“Blues” ain’t good for the heart

Research in recent decades suggests that depression and coronary heart disease (CHD) have a bidirectional relationship. Depression, independent of other risk factors in an otherwise healthy person, doubles the risk of developing CHD.[1] Depression is seen in about 20% of the patients hospitalized with acute coronary syndromes either at admission or in the immediate period following recovery from CHD.[2]

DEPRESSION IN PATIENTS WITH CORONARY HEART DISEASE

Cross-sectional studies have reported that between 19 and 66% of the patients with myocardial infarction (MI) have depressive and anxiety symptoms,[3,4] and a significant proportion of these patients (17–44%) are diagnosed with major depression.[5–7] In addition, major depression is also common following coronary bypass surgery[8] and in patients with unstable angina.[9] Thus, these studies suggest that the prevalence rate of depression among patients with CHD is far greater than the 12-month prevalence rate of 6.6% reported in the community.[10]

IMPACT OF DEPRESSION ON PRE-EXISTING CORONARY HEART DISEASE

Over the last two decades, evidence has accumulated for the adverse impact of depression in patients with CHD. In one of the earliest studies in this area, Frasure Smith et al.[11] in their study of depression and coronary heart disease in 222 patients post MI, those diagnosed with major depression on a modified version of the Diagnostic Interview Schedule had an adjusted hazard ratio of 3.44 (95% CI 2.25–4.63) for mortality over 6 months of follow-up compared with the controls. This was approximately equivalent to the risk engendered by clinical factors such as diminished left ventricular function and past history of MI. In a subsequent study, the same group of investigators followed-up this cohort over 18 months.[12] Although baseline depression still predicted mortality at 18 months, its impact mainly occurred in the first 6 months. Similar findings of high mortality in subjects with unstable angina and comorbid depression have been reported.[9] In addition, depression also has a negative impact on survival rates following coronary artery bypass graft (CABG). Two studies reported that the presence of depression at baseline prior to CABG was an independent predictor of cardiovascular mortality post-CABG.[13,14] There is also a dose–response relationship between depression and death due to adverse cardiac events,[15] with increased baseline depression scores being associated with a higher risk of cardiac mortality.[16]

DEPRESSION AND THE RISK OF DEVELOPMENT OF CORONARY HEART DISEASE

Several prospective studies have reported depression as a risk factor for the development of CHD, and this risk is independent of other cardiovascular risk factors. In a large prospective community-based study, patients with a history of dysphoria or depression had 4.5-times relative risk (RR) of having an acute MI compared with non-depressed subjects independent of other cardiovascular risk factors.[17] It was also noted in this study that the risk of developing CHD was linked to the severity of depression, with an RR of 4.5 for developing CHD in subjects with major depression as opposed to 2.1 for subjects with dysphoria. A metaanalysis of studies in this area reported an RR of 1.64 for the development of CHD in subjects with depression.[1]

PATHOPHYSIOLOGICAL LINK BETWEEN DEPRESSION AND CORONARY HEART DISEASE

Depression and lifestyle behavior

There exist several possible mechanisms that underlie the relationship between depression and CHD. Depression is associated with unhealthy lifestyle; depressed patients have a sedentary lifestyle, more likely to smoke and consume alcohol and are overweight/obese.[18–20] Depression is also associated with non-compliance to medical treatment. In a metaanalysis, DiMatteo et al.[21] reported that depression is linked to non-adherence to treatment recommendations, with an OR of 3.03 (95% CI 1.964–4.89); non-compliant patients are almost three-times more likely to die in the first year of follow-up post-MI compared with those considered compliant.[22] Similarly, depressed patients are less likely to participate in cardiac rehabilitation such as adopting an exercise program.[23] Exercise also has a positive impact on depression[24] and CHD.

DEPRESSION AND CARDIAC AUTONOMIC REGULATION

Patients with depression are known to have decreased heart rate variability (HRV).[25,26] HRV (beat-to-beat alterations in heart rate) is a dynamic measure of cardiac autonomic regulation. In one of the earliest studies, Kleiger et al.[27] showed that decreased HRV was independently associated with an increased risk for mortality in post-MI patients. Numerous studies have since confirmed this association between decreased HRV, especially the vagal component and mortality, in high-risk populations as well as those living in the community. Low-HRV has been observed in patients with depression and in depressed patients with CHD compared with non-depressed subjects.[28–30] In addition, many medications used in the treatment of depression adversely impact HRV.[31,32]

DEPRESSION AND INFLAMMATORY PROCESSES

Pro-inflammatory cytokines such as tissue necrosis factor (TNF), interleukin-1 (IL-1) and IL-6 have been implicated in the etiopathogenesis of CHD.[33] Elevated levels of pro-inflammatory markers have also been reported in patients with major depression,[34] raising the possibility that inflammatory processes may be involved in both the onset of depression and CHD.

OTHER MECHANISMS

A variety of other mechanisms have been proposed that underlie the association between depression and risk of CHD. These include elevated endothelin levels in patients with depression, which has been linked to a higher risk of plaque rupture,[35] a greater risk of diabetes and insulin resistance in depression,[36,37] elevated platelet reactivity[38] and altered coronary reserve flow impacting microvascular circulation in depression.[39]

TREATMENT OF DEPRESSION IN PATIENTS WITH CORONARY HEART DISEASE

While treatment of depression in patients with CHD offers the potential of improving quality of life and cardiac outcomes, only few studies have empirically studied the efficacy of treatment of depression in patients with CHD. The SADHART study examined the safety and efficacy of sertraline in patients with major depressive disorder and a recent MI or unstable angina.[40] The findings showed a modest decrease in depressive symptoms in patients with sertraline versus placebo, but the study lacked statistical power to examine the impact of treatment of depression on clinical end points. In another study, ENRICHD investigators examined the impact of psychosocial intervention on outcomes in patients with depression and CHD.[41] Results from this randomized trial using cognitive behavior therapy in post-MI patients with depression showed that there was a small decrease in the depressive symptoms but no clear effect on survival. In a more recent randomized trial of antidepressants (Citalopram) and interpersonal therapy (IPT) compared with routine clinical management in 284 patients with major depressive disorder (MDD) and CHD, there was no significant difference between IPT and clinical management; however, citalopram was superior to placebo in reducing the hamilton depression rating scale (HAM-D) scores and demonstrated better remission rates (35.9% vs 22.5%).[42] However, this study did not examine the effects of treatment of depression on cardiac clinical outcomes. A recent randomized trial incorporating the concept of enhanced depressive care for patients with persistent depression in 237 post-acute coronary syndrome patients showed a significant reduction in depressive symptoms and modest improvement in cardiac prognosis.[43]

There is robust evidence for an association between depression and CHD from both epidemiological and clinical studies. In addition, depression confers a poor outcome in patients with a recent MI and in patients with unstable angina. While the pathophysiological basis for this link still remains uncertain, various studies in the recent decade have suggested several possible mechanisms. Treatment studies indicate safety of antidepressants such as sertraline and citalopram in the treatment of depression in patients with CHD, but more studies are needed to demonstrate the impact of treatment of depression on hard cardiac clinical end points. There is preliminary indication from efficacy studies that medication is perhaps more effective than psychosocial interventions, and is in line with recent observations that somatic symptoms but not cognitive symptoms of depression are associated with an increased risk of 12-month all-cause mortality.[44] A recent randomized study that is examining the effects of exercise and antidepressant therapy on depression and cardiac outcomes (UPBEAT trial) has the potential to open new avenues for treatment intervention.[45] More comprehensive studies are also needed to understand the interactions between depression and other risk factors for CHD that will enable development of more focused intervention.