International Journal of Psychiatry in Clinical Practice, 2005; 9(3): 157
/167

REVIEW ARTICLE

The relationship between depression and cardiovascular disease

STEPHEN MCCONNELL, FELICE N. JACKA, LANA J. WILLIAMS, SEETAL DODD & MICHAEL BERK Department of Clinical and Biomedical Sciences: Barwon Health, The University of Melbourne, Victoria, Australia

Abstract Evidence from epidemiological studies has established that depression is a risk factor for the development of cardiovascular disease (CVD) and that the comorbidity of depression with pre-existing CVD worsens the prognosis for sufferers of CVD. Depression has also been associated with other behaviours that impact on CVD, such as medication non-compliance, and an unwillingness to adopt an exercise program, that reduce the likelihood of successful rehabilitation from CVD. Published literature on the current knowledge of the association between depression and CVD is reviewed in this paper.

Key Words: Depression, cardiovascular, myocardial infarction

Introduction Cardiovascular disease (CVD) and depression are two of the most prevalent diseases in western society. CVD imposes the highest public health costs on the Australian healthcare system and in 1998 was the leading cause of death in Australia [1]. It is also the leading cause of disability worldwide [2]. The World Health Organisation projects that, by the year 2020, depression will remain a leading cause of disability, second only to cardiovascular disease, accounting for 11% of the world’s total disease burden [2]. Literature was reviewed after conducting a search of Medline using PubMed and a hand search of relevant literature. Prevalence of depression Epidemiological surveys have reported varying prevalence rates for depression, which may in part relate to different types of diagnostic tools being used. Furthermore, this discrepancy may be due to the diagnostic criteria for depression changing over time [3]. The Epidemiological Catchment Area (ECA) study reported major depressive disorder (MDD) 12-month prevalence rates of 1.7
/3.4% and lifetime estimates of 3.0
/5.9% [4]. The National Comorbidity Survey (NCS) found substantially higher MDD prevalence estimates of 8.6% for 12-month and 14.9% for lifetime [5], while the National Comorbidity Survey Replication study, published

in 2003, reported 12-month prevalence rates for MDD of 6.6% and a lifetime prevalence rate of 16.2% [6]. In Australia the ‘‘National Survey of Mental Health and Well-Being (NSMHWB)’’ (1997), demonstrated 12-month prevalence rates of depressive disorders to be 5.8% in the adult population [7]. CVD and women In the US, mortality attributable to CVD is now greater in women than men, with coronary artery disease (CAD) accounting for the majority of CVD deaths. CVD-related deaths outnumber the next seven causes of death in women, combined, and translate into approximately one death every minute [8]. Women are also twice as likely to die from coronary artery bypass surgery compared to men, and women less than 65 years of age are more than twice as likely to die from acute MI compared to similar aged men [9]. Despite such gender differences in CAD-related morbidity and mortality, clinical trials in CAD have tended to either underrepresent women or lack gender-specific reporting, which continues to ‘‘limit the available knowledge and evidence-based medicine needed to devise optimal managements for women with CAD’’ [10]. New research is starting to indicate that there are important gender-based differences in the pathophysiology, clinical presentation, diagnostic strategies,

Correspondence: Seetal Dodd, The University of Melbourne, Department of Clinical and Biomedical Sciences: Barwon Health, PO Box 281, Geelong 3220, Australia. Tel: /61 3 5226 7666; Fax: /61 3 5226 7436. E-mail: [email protected]

(Received 11 October 2004; accepted 20 March 2005) ISSN 1365-1501 print/ISSN 1471-1788 online # 2005 Taylor & Francis DOI: 10.1080/13651500510029138

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response to therapies and adverse outcomes in CAD, with ongoing exploration of these sex related differences being necessary to hopefully inform clinical interventions to improve outcomes in women [9]. Depression and CAD Depression frequently occurs in association with chronic medical conditions. An interaction between mind and body has been referred to for centuries in folklore and the arts, with well-known sayings such as ‘‘dying of a broken heart’’ alluding, in particular, to the relationship between emotions and the heart. One of the earliest scientific attempts to link excess mortality of people suffering depression compared to the general population (not including suicide) was by Malzberg in 1937. He compared the mortality rate of patients with ‘‘involutional melancholia’’ in the New York State civil hospital system and the rate in the general population of the state. He found that their age-adjusted mortality rate was approximately 6 times that of the general population, with 40% of these deaths due to ‘‘diseases of the heart’’ [11]. The study however confounded the influence of involutional melancholia with that of chronic institutionalisation. Post World War 2, in the era in which psychiatry was predominated by psychoanalytic and personality theories, most of the work relating heart disease to psychological states focused mainly on type A personality [12]. Ongoing studies have demonstrated mixed results, with some demonstrating positive associations between type A behaviour and coronary heart disease risk [13] and acute myocardial infarction (AMI) [14], and others reporting no correlation between type A behaviour and abnormalities in sympathetic or cardiovascular reactivity [15], myocardial infarction, or 10-year prognosis after myocardial infarction [16,17]. A meta-analysis of research in this area identified that null findings were due to range-restriction biases, where only diseased people were selected for study, self-report measures of type A behaviour, which were more likely to produce null findings, and finally the use of myocardial infarction as the disease criterion. This meta-analysis supported an association between type A behaviour, as assessed by structured clinical interview, and cardiovascular disease [18]. Depression and development of CAD Multiple prospective studies have demonstrated depression to be an independent risk factor for the development of CAD in patients (see Table I). Several large prospective or longitudinal studies demonstrated that patients with depression had a 1.7
/4.5 times increased risk of developing cardiovascular disease [19
/21]. These studies vary widely in the variety of assessment tools and types of

populations studied. Studies reporting relative risks of 2.0 or less have tended to assess depression via self-report questionnaires [19]. Studies reporting no relationship between depression and development of CAD have also used self-report depression questionnaires as opposed to structured interviews and clinical diagnoses [22]. The risk of developing CAD appears to also vary with the severity of depression. The highest risk is associated with major depression compared to subclinical symptoms of depression. Examples include Pratt et al. [21] who reported a relative risk (RR) of 4.5 for developing CAD among community residents with major depression, compared to a RR of 2.1 for those with a history of dysphoria, while Aromaa et al. [23] found an RR of 3.36 for major depression associated with onset of CAD. Studies also vary in looking at the temporal relationship between depression and onset of CAD. Prediction of CAD or cardiac mortality has been found with a history of major depression [21,24,25], current depression symptoms [20], and a diagnosis of clinical depression [21,23,26]. It is important to note that some of the early epidemiological and prospective studies did not control for pre-existing cardiovascular risk factors. A recent meta-analysis of the studies in this field estimated a combined overall relative risk of 1.64 for the contribution of depression to the onset of CAD [27]. Overall the studies show that even low levels of depressive symptoms are associated with an increased mortality risk after AMI [28]. Depression and impact on pre-existing CAD Over the last 20 years evidence has accumulated for the adverse impact of the presence of depression on patients with CAD, including those with a recent myocardial infarction (MI). Studies looking at prevalence of depression in patients with CAD initially reported figures from 18 to 60% [29
/33]. More recent studies have reported relatively consistent levels of depression in patients with CAD. Two studies which looked at patients undergoing diagnostic coronary angiography showed prevalence of major depression of 18% [34] and 17% [35], respectively. Hance [35] also found a similar rate for minor depression. Studies looking at patients after acute myocardial infarction (MI) have reported prevalence rates of depression ranging from 16 to 23% [36
/38]. In one study, 45% of patients post-MI were suffering minor and major depression, with 18% of them suffering major depression according to diagnostic criteria [36]. Carney [34] investigated depression in patients with coronary artery disease (CAD) and found that depression was not related to measures of more advanced CAD or associated with greater levels of disability. This is despite the occurrence of

Depression and CVD

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Table I. Depression and the development of CAD. Source

Sample

Study design

Depression Measure

Comment

Wassertheil-Smoller 93,676 females et al. [107]

Prospective cohort study of participants enrolled in the Women’s Health Initiative Observational Study (WHI-OS).

Centre for Epidemiological Studies Depression Scale

Depression was significantly related to risk factors for CVD, history of cardiovascular morbidity and was an independent predictor of CVD.

Cohen et al. [25]

Prospective cohort study of participants enrolled in a hypertension control program during 1981
/1994.

Self-reported

Self-reported depression was associated with myocardial infarction in treated hypertensive patients without prior cardiovascular disease.

Penninx et al. [108] 3701 participants

Prospective cohort study of cardiovascular events

Centre for Epidemiological Studies Depression Scale

Newly depressed (depressed at baseline but not at 3 and 6 years before baseline) older men, but not women, were approximately twice as likely to have a CVD event than those who were never depressed.

Sesso et al. [109]

1305 males

Prospective cohort study of participants in the Normative Aging Study.

Minnesota Multiphasic Personality Inventory (MMPI-2D) (MMPI2DEP) & Symptom Checklist-90 (SCL-90)

Depression measured by any of the three depression scales was associated with an increased risk of coronary heart disease (CHD).

Barefoot et al. [110] 409 males 321 females

Prospective study of residents from Copenhagen, Denmark born in 1914

Minnesota Multiphasic Personality Inventory (MMPI)

At the 27 year follow-up,  / depressive scores were associated with  / risks for Acute Myocardial Infarction (AMI) and early mortality.

Pratt et al. [21]

1551 participants

A prospective study of partici- National Institute of A history of depression was assopants in the Baltimore ECA Mental Health Diagnostic ciated with odds of MI more than Follow-up Study Interview 4 times higher than that among individuals with no history.

Aromaa et al. [23]

5355 participants

Prospective study of participants in the Mini-Finland Health Survey

Present State Exam & General Health Questionnaire

At the 6 year follow-up, the risk of mortality was  / in those with depression, independent of whether cardiovascular disease was present or not at entry of the study.

Anda et al. [20]

2832 participants

Prospective study of participants in the National Health Examination Follow-up Study

General Well-Being Schedule

Depressed affect and hopelessness was associated with  / risk of nonfatal ischemic heart disease (IHD)

3541 males 2023 females

depression in other medical illnesses usually being significantly associated with severity of the physical illness. A review by Rudisch [39] cites studies that have found degree of functional impairment post-MI and overall medical burden to be predictive of depression in cardiac patients. Depression and its relationship to CAD has been most extensively studied in patients who have suffered acute myocardial infarction (MI). Patients who have suffered a recent MI and are depressed have an approximate two- to four-fold risk of mortality compared to non-depressed patients [28,37,38]. All these studies remained positive for risk of mortality post-MI, conferred by depression, after adjustment for medical and demographic risk factors. One of the earlier and arguably most influential research in this area was by Frasure-Smith et al. [37]. In this study of 222 patients post-MI,

participants with major depression, diagnosed via a modified version of the Diagnostic Interview Scale (DIS), were followed over the course of 6 months. An adjusted hazard ratio of 3.44 (95% CI 2.25
/ 4.63) for mortality was found for patients with major depression, compared to controls, which was approximately equivalent to risk caused by negative prognostic clinical factors such as diminished left ventricular function and past history of MI. The authors subsequently followed up the impact of depression in this cohort over 18 months [38]. It found that although baseline major depression still predicted mortality at 18 months, its impact occurred mainly in the first 6 months. The Beck Depression Inventory (BDI) had also been used in the study, and in contrast to the DIS, the impact of raised baseline BDI scores (]/10, the point usually used to distinguish mild to moderate depression

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Table II. Depression and impact on pre-existing CAD. Source

Sample

Study design

Depression Measure

Comment

Blumenthal et al. [48]

817 participants

Prospective study of cardiac events after coronary artery bypass graft (CABG) surgery

Centre for Results indicated that moderate to Epidemiological severe depression before surgery and Studies Depression Scale persistent depression increases risk of (CES-D) mortality.

Burg et al. [49]

89 participants

Prospective study investigating CABG.

Beck depression inventory (BDI)

Depressive symptoms before CABG surgery appeared to be a contributor to long-term mortality

Lesperance et al. [45]

896 participants

Follow up study of post-MI patients

BDI

Depression symptomatology during admission for MI is more closely linked to long-term survival than the level at 1 year

Bush et al. [28]

158 males 113 females

Prospective study of patients with acute myocardial infarction (AMI) during 1995
/1996.

Structured Clinical An  / mortality rate was observed in Interview for DSM III-R patients with severe depression and observed at very low (not clinically (SCID-NP) & BDI significant) levels of depression.

Connerney et al. [47]

207 males 102 females

Prospective study looking at the effect of depression on outcomes after coronary artery bypass graft (CABG) surgery.

US National Institute of Mental Health diagnostic interview schedule (DSM IV) & BDI

After CABG surgery, depression is a risk factor for future cardiac events.

Lesperance et al. [46]

430 participants

Prospective study investigating the impact of depression following hospitalisation for unstable angina during 1994
/1996

BDI

Depression was associated with an  / risk of cardiac events during the following year.

Barefoot et al. [111]

1250 males

Prospective study of patients with coronary artery disease

Zung Self-Rating Depression Scale (SDS)

Depression may be persistent or frequently recurrent in CAD patients and is associated with mortality.

Hance et al. [35]

200 participants

Prospective study of patients with coronary heart disease

Psychiatric diagnostic interviews

Major and minor depression is common and rather persistent in patients with coronary heart disease.

Lesperance et al. [42]

222 participants

Prospective study of patients with AMI

DIS & BDI

Depression whilst patients were hospitalised for AMI was associated with an  / risk of mortality over 18 months.

Frasure-Smith et al. [38] 222 participants

Follow up study examining the impact of depression on MI patients over 18 months

National Institute of Mental Health Diagnostic Interview Schedule (DIS) & BDI

A significant predictor of 18-month mortality was depression whilst hospitalised with MI.

Frasure-Smith et al. [37] 222 participants

Prospective evaluation of the impact of depression on myocardial infarction (MI) patients

National Institute of Mental Health Diagnostic Interview Schedule (DIS)

Major depression in patients hospitalised following MI is an independent risk factor for mortality at 6 months.

Schleifer et al. [36]

283 participants

Prospective study of patients admitted to cardiac care units for myocardial infarction

Schedule for Affective Disorders and Schizophrenia (SADS)

Initially, a large portion of the sample (45%) met diagnostic criteria for major or minor depression and 33% did 3
/4 months later.

Carney et al. [34]

50 participants

Cross sectional study of patients with coronary artery disease (CAD)

Psychiatric diagnostic interviews based on DSM-III criteria & BDI

Depression was not related to the extent or degree of CAD

from normal) remained over the whole 18 months. The BDI identified a number of patients at baseline who did not meet DSM-III-R symptoms criteria for major depression but who died later in the year. The authors hypothesised that subsyndromally elevated BDI scores may predict later post-discharge development of major depression in those who died.

Other authors and studies have looked at the question of whether the presence of some subclinical depressive symptoms directly increases the risk of mortality. Subsyndromal depression often precedes the development of minor and major depression [40]. In a study by Hance [35], 42% of the cardiac patients with minor depression developed major

Depression and CVD depression over the following 12 months. Subsyndromal depression has also been regarded by some authors [41] as being a temporal variant of major depression, with many individuals moving between syndromal and subsyndromal depression over time. Similar results were found by Lesperance et al. [42] who conducted one of the few studies evaluating the occurrence of major depression both before and during the year after an MI. They found that 41% who were found to only suffer major depression in the follow-up period (post discharge) had BDI scores ]/10 at baseline. This study also found that a past history of major depression influenced both post-MI depression and mortality. The MI patients with a past history of depression were not only more likely to become depressed while in hospital and post-discharge, but also to have more severe depression according to BDI scores. Another study by these authors demonstrated that major depression, depressive symptoms, anxiety, and history of major depression all significantly predicted cardiac events, independently of each other [43]. Bush et al. [28] demonstrated that the presence of subclinical depressive symptoms was associated with increased mortality following an AMI, suggesting that subsyndromal symptoms should be added to the group of potentially modifiable post-MI risk factors. While even a few symptoms of depression may, therefore, increase the risk of death there does appear to be a ‘‘dose
/response’’ relationship between depression and the risk of death, as studies have demonstrated that relative risks tend to be higher for major depression than for subsyndromal depressive symptoms. In one study an increasing risk of 15-year cardiac mortality was associated with increasing baseline depression symptoms in cardiac catheterisation patients [44] and another study found 4-month post-MI mortality was related to increasing severity of in-hospital depression scores [28]. In a recent 5-year follow-up of MI patients assessed for depression during admission and 1 year later [45], a significant dose
/response relationship was found between depression and death, particularly over the longer term. An improvement in depressive symptoms was also associated with less cardiac mortality only in patients with mild depression, while patients with higher initial scores had worse long-term prognosis irrespective of symptom changes. While there is now considerable evidence to demonstrate a relationship between depression and cardiac events post-MI, there has been only one study published regarding the effects of depression on patients with unstable angina [46]. In this study, 41.4% of the 430 patients admitted to hospital for unstable angina had depression (BDI]/10) and 15.1% had major depression, as measured by the DIS. These depressed patients, compared to non-depressed patients, had a higher rate of

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mortality or nonfatal MI during the course of the next year, with an adjusted odds ratio of 6.73. There is also a less rigorous study of depression in coronary artery bypass graft (CABG) patients. Connerney et al. [47] interviewed 309 patients 4
/ 10 days after surgery and found 20% to have major depression, as measured by the DIS. These patients were then monitored over the next 12 months. Results demonstrated that major depression was an independent risk factor for coronary events with a relative risk of 2.3, but that these patients were not at higher risk of death within the first year post-CABG. Blumenthal [48] measured depression in 817 patients undergoing CABG using the Centre for Epidemiological Studies Depression Scale (CES-D). These patients were assessed before surgery, at 6 months after CABG, and then followed-up for 12 months. After controlling for age, sex, number of grafts, diabetes, smoking, left ventricular ejection fraction and previous MI, patients with moderate to severe depression at baseline and mild or moderate to severe depression persisting from baseline to 6 months had higher rates of death compared to non-depressed patients. In another recent study of 89 veterans, the presence of depression prior to CABG was an independent predictor of 2-year cardiovascular mortality post-CABG [49]. Considering the more limited findings in the above two populations, further study is needed to confirm the importance of the impact of depression on prognosis in unstable angina and post-coronary artery bypass surgery. Mechanisms of Interaction While there is increasing evidence for a link between depression, heart disease and an associated increase in cardiac morbidity and mortality, the mechanisms that underlie this relationship remain unclear. However, while the study of depression and its interaction with cardiovascular disease is complex, there are a number of possible behavioural and pathophysiological mechanisms. Depression may affect a person’s behaviour, which could in turn affect the development and course of CVD by encouraging nonadherence to cardiac prevention and treatment regimes, or by influencing other cardiovascular risk factors such as smoking, hypertension or diabetes. Physiological mechanisms proposed include depression being associated with cardiac rhythm disturbances, increased platelet aggregation, inflammatory processes and hypothalamic
/pituitary
/adrenocortical axis (HPA) and sympathoadrenal (SA) hyperactivity [82]. Depression and health-related behaviour Depression is a risk factor for non-compliance in many medical conditions. A recent meta-analysis

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demonstrated that patients suffering depression are 3 times as likely to be non-compliant with medical treatment regimes compared to non-depressed patients [50]. Patients who do not adhere well to their prescribed medical treatment regimes are almost 3 times as likely to die in the first year of follow-up post-MI, than those considered compliant [51,52]. Patients who are depressed are also less likely to follow advice to adopt an exercise program following an acute coronary event [53]. Numerous prospective observational studies have reported that more physically fit people have a substantially lower risk of CAD/ CVD and all-cause mortality compared to less active counterparts [54
/56]. The exercise component of cardiac rehabilitation also reduces mortality [57]. The effect of exercise on depression has also been the subject of research, with past meta-analyses demonstrating the benefit of exercise in depression [58,59]. However, these meta-analyses pooled data from a range of study types that included uncontrolled studies and non-randomised controlled trials. Lawlor et al. [60] performed a systematic review of randomised controlled trials looking at the effectiveness of exercise as an intervention in the management of depression. They found its effectiveness could not be determined because of a lack of good quality research on clinical populations with adequate follow-up. Patients with depression have a greater dropout rate from cardiac rehabilitation programs post-MI [61,62] and demonstrate poor adherence to aspirin therapy for secondary prevention of CAD [63]. Patients with baseline depression after acute-MI also admit to being less likely to be following recommendations to reduce cardiac risk 4 months after discharge from hospital when compared to nondepressed patients [64].

Biological factors implicated in the relationship between depression and CAD HPA and sympathoadrenal (SA) hyperactivity Evidence of HPA hyperactivity in medication-free patients with major depression, leading to elevated cortisol, has been consistently shown by many studies [65]. Elevated cortisol contributes to the development of atherosclerosis by inducing hypercholesterolemia, hypertriglyceridemia and hypertension [65], endothelial dysfunction [66], injury to vascular endothelial cells and intima, and inhibition of healing [65]. Many patients with depression also exhibit SA hyperactivity, leading to elevated plasma norepinephrine (NE) and a hypersecretory catecholamine response to orthostatic challenge [67,68]. The increase in catecholamines may contribute to development of CVD via effects on cardiac function such as increased resting heart rate [69], impaired platelet

function and vascular homeostasis [70,71]. It is important to note, however, that elevated cortisol is more common in patients with major depression, particularly of the melancholic subtype [72], which is often a more severe subtype of depression [73]. Epidemiological studies demonstrate that even subclinical depressive symptoms are associated with increased mortality after AMI [28], which may be indicative of a minimal role for HPA overactivity in the mooted association between depression and CVD. Cardiac rhythm disturbances Patients with depression have been shown to have reduced heart rate variability (HRV) [74
/77], which may be related to poor prognosis and sudden cardiac death in patients with CVD [78,79]. HRV is the standard deviation of successive R-to-R intervals in normal sinus rhythm, which is associated with the interaction between and balance of sympathetic and parasympathetic input on the cardiac pacemaker [80]. A high level of HRV is present in individuals with good cardiac function [75,80]. Patients with CAD who are depressed have been shown to be significantly more likely to have episodes of ventricular tachycardia measured by 24-hour halter monitor compared to non-depressed patients [81]. Depression has also been associated with excessive premature ventricular complexes (PVC) (]/10 per hour) in patients followed for 18 months post-MI. Excess PVCs are a powerful predictor of mortality [38]. The decreased HRV and high risk of fatal arrhythmias seen in depressed post-MI patients may be explained by the combination of decreased parasympathetic control and increased sympathetic stimulation [82]. Altered platelet function Depression may exert its negative influence on CVD by influencing platelet function. Platelet aggregation itself has been clearly found to have an important role in the pathogenesis of atherosclerosis [82,83]. Depression has been found, in a number of studies, to be associated with heightened platelet activation [84
/88]. However, Maes [84] found no abnormality in platelet activation in response to ADP or collagen in depressed patients. Platelet aggregation and coronary vasoconstriction may also be induced by serotonin, secreted by platelets, which is mediated via platelet 5-HT2 receptors [65]. Platelet 5-HT2 receptor binding density may be increased in depressed patients [85
/89]. In these studies 5-HT2 binding-site density decreased in patients with improvement in depression, suggesting a state-dependent change in receptor function. Severity of depression also may be

Depression and CVD important, with platelet hyperactivity only being measured in MDD and not in subsyndromal depression [85]. Decreased platelet serotonin transporter sites have also been detected in depressed patients [86,87]. Therefore more serotonin could be exposed to the increased numbers of platelet 5-HT2 receptors, thereby potentially enhancing platelet aggregation [88]. Studies have shown that the selective serotonin reuptake inhibitors (SSRIs) paroxetine and sertraline reduce platelet activation in depressed patients [89
/ 91]. More recently, findings from the Sertraline antiDepressant Heart Attack Randomised Trial (SADHART) showed that depressed, post
/acute coronary syndrome patients being treated with sertraline had reduced platelet/endothelial activation despite widespread anti-platelet treatments such as aspirin and clopidogrel [92]. The ability of the SSRIs to decrease platelet activation does not appear to be associated with the antidepressant effect of the medication, and furthermore, non-SSRI antidepressants do not appear to immediately normalise increased platelet activity despite being effective in resolving depression [80]. Inflammation Inflammation mediated by proinflammatory cytokines such as tissue necrosis factor (TNF), interleukin (IL)-1 and IL-6 have been implicated in the pathogenesis of atherosclerosis and CAD [93]. Elevated plasma levels of inflammatory markers have been demonstrated in depressed patients with and without CVD [94
/98]. Depression may contribute to CAD by enhancing inflammatory responses to endothelial damage and subsequent accelerated progression of atherosclerosis and plaque rupture [82,94]. Overall there is mounting evidence that inflammation could be one of the major pathways linking depression to the development of CAD. However, there is literature demonstrating that inflammation causes depression, so the possibility that an inflammatory process mediates the onset of both depression and CAD cannot be completely ruled out [82]. Treatment of depression in patients with CAD When considering treating depression in patients with CVD, the clinician is mainly interested in whether the chosen treatment is safe and whether it will be effective in patients with heart disease. Furthermore, it needs to be considered whether the treatment of depression contributes to reducing the risk of the development of CAD, and an associated reduction in morbidity/mortality, in patients with established CAD. Regarding the issue of effectiveness, tricyclic antidepressants (TCAs) and SSRIs have been shown in open or comparator trials to be effective in patients

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with CAD [80]. However, with respect to safety, the TCAs have been shown to have adverse cardiovascular effects with associated increased risk of cardiac morbidity and mortality, especially in overdose [97]. In regards to safety of the SSRIs in CAD, fluoxetine was shown to be safe in a small sample of depressed elderly patients with cardiac disease [98]. Paroxetine was compared to nortriptyline in depressed patients with CAD. Both treatments were equally effective but paroxetine was better tolerated and less likely to produce cardiovascular side effects [99]. The largest study of antidepressant treatment in patients with CAD is the SADHART study (Sertraline Antidepressant Heart Attack Randomized Trial) [100]. This international, multi-site study was the first double blind, randomised, placebo-controlled trial looking at the safety and efficacy of sertraline treatment of major depressive disorder in patients hospitalised for acute MI or unstable angina. There was no difference in follow-up depression scores on the HAM-D in patients with no past history of depression, when comparing sertraline to placebo. In contrast, when looking at patients with a past history of recurrent depression, the sertraline group had significant improvements in depression scores, when compared to the placebo group. There were also 23% fewer life-threatening adverse events in the sertraline group, but this was not statistically significant. Importantly, there was no significant difference in mortality-reduction, although the total number of deaths was very small (two in sertraline group versus five in the placebo group). There have been very limited or no specific studies examining the use of other antidepressants, such as buproprion and venlafaxine, in patients with CAD. The findings of the Myocardial Infarction and Depression-Intervention Trial (MIND-IT) looking at whether mirtazapine can improve cardiac prognosis in depressed patients post-MI has not yet been published [101]. In summary, SSRIs appear to be a safe and effective choice when considering antidepressant therapy for depression in CAD, although to date the SADHART study is the only published placebocontrolled trial in this area. As yet, the clinical treatment of depression has not yet been clearly shown to improve cardiac morbidity and mortality in patients with CAD, or reduce the incidence of CAD. Well-designed studies are needed in this area. Several small clinical trials have found that cognitive-behavioural therapy (CBT) improves anxiety and depression in patients with CAD, thereby aiding in the modification of cardiac risk factors [24,102
/ 104]. In the large ENRICHD (Enhancing Recovery in Coronary Heart Disease) randomised controlled clinical trial, 2481 patients with evidence of depression after MI were either given CBT (supplemented with sertraline where indicated) or usual care. The primary aim of ENRICHD was to assess whether

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treatment of depression (and low perceived social support) with CBT reduced mortality and morbidity. The results showed no benefit on the primary aim and modest improvement on depression and social support compared to usual care (which also showed substantial improvement) [105]. More welldesigned studies studying psychological interventions for depression in CAD are also needed. It is evident from the studies reviewed here that depression plays an important role in the development of CAD and the negative outcomes for patients post-MI. Furthermore, there is a clear relationship between depression and other cardiovascular risk factors. Much further research still remains to be conducted. In particular, as already discussed above, women may have specific differences in most aspects of CVD that need to be further explored. One recent review article concluded that the study of psychosocial factors in women with CVD is an important area of research still to be undertaken in the prevention and treatment of CVD [106]. With respect to the relationship between depression and cardiovascular risk factors such as obesity, there are either minimal studies and/or mixed results. More comprehensive studies that investigate the direct role of depression on CVD as well as the interplay between depression and other risk factors for CVD are warranted. Key points . Depression is an independent risk factor for CVD . Comorbid depression worsens patient outcomes in CVD . CVD patients with depression are less likely to adhere to rehabilitation and medication programs for CVD . Clinicians must be vigilant to check for and treat depression in CVD patients

be eliminated from the DSM-V. Arch Gen Psychiatry 2003; 60:1117
/22. Robins LN, Reiger DA, editors. Psychiatric disorders in America: The Epidemiologic Catchment Area Study. New York: Free Press; 1991. Kessler RC, McGonagle KA, Zhao S, Nelson CB, Hughes M, Eshleman S, Witchen HU, Kendler KS. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey. Arch Gen Psychiatry 1994;51:8
/19. Kessler RC, Berglund P, Demler O, Jin R, Koretz D, Merikangas KR, et al. The epidemiology of major depressive disorder: Results from the National Comorbidity Survey Replication (NCS-R). J Am Med Assoc 2003;289: 3095
/105. Henderson S, Andrews G, Hall W. Australia’s mental health: an overview of the general population survey. Aust NZ J Psychiatry 2000;34:197
/205. Mosca L, Appel LJ, Benjamin EJ, Berra K, ChandraStrobos N, Fabuoni RP, et al. Evidence-based guidelines for cardiovascular disease prevention in women. Circulation 2004;109:672
/93. Wenger NK. You’ve come a long way, baby. Cardiovascular health and disease in women. Problems and prospects. Circulation 2004;109:558
/60. Wenger NK. Coronary heart disease: The female heart is vulnerable. Prog Cardiovasc Dis 2003;46:199
/229. Malzberg B. Mortality among patients with involutional melancholia. Am J Psychiatry 1937;93:1231
/8. Glassman AH, Shapiro PA. Depression and the course of coronary artery disease. Am J Psychiatry 1998;155:4
/11. Hendrix WH, Hughes RL. Relationship of trait, Type A behavior, and physical fitness variables to cardiovascular reactivity and coronary heart disease risk potential. Am J Health Promot 1997;11:264
/71. Coelho R, Ramos E, Prata J, Maciel MJ, Barros H. Acute myocardial infarction: Psychosocial and cardiovascular risk factors in men. J Cardiovasc Risk 1999;6:157
/62. Schroeder KE, Markiewicz K, Kato M, Pesek C, Phillips B, Davidson D, et al. Personality type and neural circulatory control. Hypertension 2000;36:830
/3. Welin CL, Rosengren A, Wilhelmsen LW. Behavioural characteristics in patients with myocardial infarction: a case-control study. J Cardiovasc Risk 1995;2:247
/54. Welin C, Lappas G, Wilhelmsen L. Independent importance of psychosocial factors for prognosis after myocardial infarction. J Intern Med 2000;247:629
/39. Miller TQ, Turner CW, Tindale RS, Posavac EJ, Dugoni BL. Reasons for the trend toward null findings in research on Type A behavior. Psychol Bull 1991;110:469
/85. Barefoot JC, Schroll M. Symptoms of depression, acute myocardial infarction, and total mortality in a community sample. Circulation 1996;93:1976
/80. Anda R, Williamson D, Jones D, Macera C, Eaker E, Glassman A, et al. Depressed affect, hopelessness, and the risk of ischemic heart disease in a cohort of U.S. adults. Epidemiology 1993;4:285
/94. Pratt LA, Ford DE, Crum RM, Armenian HK, Gallo JJ, Eaton WW. Depression, psychotropic medication, and risk of myocardial infarction. Prospective data from the Baltimore ECA follow-up. Circulation 1996;94:3123
/9. Vogt T, Pope C, Mullooly J, Hollis J. Mental health status as a predictor of morbidity and mortality: A 15-year followup of members of a health maintenance organization. Am J Public Health 1994;84:227
/31. Aromaa A, Raitasalo R, Reunanen A, Impivaara O, Heliovaara M, Knekt P, et al. Depression and cardiovascular diseases. Acta Psychiatr Scand Suppl 1994;377:77
/ 82. Enhancing Recovery in Coronary Heart Disease (ENRICHD) study intervention: Rationale and design. Psychosom Med 2001;63:747
/755. /

/

[4]

[5]

/

[6]

/

/

[7]

/

[8]

/

[9]

/

/

/

[10]

/

/

[11]

/

[12]

/

/

/

[13]

/

[14]

/

[16]

/

/

/

[17]

/

[18]

[19]

The authors have no conflict of interest with any commercial or other associations in connection with the submitted article.

[20]

/

/

[21]

References [1] Australian Institute Of Health And Welfare. Cardiovascular Disease, www.aihw.gov.au/publications/cvd. [2] Murray CJL, Lopez AD, Harvard School of Public Health, World Health Organization, World Bank. The global burden of disease: A comprehensive assessment of mortality and disability from diseases, injuries, and risk factors in 1990 and projected to 2020: Summary (Published by the Harvard School of Public Health on behalf of the World Health Organization and the World Bank; Distributed by Harvard University Press, Cambridge, MA, 1996). [3] Kessler RC, Merikangas KR, Berglund P, Eaton WW, Koretz DS, Walters EE, et al. Mild disorders should not

/

/

[23]

/

/

/

[22]

/

/

/

Statement of interest

/

/

/

[15]

/

/

/

[24]

/

/

Depression and CVD [25] Cohen HW, Madhavan S, Alderman MH. History of treatment for depression: Risk factor for myocardial infarction in hypertensive patients. Psychosom Med 2001;63: 203
/9. [26] Ford DE, Mead LA, Chang PP, Cooper-Patrick L, Wang NY, Klag MJ. Depression is a risk factor for coronary artery disease in men: The precursors study. Arch Intern Med 1998;158:1422
/6. [27] Wulsin LR, Singal BM. Do depressive symptoms increase the risk for the onset of coronary disease? A systematic quantitative review. Psychosom Med 2003;65:201
/10. [28] Bush DE, Ziegelstein RC, Tayback M, Richter D, Stevens S, Zahalsky H, Fauerbach JA. Even minimal symptoms of depression increase mortality risk after acute myocardial infarction. Am J Cardiol 2001;88:337
/41. [29] Cay EL, Vetter N, Philip AE, Dugard P. Psychological status during recovery from an acute heart attack. J Psychosom Res 1972;16:425
/35. [30] Hackett TP, Cassem NH, Wishnie HA. The coronary-care unit. An appraisal of its psychologic hazards. New Engl J Med 1968;279:1365
/70. [31] Kurosawa H, Shimizu Y, Nishimatsu Y, Hirose S, Takano T. The relationship between mental disorders and physical severities in patients with acute myocardial infarction. Jpn Circ J 1983;47:723
/8. [32] Wynn A. Unwarranted emotional distress in men with ischaemic heart disease (IHD). Med J Aust 1967;2:847
/51. [33] Stern JJ, Pascale L, Ackerman A. Life adjustment post myocardial infarction: determine predictive variables. Arch Intern Med 1977;137:1680
/5. [34] Carney RM, Rach MW, Tevelde A, Saini J, Clark K, Jaffe AS. Major depressive disorder in coronary artery disease. Am J Cardiol 1987;60:1273
/5. [35] Hance M, Carney RM, Freedland KE, Skala J. Depression in patients with coronary heart disease. A 12-month followup. Gen Hosp Psychiatry 1996;18:61
/5. [36] Schleifer SJ, Macari-Hinson MM, Coyle DA, Slater WR, Kahn M, Gorlin R, et al. The nature and course of depression following myocardial infarction. Arch Intern Med 1989;149:1785
/9. [37] Frasure-Smith N, Lesperance F, Talajic M. Depression following myocardial infarction. Impact on 6-month survival. J Am Med Assoc 1993;270:1819
/25. [38] Frasure-Smith N, Lesperance F, Talajic M. Depression and 18-month prognosis after myocardial infarction. Circulation 1995;91:999
/1005. [39] Rudisch B, Nemeroff CB. Epidemiology of comorbid coronary artery disease and depression. Biol Psychiatry 2003;54:227
/40. [40] Judd LL, Akiskal HS, Paulus MP. The role and clinical significance of subsyndromal depressive symptoms (SSD) in unipolar major depressive disorder. J Affect Disord 1997;45:5
/17; discussion 17
/18. [41] Judd LL, Schettler PJ, Akiskal HS. The prevalence, clinical relevance, and public health significance of subthreshold depressions. Psychiatr Clin North Am 2002;25:685
/98. [42] Lesperance F, Frasure-Smith N, Talajic M. Major depression before and after myocardial infarction: Its nature and consequences. Psychosom Med 1996;58:99
/110. [43] Frasure-Smith N, Lesperance F, Talajic M. The impact of negative emotions on prognosis following myocardial infarction: Is it more than depression? Health Psychol 1995; 14:388
/98. [44] Barefoot JC, Helms MJ, Mark DB, Blumenthal JA, Claiff RM, Haney TL, et al. Depression and long-term mortality risk in patients with coronary artery disease. Am J Cardiol 1996;78:613
/7. [45] Lesperance F, Frasure-Smith N, Talajic M, Bourassa MG. Five-year risk of cardiac mortality in relation to initial severity and one-year changes in depression symptoms after myocardial infarction. Circulation 2002;105:1049
/53. /

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

165

[46] Lesperance F, Frasure-Smith N, Juneau M, Theroux P. Depression and 1-year prognosis in unstable angina. Arch Intern Med 2000;160:1354
/60. [47] Connerney I, Shapiro PA, McLaughlin JS, Bagiella E, Sloan RP. Relation between depression after coronary artery bypass surgery and 12-month outcome: A prospective study. Lancet 2001;358:1766
/71. [48] Blumenthal JA, Lett HS, Babyak MA, White W, Smith PK, Mark DB, et al. Depression as a risk factor for mortality after coronary artery bypass surgery. Lancet 2003;362: 604
/9. [49] Burg MM, Benedetto MC, Soufer R. Depressive symptoms and mortality two years after coronary artery bypass graft surgery (CABG) in men. Psychosom Med 2003;65:508
/10. [50] DiMatteo MR, Lepper HS, Croghan TW. Depression is a risk factor for noncompliance with medical treatment: Meta-analysis of the effects of anxiety and depression on patient adherence. Arch Intern Med 2000;160:2101
/7. [51] Gallagher EJ, Viscoli CM, Horwitz RI. The relationship of treatment adherence to the risk of death after myocardial infarction in women. J Am Med Assoc 1993;270:742
/4. [52] Horwitz RI, Viscoli CM, Berkman L, Donaldson RM, Horwitz SM, Murray CJ, et al. Treatment adherence and risk of death after a myocardial infarction. Lancet 1990; 336:542
/5. [53] Guiry E, Conroy RM, Hickey N, Mulcahy R. Psychological response to an acute coronary event and its effect on subsequent rehabilitation and lifestyle change. Clin Cardiol 1987;10:256
/60. [54] Manson JE, Greenland P, LaCroix AZ, Stefanick ML, Mouton CP, Oberman A, et al. Walking compared with vigorous exercise for the prevention of cardiovascular events in women. New Engl J Med 2002;347:716
/25. [55] Myers J, Prakash PS, Froelicher V, Do D, Partington S, Atwood JE. Exercise capacity and mortality among men referred for exercise testing. New Engl J Med 2002;346: 793
/801. [56] Tanasescu M, et al. Exercise type and intensity in relation to coronary heart disease in men. J Am Med Assoc 2002;288: 1994
/2000. [57] Oldridge NB, Guyatt GH, Fischer ME, Rimm AA. Cardiac rehabilitation after myocardial infarction. Combined experience of randomized clinical trials. J Am Med Assoc 1988;260:945
/50. [58] Craft LL, Landers DM. The effects of exercise on clinical depression and depression resulting from mental illness: A meta-regression analysis. J Sport Exerc Psychol 1998;20: 339
/57. [59] North TC, McCullagh P, Tran ZV. Effect of exercise on depression. Exerc Sport Sci Rev 1990;18:379
/415. [60] Lawlor DA, Hopker SW. The effectiveness of exercise as an intervention in the management of depression: Systematic review and meta-regression analysis of randomised controlled trials. Br Med J 2001;322:763
/7. [61] Blumenthal JA, Williams RS, Wallace AG, Williams RB Jr, Needles TL. Physiological and psychological variables predict compliance to prescribed exercise therapy in patients recovering from myocardial infarction. Psychosom Med 1982;44:519
/27. [62] Glazer KM, Emery CF, Frid DJ, Banyasz RE. Psychological predictors of adherence and outcomes among patients in cardiac rehabilitation. J Cardiopulm Rehabil 2002;22: 40
/6. [63] Carney RM, Freedland KE, Eisen SA, Rich MW, Jaffe AS. Major depression and medication adherence in elderly patients with coronary artery disease. Health Psychol 1995;14:88
/90. [64] Ziegelstein RC, Fauerbach JA, Stevens SS, Romanelli J, Richter DP, Bush DE. Patients with depression are less likely to follow recommendations to reduce cardiac risk during recovery from a myocardial infarction. Arch Intern Med 2000;160:1818
/23. /

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

166

S. McConnell et al.

[65] Musselman DL, Evans DL, Nemeroff CB. The relationship of depression to cardiovascular disease: Epidemiology, biology, and treatment. Arch Gen Psychiatry 1998;55: 580
/92. [66] Rajagopalan S, Brook R, Rubenfire M, Pitt E, Young E, Pitt B. Abnormal brachial artery flow-mediated vasodilation in young adults with major depression. Am J Cardiol 2001;88: 196
/8 (A7). [67] Gold PW, Gabry KE, Yasuda MR, Chrousos GP. Divergent endocrine abnormalities in melancholic and atypical depression: Clinical and pathophysiologic implications. Endocrinol Metab Clin North Am 2002:31:37
/62, vi. [68] Maas JW, Katz MM, Koslow SH, Swann A, Davis JM, Berman N, et al. Adrenomedullary function in depressed patients. J Psychiatr Res 1994;28:357
/67. [69] Lechin F, van der Dijs B, Orozco B, Lechin ME, Baez S, Lechin AE, et al. Plasma neurotransmitters, blood pressure, and heart rate during supine-resting, orthostasis, and moderate exercise conditions in major depressed patients. Biol Psychiatry 1995;38:166
/73. [70] Anfossi G, Trovati M. Role of catecholamines in platelet function: Pathophysiological and clinical significance. Eur J Clin Invest 1996;26:353
/70. [71] Gerritsen ME. Physiological and pathophysiological roles of eicosanoids in the microcirculation. Cardiovasc Res 1996;32:720
/32. [72] Gold PW, Chrousos GP. Clinical studies with corticotropin releasing factor: Implications for the diagnosis and pathophysiology of depression, Cushing’s disease, and adrenal insufficiency. Psychoneuroendocrinology 1985;10:401
/19. [73] Schotte CK, Maes M, Cluydts R, Cosyns P. Cluster analytic validation of the DSM melancholic depression. The threshold model: Integration of quantitative and qualitative distinctions between unipolar depressive subtypes. Psychiatry Res 1997;71:181
/95. [74] Agelink MW, Boz C, Ullrich H, Andrich J. Relationship between major depression and heart rate variability. Clinical consequences and implications for antidepressive treatment. Psychiatry Res 2002;113:139
/49. [75] Carney RM, Blumenthal JA, Stein PK, Watkins L, Catellier D, Berkman LF, et al. Depression, heart rate variability, and acute myocardial infarction. Circulation 2001;104: 2024
/8. [76] Gorman JM, Sloan RP. Heart rate variability in depressive and anxiety disorders. Am Heart J 2000;140:77
/83. [77] Stein PK, Carney RM, Freeland KE, Skala JA, Jaffe AS, Kleiger RE, et al. Severe depression is associated with markedly reduced heart rate variability in patients with stable coronary heart disease. J Psychosom Res 2000;48: 493
/500. [78] Bigger JT, Fleiss JL, Rolnitzky LM, Steinman RC. The ability of several short-term measures of RR variability to predict mortality after myocardial infarction. Circulation 1993;88:927
/34. [79] van Ravenswaaij-Arts CM, Kollee LA, Hopman JC, Stoelinga GB, van Geijn HP. Heart rate variability. Ann Intern Med 1993;118:436
/47. [80] Roose SP. Treatment of depression in patients with heart disease. Biol Psychiatry 2003;54:262
/8. [81] Carney RM, Freedland KE, Rich MW, Smith LJ, Jaffe AS. Ventricular tachycardia and psychiatric depression in patients with coronary artery disease. Am J Med 1993;95:23
/ 8. [82] Joynt KE, Whellan DJ, O’Connor CM. Depression and cardiovascular disease: mechanisms of interaction. Biol Psychiatry 2003;54:248
/61. [83] Sheps DS, Sheffield D. Depression, anxiety, and the cardiovascular system: The cardiologist’s perspective. J Clin Psychiatry 2001;62(Suppl 8):12
/16; discussion 17
/ 18. /

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

[84] Maes M, Van der Planken M, Van Gastel A, Desnyder R. Blood coagulation and platelet aggregation in major depression. J Affect Disord 1996;40:35
/40. [85] Berk M, Plein H. Platelet supersensitivity to thrombin stimulation in depression: A possible mechanism for the association with cardiovascular mortality. Clin Neuropharmacol 2000;23:182
/5. [86] Paul SM, Rehavi M, Skolnick P, Ballenger JC, Goodwin FK. Depressed patients have decreased binding of tritiated imipramine to platelet serotonin ‘‘transporter’’. Arch Gen Psychiatry 1981;38:1315
/7. [87] Briley MS, Langer SZ, Raisman R, Sechter D, Zarifian E. Tritiated imipramine binding sites are decreased in platelets of untreated depressed patients. Science 1980;209:303
/5. [88] Cerrito F, Lazzaro MP, Gaudio E, Arminio P, Aloisi G. 5HT2-receptors and serotonin release: their role in human platelet aggregation. Life Sci 1993;53:209
/15. [89] Musselman DL, Marzec UM, Manatunga A, Penna S, Reemsnyder A, Knight BT, et al. Platelet reactivity in depressed patients treated with paroxetine: Preliminary findings. Arch Gen Psychiatry 2000;57:875
/82. [90] Serebruany VL, Gurbel PA, O’Connor CM. Platelet inhibition by sertraline and N-desmethylsertraline: A possible missing link between depression, coronary events, and mortality benefits of selective serotonin reuptake inhibitors. Pharmacol Res 2001;43:453
/62. [91] Serebruany VL, O’Connor CM, Gurbel PA. Effect of selective serotonin reuptake inhibitors on platelets in patients with coronary artery disease. Am J Cardiol 2001; 87:1398
/400. [92] Serebruany VL, Glassman AH, Malinin AI, Nemeroff CB, Musselman DL, van Zyl LT, et al. Platelet/endothelial biomarkers in depressed patients treated with the selective serotonin reuptake inhibitor sertraline after acute coronary events: The Sertraline AntiDepressant Heart Attack Randomized Trial (SADHART) Platelet Substudy. Circulation 2003;108:939
/44. [93] Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation 2002;105:1135
/43. [94] Danner M, Kasl SV, Abramson JL, Vaccarino V. Association between depression and elevated C-reactive protein. Psychosom Med 2003;65:347
/56. [95] Bunker SJ, Colquhoun DM, Esler MD, Hickie IB, Hunt D, Jelinek VM, et al. ‘Stress’ and coronary heart disease: psychosocial risk factors. Med J Aust 2003;178:272
/6. [96] Jiang W, Babyak MA, Rozanski A, Sherwood A, O’Connor CM, Waugh RA, et al. Depression and increased myocardial ischemic activity in patients with ischemic heart disease. Am Heart J 2003;146:55
/61. [97] Cohen HW, Gibson G, Alderman MH. Excess risk of myocardial infarction in patients treated with antidepressant medications: Association with use of tricyclic agents. Am J Med 2000;108:2
/8. [98] Roose SP, Glassman AH, Attia E, Woodring S, Giardina EG, Bigger JT Jr. Cardiovascular effects of fluoxetine in depressed patients with heart disease. Am J Psychiatry 1998;155:660
/5. [99] Nelson JC, Kennedy JS, Pollock BG, Laghrissi-Thode F, Narayan M, Nobler MS, et al. Treatment of major depression with nortriptyline and paroxetine in patients with ischemic heart disease. Am J Psychiatry 1999;156: 1024
/8. [100] Glassman AH, O’Connor CM, Califf RM, Swedberg K, Schwartz P, Bigger JT Jr, et al. Sertraline treatment of major depression in patients with acute MI or unstable angina. J Am Med Assoc 2002;288:701
/9. [101] van den Brink RH, van Melle JP, Honig A, Schene AH, Crijns HJ, Lambert FB, et al. Treatment of depression after myocardial infarction and the effects on cardiac prognosis and quality of life: Rationale and outline of the Myocardial INfarction and Depression-Intervention Trial (MIND-IT). Am Heart J 2002;144:219
/25. /

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

Depression and CVD [102] Bennett P, Carroll D. Cognitive-behavioural interventions in cardiac rehabilitation. J Psychosom Res 1994;38:169
/82. [103] Blumenthal JA, Wei J. Psychobehavioral treatment in cardiac rehabilitation. Cardiol Clin 1993;11:323
/31. [104] Williams RB, Littman AB. Psychosocial factors: Role in cardiac risk and treatment strategies. Cardiol Clin 1996;14: 97
/104. [105] Berkman LF, Blumenthal J, Burg M, Carney RM, Catellier D, Cowan MJ, et al. Effects of treating depression and low perceived social support on clinical events after myocardial infarction: The Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) Randomized Trial. J Am Med Assoc 2003;289:3106
/16. [106] Graves KD, Miller PM. Behavioral medicine in the prevention and treatment of cardiovascular disease. Behav Modif 2003;27:3
/25. [107] Wassertheil-Smoller S, Shumaker S, Ockene J, Talavera GA, Greenland P, Cochrane B, et al. Depression and /

/

/

/

/

/

/

/

167

cardiovascular sequelae in postmenopausal women. The Women’s Health Initiative (WHI). Arch Intern Med 2004; 164:289
/98. Penninx BW, Guralnik JM, Mendes de Leen CF, Pahor M, Visser M, et al. Cardiovascular events and mortality in newly and chronically depressed persons /70 years of age. Am J Cardiol 1998;81:988
/94. 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;82:851
/6. Barefoot JC, Larsen S, von der Lieth L, Schroll M. Hostility, incidence of acute myocardial infarction, and mortality in a sample of older Danish men and women. Am J Epidemiol 1995;142:477
/84. Barefoot JC, Brummett BH, Helms MJ, Mark DB, Siegler IC, Williams RB. Depressive symptoms and survival of patients with coronary artery disease. Psychosom Med 2000;62:790
/5. /

/

[108]

/

/

[109]

/

/

[110]

/

/

[111]

/

/

/

/