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Depression and Cardiovascular Disease

Depression and Cardiovascular Disease


  • Depression is associated with a 3- to 4-fold increase in the risk of recurrent cardiac events and death in patients with coronary artery disease.
  • Increased platelet reactivity that causes increased platelet aggregation and thrombus formation may play a strong role in linking depression and coronary heart disease.
  • Inflammatory markers that are increased in patients with depression have also been linked to congestive heart failure, atherosclerosis, myocardial infarction, and stroke.
  • In treating depressed patients with cardiovascular disease, the psychiatrist should use therapeutically effective doses of antidepressants, while keeping in mind other factors such as concurrent medications, age, and so forth.

Depression is a risk factor for cardiovascular disease and death in many ways, directly and indirectly. It is independently linked to smoking, diabetes, and obesity—all of which are risk factors for coronary heart disease (CHD).1 Depressed patients are more likely to be noncompliant with treatment recommendations, including diet, medications, and keeping appointments, and are more likely to delay presentation for treatment with an acute coronary event.2-4 However, depression often goes unrecognized by nonpsychiatric physicians.5-7

Comorbidity of Depression and CHD

Several large meta-analyses and reviews show that even after controlling for traditional risk factors for coronary artery disease, depression is independently associated with a 1.5- to 2-fold increase in the risk for coronary artery disease. Rugulies8 shows an overall relative risk (RR) for the development of CHD of 1.64 (95% confidence interval [CI], 1.29 to 2.08) in depressed patients and 2.69 (95% CI, 1.63 to 4.43) in the subset of patients with major depressive disorder (MDD).

The INTERHEART study, which evaluated more than 25,000 patients from 52 countries, looked at multiple risk factors for acute myocardial infarction.9 The investigators found that after controlling for multiple variables, a psychosocial factor index—a combined measurement of depression, general stress, life events, and locus of control—was a stronger risk factor for acute myocardial infarction than hypertension, diabetes, or obesity. Being depressed for 2 or more weeks was associated with an odds ratio (OR) of 1.55 (95% CI, 1.42 to 1.69) for acute myocardial infarction.

An analysis from the EPIC-Norfolk prospective study 6- to 10-year follow-up showed that participants who had had major depression during the year preceding their baseline assessment were 2.7 times more likely to die of ischemic heart disease, even after controlling for multiple other cardiac risk factors and antidepressant use.10

Depression in patients with preexisting cardiac disease is closely tied to negative outcomes. Overall, depression is associated with a 3- to 4-fold increase in the risk of recurrent cardiac events and death. It is predictive of future cardiac mortality and morbidity in patients with coronary artery disease without recent cardiac events, as well as mortality and morbidity in patients with a recent myocardial infarction.11-13 Depression also predicts morbidity and mortality in patients who have had coronary artery bypass procedures, as assessed over follow-up periods ranging from 2 to 12 years, and mortality and rehospitalization rates in patients with established congestive heart failure.14-18

Shared Pathophysiology of Depression and CHD

Several biological mechanisms have been proposed to explain the link between depression and CHD. There is significant physiological overlap among these various mechanisms, and different subtypes or aspects of depression may be associated with different physiological processes.

Increased platelet reactivity that causes increased platelet aggregation and thrombus formation may play a strong role in linking depression and CHD. In response to activation, platelets secrete serotonin, which acts on 5-HT2 receptors as a weak direct agonist to promote aggregation on the platelets, amplifies platelet aggregation response to other agonists, and induces the vasoconstriction of arteries.19,20

Depression has been linked to increased platelet 5-HT2 receptor binding and specifically to increased density of platelet 5-HT2 receptors, particularly in patients who have considered or attempted suicide.21,22 Musselman and colleagues23 reported that treatment with paroxetine for 6 weeks reduced platelet activation in 15 depressed patients, and Atar and colleagues24 reported that escitalopram also had an antiplatelet effect in 20 healthy participants. Whether these effects are of clinical importance remains to be seen.

Increased inflammatory response has been found in individuals with depression, including elevations of proinflammatory cytokines (eg, interleukin [IL]-1, IL-6, and tumor necrosis factor) as well as acute phase proteins (eg, C-reactive protein).25-29 These inflammatory markers have been linked in a number of studies to congestive heart failure, atherosclerosis, myocardial infarction, and stroke.30-31

Attempts to prove that there is an additive effect of depression on the elevated level of cytokines that is normally found in patients with heart disease have met with varied results. Lesprance and colleagues32 showed a significant association between depression and elevated levels of an endothelial activation marker—soluble intracellular adhesion molecule 1—in 481 patients tested 2 months after an acute coronary syndrome. They also found that depressed patients not taking statins had significantly higher C-reactive protein levels than patients who were not depressed. However, there were no differences in IL-6 levels between depressed patients and those who were not depressed. Schins and colleagues33 found no significant difference between inflammatory markers, including IL-6, C-reactive protein, and tumor necrosis factor-a in patients with and without depression who had had a myocardial infarction, even though the levels were above normal in both groups.

Depression is associated with more hypothalamic-pituitary-adrenal axis activity, as shown by increased corticotropin-releasing factor, higher cortisol levels, more catecholamines (adrenaline and noradrenaline), and resistance to the dexamethasone suppression test.34 Findings from a study by Otte and colleagues35 indicate that depression is significantly associated with elevated cortisol levels in patients with CHD. Catecholamines cause vasoconstriction and volume expansion, which can be beneficial in the short-term fight-or-flight response to acute threats but in a chronic state can eventually lead to heart failure. Elevated levels of catecholamines are linked to mortality from left ventricular dysfunction and heart failure.36,37

Depression is linked to derangements in autonomic cardiovascular control, with excessive sympathetic activity, and decreased parasympathetic cardiac modulation, as indicated by several studies of heart rate variability—an index of cardiac autonomic control.38,39 Reduced vagal (parasympathetic) modulation of the heart makes the heart more vulnerable to sudden death and arrhythmias. Low heart rate variability is also associated with a worse prognosis in congestive heart failure and after a myocardial infarction.40

The arterial endothelium plays a critical role in vascular tone and the maintenance of circulatory homeostasis. Impaired endothelial function is a known marker of cardiovascular risk, and arterial endothelial function has been found to be impaired in patients with depression.41,42


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