Depression, which is characterized by sadness, loss of interest, anhedonia, lack of appetite, feelings of guilt, low self-esteem or self-worth, sleep disturbance, feelings of tiredness, and poor concentration, is one of the commonest mental disorders worldwide and is estimated to affect over 300 million people globally. Reference Aleksandrova, Phillips and Wang1 Moreover, it affects the individual’s well-being and ability to perform socially defined roles and tasks. Reference Buist-Bouwman, De Graaf, Vollebergh, Alonso, Bruffaerts and Ormel2 The global point prevalence rate was 4.7% (4.4%–5.0%), and the pooled annual incidence was 3.0% (2.4%–3.8%). Reference Ferrari, Somerville and Baxter3 Although the pathophysiology of major depressive disorder (MDD) remains unclear, a number of factors, including biogenic amine deficiency, neurogenesis, genetic, environmental, immunologic, and endocrine factors, were suggested to be associated with MDD development. Reference Jesulola, Micalos and Baguley4
In addition, depression has been associated with shortened life expectancy and impaired quality of life. Reference Cuijpers, Vogelzangs, Twisk, Kleiboer, Li and Penninx5,Reference O’Neil, Stevenson, Williams, Mortimer, Oldenburg and Sanderson6 Mortality risk over relatively short periods could be attributed to unnatural causes of death, including suicide and unintentional injuries. Reference Cuijpers and Smit7,Reference Gilman, Sucha, Kingsbury, Horton, Murphy and Colman8 By contrast, mortality risk over longer periods may be due to chronic physical conditions associated with depression, such as cerebrocardiovascular diseases and metabolic disorders. Reference Cuijpers and Smit7,Reference Gilman, Sucha, Kingsbury, Horton, Murphy and Colman8 Indeed, evidence confirmed the elevated risks of cerebrocardiovascular and metabolic diseases among patients with MDD. Reference Miettola, Niskanen, Viinamäki and Kumpusalo9–Reference Dong, Zhang, Tong and Qin11 Similarly, other psychiatric disorders, including schizophrenia or bipolar disorder, were also found to have higher risks of metabolic and cerebrocardiovascular diseases. Reference Chen, Pan and Hsu12–Reference Vancampfort, Vansteelandt and Correll14
Researchers further assessed whether individuals, especially the first-degree relatives (i.e., siblings), at increased familial risk of psychiatry disorders, may have elevated rates of cerebrocardiovascular or metabolic diseases. Reference Fernandez-Egea, Bernardo and Donner15–Reference Huang, Chen and Huang21 Toma et al. revealed that cardiovascular risk score based on the sum of the presence of diabetes, hypertension, obesity, dyslipidemia, stroke, angina, and myocardial infarction was highest among adolescents with bipolar disorder having familial bipolar disorder, intermediate among adolescents with bipolar disorder having no familial bipolar disorder and lowest in healthy comparisons without bipolar disorder and familial bipolar disorder. Reference Toma, Fiksenbaum, Omrin and Goldstein17 Sobczak et al. found the healthy first-degree relatives of patients with bipolar disorder were prone to having increased level of omega-6 polyunsaturated fatty acids and lower level of high-density lipoprotein cholesterol. Reference Sobczak, Honig and Christophe18 Mannie et al. demonstrated that the individuals with a family history of depressive disorder had elevated systolic blood pressure and diminished insulin sensitivity compared with those without family history. Reference Mannie, Williams, Diesch, Steptoe, Leeson and Cowen20 The major limitations of the aforementioned studies included small sample size, cross-sectional study design, and only inclusion of young subjects that may limit the generalizability.
In the current study, using the Taiwan National Health Insurance Research Database (NHIRD), with a large sample size and longitudinal study design, we investigated the risks of metabolic diseases, namely type 2 diabetes mellitus, hypertension, and dyslipidemia, and the risks of cerebrocardiovascular diseases, namely stroke and ischemic heart disease, among the unaffected siblings of patients with MDD. We hypothesized that the unaffected siblings of patients with MDD have an increased risk of subsequent metabolic and cerebrocardiovascular diseases during the follow-up period compared with the controls.
Methods
Data source
Taiwan National Health Research Institute audits and releases the Taiwan NHIRD for scientific and study purposes. Individual medical records included in the NHIRD are anonymous to protect patient privacy. Comprehensive information on insured individuals is included in the database, including demographic data, dates of clinical visits, disease diagnoses, and medical interventions. In this study, using each resident’s unique personal identification number, all of the information was linked. Subsequently, following the method of Kuo et al. and Cheng et al., family kinships in the NHIRD were used for genealogy reconstruction. Reference Kuo, Grainge and Valdes22,Reference Cheng, Chang and Chen23 The diagnostic codes used were based on the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM). The NHIRD has been used extensively in many epidemiologic studies in Taiwan. Reference Cheng, Chang and Chen23–Reference Chen, Su and Chen26
Inclusion criteria for the unaffected siblings of patients with MDD and the control group
Individuals who were born before 1990 and had the siblings with MDD (ICD-9-CM codes: 296.2x, 296.3x) but had no personal diagnosis of severe mental disorders (ICD-9-CM codes: 295, 296, 297) at any time were enrolled as the study group. The age-, sex-, income-, level-of-urbanization-and birth-time-matched (1:4) control group was randomly identified after eliminating the study cases, those who had been given a diagnosis of severe mental disorders at any time, and those with any sibling with severe mental disorders. The study and control groups were included and followed from 1996 to the end of 2011. The occurrence of metabolic (type 2 diabetes, hypertension, dyslipidemia, obesity) and cerebrocardiovascular (stroke, ischemic heart diseases) diseases was identified during the follow-up period. Metabolic and cerebrocardiovascular diseases were diagnosed by board-certified physicians. Level of urbanization (level 1 to level 5; level 1: most urbanized region; level 5: least urbanized region) was also assessed for our study. Reference Liu, Hung, Chuang, Chen, Weng and Liu27 This study was approved by the Institutional Review Board of Taipei Veterans General Hospital.
Statistical analysis
For between-group comparisons, the F test was used for continuous variables and Pearson’s X 2 test for nominal variables, where appropriate. After adjusting for demographic data (age, sex, income, and level of urbanization), logistic regression models were used to investigate the odds ratios (OR) of subsequent metabolic diseases (type 2 diabetes, hypertension, dyslipidemia, obesity) between study and control cohorts. Logistic regression models with the additional adjustment of metabolic diseases were performed to assess the likelihoods of subsequent cerebrocardiovascular diseases (stroke, ischemic heart disease) between study and control groups. In addition, logistic regression analyses stratified by sex were also examined to clarify the role of sex in the risks of subsequent metabolic and cerebrocardiovascular diseases. A 2-tailed p-value of less than 0.05 was considered statistically significant. All data processing and statistical analyses were performed with Statistical Package for Social Science (SPSS) version 19 software (SPSS Inc.) and Statistical Analysis Software (SAS) version 9.1 (SAS Institute, Cary, NC).
Results
The demographic characteristics and prevalence of metabolic and cerebrocardiovascular diseases of the study sample were listed in Table 1. In all, 22,438 unaffected siblings of patients with MDD and 89,752 controls were enrolled in our study, with an average age of 32.81 ± 8.22 years. The unaffected siblings of patients with MDD had the higher prevalence of metabolic diseases, such as hypertension (5.0% vs. 4.5%, p = 0.007), dyslipidemia (5.6% vs. 4.8%, p < 0.001), obesity (1.7% vs. 1.5%, p = 0.028), and cerebrocardiovascular diseases, such as ischemic heart disease (2.1% vs. 1.7%, p < 0.001), any stroke (1.3% vs. 1.1%, p = 0.006), and ischemic stroke (0.6% vs. 0.4%, p = 0.005) compared with the controls (Table 1).
Table 1. Demographic data and prevalence of the metabolic and cerebrocardiovascular disorders among the siblings of patients with major depression and controls
NTD: new Taiwan dollar; SD: standard deviation.
Logistic regression analyses with an adjustment of demographic data (age, sex, level of urbanization, and income) found that the unaffected siblings of patients with MDD were more likely to have hypertension (OR: 1.12, 95% CI: 1.04–1.21), dyslipidemia (OR: 1.21, 95% CI: 1.13–1.29), and obesity (OR: 1.14, 95% CI: 1.01–1.27) later in life compared with the controls (Table 2). Further analyses with additional adjustment of metabolic diseases found that the unaffected siblings of patients with MDD had increased risks of developing any stroke (OR: 1.18, 95% CI: 1.03–1.35), ischemic stroke (OR: 1.30, 95% CI: 1.06–1.60), and ischemic heart disease (OR: 1.21, 95% CI: 1.08–1.36) during the follow-up period compared with the control group (Table 3). Subanalyses stratified by sex reported that brothers of patients with MDD had the elevated risks of developing hypertension (OR: 1.16, 95% CI: 1.06–1.26), dyslipidemia (OR: 1.22, 95% CI: 1.12–1.33), ischemic stroke (OR: 1.33, 95% CI: 1.03–1.71), and ischemic heart disease (OR: 1.20, 95% CI: 1.04–1.40) compared with the controls; sisters of patients with MDD were prone to developing dyslipidemia (OR: 1.18, 95% CI: 1.05–1.32), type 2 diabetes (OR: 1.20, 95% CI: 1.04–1.38), obesity (OR: 1.16, 95% CI: 1.00–1.34), and ischemia heart disease (OR: 1.23, 95% CI: 1.02–1.48) (Tables 2 and 3).
Table 2. Logistic regression analyses of the metabolic disorders among the siblings of patients with major depression and controls a
OR: Odds ratio; CI: Confidence interval.Bold type means the statistical significance.
a Adjusted for demographic data.
Table 3. Logistic regression analyses of the cerebrocardiovascular disorders among the siblings of patients with major depression and controls a
OR: Odds ratio; CI: Confidence interval. Bold type means the statistical significance.
a Adjusted for demographic data and metabolic diseases.
Discussion
Our findings supported the study hypothesis that the unaffected siblings of patients with MDD exhibit a higher prevalence of subsequent metabolic and cerebrovascular diseases, especially dyslipidemia, ischemic stroke, and ischemic heart disease compared with the controls. In addition, the unaffected sisters of patients with MDD were more likely to develop type 2 diabetes later in life compared with the controls.
Studies have found an association between the family history of severe mental disorders and cardiometabolic diseases. Huang et al. reported an increased risk of type 2 diabetes among the unaffected siblings of patients with schizophrenia. Reference Huang, Chen and Huang21 Mannie et al. assessed the cardiometabolic conditions between healthy controls and young people who had no personal history of depression but had a family history of depressive illness and demonstrated that those with a family history of depression had elevated systolic blood pressure and arterial stiffness and diminished insulin sensitivity compared with the controls. Reference Mannie, Williams, Diesch, Steptoe, Leeson and Cowen20 They suggested that young people who had a family history of depression were more likely to have an altered cardiovascular risk profile in young adulthood even if depressive symptoms were absent, which may be due to the common risk factors between MDD and cardiometabolic diseases.
Our findings of the increased likelihoods of metabolic and cerebrocardiovascular diseases in the unaffected siblings of patients with MDD were in agreement with those of Mannie et al. Reference Mannie, Williams, Diesch, Steptoe, Leeson and Cowen20 The genetic liability, common environmental factors, and epigenetic interactions may contribute to the familial coaggregation of MDD and metabolic and cerebrocardiovascular diseases. Reference Natsuaki, Ge and Leve28–Reference Della-Morte, Guadagni and Palmirotta31 The hypothesis of a genetic overlap between depression and metabolic and cerebrocardiovascular diseases has been supported by studies describing coshared genetics and possible risk gene pathway. Reference McCaffery, Duan and Frasure-Smith32,Reference Amare, Schubert, Klingler-Hoffmann, Cohen-Woods and Baune33 For instance, the 12q chromosome has been linked to depression, hypertension, dyslipidemia, obesity, stroke, and ischemic heart disease. Reference Abkevich, Camp and Hensel34–Reference Sherva, Miller and Pankow37 Amare et al. reviewed 24 cardiovascular and metabolic disease genes implicated in depression, bipolar disorder, or both and found that BDNF, CREB1, GNAS, and POMC played crucial roles in the pathophysiology of both cardiometabolic diseases and mood disorders. Reference Amare, Schubert, Klingler-Hoffmann, Cohen-Woods and Baune33 Thus, at least one or a few genes or gene variants across these loci may explain the pleiotropic or comorbid linkage of the aforementioned phenotypes.
The pathophysiology underlying the association between depression vulnerability and cardiometabolic diseases is unknown. Lower central serotonergic responsivity, a biomarker of depression vulnerability, has been suggested to be associated with cardiometabolic risks and carotid artery atherosclerosis. Reference Muldoon, Mackey, Williams, Korytkowski, Flory and Manuck38,Reference Muldoon, Mackey, Sutton-Tyrrell, Flory, Pollock and Manuck39 Muldoon et al. revealed that lower central serotonergic responsivity was associated with obesity, dyslipidemia, higher systolic and diastolic blood pressure, greater insulin resistance, and less physical activity. Reference Muldoon, Mackey, Williams, Korytkowski, Flory and Manuck38 Muldoon et al. further reported that a 1 standard deviation lower prolactin response was associated with the greater intima-media thickness of carotid artery and found that the metabolic syndrome mediated, but did not fully account for, the association between lower central serotonergic responsivity and greater intima-media thickness. Reference Muldoon, Mackey, Sutton-Tyrrell, Flory, Pollock and Manuck39 Beyond the serotonergic hypothesis of depression vulnerability and cardiometabolic risks, the dysregulated hypothalamic–pituitary–adrenal (HPA) axis may play a crucial role in this relationship. Reference Mannie, Harmer and Cowen40 Mannie et al. compared 49 young people who had not been depressed themselves but who had a family history of MDD with a group of 55 participants who had no personal and family history of depression and demonstrated that at-risk young people had a higher level of waking salivary cortisol than the comparison subjects on both workdays and nonworkdays. Reference Mannie, Harmer and Cowen40 Previous studies have suggested that an alteration of HPA axis, such as cortisol hypersecretion, was significantly related to the risks of metabolic and cardiovascular diseases. Reference Vargas, Junco, Gomez and Lajud41–Reference Burford, Webster and Cruz-Topete43
The role of sex in the risk of metabolic and cerebrocardiovascular diseases between study and control groups was another interesting finding in our study. Block et al. suggested that younger female patients with MDD were more likely to have metabolic diseases than those without MDD, and they further found that age may extenuate this association. Reference Block, Schipf and Van der Auwera44 Gil et al. found a significant relationship of depressive symptoms with elevated glucose levels in women and with obesity in men. Reference Gil, Radziłłowicz and Zdrojewski45 Furthermore, depressive symptoms were considered to be associated with metabolic diseases among Japanese urban men. Reference Nishina, Nishina, Ohira, Makino and Iso46 Alemany et al. hypothesized that metabolic disease is a maturity-onset disease, and levels of androgens and estrogens could account for differences between the sexes and delayed manifestation of metabolic syndrome by counterbalancing the pathogenetic force of glucocorticoids toward metabolic syndrome. Reference Alemany47 The fluctuations of sex hormones that flag reproductive events in women may affect metabolic and neurochemical pathways that are linked to both MDD and metabolic and cerebrocardiovascular diseases. Reference Soares and Zitek48 Additional studies are required to investigate the effect of sex on metabolic and cerebrocardiovascular diseases between patients with MDD and their relatives.
This study had several limitations. First, the prevalence of cerebrocardiovascular disease and MDD may be underestimated because only those who sought medical help and consultation were enrolled. However, the diagnoses of metabolic and cerebrocardiovascular diseases were made by board-certified physicians. Therefore, the diagnostic validity was improved. In addition, the other clinical scenario of undetected or untreated depression and other psychiatric disorders in unaffected relatives may be also possible. Not only risks of metabolic and cerebrocardiovascular diseases but also risks of mental disorders should be closely monitored among unaffected relatives, such as siblings in current study. Second, the prevalence of metabolic and cerebrocardiovascular diseases rise with age. In current study, the lifetime prevalence of metabolic and cerebrocardiovascular diseases may be underestimated owing to the not-long-enough (15 years) follow-up duration. Future studies with a longer follow-up duration (>15 years) would be required to validate our findings. Third, some factors, such as environmental factors, personal lifestyle, education, occupation, and engagement in physical activity, were not available in the Taiwan NHIRD. Therefore, we could not examine the influence of these factors.
In conclusion, the unaffected siblings of patients with MDD had a slightly higher risk of subsequent hypertension, dyslipidemia, obesity, ischemic stroke, and ischemic heart disease later in life compared with the controls. The unaffected sisters of patients with MDD were more likely to develop type 2 diabetes later in life compared with the controls. Our study revealed a familial coaggregation between MDD and metabolic and cerebrocardiovascular diseases in a large sample. Our findings suggest that clinicians should pay more attention to the cardiometabolic health of the unaffected siblings of patients with MDD. Screening those siblings of patients with MDD to evaluate the risk of metabolic and cerebrocardiovascular diseases, even those siblings without MDD per se, may be a valuable strategy of risk stratification in public health. Additional studies are required to investigate the shared pathophysiology between MDD and cardiometabolic diseases.
Acknowledgements
We thank Mr I-Fan Hu for his friendship and support.
We thank Dr JRL, Prof TLP, and Dr MHC, who designed the study, wrote the protocol and manuscripts, Dr JWH, Dr YMB, Dr TPS, Dr CTL, Dr SJT, Dr KLH, and Dr WCL, who assisted with the preparation and proof-reading of the manuscript, and Dr YMB, Dr MHC, and Dr TJC, who provided the advices on statistical analysis.
Financial support
The study was supported by grant from Taipei Veterans General Hospital (V103E10-001, V104E10-002, V105E10-001-MY2-1, V105A-049, V106B-020, V107B-010, V107C-181) and Ministry of Science and Technology, Taiwan (107-2314-B-075-063-MY3, 108-2314-B-075-037). The funding source had no role in any process of our study.
Conflict of interest
None.
Ethical standards
None.
