Depression and Cardiovascular Disease

Psychiatric TimesPsychiatric Times Vol 25 No 9
Volume 25
Issue 9

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


  • 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.5-7Comorbidity 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.14-18Shared 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.41,42Treating Depression Comorbid with Cardiovascular Disease

Depression can be safely treated in patients with coronary artery disease. One common mistake that physicians make is to undertreat patients who have mild congestive heart failure. Patients with severe congestive heart failure have reduced cardiac output, hepatic congestion, and renal impairment, which affects absorption, metabolism, and elimination of medications. However, allowing for necessary adjustments, the psychiatrist should use therapeutically effective doses of antidepressants, while keeping in mind other factors such as concurrent medications, age, and so forth.

Tricyclic antidepressants are not recommended as a first-line treatment option, even though they are as effective as SSRIs for treating depression. They cause orthostatic hypotension and delayed cardiac conduction, and can trigger ventricular arrhythmias when overdosed. Orthostatic hypotension can pose a significant risk for falls in elderly patients, and patients with heart disease often take medications (eg, diuretics, vasodilators) that can increase this risk. Tricyclic antidepressants are type 1A antiarrhythmic agents that prolong atrial and ventricular depolarization and widen P-R, QRS, and QT intervals. Studies have shown that QTc intervals of more than 440 milliseconds, and especially more than 500 milliseconds, are associated with an increased risk of sudden death.43 Type 1A antiarrhythmic agents have also been shown to increase mortality in patients who had had a myocardial infarction with premature ventricular contractions.43

Two small open-label trials initially demonstrated the safety but also relatively low efficacy of fluoxetine.44,45 A trial that compared paroxetine with nortriptyline in patients with left ventricular dysfunction found that both medications were effective but that the patients in the paroxetine group had significantly fewer adverse cardiac effects.46 Strik and colleagues47 published a randomized double-blind study that compared fluoxetine with placebo in patients who had had a myocardial infarction. Fluoxetine had no significant cardiac effects, although it was significantly more effective than placebo for patients with mild depression.

There have been 2 large double-blind studies of SSRIs in cardiac patients. In the Sertraline Antidepressant Heart Attack Randomized Trial (SADHART), 369 patients who had had a recent acute coronary syndrome (acute myocardial infarction or unstable angina) were randomized within 30 days of the coronary event to receive either sertraline or placebo.48,49 Sertraline at dosages of 50 to 200 mg daily was associated with a modest improvement in mood that was significant in patients with a history of at least 1 depressive episode or more severe depression, and there was no difference from placebo in heart rate, blood pressure, cardiac conduction, or left ventricular ejection fraction.

One study, the Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy (CREATE), looked at 284 patients with stable, documented coronary artery disease, a major depressive episode of at least 4 weeks, and a Hamilton depression rating (HAM-D) score of 20 or more. Patients were randomized to receive citalopram or placebo, as well as clinical management supplemented by interpersonal psychotherapy compared with clinical management alone.50 Citalopram for 12 weeks at a mean dosage of 33.1 mg daily was more efficacious than placebo and did not cause any adverse cardiovascular effects. Interpersonal psychotherapy conferred no significant benefit.

There has been 1 other large randomized controlled trial of antidepressants in patients with cardiac disease. In the Myocardial Infarction and Depression–Intervention Trial (MIND-IT), 2177 patients who were hospitalized for an acute myocardial infarction were evaluated for depression as defined by the International Classification of Diseases (ICD-10).51 The patients who met criteria and were eligible for the study were randomized to receive either care as usual (n = 122) or intervention (n = 209). A subset of participants in the intervention arm were randomized to mirtazapine, 30 to 45 mg daily, or placebo. Mirtazapine treatment was superior to placebo for some depression measures at 8 and 24 weeks.52 The remainder of the patients in the intervention arm received a variety of interventions for 6 months of treatment. At the 18-month follow-up, there were no significant differences between the intervention and control groups in Beck Depression Inventory (BDI) scores or presence of ICD-10–defined depression.

The Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) trial compared a cognitive-based psychosocial intervention-aimed at improving depression and increasing social supports-with usual medical care; 2481 patients with an acute myocardial infarction and either depression or poor social support were enrolled. Participants in the active treatment group attended a median of 11 individual sessions in 6 months, plus group therapy when feasible, and were referred to psychiatrists for possible antidepressant treatment if their HAM-D score was higher than 24 or they had less than a 50% reduction in their BDI scores after 5 weeks. The trial found that there was a statistically significant diminution in depressive symptoms and social isolation in the active intervention arm compared with the usual-care group. However, both groups showed substantial improvement at the 6-month follow-up; HAM-D scores improved by 10 points in the cognitive behavioral therapy group and by almost 9 points in the usual-care group.53Does Depression Treatment Reduce the Risk of Cardiac Events?

There is no clear evidence that treatment of depression reduces the risk of having a cardiac event. However, a large retrospective case-control study by Sauer and colleagues54 compared patients who were smokers and had been hospitalized with a first myocardial infarction with controls. After adjusting for numerous confounding variables, the OR for myocardial infarction among current SSRI users compared with nonusers was 0.35 (95% CI, 0.18 to 0.68; P < .01).

In a larger study of patients who had been hospitalized with a first myocardial infarction (both smokers and nonsmokers) compared with community controls, SSRI use overall was not associated with a significant reduction in risk of myocardial infarction. However, use of SSRIs that have a high affinity for the serotonin transporter-paroxetine, fluoxetine, and sertraline-was associated with a reduced risk of myocardial infarction. Users of other SSRIs or tricyclics did not have any significant difference in risk compared with nonusers, but overall there was a significant trend (P < .01) toward increased protective effect with an increased degree of affinity for the serotonin transporter.55

These 4 prospective, randomized, clinical studies-ENRICHD, SADHART, CREATE, and MIND-IT-have failed to show statistically significant cardiovascular benefits of treatment for depression. In the ENRICHD trial, there was no difference in recurrent myocardial infarction or mortality between the active and control groups. Patients taking antidepressants, particularly SSRIs, did have a significantly lower risk of both outcomes, but the use of antidepressants was not randomized.56

The SADHART study was designed to test the safety of sertraline in patients with heart disease-not to detect differences in cardiac outcomes.48,49 However, results of the study show a clear trend towards improved outcomes in the group treated with sertraline, with an RR of 0.77 for cardiac events (32 events in the sertraline arm and 41 events in the placebo arm). However, because of the low total number of cardiac events in the subject groups, this result is statistically nonsignificant.

As with SADHART, CREATE was underpowered to show any significant difference in cardiac outcomes.50 However, unlike SADHART, there was no trend toward improved cardiac outcomes with citalopram; there were 6 cardiovascular events in the citalopram arm and 6 events in the placebo arm. Of note, study participants started treatment an average of 18 months after their index event, unlike the participants in SADHART and ENRICHD, who usually began treatment in the first month.

In MIND-IT, there was no significant difference between the active intervention and usual-care groups in the number of cardiac events-myocardial infarction, cardiac death, revascularization, heart failure, myocardial ischemia, or ventricular arrhythmias-at 18 months.52 There was also no significant difference between those in the active group who received treatment with mirtazapine, citalopram, or other antidepressants (n = 90), and the usual-care group.


Modern treatment of depression is reasonably safe and effective for patients with cardiac disease, but treatment that has greater effectiveness than has been demonstrated so far would be highly desirable. Although depression treatment has not yet been shown to improve cardiac outcomes in depressed patients with heart disease, it is likely that it improves quality of life and functional status in cardiac patients.57




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