The American Heart Association science advisory on depression and coronary heart disease: An exploration of the issues raised

Medication adherence

One obvious but important way antidepressant drug therapy could prevent death or MI is by improving adherence to post-MI cardiovascular drugs. Four or five classes of cardiac drugs have each been proven to improve survival following ACS (aspirin, beta-blockers, statins, and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers), and when all are taken regularly, mortality is reduced by about half.^38,39 In addition, antihypertensive and antidiabetic drugs are often needed to control blood pressure or blood glucose. However, patients have to actually take these drugs to receive their benefit. Depression in the setting of CHD, especially ACS, is a risk indicator for lack of adherence to medical therapy, mental health therapy, or both.

DiMatteo et al conducted a meta-analysis to test the hypothesis that anxiety and depression might explain poor adherence to treatment recommendations and result in poor medical outcomes.¹⁵ Of the 25 trials that met the inclusion criteria, 13 studied anxiety and 12 studied depression. The associations between anxiety and nonadherence were small and not statistically significant, but depression was strongly associated with nonadherence to medications (odds ratio = 3.03; 95% confidence interval, 1.96–4.89). In other words, depressed patients were three times as likely as nondepressed patients to be nonadherent to treatment recommendations. The authors speculated that depression might increase nonadherence in the following ways: (1) the hopelessness of depression might reduce patients’ hope in the therapy, (2) depression may cause withdrawal from family and social networks that otherwise would provide support and assistance, or (3) the impaired cognitive dysfunction associated with depression may impair memory and follow through on treatment recommendations.¹⁵

The findings from this meta-analysis could reflect depression causing medication nonadherence or vice versa. To establish the sequence, Rieckmann et al measured adherence to aspirin therapy during a 3-month period in a consecutive cohort of 172 patients (25 to 85 years old) recruited within 1 week of hospitalization for ACS.⁴⁰ Severity of depressive symptoms was quantified using the BDI during hospitalization and at 1 and 3 months after discharge. Adherence was defined as taking aspirin as prescribed on at least 80% of days. Using an electronic monitoring system that recorded the date and time when the aspirin bottle cap was opened, the study found that more than 30% of patients with post-ACS depression were nonadherent to their aspirin therapy compared with only 15% of nondepressed patients.⁴⁰ The more severe patients’ depressive symptoms were, the greater the nonadherence to aspirin therapy. Moreover, a lagged correlation statistical model determined that improvement in depression preceded improvement in medication adherence.

SADHART was conducted under the new drug application for sertraline,¹⁶ which required that the use of trial drugs be under strict compliance to protocol, sponsor monitoring, and auditing by the US Food and Drug Administration. Drug use data were complete in 98.1% of participants. Adherence was measured using tablet counts. Depressed patients who had a large improvement in depression during blinded drug therapy (sertraline or placebo) showed improved adherence to the blinded therapy. To determine whether depression improved before medication adherence improved, researchers compared responders’ medication adherence before and after their improvement in depression. Medication adherence increased following remission of depression in 128 of 187 participants (68.4%) who remitted on trial medication (remission was defined as a Clinical Global Impression–Improvement score of 1). This sequence of change (improved depression before improved medication adherence) occurred significantly more often than would be expected by chance (P < .001). This finding suggests that improvement in depression is driving improved medication adherence.

Because persistent depression is associated with increased mortality rates and reduced medication adherence, physicians need to not only aggressively treat depression but also diligently promote adherence to guideline-defined cardiovascular drug therapy. If depression doesn’t improve, additional measures should be initiated not only to improve depression but also to achieve adherence to cardiovascular drug therapy (eg, assistance from spouse, child, or visiting nurse; calls by case manager; electronic health record monitoring of drug prescription refills). When depression is found during clinical encounters or by screening, nonadherence to drug treatment is much more likely and should be sought vigilantly.

Adherence to lifestyle recommendations

Ziegelstein et al have shown that depressed patients have poorer adherence to lifestyle recommendations (diet, exercise, smoking cessation).⁴¹ The Heart and Soul Study, a prospective cohort study of 1,017 outpatients with stable CHD, attempted to determine why depressive symptoms (as determined by PHQ-9 self-report) are associated with an increased risk of cardiovascular events.⁴² Participants were predominantly older men, about half of whom were recruited from Veterans Administration hospitals. A total of 341 cardiovascular events occurred during a mean follow-up of 4.8 years. Participants with baseline depressive symptoms had a 50% greater rate of cardiovascular events during the study period compared with participants without depressive symptoms. However, no significant association between depressive symptoms and cardiovascular events remained after adjustment for health behaviors—most strikingly, physical activity.⁴² This finding was consistent with an earlier study that found that exercise therapy plus antidepressant medication could reduce the risk of cardiovascular events in patients with depression.⁴³ The ongoing Understanding Prognostic Benefits of Exercise and Antidepressant Therapy (UPBEAT) study is comparing the effects of exercise and antidepressant medication on depression and biomarkers of cardiovascular risk in patients with depressive symptoms and CHD.⁴⁴ The study’s longer-term goal is to identify an intervention that improves both depression and cardiovascular disease outcomes.

CONCLUSIONS

The USPSTF recommends screening for depression in adults. The PHQ-2 is an efficient first-step screening tool that can identify many depressed patients who would otherwise go undetected. It is clear that SSRIs are safe in cardiac patients, can reduce depression, and can improve medication adherence, but it is not enough to screen and report depression. Optimal benefit depends on having (1) a primary care provider who is familiar with managing depression, (2) a case manager with a mental health background to follow and support patients, and (3) regular supervision of the case manager by a psychiatrist or psychologist. Cardiologists see large numbers of patients with chronic CHD, ACS, or recent coronary artery bypass graft surgery who are at high risk for depression. The AHA advisory recommends a care model that is practical for CHD patients with depression. Such a care model must be based on detection of depression and referral to a practice that has resources and knowledge to manage it well.