SEARCH

SEARCH BY CITATION

Keywords:

  • anxiety disorder;
  • bipolar disorder;
  • cardiovascular disease;
  • comorbidity;
  • major depressive disorder

Abstract

  1. Top of page
  2. Abstract
  3. METHOD
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSION
  7. REFERENCES

Aims:  Accumulating evidence from Caucasian patients has shown that depression, bipolar and anxiety disorders are associated with an increased risk of cardiovascular diseases (CVD), but reports in the Asian population are limited, and age effect is rarely investigated. This population-based study was carried out to examine and compare the CVD comorbidities among patients with mood and anxiety disorders in different age groups.

Method:  A 4-year cross-sectional survey was carried out using the Taiwan National Health Insurance Research Database from 2000 to 2003.

Results:  An average total of 1 031 557 patients with mood and anxiety disorders were enrolled as study participants, including 76 430 cases of major depressive disorder, 41 557 cases of bipolar disorder, and 913 570 cases of anxiety disorder. When compared with the insured population without mood or anxiety disorders (average 21 356 304 people), the average relative risk (RR) of developing ischemic heart disease and hypertensive disorders in 1 031 557 study participants was 2.0 and 2.05, respectively. The highest RR was found in the age group under 20 years (RR = 4.74 and 4.08, respectively), and the lowest RR in the age group equal to or older than 65 years (RR = 0.47 and 0.58, respectively).

Conclusions:  Taiwanese patients with mood and anxiety disorders experience high cardiovascular morbidity, especially patients with anxiety disorders. Age acted as an important modifier variable that influenced the relationship between mood, anxiety disorder and CVD. This study highlights the need for future research in different age groups, in order to elucidate the causality and the trajectory of developing CVD among patients with mental disorders.

CARDIOVASCULAR DISEASES (CVD) and psychiatric disorders often coexist and the associations between these have received significant attention. Depression and anxiety are the two psychiatric disorders most widely studied in this field. Over the past years, accumulating evidence has shown that depression symptoms or a history of depression were independent risk factors for the future onset, progression, and recurrence of CVD,1–5 and depression was found to be predictive of future cardiac mortality and morbidity.6 Recent reports indicated that the association may result from the progression of coronary artery atherosclerosis.7,8 Various theories have been proposed to elucidate the correlation between depression and CVD. Unhealthy habits, such as smoking,9 obesity,10 a sedentary lifestyle, and maladaptive effect on adherence to medical regimens in patients with depression are all related to increased risks of CVD. Also, the deregulation of the hypothalamic-pituitary-adrenal (HPA) axis and the autonomic nervous system in depressed patients may contribute to platelet function impairment, decreased heart rate variability, and altering immune responses, which underlies the etiology of CVD.11–14

As well as depression, anxiety disorders have been hypothesized to indicate elevated CVD risk.15 Earlier work has confirmed that anxiety symptoms predict future CVD as well as subsequent CVD mortality. Anxiety-related noradrenaline and HPA axis hyperactivity, excessive sympathetic nervous system activation, reduced parasympathetic innervation to the heart, impaired neuronal reuptake of noradrenaline, and elevated levels of several cytokines and neuropeptides, may play important roles.16,17

Until recently, not so much attention has been directed to examine the correlation between bipolar disorder and CVD. Beyer et al. reported that the most common medical conditions in bipolar outpatients were endocrine and metabolic diseases.18 Also, an unhealthy lifestyle, such as comorbid substance use, which is common in bipolar patients, may contribute to metabolic syndrome, and increases the risk of developing CVD.

However, most previous reports have been about Caucasian patients and the reports from the Asian population are limited. According to data provided by the Taiwanese Department of Health Executives, cardiovascular disease is one of the leading causes of mortality in Taiwan. The present study investigated the prevalence of the two most common cardiovascular diseases (ischemic heart diseases and hypertensive diseases), among patients with mood disorders (major depressive disorders, bipolar disorders) and anxiety disorders. The aim of this population-based study was to evaluate and compare the comorbidity of CVD with different psychiatric disorders across all age groups.

METHOD

  1. Top of page
  2. Abstract
  3. METHOD
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSION
  7. REFERENCES

In Taiwan, the National Health Insurance Program, a compulsory health insurance managed by the National Health Institutes (NHI), covers more than 96% of the general population.19 The NHI has the National Health Insurance Research Database (NHIRD), which contains information of insured residents, including age, gender, prescription drugs, prescription date, and the diagnosis for the prescription. The NHIRD uses International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) diagnoses. The researchers in Taiwan can apply a specific dataset from the NHIRD with protocols to identify target patients for specific study goals. Physical illness can be diagnosed by physical exams or laboratory results, however psychiatric diagnosis especially needs to be made by psychiatrists after professional clinical interviews. Thus we established a 4-year (2000 to 2003) nationwide psychiatric database that only included patients who were under active psychotropic medications, in order to validate the state of their psychiatric illness and omit non-accurate diagnosis by non-specialists. The Anatomical Therapeutic Chemical (ATC) codes were used,20 and a total of 1024 psychotropic drugs were collected in our study, including antipsychotics, anxiolytics, hypnotics, sedatives, antidepressants, centrally active sympathomimetics, psycholeptics, psychoanaleptics and some antiepileptics medications, such as benzodiazepine derivatives, carboxamide derivatives and fatty acid derivatives. During the 4-year period, this nationwide psychiatric database included an average of 10 600 000 patients with psychotropic treatments in each year. Among them, those who were diagnosed with major depressive disorder (MDD, ICD-9 codes: 296.20–296.36), bipolar disorder (BD, ICD-9 codes: 296.00 through 296.16, 296.40 through 296.90), and anxiety disorder (AD, ICD codes: 300) were identified and enrolled as our target study participants. If enrollees had multiple diagnoses in that year, the diagnostic hierarchy was BD, MDD and AD. Thus, each study patient had one principal diagnosis of a psychiatric disorder. Then, the comorbidity of two categories of CVD was investigated for all study enrollees, including ischemic heart (IHD) diseases (ICD codes 410 through 414), and hypertensive diseases (ICD-9 codes 401 through 405).

The prevalence rates of IHD and hypertensive diseases of the entire insured Taiwanese population were obtained by the statistics information services of NHI (http://www.doh.gov.tw/statistic/index.htm).We compared the prevalence rates of IHD and hypertensive diseases in patients with mood and anxiety disorders with that of the entire Taiwanese insured population without mood or anxiety disorders. In order to investigate the trends in CVD comorbidities by age, we divided all study participants and the entire insured population into four age groups: below 20 years, 20 to 44 years, 45 to 64 years, and equal or older than 65 years. The regular descriptive statistics were displayed. All the data preparation and statistical analyses were conducted using SAS (SAS Institute, Cary, NC, USA).

RESULTS

  1. Top of page
  2. Abstract
  3. METHOD
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSION
  7. REFERENCES

The NHIRD covered on average 21 727 068 civilian residents in Taiwan from 2000 to 2003. On average, a total of 1 031 557 patients of mood and anxiety disorders were enrolled as study subjects, including 76 430 cases of MDD, 41 557 cases of bipolar disorder, and 913 570 cases of anxiety disorders. The average prevalence of MDD was 0.36% (range: 0.3% to 0.43%); 0.19% for BD (range: 0.16% to 0.21%); and 4.37% for AD (range: 3.65% to 4.5%). The prevalence of MDD, bipolar and anxiety disorders increased slightly during the 4-year period. Anxiety disorders were generally more prevalent compared with MDD and bipolar disorders. Table 1 presents gender distributions and prevalence rates of each category of psychiatric disorders from 2000 to 2003. Over this time period, the female sex was predominant, with average odds ratio (OR) of 1.66 for MDD, 1.34 for bipolar, and 1.69 for anxiety disorders.

Table 1. Prevalence of MDD, Bipolar and Anxiety disorders in Taiwan, 2000–2003
Year2000200120022003
  1. MDD, major depressive disorder; OR, odds ratio.

MDD    
 Prevalence,%(n)0.3 (58 403)0.35 (75 912)0.35 (77 404)0.43 (94 000)
 Gender (n)    
  Female(35 882) OR:1.62(46 903) OR:1.62(48 359) OR:1.66(59 406) OR:1.72
  Male(22 521)(29 009)(29 045)(34 594)
Bipolar disorder    
 Prevalence,%(n)0.2 (42 733)0.2 (43 173)0.16 (34 660)0.21 (45 329)
 Gender (n)    
  Female(24 444) OR:1.35(24 868) OR:1.36(19 673) OR:1.31(26 026) OR:1.35
  Male(18 289)(18 305)(14 987)(19 303)
Anxiety disorder    
 Prevalence,%(n)4.3 (920 552)4.50 (973 977)3.65 (797 824)5.03 (961 926)
 Gender (n)    
  Female(574 899) OR:1.70(612 930) OR:1.70(500 208) OR:1.68(604 130)OR:1.69
  Male(345 653)(361 047)(297 616)(357 796)
Entire insured populationN = 21 400 826N = 21 653 555N = 21 869 478N = 21 984 415

Age distributions for MDD, bipolar and anxiety disorders were examined from 2000 to 2003. In each category of psychiatric disorders, patients were divided into four age groups. Similar age distributions were found during this 4-year period. During 2003, MDD (45.8%) and BD (45.8%) showed a peak among 20- to 44-year-old patients. However, AD showed a peak among the 45- to 65-year-old patients (38.2%).

Table 2 shows the prevalence rates of CVD comorbidities among patients with mood and anxiety disorders. The average prevalence of IHD and hypertensive diseases was more than twice as high in patients with anxiety disorders (7.23%) compared with patients with BD (3.45%) and MD (2.92%). When compared with the entire insured population without mood or anxiety disorders, the average relative risk (RR) for all study participants to develop IHD and hypertensive diseases was 2.0 and 2.05, respectively. There was no significant gender difference for prevalence of CVD comorbidity during the 4-year period.

Table 2. Prevalence rate of CVD among patients with mood and anxiety disorders
Year2000200120022003Average
  1. CVD, cardiovascular disease; MDD, major depressive disorder; IHD, ischemic heart disease; RR, relative risk of developing IHD or hypertensive disorders in study participants when compared with entire insured population without mood or anxiety disorders.

Prevalence rate of IHD, %     
 All enrollees5.96.16.46.56.23
  MDD3.22.92.63.02.92
  Bipolar disorders4.13.62.83.33.45
  Anxiety disorders7.47.57.07.07.23
 Insured population without mood or anxiety disorders3.22.643.33.33.11
 RR for all enrollees to develop IHD1.842.311.941.972.00
Prevalence rate of hypertensive diseases, % (n)     
 All enrollees17.316.818.118.117.6
 MDD11.410.59.29.510.1
 Bipolar disorders14.613.311.413.013.08
 Anxiety disorders17.917.517.618.017.75
 Insured population without mood or anxiety disorders8.078.428.79.28.6
 RR for all enrollees to develop hypertensive disorders2.142.002.081.972.05

Table 3 presents the trends of CVD comorbidities in different age groups. During the 4-year period, the prevalence of IHD and hypertensive diseases comorbidity increased proportionally to age, and were most frequent among patients older than 65 years for all diagnoses of MDD, bipolar and anxiety disorders.

Table 3. Age distribution of CVD comorbidity from 2000 to 2003
YearPrevalence of IHD, %Prevalence of hypertensive diseases, %
20002001200220032000200120022003
  1. IHD, ischemic heart disease; MDD, major depressive disorder; CVD, cardiovascular disease.

MDD        
 <200.10.20.10.40.30.30.10.2
 20–440.90.70.70.83.02.51.92.1
 45–644.03.53.13.915.114.813.013.6
 ≥656.97.46.57.524.123.821.522.9
Bipolar        
 <200.30.20.10.20.20.30.20.5
 20–441.31.00.71.14.13.83.43.9
 45–645.24.84.14.519.818.416.618.9
 ≥659.38.66.87.332.630.726.028.4
Anxiety        
 <201.01.00.90.80.60.50.40.3
 20–442.92.82.52.45.35.15.15.1
 45–648.38.57.97.921.821.421.521.9
 ≥6513.513.712.812.932.432.031.432.2
Insured population without mood or anxiety disorders
 <200.10.090.090.0940.0890.080.0780.072
 20–440.740.630.700.672.092.142.162.28
 45–646.395.026.086.0219.119.2819.119.99
 ≥6521.4817.5720.7821.1547.048.1247.8750.39

The RR for study participants to develop CVD when compared with the insured population without mood or anxiety disorder of the same age group was examined. Table 4 shows that the average RR of developing CVD was highest in study participants under 20 years, and then gradually decreases with age. The average RR for MDD and bipolar patients to develop IHD decreased from 2.19 and 2.11, respectively, in youth (aged under 20 years), to 0.35 and 0.4, respectively, in elderly patients (age older than 65 years). Also, the average RR for MDD and bipolar patients to develop hypertensive disorders decreased from 2.8 and 3.86, respectively, in youth, to 0.48 and 0.61, respectively, in the elderly. Similar patterns were observed in patients with AD. The average RR for patients with AD to develop IHD decreased from 9.88 in youth to 0.66 in the elderly and the average RR of developing hypertensive diseases decreased from 5.56 in youth to 0.67 in the elderly.

Table 4. Relative risk of developing IHD/hypertensive diseases by age group
Year2000200120022003Average2000200120022003Average
RR of IHDRelative risk of hypertensive diseases
  1. IHD, ischemic heart disease; RR, relative risk of developing IHD or hypertensive disorders in study participants when compared with entire insured population without mood or anxiety disorders; MDD, major depressive disorder; Average RR, average relative risk.

Age groups          
<20 years          
 MDD12.41.14.262.193.43.751.282.782.8
 Bipolar32.21.12.132.112.23.752.566.943.86
 Anxiety1011108.519.886.76.255.134.175.56
Average RR4.75.24.14.974.744.14.582.994.634.08
20–44 years          
 MDD1.221.1111.191.131.431.170.880.921.1
 Bipolar1.761.5811.641.501.961.781.571.711.76
 Anxiety3.94.43.573.583.862.532.382.362.242.38
Average RR2.292.361.862.142.161.971.781.61.621.74
45–64 years          
 MDD0.6250.70.510.650.620.790.770.680.680.73
 Bipolar0.810.960.670.750.81.030.950.870.940.95
 Anxiety1.31.71.31.311.41.141.11.131.091.12
Average RR0.911.120.830.90.940.990.940.890.90.93
≥65 years          
 MDD0.320.420.310.350.350.510.490.450.450.48
 Bipolar0.430.50.3270.340.40.690.640.540.560.61
 Anxiety0.630.780.6150.610.660.690.670.660.640.67
Average RR0.460.570.4170.430.470.630.60.550.550.58

Overall, there was no significant gender difference in CVD prevalence for any category of psychiatric disorder.

DISCUSSION

  1. Top of page
  2. Abstract
  3. METHOD
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSION
  7. REFERENCES

This study is the first population-based study in Taiwan to determine and compare medical comorbidities among patients with different psychiatric diseases. Our results confirmed the high CVD comorbidities among patients with mood and anxiety disorders, and several key findings emerged from this study.

First, our findings show that the association between MDD and CVD is actually not stronger than the association between bipolar, anxiety disorder and CVD. Accumulating literature has already confirmed the strong association between depression and CVD comorbidity, and recent studies that have started focusing on bipolar disease, have indicated that bipolar patients may have higher risk of developing IHD/hypertensive diseases through various physiological mechanisms (such as metabolic syndrome).21–23 Interestingly, we found that the prevalence rates of IHD and hypertensive diseases in the bipolar population were actually higher than in MDD patients and this held true during the 4-year period. In addition, our findings show that the prevalence rates of IHD/hypertensive diseases were highest among patients with anxiety disorder. One possibility was that the independent association of anxiety symptoms (but not depressive symptoms) denoted a greater cardiac risk.24,25 Another explanation was that the illness behavior might affect our findings. For example, previous studies have demonstrated that anxiety patients have more cardiac-event-related complaints (such as dyspnea, palpitations and chest pains),26 and more often consult physicians for evaluations of cardiac symptoms,27,28 which increase the sensitivity of detecting cardiac disease. Moreover, our result was from claimed data, which could be affected by help seeking behavior. However, it is more likely that the impact of anxiety on CVD is still under-estimated because of our selection hierarchy (diagnostic hierarchy was BD, MDD and AD). We suggest that the correlation between CVD, bipolar and anxiety disease should be given more attention.

Second, our findings show an aging effect on CVD comorbidities in each category of psychiatric disorders during the 4-year period. Generally, risk factors for developing CVD are perceived to increase with age in the general population. The negative effects of psychiatric symptoms on elderly populations and the age-associated changes in vasculature (vascular intimal thickness, stiffness, altered regulations of vascular tone) and cardiac functions (left ventricular wall thickness, reduced cardiovascular reserve), which were thought to be part of ‘normal aging’ may be extrapolated as risk factors for developing cardiovascular disease.29–31

However, not much research attention has focused on comparing the association between CVD comorbidity and psychiatric diseases by specific age groups. Until recently, only a few studies focusing on cardiovascular disease in adolescents with psychiatric illness have shown that the correlation is strong.32–38 Interestingly, our results showed that when compared with entire insured populations without mood or anxiety disorders and stratified with age groups, the RR of developing IHD and hypertensive diseases was found to be highest in study participants below 20 years; and this held true for all diagnosis of MDD, BD and AD during the 4-year period. In contrast to the above findings, the RR of developing IHD and hypertensive diseases was found to be the lowest in study participants equal to or older than 65 years of age. Although previous cohort studies have indicated that cardiovascular disorders increase mortality in geriatric populations with mood and anxiety disorder,39–43 it was difficult for us to conclude directly that the lowest RR of developing CVD comorbidity in our geriatric participants was due to a different survival rate. However, recent research findings have demonstrated that the aging process over time might change defined cardiac risk factors. For example, a heightened hypothalamic activity, the physiological mechanism, which links mental illness with CVD, actually decreases with age and may not exaggerate cardiac functions in the elderly as we suspected.36 We suggest that age acts as an important modifier variable that influences the relationship between mood disorder, anxiety disorder and CVD.

Third, our data show that mood and anxiety disorders are more prevalent in female patients than male patients, which is consistent with previous epidemiological reports;44 and biological factors, genetic and psychosocial factors in female patients and the interaction in between may explain the above female predominance in the prevalence of mood and anxiety disorders.45–48 Moreover, we found that there was no significant gender difference in CVD prevalence rates among all study participants, and this result echoed recent findings that indicated that male and female patients with mood and anxiety disorder shared the equivalent level of risk to develop CVD.4,49 One cross-sectional study suggested that the link between CVD and mental health was moderated by both age and gender, and mental health status was associated with significant risk of developing CVD primarily among female patients between 45 and 74 years of age.50

Another prospective follow-up study showed that among post-myocardial infarction (MI) patients, 35 to 79 years of age at baseline, female patients had an increased risk of developing both anxiety and depression in the first 2 years post-MI, followed by a significant symptom reduction, and in contrast, the risk for depression in male patients increased after 2 years post-MI.51 Because systemic gender studies in medicine and mental health are still lacking and lack different study design,52 the gender effects on comorbidity of CVD among patients with mood and anxiety disorder is still inconclusive and need to be further investigated.

Several limitations of our study must be addressed here. First, the analysis was from claimed data that was definitely influenced by medical resource utilization behavior. Also, we focused on patients with active psychotropic medications, and this may explain why the prevalence of mood and anxiety disorder in our study was lower than survey epidemiological data. However, our results in the prevalence rates of mood and anxiety disorders were consistent with previous Taiwan NHRID report by Chien et al.53 Second, the validity of diagnoses in claimed data and the limitation of claimed data always need to be considered; but our findings were consistent during this 4-year period and it is reasonable to place confidence in the validity of our findings.

In addition to these limitations, the burden of physical illness may contribute to a bidirectional relationship between psychiatric disorders and physical illness and there are various pathways to develop CVD. Although it was not possible to define the causality and/or underlying pathway of developing CVD by our cross-sectional study methods, our results revealed the disparity of the relative risk to develop CVD comorbidity in different age groups. The interactions of gender differences, genetic factors, individual physiological mechanisms, aging effects and psychosocial factors are complex and entangled. Whether and how these variables contain the causal factors and their impact on psychiatric patients' health needs to be further examined.

CONCLUSION

  1. Top of page
  2. Abstract
  3. METHOD
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSION
  7. REFERENCES

Our results support the theory that Taiwanese patients with mood and anxiety disorders are at higher risk of cardiovascular morbidity, especially patients with anxiety disorders. When compared with the entire insured population without mood or anxiety disorders of the same age, the highest RR was found in study participants less than 20 years of age, and the lowest RR was found in the age group older than 65 years. We suggest that age acts as an important modifier variable that influences the relationship between mood disorder, anxiety disorder and CVD. This study highlights the need for future research in different age groups, in order to elucidate the causality and the trajectory of developing CVD among patients with mental disorders.

REFERENCES

  1. Top of page
  2. Abstract
  3. METHOD
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSION
  7. REFERENCES
  • 1
    Carney RM, Rich MW, Freedland KE et al. Major depressive disorder predicts cardiac events in patients with coronary artery disease. Psychosom. Med. 1988; 50: 627633.
  • 2
    Rugulies R. Depression as a predictor for coronary heart disease: A review and meta-analysis. Am. J. Prev. Med. 2002; 23: 5161.
  • 3
    Sesso HD, Kawachi I, Vokonas PS, Sparrow D. Depression and the risk of coronary heart disease in the Normative Aging Study. Am. J. Cardiol. 1998; 82: 851856.
  • 4
    Ferketich AK, Schwartzbaum JA, Frid DJ, Moeschberger ML. Depression as an antecedent to heart disease among women and men in the NHANES I study. National Health and Nutrition Examination Survey. Arch. Intern. Med. 2000; 160: 12611268.
  • 5
    Wassertheil-Smoller S, Shumaker S, Ockene J et al. Depression and cardiovascular sequelae in postmenopausal women. The Women's Health Initiative (WHI). Arch. Intern. Med. 2004; 164: 289298.
  • 6
    Katon WJ. Clinical and health services relationships between major depression, depressive symptoms, and general medical illness. Biol. Psychiatry 2003; 54: 216226.
  • 7
    Yang EH, Lerman S, Lennon RJ, Simari RD, Lerman LO, Lerman A. Relation of depression to coronary endothelial function. Am. J. Cardiol. 2007; 99: 11341136.
  • 8
    Wang HX, Mittleman MA, Leineweber C, Orth-Gomer K. Depressive symptoms, social isolation, and progression of coronary artery atherosclerosis: The Stockholm Female Coronary Angiography Study. Psychother. Psychosom. 2006; 75: 96102.
  • 9
    Fergusson DM, Goodwin RD, Horwood LJ. Major depression and cigarette smoking: Results of a 21-year longitudinal study. Psychol. Med. 2003; 33: 13571367.
  • 10
    Pine DS, Goldstein RB, Wolk S, Weissman MM. The association between childhood depression and adulthood body mass index. Pediatrics 2001; 107: 10491056.
  • 11
    Carney RM, Blumenthal JA, Stein PK et al. Depression, heart rate variability, and acute myocardial infarction. Circulation 2001; 104: 20242028.
  • 12
    Knox SS. Psychosocial stress and the physiology of atherosclerosis. Adv. Psychosom. Med. 2001; 22: 139151.
  • 13
    Girod JP, Brotman DJ. Does altered glucocorticoid homeostasis increase cardiovascular risk? Cardiovasc. Res. 2004; 64: 217226.
  • 14
    Yates WR, Mitchell J, John Rush A et al. Clinical features of depression in outpatients with and without co-occurring general medical conditions in STAR*D: Confirmatory analysis. Prim. Care. Companion J. Clin. Psychiatry 2007; 9: 715.
  • 15
    Kubzansky LD, Kawachi I, Weiss ST, Sparrow D. Anxiety and coronary heart disease: A synthesis of epidemiological, psychological, and experimental evidence. Ann. Behav. Med. 1998; 20: 4758.
  • 16
    Yasunari K, Matsui T, Maeda K, Nakamura M, Watanabe T, Kiriike N. Anxiety-induced plasma norepinephrine augmentation increases reactive oxygen species formation by monocytes in essential hypertension. Am. J. Hypertens. 2006; 19: 573578.
  • 17
    Gorman JM, Sloan RP. Heart rate variability in depressive and anxiety disorders. Am. Heart J. 2000; 140 (Suppl. 4): 7783.
  • 18
    Beyer J, Kuchibhatla M, Gersing K, Krishnan KR. Medical comorbidity in a bipolar outpatient clinical population. Neuropsychopharmacology. 2005; 30: 401404.
  • 19
    Chien IC, Chou YJ, Lin CH, Bih SH, Chou P, Chang HJ. Prevalence and incidence of schizophrenia among national health insurance enrollees in Taiwan, 1996–2001. Psychiatry Clin. Neurosci. 2004; 58: 611618.
  • 20
    World Health Organization Collaborating Center for Drug Statistics Methodology. Guidelines for ATC Classification and DDD Assignment, 3rd edn. Oslo: WHO Collaborating Center for Drug Statistics Methodology, 2000.
  • 21
    Jankovic S, Vlajinac H, Bjegovic V et al. The burden of disease and injury in Serbia. Eur. J. Public Health 2007; 17: 8085.
  • 22
    McElroy SL. Diagnosing and treating comorbid (complicated) bipolar disorder. J. Clin. Psychiatry 2004; 65 (Suppl. 15): 3544.
  • 23
    Kilbourne AM, Post EP, Bauer MS et al. Therapeutic drug and cardiovascular disease risk monitoring in patients with bipolar disorder. J. Affect. Disord. 2007; 102: 145151.
  • 24
    Rothenbacher D, Hahmann H, Wusten B, Koenig W, Brenner H. Symptoms of anxiety and depression in patients with stable coronary heart disease: Prognostic value and consideration of pathogenetic links. Eur. J. Cardiovasc. Prev. Rehabil. 2007; 14: 547554.
  • 25
    Von Kanel R, Dimsdale JE, Adler KA, Patterson TL, Mills PJ, Grant I. Effects of depressive symptoms and anxiety on hemostatic responses to acute mental stress and recovery in the elderly. Psychiatry Res. 2004; 126: 253264.
  • 26
    Demiryoguran NS, Karcioglu O, Topacoglu H et al. Anxiety disorder in patients with non-specific chest pain in the emergency setting. Emerg. Med. J. 2006; 23: 99102.
  • 27
    Stewart DE. Physical symptoms of depression: Unmet needs in special populations. J. Clin. Psychiatry 2003; 64 (Suppl. 7): 1216.
  • 28
    Logue MB, Thomas AM, Barbee JG et al. Generalized anxiety disorder patients seek evaluation for cardiological symptoms at the same frequency as patients with panic disorder. J. Psychiatr. Res. 1993; 27: 5559.
  • 29
    Narita K, Murata T, Hamada T et al. Association between trait anxiety and endothelial function observed in elderly males but not in young males. Int. Psychogeriatr. 2007; 19: 947954.
  • 30
    Lakatta EG, Levy D. Arterial and cardiac aging: Major shareholders in cardiovascular disease enterprises: Part II: The aging heart in health: Links to heart disease. Circulation 2003; 107: 346354.
  • 31
    Lakatta EG, Levy D. Arterial and cardiac aging: Major shareholders in cardiovascular disease enterprises: Part I: Aging arteries: A ‘set up’ for vascular disease. Circulation 2003; 107: 139146.
  • 32
    Goodman E, Whitaker RC. A prospective study of the role of depression in the development and persistence of adolescent obesity. Pediatrics 2002; 110: 497504.
  • 33
    Sinaiko AR, Steinberger J, Moran A et al. Relation of body mass index and insulin resistance to cardiovascular risk factors, inflammatory factors, and oxidative stress during adolescence. Circulation 2005; 111: 19851991.
  • 34
    Lau BW. Does the stress in childhood and adolescence matter? A psychological perspective. J. R. Soc. Health 2002; 122: 238244.
  • 35
    Banki CM, Bissette G, Arato M, O'Connor L, Nemeroff CB. CSF corticotropin-releasing factor-like immunoreactivity in depression and schizophrenia. Am. J. Psychiatry 1987; 144: 873877.
  • 36
    Kudielka BM, Buske-Kirschbaum A, Hellhammer DH, Kirschbaum C. HPA axis responses to laboratory psychosocial stress in healthy elderly adults, younger adults, and children: Impact of age and gender. Psychoneuroendocrinology 2004; 29: 8398.
  • 37
    Bethell J, Rhodes AE. Adolescent depression and emergency department use: The roles of suicidality and deliberate self-harm. Curr. Psychiatry Rep. 2008; 10: 5359.
  • 38
    Birmaher B, Axelson D. Course and outcome of bipolar spectrum disorder in children and adolescents: A review of the existing literature. Dev. Psychopathol. 2006; 18: 10231035.
  • 39
    Penninx BW, Beekman AT, Honig A et al. Depression and cardiac mortality: Results from a community-based longitudinal study. Arch. Gen. Psychiatry 2001; 58: 221227.
  • 40
    Shulman KI, Herrmann N. The nature and management of mania in old age. Psychiatr. Clin. North Am. 1999; 22: 649665, ix.
  • 41
    Mykletun A, Bjerkeset O, Dewey M, Prince M, Overland S, Stewart R. Anxiety, depression, and cause-specific mortality: The HUNT study. Psychosom. Med. 2007; 69: 323331.
  • 42
    Allgulander C, Lavori PW. Excess mortality among 3302 patients with ‘pure’ anxiety neurosis. Arch. Gen. Psychiatry 1991; 48: 599602.
  • 43
    Kisely S, Smith M, Lawrence D, Cox M, Campbell LA, Maaten S. Inequitable access for mentally ill patients to some medically necessary procedures. CMAJ 2007; 176: 779784.
  • 44
    Brown CS. Depression and anxiety disorders. Obstet. Gynecol. Clin. North Am. 2001; 28: 241268.
  • 45
    Kuehner C. Gender differences in unipolar depression: An update of epidemiological findings and possible explanations. Acta Psychiatr. Scand. 2003; 108: 163174.
  • 46
    Rapkin AJ, Mikacich JA, Moatakef-Imani B, Rasgon N. The clinical nature and formal diagnosis of premenstrual, postpartum, and perimenopausal affective disorders. Curr. Psychiatry Rep. 2002; 4: 419428.
  • 47
    Pigott TA. Anxiety disorders in women. Psychiatr. Clin. North Am. 2003; 26: 621672, vi–vii.
  • 48
    Mizuno T, Aoki M, Shimada Y et al. Gender difference in association between polymorphism of serotonin transporter gene regulatory region and anxiety. J. Psychosom. Res. 2006; 60: 9197.
  • 49
    Cardenas J, Frye MA, Marusak SL et al. Modal subcomponents of metabolic syndrome in patients with bipolar disorder. J. Affect. Disord. 2008; 106: 9197.
  • 50
    Keyes CL. The nexus of cardiovascular disease and depression revisited: The complete mental health perspective and the moderating role of age and gender. Aging Ment. Health 2004; 8: 266274.
  • 51
    Bjerkeset O, Nordahl HM, Mykletun A, Holmen J, Dahl AA. Anxiety and depression following myocardial infarction: Gender differences in a 5-year prospective study. J. Psychosom. Res. 2005; 58: 153161.
  • 52
    Moller-Leimkuhler AM. Gender differences in cardiovascular disease and comorbid depression. Dialogues Clin. Neurosci. 2007; 9: 7183.
  • 53
    Chien IC, Chou YJ, Lin CH, Bih SH, Chou P. Prevalence of psychiatric disorders among National Health Insurance enrollees in Taiwan. Psychiatr. Serv. 2004; 55: 691697.