The continuum between depressive episode and depressive disorder: what is the role of stress and cardiovascular risk factors?




Silla M. CONSOLI, MD, PhD
Paris-Descartes University of Medicine, Department of Clinical Psychology and Consultation-Liaison Psychiatry
Assistance Publique-Hôpitaux de Paris, European Georges Pompidou Hospital
Paris, FRANCE

The continuum between depressive episode and depressive disorder: what is the role of stress and cardiovascular risk factors?

by S. M. Consoli, France

Anetwork of complex relationships exists between stress, depressive mood or the spectrum of depressive disorder, and cardiovascular disease, in particular coronary heart disease. Depressive mood and major depressive episodes can both be considered as risk factors for the development of cardiovascular disease, even after controlling for behaviors at risk for cardiovascular disease. Recurrent depression, but not single major depressive episode, is associated with the development of atherosclerosis and arterial calcifications. Type A behavior pattern and, more recently, work stress and cynical hostility, were also examined as predictors of cardiovascular disease. Incident post–myocardial infarction depression predicts cardiac mortality and new onset of cardiac events. Coronary heart disease and depression share common genetic vulnerabilities (eg, serotonin transporter [5-HTT] polymorphism), which interact with environmental factors and medical triggers, such as acute coronary syndrome. The continuum between depressive episode and depressive disorder, applied to cardiovascular patients, and the respective times of onset of cardiac events and depressive symptomatology, must be taken into account in order to determine the appropriate time and type of mood disorder treatment.

Medicographia. 2011;33:138-144 (see French abstract on page 144)



Avery large number of publications have been dedicated, during the past two decades, to the complex relationships between stress, depressive mood or the spectrum of depressive disorder, and cardiovascular disease, in particular coronary heart disease.1-9

To disentangle these complex relationships, we will successively address the following issues, which are important to understand in order to make causal inferences and, consequently, design preventive interventions:
_ Depressive mood, major depressive episode (MDE), or recurrent depression as risk factors for cardiovascular disease.
_ Stress and coronary heart disease.
_ Prognostic value of depression following a coronary event, according to depression type.
_ Common genetic factors for cardiovascular disease, depression, and depression responsiveness to an antidepressant.
_ Stress and cardiovascular condition as risk factors for depressive recurrence.

Depressive mood, MDE, or recurrent depression as risk factors for cardiovascular disease

The possibility that depression has an impact on the development of coronary heart disease (CHD) or atherosclerotic lesions in initially healthy subjects has led to controversial findings. In 1987, Booth-Kewley and Friedman showed in ametaanalysis a strong association between depression and CHD, but most of the studies included in that review were crosssectional.10 Actually, in the late 80s, very few studies used a prospective cohort design. This situation changed in the next decade, but most of the studies assessed depressive symptomatology using self-administered questionnaires, without any standardized interview for performing Diagnostic and Statistical Manual of Mental Disorders, 3rd or 4th Editions (DSM-III or DSM-IV) diagnoses ofMDE or depressive disorder.

In a further meta-analysis based on 11 selected studies, clinical depression was assessed only in three of the studies, whereas in the remaining eight studies, depressive mood was measured alone.3 In this meta-analysis, pooling all the studies, overall relative risk (RR) for the development of CHD in depressed subjects was 1.64 (95% confidence interval [CI], 1.29-2.08), but clinical depression (RR, 2.69; 95% CI, 1.63- 4.43) was a stronger predictor than depressive mood (RR, 1.49, 95% CI: 1.16-1.92). Among the studies using a clinical diagnosis of depression, the nationally representative Mini- Finland Health Survey covered 8000 individuals and consisted of a 6.6-year follow-up: an increased risk of coronary death was found in clinically depressed persons, both with and without cardiovascular diseases at entry. The authors concluded that “the hypothesis that depression is a cause of cardiovascular diseases requires further study.”11

In a study based on a follow-up of a survey of psychiatric disorders in the general population—the Baltimore cohort of the Epidemiologic Catchment Area (ECA) Study—a history of MDE or dysphoria (2 weeks of sadness) was assessed in 1981 using the Diagnostic Interview Schedule (DIS), a widely used tool in psychiatric epidemiology, and self-reported myocardial infarction (MI) was assessed in 1994.12 The odds ratio (OR) for MI associated with a history of MDE was 4.54 (95% CI, 1.65-12.44), independent of coronary risk factors, whereas the OR for MI associated with a history of dysphoria was 2.07 (95% CI, 1.16-3.71). Moreover, the use of tricyclic antidepressants and benzodiazepines was not predictive of MI.

The Johns Hopkins Precursors Study was a prospective, observational study of 1190 male medical students who were enrolled between 1948 and 1964 and who continued to be followed up.13 During a median of 37 years follow-up, the incidence of clinical depression was measured by means of mailed surveys with direct questions concerning the occurrence of depression and associated treatment. Self-reports of depression were confirmed by a committee of physician reviewers who were unaware of the study hypothesis. The cumulative incidence of clinical depression was 12%. Subjects who developed clinical depression drank more coffee than those who did not, but did not differ in terms of cardiovascular risk factors (baseline blood pressure, serum cholesterol levels, smoking status, physical activity, obesity, or family history of coronary artery disease). Multivariate analysis showed that clinical depression was associated with greater risk for subsequent CHD (RR, 2.12; 95% CI, 1.24-3.63) or MI (RR, 2.12; 95% CI, 1.11-4.06), and was still an independent risk factor for CHD 10 years after the onset of depression (RR, 2.1; 95% CI, 1.1-4.0).

In another study, after controlling for known cardiovascular risk factors, a self-reported history of treatment for depression was also independently associated with subsequent MI in 5564 treated hypertensive patients without prior cardiovascular disease (hazard ratio [HR], 2.10; 95% CI: 1.04-4.23).14

None of these studies separately assessed the predictive value of single MDE vs recurrent MDE regarding the development of cardiovascular diseases. This was the purpose of a series of studies on female populations. In 336 healthy middleaged women from 1 of the 7 sites of the Study of Women’s Health Around the Nation, a prospective study of the perimenopausal transition, carotid plaque was assessed using a B-mode ultrasonography and psychiatric diagnoses were assessed using the Structured Clinical Interview for the DSM-IV Axis I Disorders–Non-Patient Edition (SCID-IV). The risk of plaque was twofold in women with a lifetime history of recurrent MDE relative to women with no history of depression (OR, 2.30; 95% CI, 1.10-4.82), whereas lifetime history of a single MDE was not associated with plaque.15 Similar findings were published regarding coronary and aortic calcifications in 58 African-American and 152 white healthy middle-aged women.16 This association was in part mediated by the waisthip ratio. A recent publication confirmed that among 149 middle- aged healthy women who reported no heart disease, stroke or diabetes at baseline, women with recurrent MDE (n=33) had greater progression of coronary artery calcification, assessed using computed tomography measures on two occasions, approximately 2¼ years apart, than did women with a single or no episodes.17

Other publications examined the role of depression timing as a risk factor for cardiovascular events, even if depressive mood was assessed using only self-administered questionnaires. In a prospective cohort of 4493 elderly Americans followed for 6 years, free of cardiovascular disease at baseline and enrolled in the Cardiovascular Health Study, the Center for Epidemiological Studies Depression Scale (CES-D) score was annually computed.18 The cumulative CES-Dmean at last visit before any cardiovascular event was associated with development of CHD and all-cause mortality, using time-dependent, proportional-hazards models. As expected, cumulative CES-D mean was higher in subjects with a history of depression at baseline and, interestingly, in women, but not in men with baseline hypertension or smoking.

In another prospective cohort study of 3701 men and women aged >70 years, CES-D depressive symptomatology was also measured on three occasions during a 6-year period to distinguish persons who were newly (depressed at baseline, but not at 3 and 6 years before baseline) and chronically depressed (depressed at baseline and at 3 or 6 years before baseline).19 Subjects were then followed for a median period of 4 years. Their risk of subsequent CVD events and all-cause mortality was compared with that of subjects who were never depressed during the 6-year period. In men, but not in women, newly depressed mood was associated with an increased risk of cardiovascular mortality, new cardiovascular events, and new CHD events, after adjustment for traditional cardiovascular risk factors. Chronic depressed mood was not associated with new cardiovascular events.

Similar results were published by Surtees et al regarding the recency of an MDE in the European Prospective Investigation of Cancer (EPIC)–Norfolk United Kingdom Prospective Cohort Study (median follow-up period of 8.5 year), consisting of 8261 men and 11 388 women 41 to 80 years of age, who were free of clinical manifestations of CHD at baseline: compared with never-depressed patients, subjects with an MDE within the last 12 months were at high risk for cardiovascular death, especially those with current MDE; no increased risk was associated with a history of lifetime depression, but not in last 12 months.20 CES-D depression score was also assessed every 6 months in the 4367 participants of the Systolic Hypertension in the Elderly Program (SHEP) followed up for 5 years.21 Cox proportional hazards regression analyses, with the CES-D score as a time-dependent variable and controlling for multiple covariates, indicated an increased risk of stroke or myocardial infarction for 5-unit increase in the CES-D score (RR,1.18; 95% CI, 1.08-1.30).

Therefore, according to the studies, the role of depression as a risk factor for cardiovascular disease appears as a time-dependent or a dose-dependent effect.

Stress and coronary heart disease

Early in the 1980s, a stress-prone personality trait defined as Type A behavior pattern, characterized by hard driving, competitive behavior, and a potential for hostility, was found in several prospective studies as associated with an increased risk for fatal as well as nonfatal CHD.22 Stress may affect healthrelated behaviors such as smoking, diet, alcohol consumption, or physical activity, which in turn may influence the risk of coronary heart disease, but, generally, results are adjusted for these confounding variables, suggesting more direct pathophysiological mediations such as endothelial dysfunction, inflammation, increased blood clotting, and decreased fibrinolysis. In further studies, due to repeated negative findings, Type A as a cardiovascular risk factor was abandoned and replaced by a more specific component of type A, namely, hostility, and especially cognitive or cynical hostility.

Type A individuals are supposed to be focused on achievement by work and to actively seek out challenging situations. Two main models of work stress have been proposed. In a prospective cohort study with a mean follow up of 25.6 years on 812 employees free from any cardiovascular disease at baseline both Karasek’s and Siegrist’s models of work stress (respectively “job strain,” a combination of high demands at work and low job control, and “effort-reward imbalance”) predicted cardiovascular mortality: HR=2.2 (95% CI, 1.2-4.2) for high job strain and 2.4 (95% CI: 1.3-4.4) for effort-reward imbalance, after adjustment for age and sex. The association remained significant after additional adjustment for smoking, physical activity, systolic blood pressure, cholesterol concentration, and body mass index.23

In the INTERHEART study (not an acronym), a case-control design on 11 119 patients with a first myocardial infarction compared with 13 648 age-matched and sex-matched controls, patients reported higher prevalence of stress at work and at home, financial stress, and major life events in the past year. The highest OR, adjusted for age, sex, geographic region and smoking, were found for permanent stress at work (OR, 2.14; 99% CI, 1.73-2.64) and permanent stress at home (OR, 2.12; 99% CI, 1.68-2.65).24

In another case-control study, 97 consecutive patients with a first episode of coronary heart disease, interviewed with Paykel’s Interview for Recent Life Events, reported significantly more life events, as well as more mood disorders than matched controls. The difference regarding life events was similar in patients with and without mood disorders and concerned all the categories of events, excepted “entrances” (introduction of new people, such as marriage), eg, “exits” (departure of a person from the social field of the subject, such as the death of a close family member), socially desirable (promotion) as well as undesirable (major financial problems) events, and controlled (initiation under subject’s control or choice) as well as uncontrolled events.25

Prognostic value of depression following a coronary event, according to depression type

About 1 in 5 acute coronary syndrome (ACS) patients meets criteria for MDE, and of these patients, 50%or more have had depression symptoms in the past. The prognostic value of depressive disorder, regarding cardiac outcome, in patients with already established CHD, is based on much more convergent findings than the role of depression as a cardiovascular risk factor in healthy individuals. As early as in late 1980s Carney et al showed in 52 patients undergoing cardiac catheterization and subsequently found to have significant CHD, that major depressive disorder was the best predictor of major cardiac events during the 12 months following catheterization. The predictive effect was independent of the severity of CHD, left ventricular ejection fraction, and smoking.26

In 1993, Frasure-Smith et al showed that major depression in 222 patients hospitalized following a MI was as an independent risk factor for mortality at 6 months (adjusted HR, 4.29; 95% CI, 3.14-5.44).27 In 1995, the same research team published its results relating to an extended follow-up period of 18 months, showing that both the Diagnostic Interview Schedule (DIS) diagnosis of MDE (OR, 3.64; 95% CI, 1.32- 10.05) and elevated Beck Depression Inventory (BDI) scores (OR, 7.82; 95% CI, 2.42-25.26) were significantly related to 18-month cardiac mortality.28 Adjusting for clinical confounding variables did not change the results, but contrary to BDI, MDE was no still predictive of cardiovascular deaths in patients who survived to 6 months. Multivariate analyses showed that anxiety and history of major depression each had an impact independent of each other, as well as of measures of cardiac disease severity.29

Many further studies replicated these first findings.5,7 The question remains whether the association between depression and mortality in patients with ACS is confounded by incomplete adjustment formeasures of known prognosticmarkers. In a prospective survey on 457 ACS subjects, neither depression measure (MDE assessed using a standardized interview or BDI score) was associated with the Global Registry of Acute Coronary Events (GRACE) risk score, the most comprehensive empirically derived index of clinical mortality predictors. MDE and depressive symptom severity each predicted mortality after controlling for GRACE score and left ventricular dysfunction (HR [adjusted for MDE], 2.51; 95% CI, 1.45-4.37).30 No significant differences were found in GRACE scores between participants with initial MDE, as compared with those with recurrent MDE.

A growing literature has recently been dedicated to the differential prognostic value of incident vs ongoing and recurrent depression in patients with ACS. De Jonge et al assessed a total of 468 MI patients for the presence of an International Classification of Diseases–10 (ICD-10) depressive disorder within the year after index MI. During the 2.5-year mean follow up period, compared with nondepressed patients, those with incident depression had an increased risk of cardiovascular events (adjusted HR, 1.76; 95% CI, 1.06 to 2.93), but not those with nonincident depression (adjusted HR, 1.39; 95% CI, 0.74 to 2.61).31 New-onset depression—but not isolated pre-MI depression—was also related to cardiac death in an 8-year follow up in 588 post-MI subjects; in the subgroup of subjects with post-MI depression, pre-MI depression did not convey any additional risk of cardiac mortality.32 Using the BDI in 750 patients who had unstable angina pectoris and myocardial infarction, 23.2% of the participants self-reported a history of depressed mood for >2 weeks, and 31.3% had elevated BDI scores at index hospitalization, with 14.0% reporting persistent depressive symptomatology with an onset before the index hospitalization. History of depressed mood was found in 44.7% of subjects with elevated BDI compared with 13.4% in the rest of the population studied. After controlling for prognostic indicators, such as cardiac disease severity, medical history, and smoking, depressive symptomatology during hospitalization was significantly predictive of mortality, but depressive history was not.33

Similar findings were published by Parker et al,34 who recently proposed a more sophisticated classification of depression in 489 patients experiencing an ACS and undergoing a standardized interview a few days following their admission, then 1 month later: the poorer cardiovascular prognosis was associated with “incident depression” (no depression at admission, but depressed at 1 month) and “recurrent depression” (history of depression prior to the admission, then new episode at 1 month assessment); the best with “no depression” (never depressed), “prior depression” and “noncontinuing depression” (depression at admission, whatever the history of depression, but no depression at 1 month); intermediate prognosis was associated with “continuing depression” (depression at admission and still depressed at 1 month).35

In the Depression after Myocardial Infarction (DepreMI) study, a naturalistic follow-up study of 475 patients admitted for MI, BDI scores during hospitalization and at 3, 6, and 12 months post-MI were analyzed, using latent class analysis. One out of 5 classes was characterized by significant and increasing depressive symptoms (4.0%). Subjects in this class had a higher risk for a new cardiovascular event compared with subjects without depressive symptoms.36

Controlled trials focused on psychosocial distress, and especially depressivemood in patients hospitalized for an ACS were rather disappointing, regarding cardiac outcomes. SADHART (Sertraline AntiDepressant Heart Attack Randomized Trial) was a double-blind, placebo controlled, randomized trial comparing the safety and antidepressant efficacy of sertraline vs placebo in 369 patients with ACS who met criteria for MDE. In this trial, baseline MDE severity and failure of MDE to improve substantially during treatment with either sertraline or placebo were strongly and independently associated with long-term mortality.37 Fifty-three percent of MDEs began before hospitalization for the index episode of ACS: they responded more frequently to sertraline than to placebo (63% vs 46%, respectively; OR, 2.0; 95% CI, 1.13-3.55) whereas depression with onset beginning after hospitalization showed a high placebo response rate (69% vs 60%, respectively).38 Multivariate analysis indicated that onset of the current episode before the index episode of ACS, history of MDE, and baseline severity independently predicted the sertraline– placebo response ratio.

In the multicenter randomized Myocardial INfarction and Depression– Intervention Trial (MIND-IT) on the effects of antidepressant treatment for post-MI depression, patients were enrolled in double-blind, placebo-controlled treatment with mirtazapine and, in the case of insufficient treatment response after 8 weeks, open treatment with citalopram. The 18-month event rate (cardiac mortality or cardiac-related hospital admission) was 25.6% among nonresponders, 11.2% among untreated control subjects, and 7.4% among responders.39 Gender differences were also noted in Linden’s meta-analysis on 23 trials comparing a psychological treatment to a control group on a total of 9856 coronary patients: the mortality benefits appeared only in men, even after controlling for age differences.40 Moreover, trials initiating treatment at least 2 months after a cardiac event showed greater mortality benefits than those initiating treatment right after the event.

Finally, a poorer cardiac outcome in patients presenting with CHD and a comorbid depressive disorder could also be explained by a suboptimal access to standard therapeutic procedures, as demonstrated by the publication of Druss et al. Compared with CHD patients with no mental disorder, the use of revascularization procedures in patients presenting with affective disorders was significantly lower (RR=0.51 for percutaneous transluminal coronary angioplasty, and RR=0.63 for coronary artery bypass graft surgery.41 The likelihood of undergoing catheterization (RR=0.65) was also lower, but among patients who underwent catheterization the reduction in the use of revascularization procedures was no longer significant (RR=0.75 for percutaneous transluminal coronary angioplasty, and RR=0.94 for coronary artery bypass graft surgery, respectively). Thus, access to and content of medical care, eg, catheterization in patients with CHD symptoms, may plausibly be influenced by depression history.

Common genetic factors for CVD, depression, and depression responsiveness to antidepressants

The association between cardiovascular disease, especially CHD, and depressive disorder, cannot be totally explained by reciprocal causal effects; common genetic factors to both vulnerabilities are also involved.

In twin studies, both depression and CHD appear heritable. In the only twin study to consider depression and CHD jointly, the correlation across heritabilities was 0.42, suggesting that nearly 20% of variability in depressive symptoms and CHD was attributable to common genetic factors.42 Genetic variation related to inflammation has been primarily examined in relation to CHD, whereas genetic variation of the serotonin system has been primarily examined in relation to depression, although both pathways are involved in CHD and depression. The S (short) allele of the serotonin transporter (5-HTT) gene was shown to reduce transcription of this gene and thus reduce serotonin reuptake. A gene-environment interaction was suggested, individuals with one or two copies of the S allele exhibiting more depressive symptoms, diagnosable depression, and suicidality in relation to stressful life events than individuals homozygous for the L (long) allele.43 In 2509 genotyped patients with MI, depressive symptoms were more common in patients with the S allele. Cardiac post-MI events were also more frequent in patients with the S allele than in those without it, and the increased risk for cardiac events became insignificant after an adjustment for depressive symptoms, indicating a possible mediating role of post-MI depression.44 CHD outpatients carrying an S allele have a higher mean score for perceived stress than L/L homozygotes45: genetic vulnerability to depression could thus interact with a physical stressing situation such a CHD condition.

Stress and cardiovascular condition as risk factors for depressive recurrence

Several characteristics have been described as contributing to depressive recurrence: age at onset/number of episodes, severity, psychiatric comorbidity, family history, internal attributions, neuroticism, poor social support, and stressful life events.46 Comorbid somatic condition has been less examined as a risk factor for depressive recurrence.

In the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study carried out in 1500 patients, subjects with recurrent depression were older, had an earlier age of onset, and were more likely to have a positive family history of depression than first-episode patients. Their mean score on the Cumulative Illness Rating Scale (CIRS)—a 14-item interview that gauges the severity/morbidity of general medical conditions relevant to different organ systems—was also higher, even though this difference was largely attributable to patients with 10 or more episodes, who reported the greatest number of comorbid medical illnesses.47

In the late 80s, Schleifer et al had already noted that depression following myocardial infarction was not associated with the severity of cardiac illness, but with the presence of noncardiac medical illnesses.48

In the Enhancing Recovery in Coronary Heart Disease (ENRICHD) clinical trial (2481 depressed or socially isolated patients with MI), the adjusted ORs for having an MDE increased linearly with medical comorbidity, as measured by a modified version of the Charlson Comorbidity Index. This relationship remained after adjusting for CHD severity. The relationship between severity of depression and medical comorbidity was also maintained after excluding somatic symptoms of depression.49

In 88 patients suffering from an ACS, a clinical interview was performed to assess current and past diagnosis ofMDE. CHD severity was assessed in all patients by coronary angiography. Neither in-hospital MDE status nor history of depression were significant predictors of CHD severity, but the interaction term between both was (higher CHD severity in patients without any history of depression and with incident depression). Follow- up analyses showed that patients with first-time, incident MDE had significantly more severe CHD compared with patients with recurrent MDE.50 Authors suggest that ACS patients without a history of depression have normal vulnerability to depression, but because their CHD is more severe than those patients with past episodes of depression, they experience a first-time reactive depression in response to the significant physiologic and psychological stress. In these patients, incident MDE can be triggered by underlying cardiac disease. Another tentative explanation is that ACS patients with incident depression appear to have more advanced coronary vascular disease and that these patients may be more vulnerable to a certain type of depression termed vascular depression. Recurrent depression in ACS patients more likely resembles depression seen in the general population. Common risk factors for depression in the general population such as lower educational level and higher neuroticism are also seen in nonincident post-MI depressed patients. For individuals with recurrent depression disease severity is not a trigger for MDE: they may experience an exacerbation of a previously existing vulnerability, which is triggered by the ACS. Time course of depression in CHD patients can thus be understood as a result of genetic vulnerability, history of mood disorders, personality, severity of CHD, and comorbid somatic factors. Such complexity likely accounts for specific difficulties in treating depression in cardiovascular patients, in addition to symptom overlap and all the other obstacles related to a condition that is associated with multiple diagnoses. _

References
1. Hemingway H, Marmot M. Psychosocial factors in the aetiology and prognosis of coronary heart disease: systematic review of prospective cohort studies. BMJ. 1999;318:1460-1467.
2. Rozanski A, Blumenthal JA, Kaplan J. Impact of psychological factors on the pathogenesis of cardiovascular disease and implications for therapy. Circulation. 1999;99;2192-221.
3. Rugulies R. Depression as a predictor for coronary heart disease. A review and meta-analysis. Am J Prev Med. 2002;23:51-61.
4. Wulsin LR, Singal BM. Do depressive symptoms increase the risk for the onset of coronary disease? A systematic quantitative review. Psychosom Med. 2003; 65:201-210.
5. Barth J, Schumacher M, Herrmann-Lingen C. Depression as a risk factor for mortality in patients with coronary heart disease: a metaanalysis. Psychosom Med. 2004;66:802-813.
6. Lett SH, Blumenthal JA, Babyak MA, et al. Depression as a risk factor for coronary artery disease: evidence, mechanisms, and treatment. Psychosom Med. 2004;66:305-315.
7. Van Melle JP, De Jonge P, Spijkerman TA, et al. Prognostic association of depression following myocardial infarction with mortality and cardiovascular events: a meta-analysis. Psychosom Med. 2004;66:814-822.
8. Nicholson A, Kuper H, Hemingway H. Depression as an aetiologic and prognostic factor in coronary heart disease: a meta-analysis of 6362 events among 146,538 participants in 54 observational studies. Eur Heart J. 2006;27:2763- 2774.
9. Pozuelo L, Tesar G, Zhang J, Penn M, Franco K, JiangW. Depression and heart disease: what do we know, and where are we headed? Cleve Clin J Med. 2009;76:59-70.
10. Booth-Kewley S, Friedman HS. Psychological predictors of heart disease: a quantitative review. Psychol Bull. 1987;101:343-362.
11. Aromaa A, Raitasalo R, Reunanen A, et al. Depression and cardiovascular diseases. Acta Psychiatr Scand Suppl. 1994;377:77-82.
12. 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;94:3123-3129.
13. 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;158:1422-1426.
14. Cohen HW, Madhavan S, Alderman MH. History of treatment for depression: risk factor for myocardial infarction in hypertensive patients. Psychosom Med. 2001;63:203-209.
15. Jones DJ, Bromberger JT, Sutton-Tyrrell K, Matthews KA. Lifetime history of depression and carotid atherosclerosis in middle-aged women. Arch Gen Psychiatry. 2003;60:153-160.
16. Agatisa PK, Matthews KA, Bromberger JT, Edmundowicz D, Chang YF, Sutton- Tyrrell K. Coronary and aortic calcification in women with a history of major depression. Arch Intern Med. 2005;165:1229-1236.
17. Matthews KA, Chang YF, Sutton-Tyrrell K, Edmundowicz D, Bromberger JT. Recurrent major depression predicts progression of coronary calcification in healthy women: study of women’s health across the nation. Psychosom Med. 2010;72:742-747.
18. Ariyo AA, Haan M, Tangen CM, et al. Depressive symptoms and risks of coronary heart disease and mortality in elderly Americans. Circulation. 2000;102: 1773-1779.
19. Penninx BW, Guralnik JM, Mendes de Leon CF, et al. Cardiovascular events and mortality in newly and chronically depressed persons > 70 years of age. Am J Cardiol. 1998;81:988-994.
20. Surtees PG, Wainwright NW, Luben RN, Wareham NJ, Bingham SA, Khaw KT. Depression and ischemic heart disease mortality: evidence from the EPIC-Norfolk United Kingdom prospective cohort study. Am J Psychiatry. 2008;165: 515-523.
21. Wassertheil-Smoller S, Applegate WB, Berge K, et al. Change in depression as a precursor of cardiovascular events. Arch Intern Med. 1996;156:553-561.
22. Haynes SG, Feinleib M, Kannel WB. The relationship of psychosocial factors to coronary heart disease in the Framingham study: 3. Eight year incidence of coronary heart disease. Am J Epidemiol. 1980;111:3758.
23. Kivimaki M, Leino-Arjas P, Luukkonen R, Riihimaki H, Vahtera J, Kirjonen J. Work stress and risk of cardiovascular mortality: prospective cohort study of industrial employees. BMJ. 2002; 325:857-861.
24. Rosengren A, Hawken S, Ounpuu S, Sliwa K, Zubaid M, Almahmeed WA, Blackett KN, Sitthi-amorn C, Sato H, Yusuf S; INTERHEART investigators. Association of psychosocial risk factors with risk of acute myocardial infarction in 11119 cases and 13648 controls from 52 countries (the INTERHEART study): case-control study. Lancet. 2004;364:953-962.
25. Rafanelli C, Roncuzzi R, Milaneschi Y, et al. Stressful life events, depression and demoralization as risk factors for acute coronary heart disease. Psychother Psychosom. 2005;74:179-184.
26. Carney RM, Rich MW, Freedland KE, et al. Major depressive disorder predicts cardiac events in patients with coronary artery disease. Psychosom Medw. 1988; 50:627-633.
27. Frasure-Smith N, Lesperance F, Talajic M. Depression following myocardial infarction: impact on 6-month survival. JAMA. 1993;270:1819-1825.
28. Frasure-Smith N, Lesperance F, Talajic M. Depression and 18-month prognosis after myocardial infarction. Circulation. 1995;91:999-1005.
29. 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;14:388-398.
30. Kronish IM, Rieckmann N, Schwartz JE, Schwartz DR, Davidson KW. Is depression after an acute coronary syndrome simply a marker of known prognostic factors for mortality? Psychosom Med. 2009;71:697-703.
31. de Jonge P, van den Brink RHS, Spijkerman TA, Ormel J. Only incident depressive episodes after myocardial infarction are associated with new cardiovascular events. J Am Coll Cardiol. 2006;48:2204-2208.
32. Dickens C, McGowan L, Percival C, et al. New onset depression following myocardial infarction predicts cardiac mortality. Psychosom Med. 2008;70:450- 455.
33. Grace SL, Abbey SE, Kapral MK, Fang J, Nolan RP, Stewart DE. Effect of depression on five-year mortality after an acute coronary syndrome. Am J Cardiol. 2005;96:1179-1185.
34. Parker GB, Hilton TM,WalshWF, et al. Timing is everything: the onset of depression and acute coronary syndrome outcome. Biol Psychiatry. 2008;64:660-666.
35. Parker G, Hyett M, Walsh W, Owen C, Brotchie H, Hadzi-Pavlovic D. Specificity of depression following an acute coronary syndrome to an adverse outcome extends over five years. Psychiatry Res. 2010. In press.
36. Kaptein KI, de Jonge P, van den Brink RH, Korf J. Course of depressive symptoms after myocardial infarction and cardiac prognosis: a latent class analysis. Psychosom Med. 2006;68:662-668.
37. Glassman AH, Bigger JT Jr, Gaffney M. Psychiatric characteristics associated with long-termmortality among 361 patients having an acute coronary syndrome and major depression: seven-year follow-up of SADHART participants. Arch Gen Psychiatry. 2009;66:1022-1029.
38. Glassman AH, Bigger JT, Gaffney M, Shapiro PA, Swenson JR. Onset of major depression associated with acute coronary syndromes: relationship of onset, major depressive disorder history, and episode severity to sertraline benefit. Arch Gen Psychiatry. 2006;63:283-288.
39. de Jonge P, Honig A, van Melle JP, et al; MIND-IT Investigators. Non response to treatment for depression following myocardial infarction: association with subsequent cardiac events. Am J Psychiatry. 2007;164:1371-1378.
40. Linden W, Phillips MJ, Leclerc J. Psychological treatment of cardiac patients: a meta-analysis. Eur Heart J. 2007;28:2972-2984.
41. Druss BG, Bradford DW, Rosenheck RA, Radford MJ, Krumholz HM. Mental disorders and use of cardiovascular procedures after myocardial infarction. JAMA. 2000;283:506-511.
42. McCaffery JM, Frasure-Smith N, Dubé MP, et al. Common genetic vulnerability to depressive symptoms and coronary artery disease: a review and development of candidate genes related to inflammation and serotonin. Psychosom Med. 2006;68:187-200.
43. Caspi A, Sugden K, Moffitt TE, et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science. 2003;301:386-389.
44. Nakatani D, Sato H, Sakata Y, et al; Osaka Acute Coronary Insufficiency Study Group. Influence of serotonin transporter gene polymorphism on depressive symptoms and new cardiac events after acute myocardial infarction. Am Heart J. 2005;150:652-658.
45. Otte C, McCaffery J, Ali S, Whooley MA. Association of a serotonin transporter polymorphism (5-HTTLPR) with depression, perceived stress, and norepinephrine in patients with coronary disease: the Heart and Soul Study. Am J Psychiatry. 2007;164:1379-1384.
46. Burcusa SL, Iacono WG. Risk for recurrence in depression. Clin Psychol Rev. 2007;27:959-985.
47. Hollon SD, Shelton RC, Wisniewski S, et al. Presenting characteristics of depressed outpatients as a function of recurrence: preliminary findings from the STAR*D clinical trial. J Psychiatr Res. 2006;40:59-69.
48. Schleifer SJ, Macari-Hinson MM, Coyle DA, et al. The nature and course of depression following myocardial infarction. Arch Intern Med. 1989;149:1785-1789.
49. Watkins LL, Schneiderman N, Blumenthal JA, et al; ENRICHD Investigators. Cognitive and somatic symptoms of depression are associated with medical comorbidity in patients after acute myocardial infarction. Am Heart J. 2003; 146:48-54.
50. Goodman J, Shimbo D, Haas DC, Davidson KW, Rieckmann N. Incident and recurrent major depressive disorder and coronary artery disease severity in acute coronary syndrome patients. J Psychiatr Res. 2008;42:670-675.

Keywords: depression; recurrence; incident episode; stress; coronary heart disease; risk factor; prognostic factor; genetic vulnerability; 5-HTT polymorphism