.8) 7,191 (26.8) 50-59 32,190 (24.0) 25,752 (24.0) 6,438 (24.0) ≥ 60 40,015 (29.8) 32,012 (29.8) 8,003 (29.8) Mean (SD) 51.5 (14.0) 51.3 (14.1) 52.1 (13.9) Urbanization level
