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Keywords:

  • coronary artery disease;
  • depression;
  • mechanisms;
  • prognosis;
  • treatment

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Evidence linking depression to increased cardiovascular risk in CAD patients
  6. Postulated mechanisms responsible for the link between depression and adverse cardiovascular events in CAD patients
  7. Depression and platelet reactivity
  8. Depression and procoagulant factors
  9. Depression and inflammation
  10. Depression and endothelial vasomotor dysfunction
  11. Depression and abnormal autonomic activity
  12. Depression and poor treatment compliance
  13. Overlap with other negative emotions
  14. The causal status of the proposed mediators in the depression–cardiovascular disease prognosis link
  15. Depression intervention studies and prognosis
  16. Psychological therapy
  17. Pharmacological therapies
  18. Can current depression treatments improve cardiovascular prognosis in CAD patients?
  19. Direct pleiotropic effects of depression treatment: implications for depressed patients with CAD
  20. Diagnosis and treatment recommendations
  21. Future directions
  22. Acknowledgements
  23. References

Summary.  Depressive symptoms are common in coronary artery disease (CAD) patients, and are associated with increased cardiac risk. Although an important relation exists between depression and CAD prognosis, the underlying pathophysiological mechanisms are poorly understood. Additionally, evidence including the recently published ENRICHD (Enhancing Recovery in Coronary Heart Disease Patients) trial suggests that depression treatments do not lower recurrent cardiac risk. The reason for the observed lack of benefit with depression treatment in CAD patients is unclear. In this review, we discuss the impact of depression in CAD patients, the possible mechanisms involved, the studies that have examined the effects of psychological and antidepressant therapies on recurrent cardiac events, and the direction that future research should take.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Evidence linking depression to increased cardiovascular risk in CAD patients
  6. Postulated mechanisms responsible for the link between depression and adverse cardiovascular events in CAD patients
  7. Depression and platelet reactivity
  8. Depression and procoagulant factors
  9. Depression and inflammation
  10. Depression and endothelial vasomotor dysfunction
  11. Depression and abnormal autonomic activity
  12. Depression and poor treatment compliance
  13. Overlap with other negative emotions
  14. The causal status of the proposed mediators in the depression–cardiovascular disease prognosis link
  15. Depression intervention studies and prognosis
  16. Psychological therapy
  17. Pharmacological therapies
  18. Can current depression treatments improve cardiovascular prognosis in CAD patients?
  19. Direct pleiotropic effects of depression treatment: implications for depressed patients with CAD
  20. Diagnosis and treatment recommendations
  21. Future directions
  22. Acknowledgements
  23. References

Despite improvements in coronary artery disease (CAD) treatment during the past several decades, CAD remains the leading cause of death in industrialized nations [1]. Further, CAD is associated with considerable patient morbidity and is presently the leading cause of premature, permanent disability in the USA [2].

Like CAD, depression is also an important public health concern. The lifetime prevalence of major depressive disorder is approximately 16%, and evidence suggests that the incidence is increasing [3]. Subsyndromal depression is even more prevalent than major depressive disorder [3]. The World Health Organization estimates that by the year 2020 depression will be second only to cardiovascular diseases in contributing to overall health impairment [4].

Depression is a common comorbid condition in CAD patients [5]. Both syndromal and subsyndromal depression are strongly associated with patient-reported health status affecting symptom burden and quality of life [6]. In addition, the presence of depression in CAD patients is associated with an increased risk of cardiovascular disease events [7]. Although the comorbidity of depression and CAD may not be novel to the practising physician, the exact mechanisms underlying the link between depression and subsequent cardiovascular events in patients with CAD remain poorly understood. Further, the most effective depression treatment for CAD patients also remains unknown. The results of the ENRICHD (Enhancing Recovery in Coronary Heart Disease Patients) trial suggests that depression treatment does not lower the risk of recurrent cardiac disease events [8]. The reason for this finding is likely to be multifactorial. To understand the impact and extent of depression in CAD patients, we must understand the underlying mechanism(s) involved, test causality, and determine which depression treatments will significantly improve both quality of life and cardiovascular disease outcomes.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Evidence linking depression to increased cardiovascular risk in CAD patients
  6. Postulated mechanisms responsible for the link between depression and adverse cardiovascular events in CAD patients
  7. Depression and platelet reactivity
  8. Depression and procoagulant factors
  9. Depression and inflammation
  10. Depression and endothelial vasomotor dysfunction
  11. Depression and abnormal autonomic activity
  12. Depression and poor treatment compliance
  13. Overlap with other negative emotions
  14. The causal status of the proposed mediators in the depression–cardiovascular disease prognosis link
  15. Depression intervention studies and prognosis
  16. Psychological therapy
  17. Pharmacological therapies
  18. Can current depression treatments improve cardiovascular prognosis in CAD patients?
  19. Direct pleiotropic effects of depression treatment: implications for depressed patients with CAD
  20. Diagnosis and treatment recommendations
  21. Future directions
  22. Acknowledgements
  23. References

We reviewed all original English-language peer-reviewed journal articles published from 1988 to 2004 obtained from a search of the MEDLINE database. The following heading terms were used: depression, depressive symptoms, myocardial infarction, coronary artery disease, death, unstable angina, etiology, biological markers, antidepressant, and treatment. We also searched the reference lists of located articles. We focused on depressive symptoms as a prognostic factor in patients with CAD. Although there is also evidence that depression is a primary risk factor [9], we do not systematically review that evidence herein, as the mechanisms and the interventions may differ. In areas where the evidence of studies of CAD patients is insufficient or contradictory, we briefly discuss relevant studies that enrolled depressed subjects without CAD. We also review depression treatment studies of CAD patients. For the prognostic studies, we included only prospective observational cohort studies. For the psychological and antidepressant treatment studies, we included only randomized controlled trials.

Evidence linking depression to increased cardiovascular risk in CAD patients

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Evidence linking depression to increased cardiovascular risk in CAD patients
  6. Postulated mechanisms responsible for the link between depression and adverse cardiovascular events in CAD patients
  7. Depression and platelet reactivity
  8. Depression and procoagulant factors
  9. Depression and inflammation
  10. Depression and endothelial vasomotor dysfunction
  11. Depression and abnormal autonomic activity
  12. Depression and poor treatment compliance
  13. Overlap with other negative emotions
  14. The causal status of the proposed mediators in the depression–cardiovascular disease prognosis link
  15. Depression intervention studies and prognosis
  16. Psychological therapy
  17. Pharmacological therapies
  18. Can current depression treatments improve cardiovascular prognosis in CAD patients?
  19. Direct pleiotropic effects of depression treatment: implications for depressed patients with CAD
  20. Diagnosis and treatment recommendations
  21. Future directions
  22. Acknowledgements
  23. References

Several studies of CAD patients [7,10–22] have demonstrated that depression, including major depressive disorder and elevated depressive symptoms, significantly and independently predicts adverse cardiovascular events. In the vast majority of the studies (Table 1), patients presenting with an acute coronary syndrome (ACS), such as a myocardial infarction (MI), were enrolled, and depression was quantified by a self-report questionnaire and/or direct structured psychiatric interview. The presence of elevated depressive symptoms or major depressive disorder predicted the occurrence of adverse cardiovascular events in these patients.

Table 1.  Overview of positive studies linking depression and cardiovascular events in coronary artery disease patients
StudyPopulationTotal sampleFollow-upSelf reportInterviewsOutcomeRisk (95% CI)
  1. BDI, Beck Depression Inventory; CES-D, Center for Epidemiologic-Depression Scale; DIS, Diagnostic Interview Schedule; DISH, The Depression Interview and Structured Hamilton; HR, hazards ratio, MBHI, Millon Behavioral Health Inventory; MI, myocardial infarction; OR, odds ratio; RR, relative risk; SCID, Structured Clinical Interview for DSM III-R. *95% CI not reported. †Reported as mean follow-up.

Carney et al. [10]Stable or unstable angina  521 yearDISComposite of MI, cardiac death, coronary revascularizationRR* 2.23
Ahern et al. [11]Post-MI 3531 yearBDIComposite of total mortality or cardiac arrestRR 1.38 (0.99, 1.93)
Ladwig et al. [12]Post-MI 560 male only6 monthsPSYCHIS- MünchenArrhythmic event; cardiac deathRR* 3.15 for arrhythmic event;  8.3 for cardiac death
Frasure-Smith et al. [13]Post-MI 22218 monthsBDIDISCardiac deathRR 7.82 (2.42, 25.26) for BDI,  3.64 (1.32, 10.05) for DIS
Barefoot et al. [14]Stable angina, unstable angina,  post-MI125019.4 yearsZung ScaleCardiac deathRR* 1.66 in first year, 1.84 in years 5–10, 1.72 > 10 years
Denollet et al. [15]Post-MI  877.9 yearsMBHIComposite of cardiac death or MIOR 7.5 (1.5, 36.4)
Kaufmann et al. [16]Post-MI 3311 yearDISTotal mortalityRR 2.33 (1.16, 4.65)
Welin et al. [17]Post-MI 27510 yearsZung ScaleCardiac death; total mortalityHR 3.54 (1.85, 6.79) for cardiac death; 2.45 (1.49, 4.02) for total mortality
Lesperance et al. [7]Unstable angina 4301 yearBDIDISComposite of cardiac death or MIOR 4.68 (1.94, 11.27) for BDI, OR not  reported for DIS
Bush el al. [18]Post-MI 2854 monthsBDISCIDTotal mortalityRR* 2.6 for BDI, 2.0 for SCID, 3.8 for BDI
Penninx et al. [19]Angina pectoris,  MI, heart failure 450 4.2 yearsCES-DDISCardiac deathRR 1.5 (0.9, 2.6) for minor depression,  3.9 (1.4, 10.9) for major depression
Shiotani et al. [20]Post-MI18281 yearZung ScaleComposite of cardiac death, MI, coronary revascularization, heart failure, unstable angina, or uncontrolled arrhythmiaOR 1.46 (1.11, 1.92)
Carney et al. [21]Post-MI 76630 monthsDISHTotal mortality; MIHR 2.4 (1.2, 4.7) for total mortality;  1.2 (0.7, 2.0) for recurrent MI
Pfiffner et al. [22]Post-MI 222 male only7 yearsPöldinger Depression ScaleTotal mortalityOR* 1.04

Although the results of a majority of the studies strongly suggest that depression in CAD patients is associated with increased cardiac morbidity and mortality, some studies have not shown an association (Table 2) [23–32]. Some proposed explanations for discrepant study results include variations in the patient population, differences in depression assessment, and whether or not depression was confounded with CAD severity [33]. Overall, despite the existence of inconclusive results, the weight of the accumulated evidence indicates that in CAD patients an important relation exists between depression and adverse cardiovascular events.

Table 2.  Overview of negative studies examining depression and cardiovascular events in coronary artery disease patients
StudyPopulationTotal sampleFollow-upSelf reportInterviewsOutcomeRisk (95% CI)
  1. BDI, Beck Depression Inventory; CBAHF, Cognitive Behavioral Assessment Hospital Form; CES-D, Center for Epidemiologic-Depression Scale; GHQ, General Health Questionnaire; HADS, Hospital Anxiety and Depression Scale; HR, hazards ratio; MI, myocardial infarction; OR, odds ratio; RR, relative risk; SCID-I-R, Structured Clinical Interview for DSM-IV; WHI-OS, Women's Health Initiative Observational Study. *95% CI not reported. † reported as median follow-up. ‡ reported as mean follow-up.

Jenkinson et al. [23]Post-MI13763 yearsPsychosocial QuestionnaireTotal mortalityRR* 1.06
Carinci et al. [24]Post-MI2449∼ 8 monthsCBAHFTotal mortalityHR 1.7 (0.9, 3.1)
Lane et al. 2000 [25], 2001 [26]Post-MI2884 months, 1 yearsBDICardiac death; total mortalityOR 1.31 (0.53, 3.24) for cardiac death at  4 months, 1.15 (0.49, 2.67) for cardiac death  1 year; no increase in total mortality associated  with depression for either follow-up period——  OR not reported for total mortality
Mayou et al. [27]Post-MI3446 and 18 monthsHADSTotal mortalityRR, OR, or HR not reported
Lauzon et al. [28]Post-MI5501 yearBDITotal mortality; recurrent ischemia, MI, heart  failure, readmission for cardiac eventHR 1.3 (0.59, 3.05) for mortality; 1.4  (1.05, 1.86) for composite of other events
Stewart et al. [29]Post-MI, unstable  angina11308.1 yearsGHQCardiac death, MI, stroke, unstable anginaHR 0.95 (0.59, 1.54) for cardiac death,  1.22 (0.97, 1.53) for composite
Wassertheil-Smoller et al. [30]Subgroup of  WHI-OS with history of cardiovascular  disease18 572 women only4.1 yearsShort Form of CES-DComposite of MI, coronary death, angina, or coronary revascularization; composite of MI or coronary death; heart failure; stroke; cardiac death; total mortality RR 0.92 (0.80, 1.05); 0.94 (0.75, 1.18);  1.14 (0.93, 1.40); 1.45 (1.11, 1.90); 1.22  (0.92, 1.61); 1.10 (0.93, 1.31) respectively
Strik et al. [31]Post-MI2063 yearsSCID-I-RComposite of total mortality or MIHR 1.10 (0.36, 3.42)
Steeds et al. [32]Post-MI13132 monthsBDITotal mortalityOR 1.8 (0.56, 6.0)

Postulated mechanisms responsible for the link between depression and adverse cardiovascular events in CAD patients

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Evidence linking depression to increased cardiovascular risk in CAD patients
  6. Postulated mechanisms responsible for the link between depression and adverse cardiovascular events in CAD patients
  7. Depression and platelet reactivity
  8. Depression and procoagulant factors
  9. Depression and inflammation
  10. Depression and endothelial vasomotor dysfunction
  11. Depression and abnormal autonomic activity
  12. Depression and poor treatment compliance
  13. Overlap with other negative emotions
  14. The causal status of the proposed mediators in the depression–cardiovascular disease prognosis link
  15. Depression intervention studies and prognosis
  16. Psychological therapy
  17. Pharmacological therapies
  18. Can current depression treatments improve cardiovascular prognosis in CAD patients?
  19. Direct pleiotropic effects of depression treatment: implications for depressed patients with CAD
  20. Diagnosis and treatment recommendations
  21. Future directions
  22. Acknowledgements
  23. References

The pathophysiological mechanisms responsible for the association between depression and adverse cardiac events in CAD patients remain poorly understood. Several mechanisms have been proposed, including increased platelet reactivity, abnormal blood coagulation, inflammatory activation, endothelial dysfunction, autonomic dysfunction, treatment non-adherence, and an overlap with other negative emotions [34–40].

Atherosclerosis is the result of a complex interaction between the arterial wall and circulating elements. The endothelium plays a pivotal role in regulating hemostatic, inflammatory, and reparative responses to local injury [1]. Endothelial dysfunction may promote inflammation, oxidation of lipoproteins and lipid accumulation, smooth muscle proliferation, extracellular matrix deposition or lysis, and thrombogenesis [41]. These processes contribute to plaque development and progression, and subsequent vulnerability and rupture [42]. Platelet-thrombus formation over a disrupted or eroded atherosclerotic plaque plays a major role in ACS onset [1].

Depression and platelet reactivity

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Evidence linking depression to increased cardiovascular risk in CAD patients
  6. Postulated mechanisms responsible for the link between depression and adverse cardiovascular events in CAD patients
  7. Depression and platelet reactivity
  8. Depression and procoagulant factors
  9. Depression and inflammation
  10. Depression and endothelial vasomotor dysfunction
  11. Depression and abnormal autonomic activity
  12. Depression and poor treatment compliance
  13. Overlap with other negative emotions
  14. The causal status of the proposed mediators in the depression–cardiovascular disease prognosis link
  15. Depression intervention studies and prognosis
  16. Psychological therapy
  17. Pharmacological therapies
  18. Can current depression treatments improve cardiovascular prognosis in CAD patients?
  19. Direct pleiotropic effects of depression treatment: implications for depressed patients with CAD
  20. Diagnosis and treatment recommendations
  21. Future directions
  22. Acknowledgements
  23. References

The severity of an ACS event is related to the magnitude and stability of the formed thrombus, modulated by a number of local and systemic thrombogenic factors including platelet reactivity [42]. Increased platelet reactivity is involved in ACS onset and is a significant predictor of cardiovascular disease outcomes after MI [43]. The importance of platelet reactivity and its inhibition is clearly demonstrated by the clinical benefits associated with the use of antiplatelet agents in CAD patients [44].

Increased platelet reactivity has been suggested as a mechanism by which depression increases adverse cardiovascular events in CAD patients [45]. Several small case–control studies have demonstrated the existence of platelet hyperreactivity in apparently healthy, depressed patients. Compared with non-depressed controls, depressed patients without CAD exhibit significantly elevated platelet glycoprotein IIb/IIIa activation (PAC1 monoclonal antibody binding) assessed by flow cytometry after orthostatic challenge [46]. In addition, higher levels of platelet factor 4 and β-thromboglobulin have been described in depressed patients with CAD compared with non-depressed controls [34,47].

Despite the evidence of exaggerated platelet reactivity in depressed CAD patients, the underlying mechanism(s) responsible for this association remain unknown. Several studies of depressed patients without CAD indicate that agonists such as collagen [48], thrombin [49] and epinephrine [50] may be involved. We previously reported increased platelet reactivity to serotonin in patients without CAD with major depression compared with matched non-depressed controls [51]. Our findings are consistent with some but not all previous reports [52,53] examining serotonin-mediated platelet reactivity in patients with depression. Serotonin is a plausible mediator as serotonergic abnormalities on platelets and central nervous system neurons have been reported in healthy depressed patients [54,55]. The observed increase in serotonin-mediated platelet reactivity may be due to the platelet serotonin 2A receptor. Depression is associated with an upregulation and/or increased sensitivity of the platelet serotonin 2A receptor, and increased response of the platelet phosphoinositide signaling system to serotonin [56].

Depression and procoagulant factors

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Evidence linking depression to increased cardiovascular risk in CAD patients
  6. Postulated mechanisms responsible for the link between depression and adverse cardiovascular events in CAD patients
  7. Depression and platelet reactivity
  8. Depression and procoagulant factors
  9. Depression and inflammation
  10. Depression and endothelial vasomotor dysfunction
  11. Depression and abnormal autonomic activity
  12. Depression and poor treatment compliance
  13. Overlap with other negative emotions
  14. The causal status of the proposed mediators in the depression–cardiovascular disease prognosis link
  15. Depression intervention studies and prognosis
  16. Psychological therapy
  17. Pharmacological therapies
  18. Can current depression treatments improve cardiovascular prognosis in CAD patients?
  19. Direct pleiotropic effects of depression treatment: implications for depressed patients with CAD
  20. Diagnosis and treatment recommendations
  21. Future directions
  22. Acknowledgements
  23. References

Intracoronary thrombosis over a disrupted or eroded atherosclerotic plaque is a pivotal event in the pathogenesis of ACS events [1]. The coagulation and fibrinolytic cascade plays an important role in the local thrombotic responses involved in ACS onset and recurrence [57]. Factors such as fibrinogen, D-dimer, von Willebrand factor antigen, and tissue plasminogen activator antigen are associated with worse cardiovascular outcomes in patients with CAD [58–61].

Several epidemiological studies have investigated the relationship between depression and procoagulant factors. In the ATTICA study, depression was associated with increased fibrinogen levels in cardiovascular disease-free persons, even after adjustment for other cardiovascular risk factors [35]. In the Coronary Artery Risk Development in Young Adults (CARDIA) Study, fibrinogen was positively associated with the presence of depression [62]. However, this association was no longer significant after controlling for gender, body mass index, exercise, ethnicity and smoking. In the Cardiovascular Health Study, which enrolled patients aged ≥ 65 years without a history of cardiovascular disease, depression was associated with both fibrinogen and factor VIIc levels, but the results were no longer significant after controlling for other cardiovascular risk factors [63]. Similar loss of significance after multivariate analysis with conventional CAD risk factors has also been observed between depression and D-dimer, a proposed marker of enhanced in vivo fibrin formation and degradation [64]. Overall, in these studies the elevation of procoagulant factors associated with depression may have been confounded by the presence of other cardiovascular risk factors.

Depression and inflammation

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Evidence linking depression to increased cardiovascular risk in CAD patients
  6. Postulated mechanisms responsible for the link between depression and adverse cardiovascular events in CAD patients
  7. Depression and platelet reactivity
  8. Depression and procoagulant factors
  9. Depression and inflammation
  10. Depression and endothelial vasomotor dysfunction
  11. Depression and abnormal autonomic activity
  12. Depression and poor treatment compliance
  13. Overlap with other negative emotions
  14. The causal status of the proposed mediators in the depression–cardiovascular disease prognosis link
  15. Depression intervention studies and prognosis
  16. Psychological therapy
  17. Pharmacological therapies
  18. Can current depression treatments improve cardiovascular prognosis in CAD patients?
  19. Direct pleiotropic effects of depression treatment: implications for depressed patients with CAD
  20. Diagnosis and treatment recommendations
  21. Future directions
  22. Acknowledgements
  23. References

Recent advances have demonstrated the important role of inflammation in promoting atherosclerosis [42]. Population-based prospective studies [65,66] support the contention that inflammation markers are significant predictors of ACS development in apparently healthy persons. In patients presenting with an ACS event, inflammatory markers also significantly predict subsequent mortality [67].

Several studies have linked depression to inflammation in patients without CAD. Levels of C-reactive protein and interleukin (IL)-6 are significantly higher in healthy depressed patients compared with matched controls [68]. The Cardiovascular Health Study showed that depressed patients had higher levels of C-reactive protein compared with non-depressed patients, even after adjusting for other potential confounders [63]. Corroborative findings from the ATTICA study revealed that C-reactive protein was independently associated with depression symptom severity [35]. There is an association between depression and other inflammatory markers. An increased expression of IL-8 and tumor necrosis factor (TNF)-α in blood monocytes following in vitro lipopolysaccharide stimulation has been observed in healthy depressed women vs. non-depressed matched controls [69].

To our knowledge, only two studies have assessed whether depression is associated with a higher level of inflammatory markers in CAD patients [36,70]. One study found that depression was associated with increased IL-1β and IL-6 levels in male patients prior to planned percutaneous coronary intervention [70]. A more recent report showed that after an ACS event, levels of soluble intercellular adhesion molecule-1 but not IL-6 or C-reactive protein were significantly higher in depressed compared with non-depressed patients [36]. These findings suggest that inflammation may be implicated in the increased cardiovascular risk observed in depressed CAD patients.

Depression and endothelial vasomotor dysfunction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Evidence linking depression to increased cardiovascular risk in CAD patients
  6. Postulated mechanisms responsible for the link between depression and adverse cardiovascular events in CAD patients
  7. Depression and platelet reactivity
  8. Depression and procoagulant factors
  9. Depression and inflammation
  10. Depression and endothelial vasomotor dysfunction
  11. Depression and abnormal autonomic activity
  12. Depression and poor treatment compliance
  13. Overlap with other negative emotions
  14. The causal status of the proposed mediators in the depression–cardiovascular disease prognosis link
  15. Depression intervention studies and prognosis
  16. Psychological therapy
  17. Pharmacological therapies
  18. Can current depression treatments improve cardiovascular prognosis in CAD patients?
  19. Direct pleiotropic effects of depression treatment: implications for depressed patients with CAD
  20. Diagnosis and treatment recommendations
  21. Future directions
  22. Acknowledgements
  23. References

Endothelial dysfunction, including vasoconstriction, leukocyte adhesion, thrombosis, and cellular proliferation in the vessel wall, is considered to be the initial process in atherosclerosis development [41]. Endothelial-dependent vasomotion is abnormal in patients with classic CAD risk factors such as hypertension, diabetes, cigarette smoking, and hyperlipidemia [71]. Halcox et al. [72] demonstrated that in the subgroup of patients with normal coronary arteries, coronary endothelial vasomotor dysfunction predicted an increased risk of cardiovascular events at long-term follow-up. In patients with CAD, a similar relationship exists between impaired baseline forearm blood flow response to acetylcholine assessed by venous occlusion plethysmography and cardiovascular prognosis [73].

Evidence suggests that depression is associated with endothelial dysfunction. Endothelial-dependent flow-mediated vasodilation assessed by brachial artery ultrasound has been found to be significantly reduced in treated depressed patients compared with matched healthy controls [37,74]. Further, in a study conducted by Chrapko et al. [75], plasma levels of nitric oxide metabolites and platelet endothelial nitric oxide synthase activity were significantly lower in healthy depressed subjects compared with non-depressed controls. These findings strongly suggest that nitric oxide dysregulations and abnormalities in vascular tone and reactivity may be involved in the depression–CAD prognosis link.

Depression and abnormal autonomic activity

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Evidence linking depression to increased cardiovascular risk in CAD patients
  6. Postulated mechanisms responsible for the link between depression and adverse cardiovascular events in CAD patients
  7. Depression and platelet reactivity
  8. Depression and procoagulant factors
  9. Depression and inflammation
  10. Depression and endothelial vasomotor dysfunction
  11. Depression and abnormal autonomic activity
  12. Depression and poor treatment compliance
  13. Overlap with other negative emotions
  14. The causal status of the proposed mediators in the depression–cardiovascular disease prognosis link
  15. Depression intervention studies and prognosis
  16. Psychological therapy
  17. Pharmacological therapies
  18. Can current depression treatments improve cardiovascular prognosis in CAD patients?
  19. Direct pleiotropic effects of depression treatment: implications for depressed patients with CAD
  20. Diagnosis and treatment recommendations
  21. Future directions
  22. Acknowledgements
  23. References

Decreased heart rate variability reflects increased sympathetic or diminished vagal tone and is an independent predictor of cardiovascular events in post-MI patients [76]. Heart rate variability has been examined and is typically reduced in depressed CAD patients [77–79]. Thus, abnormal autonomic function has been postulated to be another mechanism by which depression in CAD patients is associated with poor cardiovascular disease prognosis. The results of a substudy [38] of the ENRICHD trial [80] found abnormal baseline parameters of heart rate variability in the depressed post-MI group compared with a non-depressed cohort. Whether the effect of depression on subsequent cardiac outcomes in CAD patients is explained by reduced heart rate variability remains unknown.

Depression and poor treatment compliance

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Evidence linking depression to increased cardiovascular risk in CAD patients
  6. Postulated mechanisms responsible for the link between depression and adverse cardiovascular events in CAD patients
  7. Depression and platelet reactivity
  8. Depression and procoagulant factors
  9. Depression and inflammation
  10. Depression and endothelial vasomotor dysfunction
  11. Depression and abnormal autonomic activity
  12. Depression and poor treatment compliance
  13. Overlap with other negative emotions
  14. The causal status of the proposed mediators in the depression–cardiovascular disease prognosis link
  15. Depression intervention studies and prognosis
  16. Psychological therapy
  17. Pharmacological therapies
  18. Can current depression treatments improve cardiovascular prognosis in CAD patients?
  19. Direct pleiotropic effects of depression treatment: implications for depressed patients with CAD
  20. Diagnosis and treatment recommendations
  21. Future directions
  22. Acknowledgements
  23. References

Depressed patients often have unhealthy lifestyles, and they frequently fail to comply with treatment recommendations [81]. Post-MI patients with symptoms of depression are less likely to exercise regularly, adhere to a diet, and take prescribed medications, including aspirin, after discharge [39,82]. Further, depression is associated with continued smoking following an adverse cardiovascular event [83].

Although no studies have been conducted to test specifically whether poor adherence to treatment affects cardiovascular outcomes in depressed CAD patients, evidence from several trials [84,85] with different medical populations suggests that poor treatment adherence, even to placebo, is associated with worse cardiovascular outcomes. For instance, in the Beta-Blocker Heart Attack Trial, patients who did not adhere well to treatment regimens after MI were significantly more likely to die at 1 year [84]. These findings suggest that treatment non-adherence may mediate the increased cardiovascular risk observed in depressed CAD patients.

Overlap with other negative emotions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Evidence linking depression to increased cardiovascular risk in CAD patients
  6. Postulated mechanisms responsible for the link between depression and adverse cardiovascular events in CAD patients
  7. Depression and platelet reactivity
  8. Depression and procoagulant factors
  9. Depression and inflammation
  10. Depression and endothelial vasomotor dysfunction
  11. Depression and abnormal autonomic activity
  12. Depression and poor treatment compliance
  13. Overlap with other negative emotions
  14. The causal status of the proposed mediators in the depression–cardiovascular disease prognosis link
  15. Depression intervention studies and prognosis
  16. Psychological therapy
  17. Pharmacological therapies
  18. Can current depression treatments improve cardiovascular prognosis in CAD patients?
  19. Direct pleiotropic effects of depression treatment: implications for depressed patients with CAD
  20. Diagnosis and treatment recommendations
  21. Future directions
  22. Acknowledgements
  23. References

In addition to depression, other negative emotions such as anxiety and anger are also associated with poor cardiovascular disease prognosis after an MI [15,86]. For the most part, the prognostic effects of these emotions have been studied separately. A recent study [40] examined the comparative effects of depression and anxiety on cardiac prognosis in post-MI patients and found that anxiety was an independent predictor of cardiac death or recurrent non-fatal MI. Although depression was associated with cardiac events, the relation was no longer present after adjusting for anxiety. These findings suggest that anxiety may mediate the increased risk of adverse cardiovascular events observed in depressed CAD patients, although studies with opposing results also exist [27]. Future studies of depression in CAD patients should consider other symptoms of emotional distress to ensure that depression is uniquely prognostic. It is possible that the lack of consistent assessment of these other emotions has led researchers to conclude erroneously that depression is an independent prognostic factor for CAD patients. The possible involvement of other negative emotions has therapeutic implications, as treatments for depression differ considerably from those aimed at reducing stress, hostility, or anxiety.

The causal status of the proposed mediators in the depression–cardiovascular disease prognosis link

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Evidence linking depression to increased cardiovascular risk in CAD patients
  6. Postulated mechanisms responsible for the link between depression and adverse cardiovascular events in CAD patients
  7. Depression and platelet reactivity
  8. Depression and procoagulant factors
  9. Depression and inflammation
  10. Depression and endothelial vasomotor dysfunction
  11. Depression and abnormal autonomic activity
  12. Depression and poor treatment compliance
  13. Overlap with other negative emotions
  14. The causal status of the proposed mediators in the depression–cardiovascular disease prognosis link
  15. Depression intervention studies and prognosis
  16. Psychological therapy
  17. Pharmacological therapies
  18. Can current depression treatments improve cardiovascular prognosis in CAD patients?
  19. Direct pleiotropic effects of depression treatment: implications for depressed patients with CAD
  20. Diagnosis and treatment recommendations
  21. Future directions
  22. Acknowledgements
  23. References

Biological mediators have been implicated in the association between depression and increased risk of adverse cardiovascular events in patients with CAD. However, most of the mechanistic studies were case–control or cross-sectional in design, and/or examined otherwise healthy patients without CAD. Further, behavioral mediators, including an overlap with other negative emotions and treatment non-adherence, also remain poorly characterized. Therefore, the possible causal status of these mediators in triggering cardiovascular events in depressed CAD patients cannot be established at this time. For example, it is not clear how depression and inflammatory status are related. It is possible that depression exacerbates the inflammatory state in patients with CAD, increasing the risk of subsequent cardiovascular events. Conversely, inflammation in CAD patients may trigger depression. In this scenario, depression may merely reflect an elevated inflammatory state in which the risk of recurrent cardiovascular events is high. The relation between depression and inflammation could also be bidirectional. Knowledge about the independent effect or degree of redundancy among these mediators is urgently needed to help clarify depression's role in cardiovascular event recurrence. It is paramount that future studies be prospective, consider several mechanisms simultaneously, and include depressed and non-depressed patients with CAD.

Depression intervention studies and prognosis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Evidence linking depression to increased cardiovascular risk in CAD patients
  6. Postulated mechanisms responsible for the link between depression and adverse cardiovascular events in CAD patients
  7. Depression and platelet reactivity
  8. Depression and procoagulant factors
  9. Depression and inflammation
  10. Depression and endothelial vasomotor dysfunction
  11. Depression and abnormal autonomic activity
  12. Depression and poor treatment compliance
  13. Overlap with other negative emotions
  14. The causal status of the proposed mediators in the depression–cardiovascular disease prognosis link
  15. Depression intervention studies and prognosis
  16. Psychological therapy
  17. Pharmacological therapies
  18. Can current depression treatments improve cardiovascular prognosis in CAD patients?
  19. Direct pleiotropic effects of depression treatment: implications for depressed patients with CAD
  20. Diagnosis and treatment recommendations
  21. Future directions
  22. Acknowledgements
  23. References

Numerous modalities effectively treat and/or ameliorate depression and its associated symptoms. This review will focus on two treatment categories: psychological and pharmacological. Evidence-based psychological depression treatments include cognitive, behavioral, and interpersonal therapies. Pharmacological therapies include the newer generation antidepressants such as the selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors, and serotonin 2A receptor antagonists and older-generation antidepressants such as the tricyclic, heterocyclic antidepressants, and monoamine oxidase inhibitors.

Psychological therapy

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Evidence linking depression to increased cardiovascular risk in CAD patients
  6. Postulated mechanisms responsible for the link between depression and adverse cardiovascular events in CAD patients
  7. Depression and platelet reactivity
  8. Depression and procoagulant factors
  9. Depression and inflammation
  10. Depression and endothelial vasomotor dysfunction
  11. Depression and abnormal autonomic activity
  12. Depression and poor treatment compliance
  13. Overlap with other negative emotions
  14. The causal status of the proposed mediators in the depression–cardiovascular disease prognosis link
  15. Depression intervention studies and prognosis
  16. Psychological therapy
  17. Pharmacological therapies
  18. Can current depression treatments improve cardiovascular prognosis in CAD patients?
  19. Direct pleiotropic effects of depression treatment: implications for depressed patients with CAD
  20. Diagnosis and treatment recommendations
  21. Future directions
  22. Acknowledgements
  23. References

The effect of psychological therapy on adverse cardiac events in depressed patients with CAD was recently examined in the ENRICHD trial [8]. This randomized controlled trial was designed to determine whether cardiac morbidity and/or mortality were reduced by treatment in post-MI patients who were depressed and/or had low social support. Post-MI patients with major depression, minor depression, or dysthymia, and/or low perceived social support (N = 2481) were randomized to usual care or psychological intervention that included an evidence-based cognitive behavior therapy [87] for up to 6 months and, if needed, adjunctive pharmacotherapy. The results showed a significant but small reduction in depression and an increased level of social support in the treatment arm. However, there were no differences in the primary outcome, death or non-fatal MI, at a mean follow-up of 41 months. In addition, there were no differences in outcome among the patients who had low perceived social supported, depression, or both.

Pharmacological therapies

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Evidence linking depression to increased cardiovascular risk in CAD patients
  6. Postulated mechanisms responsible for the link between depression and adverse cardiovascular events in CAD patients
  7. Depression and platelet reactivity
  8. Depression and procoagulant factors
  9. Depression and inflammation
  10. Depression and endothelial vasomotor dysfunction
  11. Depression and abnormal autonomic activity
  12. Depression and poor treatment compliance
  13. Overlap with other negative emotions
  14. The causal status of the proposed mediators in the depression–cardiovascular disease prognosis link
  15. Depression intervention studies and prognosis
  16. Psychological therapy
  17. Pharmacological therapies
  18. Can current depression treatments improve cardiovascular prognosis in CAD patients?
  19. Direct pleiotropic effects of depression treatment: implications for depressed patients with CAD
  20. Diagnosis and treatment recommendations
  21. Future directions
  22. Acknowledgements
  23. References

Because the SSRIs are the best studied, they are considered the first choice for the pharmacological treatment of depressed CAD patients [88]. Ease of administration and a better cardiovascular safety profile have made SSRIs more appealing than the older-generation antidepressants [89,90].

The safety of SSRIs in post-MI depressed patients has been tested in two placebo-controlled trials [91,92]. In the first study [91], 54 post-MI depressed patients were randomized to the SSRI fluoxetine or placebo. Patients were required to have moderate to severe depressive symptoms, with a score higher than 17 on the 17-item Hamilton Depression (HAM-D) scale. There were no significant differences in cardiovascular outcomes between the two groups after 25 weeks of follow-up. A strong trend toward better improvement in depressive symptoms in the fluoxetine group compared with the placebo group was observed, although this finding was not statistically significant. A relatively high response rate in the placebo arm (36%) may have explained the lower than expected clinical benefit of fluoxetine.

In the second placebo-controlled trial, SADHART (Sertraline Antidepressant Heart Attack Randomized Trial) [92], 369 post-MI or unstable angina patients with major depressive disorder were randomized to placebo or to the SSRI sertraline for 24 weeks. Depression severity was assessed by the HAM-D and CGI-I (Clinical Global Impression Improvement) scales. There was no statistically significant difference in left ventricular ejection fraction, the primary safety endpoint, between the two arms. There were also no differences in heart rate, blood pressure, heart rate variability, incidence of ventricular arrhythmias, and rates of adverse cardiovascular events. Sertraline use was associated with modest reductions in CGI-I scores compared with placebo; HAM-D scores were not different between the arms after treatment. A consistent improvement in depressive symptoms was observed only in two subgroups: patients with any prior history of major depressive disorder, and patients with two prior episodes of major depressive disorder and moderate to severe depressive symptoms (HAM-D score = 18). There was a relatively high response rate of 53% in the placebo arm.

These studies clearly support the cardiovascular safety profile of SSRIs in the treatment of post-ACS depressed patients. However, neither trial was powered to detect differences in the occurrence of adverse cardiac outcomes with pharmacological treatment of depression. The effect of the antidepressant, mirtazapine (Remeron; Organon Inc., Roseland, NJ, USA), a serotonin and norepinephrine reuptake inhibitor, on cardiovascular events is currently being assessed in the ongoing MIND-IT (Myocardial INfarction and Depression-Intervention Trial) [93]. Patients with post-MI depression are enrolled and randomized to either usual care or staged pharmacological therapy. In the therapy arm, patients are further randomized to the antidepressant mirtazapine or placebo. After 8 weeks of antidepressant treatment, in case of refusal or non-response, open label treatment with the SSRI citalopram is offered. Tailored referral is the next and final stage of intervention in patients whose symptoms do not respond to citalopram use. The primary outcome of the study is the occurrence of cardiac death, MI, unstable angina, heart failure, or ventricular tachyarrhythmias at an average follow-up of 27 months. This study is unique because it is the first antidepressant treatment trial of CAD patients powered for cardiovascular outcomes. The results of MIND-IT will help clarify the efficacy of the reduction of depressive symptoms on cardiovascular outcomes in patients with CAD, although the ability to determine whether mirtazapine, citalopram, or tailored therapy is responsible for an improvement in cardiac prognosis is limited by the trial's design.

Can current depression treatments improve cardiovascular prognosis in CAD patients?

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Evidence linking depression to increased cardiovascular risk in CAD patients
  6. Postulated mechanisms responsible for the link between depression and adverse cardiovascular events in CAD patients
  7. Depression and platelet reactivity
  8. Depression and procoagulant factors
  9. Depression and inflammation
  10. Depression and endothelial vasomotor dysfunction
  11. Depression and abnormal autonomic activity
  12. Depression and poor treatment compliance
  13. Overlap with other negative emotions
  14. The causal status of the proposed mediators in the depression–cardiovascular disease prognosis link
  15. Depression intervention studies and prognosis
  16. Psychological therapy
  17. Pharmacological therapies
  18. Can current depression treatments improve cardiovascular prognosis in CAD patients?
  19. Direct pleiotropic effects of depression treatment: implications for depressed patients with CAD
  20. Diagnosis and treatment recommendations
  21. Future directions
  22. Acknowledgements
  23. References

At present, there is little evidence to support the contention that depression treatment improves cardiac prognosis. Several important issues remain. First, do psychological and pharmacological therapies substantially reduce depressive symptoms in CAD patients? Although there is some evidence to suggest that depression treatments are effective in patients with medical illnesses, placebo-controlled treatment trials have generally excluded depressed patients with medical comorbid conditions such as CAD [94]. The small treatment differences between the active intervention and control groups in the reviewed randomized trials may reflect the lack of efficacy of these treatment modalities in a medically comorbid patient population. Another possible explanation for the lack of a differential treatment effect is the relatively high spontaneous remission rates or the possibly short natural history of depressive symptom elevation that occurs in the absence of treatment after an MI [95,96]. In addition, a higher than expected antidepressant use in the usual care group also may have played a role in the high ‘spontaneous’ remission rates in the ENRICHD trial [8]. Whatever the reason, it is unlikely that such small relative differences in depression symptom severity between the control and intervention groups would have ultimately led to meaningful reductions in adverse cardiovascular events.

Second, what is the optimal timing of treatment initiation? In the ENRICHD trial [8], depressed patients were enrolled and treated within 28 days of the MI. Patients were eligible if depression had been present for at least 7 days and they had one prior episode of depression, or depression had been present for at least 14 days if they had no history of depression. In SADHART [92], patients were enrolled within 30 days of their hospitalization, and depression had to be present for a minimum of 2 weeks before randomization. Although there was a clear scientific rationale for requiring a minimum duration of depressive symptoms, treatment may have to be started even earlier (i.e. in the hospital) in depressed patients for a beneficial effect on prognosis to be seen. Other disease states may show a similar time-to-treatment dependency; the earlier treatment is initiated, the better the prognosis [97].

Third, what is the appropriate duration of the depression intervention? In the ENRICHD trial [8], the maximum duration of depression treatment was 6 months. In SADHART [92], the antidepressant sertraline was administered for approximately 6 months. These treatment periods may be too short, as a longer duration of therapy may be required in order for cardiovascular treatment benefits to be seen. The appropriate duration of depression treatment for CAD patients is unknown.

Direct pleiotropic effects of depression treatment: implications for depressed patients with CAD

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Evidence linking depression to increased cardiovascular risk in CAD patients
  6. Postulated mechanisms responsible for the link between depression and adverse cardiovascular events in CAD patients
  7. Depression and platelet reactivity
  8. Depression and procoagulant factors
  9. Depression and inflammation
  10. Depression and endothelial vasomotor dysfunction
  11. Depression and abnormal autonomic activity
  12. Depression and poor treatment compliance
  13. Overlap with other negative emotions
  14. The causal status of the proposed mediators in the depression–cardiovascular disease prognosis link
  15. Depression intervention studies and prognosis
  16. Psychological therapy
  17. Pharmacological therapies
  18. Can current depression treatments improve cardiovascular prognosis in CAD patients?
  19. Direct pleiotropic effects of depression treatment: implications for depressed patients with CAD
  20. Diagnosis and treatment recommendations
  21. Future directions
  22. Acknowledgements
  23. References

Similar to statins, whose clinical benefits may be in part related to their non-lipid-dependent, direct pleiotropic effects [98,99], antidepressants may also have important direct effects on the biological mediators involved in CAD progression and ACS recurrence.

Several studies have examined the effects on platelet reactivity of oral administration of SSRIs. The administration of paroxetine for 6 weeks significantly decreased platelet reactivity in depressed patients without CAD [100]. Paroxetine also significantly reduced plasma levels of β-thromboglobulin and platelet factor 4 in CAD patients [34]. Similar effects on platelet reactivity have been described after treatment with the SSRI sertraline [101,102].

Because significant improvements in depressive symptoms were observed in these mechanism studies, it is not known whether the effect on platelet reactivity was due to the antidepressant's direct pleiotropic effects, symptomatic improvement of depression (an indirect effect), or both (a net effect). Whereas antidepressant efficacy is equipotent among SSRIs [103], the results of in vitro studies have confirmed that they have divergent direct effects on platelet reactivity. When added to human blood samples, sertraline inhibits in vitro platelet reactivity as assessed by optical aggregometry, flow cytometry, and the rapid platelet-function assay [104]. The mechanism underlying this direct inhibitory effect on platelet reactivity is unknown. We have previously shown that paroxetine, in contrast to sertraline, increases in vitro platelet reactivity and thrombosis, and this effect may be related to nitric oxide inhibition [105,106].

To our knowledge, no study has prospectively compared the relative net effects of the oral administration of different SSRIs on platelet reactivity over time. Although paroxetine and sertraline reduce depressive symptoms to a similar degree [107], it is possible that sertraline inhibits platelet reactivity to a greater net degree than paroxetine, because sertraline directly inhibits platelet reactivity, in contrast to paroxetine, which may directly increase it (Table 3). In addition to the effect of antidepressants on platelet reactivity, in vitro studies also showed that antidepressants modulate the immune system [108]. These findings are suggestive that different SSRIs do not share the same direct pleiotropic properties.

Table 3.  Possible differential effects on platelet reactivity with depression treatment
TreatmentIndirect effect on platelet reactivity via symptomatic depression improvementDirect effect on platelet reactivityNet effect on platelet reactivity
PsychotherapyDecreaseNoneDecrease
SertralineDecreaseDecreaseSubstantial decrease
ParoxetineDecreaseIncrease via nitric oxide inhibitionDecrease, but less than psychotherapy
Other antidepressantsDecreaseUnknown effectUnknown effect

Given the important role of platelet reactivity, inflammation, and other biological mediators in the formation of atherosclerosis and ACS onset, the effect of antidepressant therapy on these mediators should be better characterized. Antidepressants that have beneficial effects on these biological processes may ultimately improve cardiovascular prognosis in CAD patients, regardless of the directionality of causal pathways (Fig. 1).

image

Figure 1. Multiple effects of antidepressants. In addition to reducing depressive symptoms, antidepressant medications may have direct, pleiotropic effects on biological processes, such as platelet reactivity and inflammation. These beneficial effects may reduce cardiovascular risk in coronary artery disease patients.

Download figure to PowerPoint

Diagnosis and treatment recommendations

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Evidence linking depression to increased cardiovascular risk in CAD patients
  6. Postulated mechanisms responsible for the link between depression and adverse cardiovascular events in CAD patients
  7. Depression and platelet reactivity
  8. Depression and procoagulant factors
  9. Depression and inflammation
  10. Depression and endothelial vasomotor dysfunction
  11. Depression and abnormal autonomic activity
  12. Depression and poor treatment compliance
  13. Overlap with other negative emotions
  14. The causal status of the proposed mediators in the depression–cardiovascular disease prognosis link
  15. Depression intervention studies and prognosis
  16. Psychological therapy
  17. Pharmacological therapies
  18. Can current depression treatments improve cardiovascular prognosis in CAD patients?
  19. Direct pleiotropic effects of depression treatment: implications for depressed patients with CAD
  20. Diagnosis and treatment recommendations
  21. Future directions
  22. Acknowledgements
  23. References

Although depression is common in CAD patients and is associated with a poor cardiovascular prognosis, depression is often underdiagnosed and consequently untreated. Lacking evidence to suggest that depression treatment lowers cardiac risk, the caring physician should be vigilant for the presence of minor and major depressive disorders at least for prognostic reasons. Psychiatric consultation or questionnaire screening may be appropriate for CAD patients at risk of depression.

In addition to affecting prognosis, depression substantially affects the quality of life of CAD patients. The Heart and Soul Study [6] assessed a range of health status outcomes in 1024 patients with stable CAD. Depressive symptoms, which were present in 20% of the patients, were strongly associated with greater symptom burden, greater physical limitation, and worse quality of life. The adverse effects of depression had an even greater impact on morbidity than left ventricular function and cardiac ischemia. Thus, it is important to improve the quality of life by reducing depressive symptoms by either psychological or pharmacological therapy. If antidepressant therapy is indicated, SSRIs appear to be the safest for depressed patients with CAD. Although the SSRI sertraline has been well studied, the specific choice of antidepressant medication should be tailored to the patient and existence of medical comorbid conditions. Physicians should account for side-effect profiles and important drug–drug interactions. Polypharmacy is the norm in the cardiovascular patient, and careful attention must be paid to potential cytochrome P-450 antidepressant–cardiovascular drug interactions [109]. The risk–benefit ratio must be considered before prescribing any medication, including an antidepressant, to a patient with underlying CAD [89].

Lastly, depression in CAD patients often accompanies other important medical comorbidities such as diabetes, hypertension, and smoking [110–112]. Special attention should be focused on the secondary prevention of adverse cardiovascular events through aggressive treatment of these other risk factors. Because depressed patients with CAD are at high risk of future cardiovascular events, the main strategy should be to manage treatment non-adherence, and achieve evidence-based goals quickly through frequent follow-ups with patients.

Future directions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Evidence linking depression to increased cardiovascular risk in CAD patients
  6. Postulated mechanisms responsible for the link between depression and adverse cardiovascular events in CAD patients
  7. Depression and platelet reactivity
  8. Depression and procoagulant factors
  9. Depression and inflammation
  10. Depression and endothelial vasomotor dysfunction
  11. Depression and abnormal autonomic activity
  12. Depression and poor treatment compliance
  13. Overlap with other negative emotions
  14. The causal status of the proposed mediators in the depression–cardiovascular disease prognosis link
  15. Depression intervention studies and prognosis
  16. Psychological therapy
  17. Pharmacological therapies
  18. Can current depression treatments improve cardiovascular prognosis in CAD patients?
  19. Direct pleiotropic effects of depression treatment: implications for depressed patients with CAD
  20. Diagnosis and treatment recommendations
  21. Future directions
  22. Acknowledgements
  23. References

Before treatment strategies can be routinely implemented, we await the results of future clinical trials in CAD patients that will help characterize the causal relation between depression, increased cardiovascular risk, and plausible mechanisms. Further studies testing the effects of depression treatment on important biological ACS mediators including platelet reactivity and inflammation should also be conducted. In vitro studies of antidepressants from the same class or across different classes as well as assessment of relevant mechanisms longitudinally during antidepressant therapy (before and after symptomatic improvement) will help determine the direct pleiotropic and net biological effects of antidepressant therapy. The study of depressed patients treated with psychological therapy also will help determine the indirect effect of depression remission on these mediators. Finally, we await the identification of depression treatments that have been tested in randomized controlled trials that will significantly reduce both depression symptoms and adverse cardiovascular outcomes in CAD patients. Depression and cardiovascular diseases are likely to be the most important causes of morbidity and mortality in this century. It is time for further research to focus on the joint presence of these two important public health concerns.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Evidence linking depression to increased cardiovascular risk in CAD patients
  6. Postulated mechanisms responsible for the link between depression and adverse cardiovascular events in CAD patients
  7. Depression and platelet reactivity
  8. Depression and procoagulant factors
  9. Depression and inflammation
  10. Depression and endothelial vasomotor dysfunction
  11. Depression and abnormal autonomic activity
  12. Depression and poor treatment compliance
  13. Overlap with other negative emotions
  14. The causal status of the proposed mediators in the depression–cardiovascular disease prognosis link
  15. Depression intervention studies and prognosis
  16. Psychological therapy
  17. Pharmacological therapies
  18. Can current depression treatments improve cardiovascular prognosis in CAD patients?
  19. Direct pleiotropic effects of depression treatment: implications for depressed patients with CAD
  20. Diagnosis and treatment recommendations
  21. Future directions
  22. Acknowledgements
  23. References
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