New frontiers in cardiovascular behavioral medicine: Comparative effectiveness of exercise and medication in treating depression

MECHANISMS LINKING DEPRESSION AND CHD

CONVENTIONAL APPROACHES TO TREATMENT OF DEPRESSION

Treatment of depression has focused on reduction of symptoms and restoration of function. Antidepressant medications are generally considered the treatment of choice.⁵⁶ In particular, second-generation antidepressants such as selective serotonin reuptake inhibitors (SSRIs) are widely prescribed.⁵⁷ Current treatment guidelines suggest 6 to 12 weeks of acute treatment followed by a continuation phase of 3 to 9 months to maintain therapeutic benefit.⁵⁸ However, meta-analyses of antidepressant medications have reported only modest benefits over placebo treatments.^59,60 In particular, active drug–placebo differences in antidepressant efficacy are positively correlated with depression severity: antidepressants are often comparable with placebo in patients with low levels of depression but may be superior to placebo among patients with more severe depression. However, the explanation for this relationship may be that placebo is less effective for more depressed patients rather than antidepressants being more effective for more depressed patients.⁵⁹

For acute treatment of MDD, approximately 60% of patients respond to second-generation antidepressants,⁶¹ with a 40% relapse rate after 1 year.⁶² A recent meta-analysis⁶⁰ of second-generation antidepressants summarized four comparative trials and 23 placebo-controlled trials and found that second-generation antidepressants were generally comparable with each other. Interestingly, despite the modest benefit of antidepressants, the percentage of patients treated for depression in the United States increased from 0.73% in 1987 to 2.33% in 1997. The proportion of those treated who received antidepressants increased from 37.3% in 1987 to 74.5% in 1997.⁶³ The percentage of treated outpatients who used antidepressants has not increased significantly since 1997, but the use of psycho therapy as a sole treatment declined from 53.6% in 1998 to 43.1% in 2007.⁶⁴ Moreover, the national expenditure for the outpatient treatment of depression increased from $10.05 billion in 1998 to $12.45 billion in 2007, primarily driven by an increase in expenditures for antidepressant medications.

Uncertainty about value of antidepressant therapy

Despite compelling reasons for treating depression in cardiac patients, the clinical significance of treating depression remains uncertain. To date, only the Enhancing Recovery in CHD Patients (ENRICHD) trial has examined the impact of treating depression in post-MI patients on “hard” clinical end points.⁶⁵ Although more than 2,400 patients were enrolled in the trial, the results were disappointing. There were only modest differences (ie, two points on the Hamilton Depression Rating Scale [HAM-D]) in reductions of depressive symptoms in the group receiving cognitive behavior therapy (CBT) relative to usual-care controls and there were no treatment group differences in the primary outcome—all-cause mortality and nonfatal cardiac events. By the end of the follow-up period, 28.0% of patients in the CBT group and 20.6% of patients in usual care had received antidepressant medication. Although a subsequent reanalysis of the ENRICHD study revealed that antidepressant use was associated with improved clinical outcomes,⁶⁶ because patients were not randomized to pharmacologic treatment it could not be concluded that SSRI use was responsible for the improved outcomes.

In a randomized trial of patients with acute coronary syndrome (the Sertraline Antidepressant Heart Attack Randomized Trial, or SADHART),⁶⁷ almost 400 patients were treated with the SSRI sertraline or with placebo. Reductions in depressive symptoms were similar for patients receiving sertraline compared with placebo in the full sample, although a subgroup analysis revealed that patients with more severe depression (ie, those patients who reported two or more previous episodes) benefited more from sertraline compared with placebo. Interestingly, patients receiving sertraline tended to have more favorable cardiac outcomes, including a composite measure of both “hard” and “soft” clinical events, compared with placebo controls. These results suggested that antidepressant medication may improve underlying physiologic processes, such as platelet function, independent of changes in depression.⁶⁸ However, because SADHART was not powered to detect differences in clinical events, there remain unanswered questions about the clinical value of treating depression in cardiac patients with antidepressant medication.

In a second sertraline trial, SADHART-HF,⁶⁹ 469 men and women with MDD and chronic systolic HF were randomized to receive either sertraline or placebo for 12 weeks. Participants were followed for a minimum of 6 months. Results showed that while sertraline was safe, its use did not result in greater reductions in depressive symptoms compared with placebo (−7.1 ± 0.5 vs −6.8 ± 0.5) and there were no differences in clinical event rates between patients receiving sertraline compared with those receiving placebo.

In an observational study of patients with HF,⁴⁴ use of antidepressant medication was associated with increased risk of mortality or hospitalization. Although the potential harmful effects of antidepressant medication could not be ruled out, a more likely interpretation is that antidepressant medication use was a marker for individuals with more severe depression, and that the underlying depression may have contributed to their higher risk. Further, patients who are depressed, despite receiving treatment, may represent a subset of treatment-resistant patients who may be especially vulnerable to further cardiac events. Indeed, worsening depression is associated with worse outcomes in HF patients⁴⁶; this is consistent with data from the ENRICHD trial, which showed that patients receiving CBT (and, in some cases, antidepressant medication) who failed to improve with treatment had higher mortality rates compared with patients who exhibited a positive response to treatment.⁷⁰

A fourth randomized trial of CHD patients, the Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy (CREATE) trial,⁷¹ used a modified “2 by 2” design; 284 CHD patients with MDD and HAM-D rating scores of 20 or greater were randomized to receive 12 weeks of (a) interpersonal therapy (IPT) plus clinical management (CM) or (b) CM only and citalopram or matching placebo. Because the same interventionists delivered the CM and IPT, patients assigned to IPT received IPT plus CM within the same (extended) session. Patients receiving citalopram had greater reductions in depressive symptoms compared with placebo, with a small to medium effect size of 0.33, and better remission rates (35.9%) compared with placebo (22.5%). Unexpectedly, patients who received just CM tended to have greater improvements in depressive symptoms compared with patients who received IPT plus CM (P < .07); no clinical CHD end points were assessed, however.

Alternative approaches needed

Taken together, these data illustrate that antidepressant medications may reduce depressive symptoms for some patients; for other patients, however, medication fails to adequately relieve depressive symptoms and may perform no better than placebo. Adverse effects also may affect a subgroup of patients and may be relatively more common or more problematic in older persons with CHD.⁷² Thus, a need remains to identify alternative approaches for treating depression in cardiac patients. We believe that aerobic exercise, the cornerstone of traditional CR, may be one such approach. Exercise is safe for most cardiac patients,^73,74 including patients with HF,⁷⁵ and, if proven effective as a treatment for depression, exercise would hold several potential advantages over traditional medical therapies: it is relatively inexpensive, improves cardiovascular functioning, and avoids the side effects sometimes associated with medication use.