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Medicine » Mental and Behavioural Disorders and Diseases of the Nervous System » "Anxiety and Related Disorders", book edited by Ágnes Szirmai, ISBN 978-953-307-254-8, Published: August 29, 2011 under CC BY-NC-SA 3.0 license. © The Author(s).

# Generalised Anxiety Disorder, Mortality and Disease: A Stronger Predictor than Major Depressive Disorder

By Anna C. Phillips
DOI: 10.5772/19467

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# Generalised Anxiety Disorder, Mortality and Disease: A Stronger Predictor than Major Depressive Disorder

Anna C. Phillips1

## 1. Introduction

This chapter will examine the associations between Generalised Anxiety Disorder (GAD) and key health outcomes, including mortality, the metabolic syndrome, and hypertension, citing relevant research and recent findings from the Vietnam Experience Study. It aims to show that GAD is as strong a determinant of such health outcomes, if not a stronger one than MDD. It also aims to illustrate the importance of considering the comorbidity of GAD with other psychiatric diagnoses when predicting mortality and other health outcomes.

Mental health disorders in the general population are relatively common (Kessler et al., 2005; Kessler, Chiu, Demler, Merikangas, & Walters, 2005). In fact, an estimated 14% of the global disease burden has been attributed to mental health disorders (World Health Organisation, 1992-1994), and this figure is likely to be an underestimate as it fails to take into consideration the association between mental health and other health conditions (Prince et al., 2007). Populations who have been exposed to traumatic events, such as war veterans, have an even higher prevalence of Generalised Anxiety Disorder (GAD) and Major Depressive Disorder (MDD) (Gaylord, 2006; Hoge, Auchterlonie, & Milliken, 2006; Reeves, Parker, & Konkle-Parker, 2005). For example, soldiers assessed a few months after returning from deployment to Afghanistan and Iraq had a GAD prevalence of around 14% and 15%, respectively, and prevalence of MDD of around 17% and 16% (Hoge et al., 2004). Others have reported depressive symptom rates as high as 19% in veterans based on prior diagnosis records (Kinder et al., 2008), and 31% using self-report measures (Hankin, Spiro, Miller, & Kazis, 1999), although some studies have shown lower rates of 6.9% and 1.7% for MDD and GAD, respectively (Sareen et al., 2007). Little has been reported about the consequences for survival of these mental health disorders in veterans.

In the general population, MDD has been associated with increased mortality rates (see e.g. O'Leary & Lee, 1996; Surtees & Barkley, 1994). Although much of this excess is attributable to non-medical causes of death such as injury and suicide, it is becoming clear that MDD also increases the risk of death from common chronic diseases such as cardiovascular disease (CVD) (Osby, Brandt, Correia, Ekbom, & Sparen, 2001). There is now substantial evidence linking depression with CVD morbidity and mortality (see e.g. Musselman, Evans, & Nemeroff, 1998; Wulsin, Vaillant, & Wells, 1999). However, much of this research has examined the impact of depressed mood rather than a diagnosis of MDD. In a recent meta-analysis of 11 studies of coronary heart disease (CHD), MDD, which had been measured in only three studies, was a much stronger predictor of CHD outcomes than depressed mood (Rugulies, 2002). Few studies have examined GAD as a risk factor for all-cause mortality, although two population studies suggest that, for causes of death other than suicide, GAD does not present a significant risk (Holwerda et al., 2007; Murphy, Monson, Olivier, Sobol, & Leighton, 1987). However, other manifestations of anxiety have been associated with an increased risk of CVD morbidity and/or mortality (see e.g. Eaker, Sullivan, Kelly-Hayes, D'Agostino, & Benjamin, 2005; Haines, Imeson, & Meade, 1987; Weissman, Markowitz, Ouellette, Greenwald, & Kahn, 1990). It would appear that no studies have measured the relationship between diagnosed GAD and CVD mortality.

The bulk of research examining the consequences of mental health disorders for chronic disease in veterans has concentrated on post-traumatic stress disorder (PTSD). For example, lifetime prevalence of PTSD was linked with an increased mortality rate (Boscarino, 2006a, 2006b). In addition, PTSD in veterans has also been associated with cardiovascular, digestive, musculoskeletal, endocrine-nutritional-metabolic, nervous system, respiratory, and nonsexually transmitted infectious diseases (J.A. Boscarino, 1997), chronic changes in immunity (Boscarino & Chang, 1999), and markers of inflammatory disorders (Boscarino, 2004). However, there appear to be few studies examining the influence of other major mental health disorders on mortality risk in veterans. In a study of PTSD and MDD in veterans, MDD was related to increased mortality following adjustment for age, demographic variables, health behaviours, and medical co-morbidities (Kinder, et al., 2008). The association between GAD and mortality in veterans does not appear to have been studied.

Given the reported high prevalence of GAD and MDD in army veterans and the significant prevalence of these disorders in the general population, their individual and combined impact merits research attention. Recently, it was possible to address this issue in the Vietnam Experience Study.

### 2.1. The Vietnam experience study

The Vietnam Experience Study is an epidemiological study commissioned by the US congress to investigate the health consequences of the military experiences of Vietnam veterans. The participants were male military personnel drawn from approximately five million US Vietnam-era army veterans whose service files were stored at the National Personnel Records Center (Vietnam Experience Study, 1987). The Centers for Disease Control, Atlanta, had access to U.S. Veteran Administration records and provided a fully anonymised dataset. Those who entered military service between January 1, 1965 and December 31, 1971; served only one term of enlistment; served at least 16 weeks of active duty; earned a military specialty other than “trainee” or “duty soldier”; at discharge from active duty had a military pay grade no higher than sergeant; and had not died during military duties were eligible for inclusion. On reviewing a random sample of 48 513 records, 1355 were found to be incomplete, 28 577 did not meet study entry criteria and 268 men died during military duties, so the final cohort included 18,313 former military personnel. Of those included in the original cohort, 17,867 were considered to be alive on December 31st 1983 and therefore eligible for active follow-up.

Information pertaining to place of service, military rank, ethnicity, and cognitive ability scores from the Army General Technical Test (hereafter referred to as “IQ”) was extracted from the military archives. Participants were designated as being Vietnam veterans if they had served at least one tour of duty in Vietnam, and as non-Vietnam veterans if they did not (this group included men who served one or more tours of duty in Korea, Germany or the US). The ethnic origin of the study members were classified as ‘white’, ‘black’, or ‘other’; the latter group comprising Hispanics, Asians, Pacific Islanders, American Indians, and Alaskan Natives.

In 1985 these participants were invited to participate in a telephone interview. Telephone directories, credit bureau searches, driver’s license and motor vehicle registration records, city directories, local records and personal field visits were all utilized to locate the whereabouts of apparently surviving men. Of those traced (N = 16 349), an interview was not possible for reasons of incarceration (N = 63), physical or mental disability (N = 20), refusal (N = 949), death during the tracing process (N = 53), or ‘other’ (N = 6). This resulted in a sample of 15,288 men (85.6% of those alive on December 31st 1983) who participated in the 1985 telephone survey (Batty et al., 2008). During the telephone survey, enquiries were made about the study participants’ socio-economic characteristics, health behaviours, and health. Socio-economic position was measured using household income in midlife. Frequency of alcohol consumption was classified as number of units consumed per week. Smoking habits and marital status were ascertained using standard questions. Participants were also asked whether or not they had a range of somatic physician-diagnosed health problems which included hypertension, cancer, diabetes and coronary heart disease (The Centers for Disease Control Vietnam Experience Study., 1988a, 1988b).

In 1986, a random sample of telephone interview respondents (N=6443) were invited to attend a three day medical examination with orientation at a single facility in Albuquerque, New Mexico, for which travel expenses and a nominal stipend were met; 4462 attended (69.3% of those invited). The mean age at medical examination was 38.3 years (range: 31.1 to 49.0). Of those invited, medical examination was not possible for reasons of incarceration (N = 26), physical or mental disability (N = 10), refusal (N = 949), death before invitation (N = 10), or ‘refusal’ (N = 372). The main reasons for refusing to participate at this stage of data collection were: work related, e.g. unable to get leave with pay; a lack of interest in the study, e.g. unable to see how it would benefit them; or personal, e.g. did not like to travel. The final number of participants with complete data after the medical examination was 4256. This group represents 23.3% of persons originally enrolled in the study. Sampling in the study is shown in Figure 1, below. For the medical examination, all men were requested to fast from 19.00 the evening before medical testing. Following the drawing of blood the following morning, cholesterol level was ascertained using a Kodak Ektachem 700 autoanalyzer (The Centers for Disease Control Vietnam Experience Study., 1988a, 1988b). Serum glucose level was determined with a standard adaptation of the glucose oxidase-peroxidase-chromogen-coupled system for glucose determination in biologic fluids (The Centers for Disease Control Vietnam Experience Study., 1988a, 1988b). Blood pressure, while seated, was measured twice in the right arm using a standard mercury sphygmomanometer; for the purposes of analyses, an average was computed. Height and weight, measured using standard protocols, were used to calculate body mass index (BMI) (kg/m2).

#### 2.1.1. Psychological morbidity

Psychological morbidity was assessed using the Diagnostic Interview Schedule (version 3A) as administered by a trained psychological technician. The Diagnostic Interview Schedule is

### Figure 1.

Sampling in the Vietnam Experience Study

a standardized questionnaire that is designed to assess the prevalence of certain psychiatric conditions according to the Diagnostic and Statistical Manual of Mental Disorders (version III) criteria of the American Psychiatric Association (APA, 1980; Robins, Helzer, & Cottler, 1987). Study participants were considered positive for GAD and MDD if they reported a pattern of symptoms in the previous 12 months that satisfied full Diagnostic and Statistical Manual of Mental Disorders (version III) criteria. Characteristics of those with and without a diagnosis of GAD are shown in Table 1.

### Table 2.

Characteristics of those who were and were not deceased

examined: older adults (Holwerda, et al., 2007) and the general population (Murphy, et al., 1987). It is also possible that anxiety may only predict mortality in men, as in one previous study where an association between anxiety disorders and mortality was found for men but not women (van Hout et al., 2004). GAD has not been previously studied in terms of CVD mortality in the general population, or in the context of mortality per se in veterans. This seems unfortunate given that it is a strong predictor of all-cause mortality in the present analyses. The present findings are consistent with the results of previous research linking MDD with all-cause mortality in the general population (e.g. O'Leary & Lee, 1996; Surtees & Barkley, 1994) and in veterans (Kinder, et al., 2008). Although many studies have considered depression as a predictor of CVD mortality, surprisingly few have examined diagnosed MDD. Of those available, both positive (Osby, et al., 2001) and null (Hallstrom, Lapidus, Bengtsson, & Edstrom, 1986; Vogt, Pope, Mullooly, & Hollis, 1994) findings have been reported. Although little attention has been paid to MDD and all-cause mortality in veterans, our findings are consistent with those of one recent study in which individuals with a diagnosis of depression were at increased risk of death over an average of two years (Kinder, et al., 2008).

Some studies have examined the prognostic importance of both symptoms of anxiety and depression and mortality in cardiac patient groups. In a review of 25 studies of chronic heart failure patients, anxiety symptoms were measured along with depression in just three studies (Pelle, Gidron, Szabo, & Denollet, 2008). Anxiety symptoms were not associated with mortality, whereas depressive symptoms significantly predicted death (Pelle, et al., 2008). A number of studies have examined both anxiety and depression symptoms and mortality in myocardial infarction patients. High depression and anxiety scores have both been found to predict all-cause mortality (Herrmann et al., 1998), and cardiac death (Denollet & Brutsaert, 1998). However, in three studies, symptoms of depression but not anxiety in multivariate models predicted all-cause or cardiac mortality (Ahern et al., 1990; Frasure-Smith & Lesperance, 2003; Frasure-Smith, Lesperance, & Talajic, 1995). Finally, neither depression nor anxiety symptoms were found to predict mortality in myocardial infarction patients (Lane, Carroll, Ring, Beevers, & Lip, 2001). Thus, in prognostic studies, it would appear that depressive symptoms may be a more stable predictor of mortality than anxiety. However, it is unclear the extent to which the results of these studies of patients with chronic inflammatory disease relate to the present aetiological study where only 1% had a diagnosis of coronary heart disease at the medical examination. It is possible that the effects of depression on mortality and the underlying mechanisms may not be identical in patient versus population-based studies. Further, none of the prognostic studies that we know of have examined psychiatric comorbidity effects on mortality.

### Figure 2.

Percentage deceased in each diagnosis category

### 2.4. Limitations

It should be conceded that there are a number of limitations to this analysis and its interpretation. First, the weaker effects for CVD in comparison to all-cause mortality may reflect the small number of deaths due to CVD in this sample resulting in lower power to detect significant associations, particularly when adjusting for a large number of covariates. Support for this assertion can be found in the hazard ratios which were of comparable size in the fully adjusted models for both all-cause and CVD mortality, but only attained significance when all-cause mortality was the outcome. Second, residual confounding as a consequence of un-measured variables cannot be wholly discounted. The present analysis, however, did adjust for a large number of potential confounding variables. Third, as this sample was exclusively male, there is the issue of generalisation. It should be noted that the previous studies with null results tested women only in one case (Hallstrom et al., 1986) and both sexes in the other (Vogt et al., 1994). It is also worth noting, though, that these studies had much smaller samples, reducing their power to detect effects on mortality. In addition, it is possible that veterans differ in other ways from the broader population. For example, one study of stable coronary heart disease that included veterans found no evidence that depression was associated with elevated levels of inflammation (Whooley et al., 2007); a finding opposite to that of many studies in non-cardiac disease patients. However, not all the patients in this study were veterans (Whooley et al., 2007). Fourth, it has been suggested that the prevalence of mental health disorders in the Vietnam Experience Study are underestimated (Dohrenwend et al., 2006, 2007). However, this criticism has mainly been levelled at estimations of PTSD prevalence. Nevertheless, it is possible that severely depressed veterans were less likely to participate in the medical examination, which may have accounted for the attenuated associations for major depression in the present analyses. However, this seems unlikely given that only 10 (<2%) veterans were unable to attend on the basis of physical/mental disability, and only 372 (<6%) refused to attend, with the main reasons being a lack of interest or unwillingness to travel. Moreover, underestimation in the present study would make the associations demonstrated between MDD, GAD, their comorbidity and mortality more compelling. Fifth, given that a diagnosis of MDD only requires two weeks of symptoms, whereas GAD requires symptoms for at least six months, it is possible that MDD diagnoses were less trustworthy. However, evidence indicates that the DSM-III criteria for diagnosis of both MDD and GAD are highly reliable (Riskind et al., 1987).

In conclusion, the present analysis in Vietnam veterans showed that MDD and GAD were positively associated with all-cause and CVD mortality. However, in the fully adjusted analyses reported, the relationships with CVD mortality were non-significant, possibly due to low statistical power. A diagnosis of both MDD and GAD proved much the strongest predictor of all-cause and CVD mortality. The effects of comorbidity of MDD and GAD, and with PTSD would suggest that future research on mental health disorders and physical health outcomes, as well as future clinical interventions, should pay more attention to comorbidity. In addition, future studies should attempt to measure and take account of a full range of factors likely to be associated with both mental and physical health.

## 3. GAD and the metabolic syndrome

The metabolic syndrome (MetS) is a prevalent cluster of symptoms (obesity, high triglyceride levels, low levels of HDL cholesterol, raised blood pressure, and high levels of fasting blood glucose or a diagnosis of diabetes) (Isomaa et al., 2001; Lakka et al., 2002; Thomas et al., 2007; Trevisan, Liu, Bahsas, & Menotti, 1998). As the metabolic syndrome increases risk for cardiovascular and all-cause mortality (Isomaa, et al., 2001; Lakka, et al., 2002; Thomas, et al., 2007; Trevisan, et al., 1998), recently there has been interest in the relationship between it and various mental health disorders.

The bulk of this research has focused on depression and although contrary indications exist (Herva et al., 2006), there is evidence of a positive association between depression and the metabolic syndrome (Dunbar et al., 2008; Heiskanen et al., 2006; Kinder, Carnethon, Palaniappan, King, & Fortmann, 2004; Koponen, Jokelainen, Keinanen-Kiukaanniemi, Kumpusalo, & Vanhala, 2008; McCaffery, Niaura, Todaro, Swan, & Carmelli, 2003; Raikkonen, Matthews, & Kuller, 2002; Skilton, Moulin, Terra, & Bonnet, 2007; Vaccarino et al., 2008). However, the vast majority of these studies were concerned with depressive symptoms; a recent review (Goldbacher & Matthews, 2007) identified only two studies examining MDD in this context. In a small study of outpatients, those who still had a diagnosis at 6-year follow-up showed a higher prevalence of the metabolic syndrome (Heiskanen, et al., 2006). In a larger scale study, a history of MDD was associated with the metabolic syndrome in women but not men (Kinder, et al., 2004). Much less attention has been paid to anxiety and the metabolic syndrome and the three most recent studies reported null findings (Herva, et al., 2006; Raikkonen, Matthews, & Kuller, 2007; Skilton, et al., 2007). However, an earlier study of women found an association between the metabolic syndrome and increased anxiety seven years later (Raikkonen, et al., 2002). These studies have all been concerned with anxiety symptoms; no study has tested the association with GAD. We were able to utilise the Vietnam Experience Study dataset in order to examine the potential links between GAD and the metabolic syndrome. In this dataset, the metabolic syndrome was defined as having at least three of: BMI > 30 kg/m2 (in the absence of waist circumference data, BMI at this threshold is regarded by World Health Organization as an acceptable substitute in defining MetS); triglycerides ≥ 1.7 mmol/l (150 mg/dl); HDL cholesterol < 1.036 mmol/l (40 mg/dl); blood pressure ≥ 130/85 mmHg or taking antihypertensive medication; fasting glucose ≥ 6.1 mmol/l (110 mg/dl) or taking diabetes medication.

### 3.1. Associations with the metabolic syndrome

Seven hundred and seventy-three (18%) of the men in the Vietnam Experience Study were identified as having the metabolic syndrome. Aside from differing on all the components of the metabolic syndrome, participants with it were slightly older, had lower IQ scores and a briefer education, were less likely to be divorced, widowed or separated and more likely to come from ethnic groups other than white or black, i.e. Hispanic. Full details of the characteristics of those with and without the metabolic syndrome are shown in Table 3.

### Table 4.

Characteristics of those with and without hypertension

Both GAD and MDD were associated with an elevated risk of hypertension in fully-adjusted models, although the association was stronger for MDD than GAD on this occasion. Of the participants with co-morbid GAD and MDD, 72 (47%) were hypertensive. Both GAD, MDD, and comorbidity were associated with an increased risk of hypertension in age-adjusted analyses, but when adjusting for all other covariates, only comorbidity was significantly related to hypertension, although there was a trend for a relationship with GAD (p =.06).

Given that antihypertensive medication can be prescribed for conditions other than hypertension, hypertension was redefined based on only physician diagnosis and measured blood pressure. This reduced the sample to 4180 and the numbers classified as hypertensive as 1329 (32%). In the separate fully adjusted models, both GAD and MDD were positively associated with hypertension defined in this alternative fashion. However, in the fully adjusted comorbidity competitive analysis, no statistically significant relationships emerged. The only association to approach significance was between co-morbidity and hypertension.

Over 30% of the sample met the main criteria for hypertension. This proportion is somewhat higher than that reported from studies with participants of a similar mean age (e.g., Patten, et al., 2009). However, in part this could reflect different definitions of hypertension; relying solely on reported diagnostic and medication status, and not including measured blood pressure, will almost certainly lead to an underestimate of prevalence. In addition, the present sample was clustered at the low end of the socio-economic spectrum. This might also help explain their relatively high prevalence of hypertension. Other analyses indicate an inverse gradient between socio-economic status and measured blood pressure, although a less consistent association between socio-economic position and hypertension treatment rates (Colhoun, Hemingway, & Poulter, 1998). In the present sample, however, household income in midlife was associated with hypertension.

Both GAD and MDD were positively associated with hypertension. The latter result is consistent with the cross-sectional and prospective outcomes from the Canadian National Population Health Survey (Patten et al., 2005; Patten, et al., 2009). We know of no previous studies that have examined the relationship between GAD and hypertension. However, a positive association between symptoms of anxiety and hypertension has been reported from NHANES and the Framingham study (Jonas, et al., 1997; Markovitz, et al., 1993), although no such relationship emerged from analysis of data from the CARDIA study (Yan, et al., 2003). In fully adjusted competitive analysis, we found that only the co-morbidity of GAD and MDD was significantly associated with an increased risk of hypertension. It is possible that co-morbidity signals more severe psychiatric dysfunction and that it is the severity of dysfunction that is associated with physical health outcomes, similar to the findings for mortality above. However, it is also possible that comorbidity reflects a greater negative disposition, and it is this which is associated with hypertension (Suls & Bunde, 2005). Whatever the case, given the high comorbidity of GAD and MDD, it is perhaps regrettable that studies of psychiatric disorders and physical health have focused almost exclusively on single disorders.

### 4.2. Limitations and mechanisms

Although we are not able to determine causality from the present cross-sectional associations, the prospective associations between MDD and hypertension (Patten et al., 2009) and symptoms of anxiety and hypertension studies (Jonas et al., 1997; Markovitz et al., 1993), cited above, make it unlikely that GAD or MDD are a psychological response to hypertension diagnosis. There are several putative pathways through which disorders such as GAD and MDD might contribute to development of hypertension. In addition, in the majority of instances in the present study, hypertension was apparently undiagnosed. Further, many of the sample had served in Vietnam. As a life event, a diagnosis of hypertension is likely to pale by comparison. The two most cited are unhealthy behaviours and physiological dysregulation. In the present analyses, the associations were still evident following adjustment for two of the most prominent unhealthy behaviours, smoking and high levels of alcohol consumption. That smokers have lower blood pressure and that alcohol consumption is positively related to hypertension are common observations (Beilin, 1987; Green, Jucha, & Luz, 1986). Although we have no data directly pertaining to the second route, others have observed altered activity of the hypothalamic-pituitary-adrenal axis in approximately 50% of depressed patients (Brown, Varghese, & McEwen, 2004), which, in turn, may increase the risk of hypertension (Torpy, Mullen, Ilias, & Nieman, 2002).

Other limitations of this analysis are that, as discussed above, the present study’s participants were all men and so there is the issue of generalisation. Indeed, in the Framingham study, symptoms of anxiety predicted hypertension in middle-aged men but not middle-aged women (Markovitz et al., 1993). Accordingly, the associations reported here may pertain only for men. In addition, the present participants were largely from the lower end of the socio-economic spectrum and thus our findings may not generalise to the population as a whole. However, these analyses again indicate the importance of GAD, as well as MDD in terms of health outcomes, and particular their comorbidity.

## 5. Conclusion

In conclusion, the analyses discussed above indicated that both GAD and MDD were individually positively related to all-cause mortality and to hypertension in male Vietnam-era veterans. However, the strongest association with both mortality and hypertension was observed for co-morbid GAD and MDD. Further, when considering another major health outcome, the metabolic syndrome, GAD but not MDD was associated with an increased prevalence of this constellation of symptoms. Depression has been the main focus for studies of psychiatric disorders and physical health outcomes. The current data suggest that future research should perhaps pay equal attention to GAD and, for some outcomes, it seems that it is particularly its co-morbidity with MDD and/or other mental disorders which might predict poorer health. Future research remains to determine the mechanisms underlying these associations with health outcomes, through prospective assessment and a thorough inclusion of both biological and behavioural covariates.

## 6. Acknowledgements

Mortality surveillance of the cohort in the post-service VES was funded by the National Center for Environmental Health, Atlanta, US. The Medical Research Council (MRC) Social and Public Health Services Unit receives funding from the MRC and the Chief Scientist Office at the Scottish Government Health Directorates. The author would also like to acknowledge the involvement of Professor Douglas Carroll, Dr Catharine Gale, and Dr G. David Batty in the analyses reported

## References

1 - D. K. Ahern, L. Gorkin, J. L. Anderson, C. Tierney, A. Hallstrom, C. Ewart, et al.1990Biobehavioral variables and mortality or cardiac arrest in the Cardiac Arrhythmia Pilot Study (CAPS). American Journal of Cardiology, 665962
2 - American Psychiatric Association,1980Diagnostic and statistical manual of mental disorders (3rd. edition). American Psychiatric Association, Washington DC.
3 - G. D. Batty, M. J. Shipley, L. Mortensen, S. H. Boyle, J. Barefoot, M. Grønbaek, et al.2008IQ in late adolescence/early adulthood, risk factors in middle-age, and later all-cause mortality in men: the Vietnam Experience Study. Journal of Epidemiology and Community Health, 62522531
4 - L. J. Beilin, 1987Epidemiology of alcohol and hypertension. Adv Alcohol Subst Abuse, 669 EOF87 EOF
5 - J. A. Boscarino, 1997Diseases among men 20 years after exposure to severe stress: implications for clinical research and medical care. Psychosomatic Medicine, 59605614
6 - J. A. Boscarino, 2004Posttraumatic stress disorder and physical illness: results from clinical and epidemiologic studies. Annals of the New York Academy of Sciences, 1032141153
7 - J. A. Boscarino, 2006aExternal-cause mortality after psychologic trauma: the effects of stress exposure and predisposition. Comparative Psychiatry, 47503514
8 - J. A. Boscarino, 2006bPosttraumatic stress disorder and mortality among U.S. Army veterans 30 years after military service. Annals of Epidemiology, 16248256
9 - J. A. Boscarino, J. Chang, 1999Higher abnormal leukocyte and lymphocyte counts 20 years after exposure to severe stress: research and clinical implications. Psychosomatic Medicine, 61378386
10 - E. S. Brown, F. P. Varghese, B. S. Mc Ewen, 2004Association of depression with medical illness: does cortisol play a role? Biological Psychiatry, 5519
11 - J. R. Chiong, 2008Controlling hypertension from a public health perspective. International Journal of Cardiology, 127151156
12 - H. M. Colhoun, H. Hemingway, N. R. Poulter, 1998Socio-economic status and blood pressure: an overview analysis. Journal of Human Hypertension, 1291110
13 - J. Denollet, D. L. Brutsaert, 1998Personality, disease severity, and the risk of long-term cardiac events in patients with a decreased ejection fraction after myocardial infarction. Circulation, 97167173
14 - B. P. Dohrenwend, J. B. Turner, N. A. Turse, B. G. Adams, K. C. Koenen, R. Marshall, 2006The psychological risks of Vietnam for U.S. veterans: a revisit with new data and methods. Science,313979982
15 - B. P. Dohrenwend, J. B. Turner, N. A. Turse, B. G. Adams, K. C. Koenen, R. Marshall, 2007Continuing controversy over the psychological risks of Vietnam for U.S. veterans. Journal of Trauma and Stress, 20449465
16 - J. A. Dunbar, P. Reddy, N. Davis-Lameloise, B. Philpot, T. Laatikainen, A. Kilkkinen, et al.2008Depression: an important co morbidity with metabolic syndrome in a general population. Diabetes Care, 3123682373
17 - E. D. Eaker, L. M. Sullivan, M. Kelly-Hayes, R. B. D’Agostino, Sr , E. J. Benjamin, 2005Tension and anxiety and the prediction of the 10-year incidence of coronary heart disease, atrial fibrillation, and total mortality: the Framingham Offspring Study. Psychosomatic Medicine, 67692696
18 - N. Frasure-Smith, F. Lesperance, 2003Depression and other psychological risks following myocardial infarction. Archives of General Psychiatry, 60627 EOF36 EOF
19 - N. Frasure-Smith, F. Lesperance, M. Talajic, 1995The impact of negative emotions on prognosis following myocardial infarction: is it more than depression? Health Psychology, 14
20 - K. M. Gaylord, 2006The psychosocial effects of combat: the frequently unseen injury. Critical Care Nursing Clinician North America, 18349357
21 - E. M. Goldbacher, K. A. Matthews, 2007Are psychological characteristics related to risk of the metabolic syndrome? A review of the literature. Annals of Behavioral Medicine, 34240 EOF252 EOF
22 - M. S. Green, E. Jucha, Y. Luz, 1986Blood pressure in smokers and nonsmokers: epidemiologic findings. American Heart Journal, 111932940
23 - A. P. Haines, J. D. Imeson, T. W. Meade, 1987Phobic anxiety and ischaemic heart disease. BMJ, 295297299
24 - T. Hallstrom, L. Lapidus, C. Bengtsson, K. Edstrom, 1986Psychosocial factors and risk of ischaemic heart disease and death in women: a twelve-year follow-up of participants in the population study of women in Gothenburg, Sweden. Journal of Psychosomatic Research, 30451459
25 - C. S. Hankin, A. Spiro, D. R. 3rd Miller, L. Kazis, 1999Mental disorders and mental health treatment among U.S. Department of Veterans Affairs outpatients: the Veterans Health Study. American Journal of Psychiatry, 15619241930
26 - T. H. Heiskanen, L. K. Niskanen, J. J. Hintikka, H. T. Koivumaa-Honkanen, K. M. Honkalampi, K. M. Haatainen, et al.2006Metabolic syndrome and depression: a cross-sectional analysis. Journal of Clinical Psychiatry, 67, 14221427
27 - C. Herrmann, S. Brand-Driehorst, B. Kaminsky, E. Leibing, H. Staats, U. Ruger, 1998Diagnostic groups and depressed mood as predictors of 22-month mortality in medical inpatients.Psychosomatic Medicine60570577
28 - A. Herva, P. Rasanen, J. Miettunen, M. Timonen, K. Laksy, J. Veijola, et al.2006Co-occurrence of metabolic syndrome with depression and anxiety in young adults: the Northern Finland 1966 Birth Cohort Study. Psychosomatic Medicine, 68213216
29 - C. W. Hoge, J. L. Auchterlonie, C. S. Milliken, 2006Mental health problems, use of mental health services, and attrition from military service after returning from deployment to Iraq or Afghanistan. Journal of the American Medical Association, 29510231032
30 - C. W. Hoge, C. A. Castro, S. C. Messer, D. Mc Gurk, D. I. Cotting, R. L. Koffman, 2004Combat duty in Iraq and Afghanistan, mental health problems, and barriers to care. New England Journal of Medicine, 3511322
31 - T. J. Holwerda, R. A. Schoevers, J. Dekker, D. J. Deeg, C. Jonker, A. T. Beekman, 2007The relationship between generalized anxiety disorder, depression and mortality in old age. International Journal of Geriatric Psychiatry, 22241249
32 - B. Isomaa, P. Almgren, T. Tuomi, B. Forsen, K. Lahti, M. Nissen, et al.2001Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care, 24683689
33 - J. R. Jennings, M. F. Muldoon, M. Hall, D. J. Buysse, S. B. Manuck, 2007Self-reported sleep quality is associated with the metabolic syndrome. Sleep, 30219223
34 - B. S. Jonas, P. Franks, D. D. Ingram, 1997Are symptoms of anxiety and depression risk factors for hypertension? Longitudinal evidence from the National Health and Nutrition Examination Survey I Epidemiologic Follow-up Study. Archives of Family Medicine, 64349
35 - R. C. Kessler, P. Berglund, O. Demler, R. Jin, K. R. Merikangas, E. E. Walters, 2005Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Archives of General Psychiatry, 62593602
36 - R. C. Kessler, W. T. Chiu, O. Demler, K. R. Merikangas, E. E. Walters, 2005Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Archives of General Psychiatry,, 62617627
37 - R. C. Kessler, Pont. R. L. Du, P. Berglund, H. U. Wittchen, 1999Impairment in pure and comorbid generalized anxiety disorder and major depression at 12 months in two national surveys. American Journal of Psychiatry, 15619151923
38 - L. S. Kinder, K. A. Bradley, W. J. Katon, E. Ludman, M. B. Mc Donell, C. L. Bryson, 2008Depression, posttraumatic stress disorder, and mortality. Psychosomatic Medicine, 70
39 - L. S. Kinder, M. R. Carnethon, L. P. Palaniappan, A. C. King, S. P. Fortmann, 2004Depression and the metabolic syndrome in young adults: findings from the Third National Health and Nutrition Examination Survey. Psychosomatic Medicine, 66316322
40 - H. Koponen, J. Jokelainen, S. Keinanen-Kiukaanniemi, E. Kumpusalo, M. Vanhala, 2008Metabolic syndrome predisposes to depressive symptoms: a population-based 7-year follow-up study. Journal of Clinical Psychiatry, 69178182
41 - H. M. Lakka, D. E. Laaksonen, T. A. Lakka, L. K. Niskanen, E. Kumpusalo, J. Tuomilehto, et al.2002The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. Journal of the American Medical Association, 28827092716
42 - D. Lane, D. Carroll, C. Ring, D. G. Beevers, G. Y. Lip, 2001Mortality and quality of life 12 months after myocardial infarction: effects of depression and anxiety. Psychosomatic Medicine, 63221230
43 - J. H. Markovitz, K. A. Matthews, W. B. Kannel, J. L. Cobb, R. B. D’Agostino, 1993Psychological predictors of hypertension in the Framingham Study. Is there tension in hypertension? Journal of the American Medical Association, 27024392443
44 - J. M. Mc Caffery, R. Niaura, J. F. Todaro, G. E. Swan, D. Carmelli, 2003Depressive symptoms and metabolic risk in adult male twins enrolled in the National Heart, Lung, and Blood Institute twin study. Psychosomatic Medicine, 65490497
45 - J. M. Murphy, R. R. Monson, D. C. Olivier, A. M. Sobol, A. H. Leighton, 1987Affective disorders and mortality. A general population study. Archives of General Psychiatry, 44473480
46 - D. L. Musselman, D. L. Evans, C. B. Nemeroff, 1998The relationship of depression to cardiovascular disease: epidemiology, biology, and treatment. Archives of General Psychiatry, 55580592
47 - D. A. O’Leary, A. S. Lee, 1996Seven year prognosis in depression. Mortality and readmission risk in the Nottingham ECT cohort. British Journal of Psychiatry, 169423429
48 - U. Osby, L. Brandt, N. Correia, A. Ekbom, P. Sparen, 2001Excess mortality in bipolar and unipolar disorder in Sweden. Archives of General Psychiatry, 58844850
49 - S. B. Patten, C. A. Beck, A. Kassam, J. V. Williams, C. Barbui, L. M. Metz, 2005Long-term medical conditions and major depression: strength of association for specific conditions in the general population. Canadian Journal of Psychiatry, 50195202
50 - S. B. Patten, J. V. Williams, D. H. Lavorato, N. R. Campbell, M. Eliasziw, T. S. Campbell, 2009Major depression as a risk factor for high blood pressure: epidemiologic evidence from a national longitudinal study. Psychosomatic Medicine, 71273279
51 - A. J. Pelle, Y. Y. Gidron, B. M. Szabo, J. Denollet, 2008Psychological predictors of prognosis in chronic heart failure. Journal of Cardiac Failure, 14341350
52 - M. Prince, V. Patel, S. Saxena, M. Maj, J. Maselko, M. R. Phillips, et al.2007No health without mental health. The Lancet, 370859877
53 - K. Raikkonen, K. A. Matthews, L. H. Kuller, 2002The relationship between psychological risk attributes and the metabolic syndrome in healthy women: antecedent or consequence? Metabolism, 5115731577
54 - K. Raikkonen, K. A. Matthews, L. H. Kuller, 2007Depressive symptoms and stressful life events predict metabolic syndrome among middle-aged women: a comparison of World Health Organization, Adult Treatment Panel III, and International Diabetes Foundation definitions. Diabetes Care, 30872877
55 - R. R. Reeves, J. D. Parker, D. J. Konkle-Parker, 2005War-related mental health problems of today’s veterans: new clinical awareness. Journal of Psychosocial Nursing and Mental Health Services, 431828
56 - J. H. Riskind, A. T. Beck, R. J. Berchick, G. Brown, R. A. Steer, 1987Reliability of DSM-III diagnoses for major depression and generalized anxiety disorder using the structured clinical interview for DSM-III. Archives of General Psychiatry, 44817820
57 - L. Robins, J. Helzer, L. Cottler, 1987Diagnostic Interview Schedule (version III-A) Training Manual. Veterans Administration, St Louis.
58 - R. Rugulies, 2002Depression as a predictor for coronary heart disease. a review and meta-analysis. American Journal of Preventative Medicine, 235161
59 - J. Sareen, B. J. Cox, T. O. Afifi, M. B. Stein, S. L. Belik, G. Meadows, et al.2007Combat and peacekeeping operations in relation to prevalence of mental disorders and perceived need for mental health care: findings from a large representative sample of military personnel. Archives of General Psychiatry, 64843852
60 - L. Sevincok, A. Buyukozturk, F. Dereboy, 2001Serum lipid concentrations in patients with comorbid generalized anxiety disorder and major depressive disorder. Canadian Journal of Psychiatry, 466871
61 - M. R. Skilton, P. Moulin, J. L. Terra, F. Bonnet, 2007Associations between anxiety, depression, and the metabolic syndrome. Biological Psychiatry, 6212511257
62 - T. M. Spruill, T. G. Pickering, J. E. Schwartz, E. Mostofsky, G. Ogedegbe, L. Clemow, et al.2007The impact of perceived hypertension status on anxiety and the white coat effect. Annals of Behavioral Medicine, 3419
63 - T. W. Strine, A. H. Mokdad, S. R. Dube, L. S. Balluz, O. Gonzalez, J. T. Berry, et al.2008The association of depression and anxiety with obesity and unhealthy behaviors among community-dwelling US adults. General Hospital Psychiatry, 30127137
64 - J. Suls, J. Bunde, 2005Anger, anxiety, and depression as risk factors for cardiovascular disease: the problems and implications of overlapping affective dispositions. Psychological Bulletin, 131260300
65 - P. G. Surtees, C. Barkley, 1994Future imperfect: the long-term outcome of depression. British Journal of Psychiatry, 164327341
66 - The Centers for Disease Control Vietnam Experience Study,1987Postservice mortality among Vietnam veterans. Journal of the American Medical Association, 257790795
67 - The Centers for Disease Control Vietnam Experience Study,1988aHealth status of Vietnam veterans. I. Psychosocial characteristics. Journal of the American Medical Association, 25927012707
68 - The Centers for Disease Control Vietnam Experience Study,1988bHealth status of Vietnam veterans. II. Physical Health. Journal of the American Medical Association, 25927082714
69 - F. Therrien, V. Drapeau, S. J. Lupien, S. Beaulieu, J. Dore, A. Tremblay, et al.2008Awakening cortisol response in relation to psychosocial profiles and eating behaviors. Physiology of Behavior, 93282288
70 - G. N. Thomas, C. M. Schooling, S. M. Mc Ghee, S. Y. Ho, B. M. Cheung, N. M. Wat, et al.2007Metabolic syndrome increases all-cause and vascular mortality: the Hong Kong Cardiovascular Risk Factor Study. Clinical Endocrinology, 66666671
71 - D. J. Torpy, N. Mullen, I. Ilias, L. K. Nieman, 2002Association of hypertension and hypokalemia with Cushing’s syndrome caused by ectopic ACTH secretion: a series of 58 cases. Annals of the New York Academy of Science, 970134144
72 - M. Trevisan, J. Liu, F. B. Bahsas, A. Menotti, 1998Syndrome X and mortality: a population-based study. Risk Factor and Life Expectancy Research Group. American Journal of Epidemiology, 148958 EOF66 EOF
73 - P. Tyrer, D. Baldwin, 2006Generalised anxiety disorder. The Lancet, 36821562166
74 - V. Vaccarino, C. Mc Clure, B. D. Johnson, D. S. Sheps, V. Bittner, T. Rutledge, et al.2008Depression, the metabolic syndrome and cardiovascular risk. Psychosomatic Medicine, 704048
75 - H. P. van Hout, A. T. Beekman, E. de Beurs, H. Comijs, H. van Marwijk, M. de Haan, et al.2004Anxiety and the risk of death in older men and women. British Journal of Psychiatry, 185399404
76 - T. Vogt, C. Pope, J. Mullooly, J. Hollis, 1994Mental health status as a predictor of morbidity and mortality: a 15-year follow-up of members of a health maintenance organization. American Journal of Public Health, 84227231
77 - M. M. Weissman, J. S. Markowitz, R. Ouellette, S. Greenwald, J. P. Kahn, 1990Panic disorder and cardiovascular/cerebrovascular problems: results from a community survey. American Journal of Psychiatry, 14715041508
78 - World Health Organisation,1992International Statistical Classification of Diseases and related health problems. WHO, Geneva.
79 - M. A. Whooley, C. M. Caska, B. E. Hendrickson, M. A. Rourke, J. Ho, S. Ali, 2007Depression and inflammation in patients with coronary heart disease: findings from the Heart and Soul Study. Biological Psychiatry, 62314320
80 - L. R. Wulsin, G. E. Vaillant, V. E. Wells, 1999A systematic review of the mortality of depression. Psychosomatic Medicine, 61617
81 - L. L. Yan, K. Liu, K. A. Matthews, M. L. Daviglus, T. F. Ferguson, C. I. Kiefe, 2003Psychosocial factors and risk of hypertension: the Coronary Artery Risk Development in Young Adults (CARDIA) study. Journal of the American Medical Association, 29021382148