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Nonpharmacologic Treatments for Depression in Patients With Coronary Heart Disease

From the Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina.

Address correspondence to James A. Blumenthal, PhD, Duke University Medical Center, Box 3119, Durham, NC 27710. Address reprint requests to Heather S. Lett, MA, Department of Psychiatry and Behavioral Sciences, Box 3119, Duke University Medical Center, Durham, NC 27710. E-mail: lett0002{at}mc.duke.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PSYCHOLOGICAL TREATMENTS EXERCISE BOTANICAL, DIETARY, AND ENERGY... SUMMARY NOTES REFERENCES

 
Objective: We review nonpharmacologic treatments for depression in patients with coronary heart disease (CHD), including psychological therapies such as cognitive behavior therapy (CBT) and interpersonal therapy (IPT), aerobic exercise, St. John’s wort (SJW), essential fatty acids (EFAs), S-Adenosylmethionine (SAMe), acupuncture, and chromium picolinate (CP).

Method: Medline searches and reviews of bibliographies were used to identify relevant articles. Each treatment was reviewed with particular attention paid to empirical support, as well as to potential mechanisms of action that might affect not only depression but also CHD endpoints.

Results: Nearly all randomized controlled trials (RCTs) of depression treatments have been conducted with non-CHD patients. These studies have provided the most support for psychological treatments, particularly CBT and IPT. Aerobic exercise, SJW, and SAMe also have considerable empirical support in otherwise healthy persons, but SJW may have undesirable side effects for CHD patients. Data for EFAs, CP, and acupuncture are limited; however, the use of aerobic exercise shows considerable promise for cardiac patients.

Conclusions: There are few RCTs of patients with clinical depression and CHD, and those that exist have significant methodological limitations. Nonetheless, there is preliminary evidence that nonpharmacologic treatments are effective for cardiac patients with depression. In terms of reducing depression, the most evidence exists for psychological treatments, particularly CBT and IPT. However, there is little evidence that such treatment would also improve CHD risk factors. Aerobic exercise offers more promise to improve both mental and physical health due to its effect on cardiovascular risk factors and outcomes and thus warrants particular attention in future trials.

Key Words: depression • coronary disease • nonpharmacologic treatment • complementary therapies • randomized clinical trials

Abbreviations: AMI = acute myocardial infarction; BT = behavior therapy; BMT = behavioral marital therapy; CBT = cognitive behavior therapy; CP = chromium picolinate; CHD = coronary heart disease; DHA = docosahexaenoic acid; ENRICHD = Enhancing Recovery in Coronary Heart Disease; EFA = essential fatty acid; EPA = ethyl-eicosapentanoate; HAM-D = Hamilton Rating Scale for Depression; IPT = interpersonal therapy; MDD = major depressive disorder; RCT = randomized controlled trial; SAMe = S-adenosylmethionine; SJW = St. John’s wort.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PSYCHOLOGICAL TREATMENTS EXERCISE BOTANICAL, DIETARY, AND ENERGY... SUMMARY NOTES REFERENCES

 
There is mounting evidence that depression is a risk factor for coronary heart disease (CHD) (1,2). As a result, there has been a great deal of interest into potential treatments for depression in cardiac patients, with the hope that successful mental health treatment might also have a favorable effect on cardiovascular and physical health outcomes. CHD patients may differ from depressed but otherwise healthy patients in ways that have important treatment implications. First, possible interactions with medications or negative side effects of treatments are important to anticipate and monitor. Patients may be older and have medical comorbidities that make it challenging to sort out depression from symptoms of organic disease. CHD patients cope with chronic disease and acute health events or procedures, a burden that may affect their willingness to participate in or suitability for emotionally challenging or time-consuming treatments. Difficulties with transportation and other logistical hurdles may also make it more difficult to treat patients with traditional therapies. To maximize improvements in health outcomes and quality of life, CHD patients with depression may benefit most from interventions that simultaneously target both depression and cardiovascular risk factors.

The following review provides an introduction to several key nonpharmacologic treatments for depression in CHD patients, including psychological treatments, aerobic exercise, and such alternative therapies as St. John’s wort (SJW), essential fatty acids (EFAs), S-Adenosylmethionine (SAMe), acupuncture, and chromium picolinate (CP). Relevant articles were identified with Medline (1966–2004) searches using the terms using the search terms "depression," "coronary disease," "exercise," "psychotherapy," "hypericum," "fatty acids, essential," "acupuncture," "s-adenosylmethionine," "chromium," and "complementary therapies." The searches were limited to studies using human subjects and available in English language. Reference sections of relevant articles were also used to identify additional studies that had not been identified by the Medline search. Where possible, large, randomized controlled trials and meta-analyses were chosen over single studies, studies of small sample size, or studies of observational or noncontrolled designs.

For each therapeutic intervention, the effects on depression are reviewed and, if evidence exists, effects on cardiovascular risk factors and clinical outcomes also are reviewed. Randomized controlled trials (RCTs) of depressed patients with CHD provide the best evidence, and such studies are emphasized when available. However, as many of these therapies are emerging, we often rely on preliminary evidence provided by studies of nonclinically depressed samples, or non-CHD samples, at times with significant design limitations.

	PSYCHOLOGICAL TREATMENTS

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Effects on Depression
In the past decade, there has been an effort to establish criteria for evidence-based psychological treatments. Chambless and Ollendick (3) summarized findings from the American Psychological Association task force report, as well as findings from other sources by designating three categories of support based on the number and quality of studies lending support for a particular intervention: Category I treatments were defined as treatments shown to be superior to placebo or another plausible treatment in at least two studies. Category II treatments were supported by at least one such study. Category III treatments were defined as treatments with less rigorous or emerging support (e.g., innovative interventions not yet adequately tested, widely practiced methods not yet included in treatment trials, and retrospective case control studies).

According to these criteria, Category I treatments for major depression (MDD) include behavioral therapy (BT), behavioral marital therapy (BMT) (for patients with marital discord), cognitive behavior therapy (CBT), and interpersonal therapy (IPT). Category II treatments also include brief dynamic therapy, self-control therapy, and social problem solving therapy.

Although empirically-supported psychological therapies for depression exist, to our knowledge only one RCT, the Enhancing Recovery in Coronary Heart Disease (ENRICHD) trial (4, 5), has tested an empirically supported treatment for clinical depression in CHD patients. Based on evidence that both low social support and depression confer a risk for poorer clinical outcomes (1, 6), patients with an acute myocardial infarction (AMI) within 1 month who also had a diagnosis of MDD, minor depression with a history of MDD, dysthymia, or low social support were randomly assigned to usual care or a psychosocial intervention. The psychosocial intervention consisted of 6 to 12 sessions or up to 6 months of individual CBT, group therapy (when feasible), and concomitant treatment with antidepressant medication for severe or persistent depression. CBT for depression focuses on behavioral activation, active problem solving, and identifying and challenging depressogenic cognitions.

Initial results of the ENRICHD trial indicate that the intervention was associated with statistically significant improvements in depression compared with usual care. However, the between-group differences were relatively modest: the treatment group showed a 57% reduction in Hamilton Rating Scale for Depression (HAM-D) scores, while the usual care group showed a roughly comparable 47% reduction (7). It is noteworthy that this magnitude of change in depression is comparable to that seen in many trials of anti-depressant medication (8), including the SADHART trial of sertraline for depression in AMI patients (9).

Several RCTs have examined the effects of psychosocial interventions, including supportive individual therapy, supportive group therapy, and stress management, on depressive symptoms in CHD patients without documented MDD (10–13). Results of these intervention studies have been mixed in terms of improving depressive symptoms. Several studies reported null findings, with no advantage for patients receiving the psychological intervention (11,12). In contrast, other studies have shown that psychological interventions are associated with improvements in depressive symptoms (10). Overall, psychosocial treatments, especially using empirically validated approaches, appear effective in reducing depression in patients with CHD.

Effects on CHD Rick Factors and Clinical Outcomes
The ENRICHD trial is the only RCT that has evaluated the effects of an empirically supported intervention on depression in CHD patients. Although the CBT intervention was associated with modest improvements in depression and low perceived social support, it was failed to reduce rates of all cause mortality or recurrent cardiac events in the overall sample, or in a subsample including only patients with depression. At the 3-year follow-up, 24.4% of the patients in the treatment group had either died or had nonfatal reinfarction, compared with 24.2% in the usual care group (7). There also was a nonsignificant trend for women in the CBT intervention to do worse than controls, which replicated an earlier nursing-based psychosocial intervention (12). However, post hoc exploratory analyses suggest that the intervention may have been effective for white males but not women or minorities, an effect not due to differences in participation in treatment, or greater reductions in depression (14).

Studies of psychological interventions for CHD patients without depression also are relevant. These studies likewise have shown mixed results for clinical outcomes. For example, in the Ischemic Heart Disease Life Stress Monitoring Program (15), 461 men with a recent AMI were randomly assigned to usual care or a psychosocial nursing intervention. Patients who reported high levels of distress during monthly phone monitoring were visited in their homes. At the 1-year follow-up, the men in the intervention group had lower rates of mortality. However, in a subsequent study known as the M-HART trial (12), 1376 male and female patients with a recent MI were randomly assigned to 12 months of the same psychosocial intervention or usual care. The 12-month follow-up data indicated that, in contrast to the earlier trial, the intervention did not reduce rates of all-cause mortality. Furthermore, there was a trend in which women who received the intervention were actually at greater risk for cardiac and all cause-mortality compared with those who received usual care only. Similarly, Jones and West (11) randomized 2328 patients with a recent AMI to usual care or seven, 2-hour sessions of a psychosocial intervention that included group and individual psychotherapy, relaxation training, and stress management. Twelve-month follow-up data revealed that the intervention did not significantly reduce depression, nor did it decrease the risk for mortality or re-infarction.

Despite some negative findings, many studies have shown that psychological interventions are able to improve health outcomes. In the Myocardial Ischemia Intervention Trial (13), 136 patients with documented CHD and recent exercise-induced ischemia were assigned to usual care, exercise training, or a CBT-based stress-management intervention. Patients who took part in the CBT-based intervention showed reduced ischemia and were less likely to suffer a cardiac event over a mean follow-up time of 38 months. Indeed, the benefits appeared to persist for up to 5 years among patients receiving stress management training, and the clinical benefits were also associated with significant changes in medical expenses (16). A 1996 meta-analytic review concluded that psychosocial interventions increase quality of life and improve clinical outcomes (17). However, there have been important studies published after this review that reported negative results (11, 12). These mixed findings, particularly with regard to the effect of psychological interventions on health outcomes for women and minorities, make further trials a priority.

	EXERCISE

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Effects on Depression
There is growing evidence, mostly from noncontrolled trials, that exercise is an effective treatment for depression (18, 19). Most of the existing studies of exercise as a treatment for depression have focused on aerobic exercise. In one of the better-controlled studies in this area (20), 156 depressed, adult patients with MDD were randomized to 4 months of treatment with supervised aerobic exercise, antidepressant medication (sertraline), or a combination of exercise and medication. Although antidepressant medication was associated with a faster reduction in depression in the first 4 weeks of treatment, exercise was as effective as antidepressant medication in treating depression by the end of the 16-week intervention. Moreover, 6-month follow-up of participants revealed that those who continued to exercise were half as likely to relapse (21).

Exercise generally is considered safe for patients with stable CHD (22). Some studies of exercise treatments for CHD patients have tracked depressive symptoms and thus have provided some insight into the potential efficacy of exercise as a treatment for depression in this population (23). Although most of the studies in the area have reported significant improvements in depression after completion of an exercise program, many have had important methodologic limitations, including the failure to include a control group. For example, Milani et al. (24) followed 338 patients (20% with elevated depressive symptoms) with a recent cardiac event who were enrolled in cardiac rehabilitation (exercise and education). After the 3-month treatment, two thirds of the patients who were initially depressed were no longer depressed.

In one of the few controlled studies in this area, Taylor et al. (25) randomized 210 male patients with a recent AMI to one of four groups: 3 weeks of symptom-limited treadmill (TM) plus home-based exercise training, TM plus supervised training in the gym, TM without a formal exercise program, and control. At baseline, 13% of the patients were characterized as moderately to severely depressed based on their scores on the HAM-D. After 6 months of the treatment, the supervised gym-training group had significant reductions in HAM-D scores compared with the no training (beyond the initial 3 weeks of TM) and control groups, whereas the home-based group did not improve significantly. Stern et al. (10) randomized 106 male patients with a recent AMI and elevated depression, anxiety, or low fitness to 12 weeks of exercise training, group therapy, or a usual care control group. At the 1-year follow-up, both the counseling and the exercise group showed improvements in depression relative to controls. In sum, evidence suggests that exercise reduces depressive symptoms in CHD patients, but more research on patients with documented MDD is needed. Exercise may be effective in part because it involves behavioral activation, a key component of CBT for depression.

Effects on CHD Outcomes and Physiologic Risk Factors
Exercise has well-documented cardiovascular benefits. Exercise training is associated with several beneficial physiologic changes, including improvements in autonomic nervous system (26) and hypothalamic pituitary adrenal axis functioning (27), endothelial function (28), hypertension (29), dyslipidemia (30), insulin resistance (31), and inflammation (32).

The role of exercise in primary prevention is well established. Epidemiologic studies have observed that physical inactivity in healthy individuals is associated with twice the risk for later developing CHD (33). Exercise interventions have also been shown to improve outcomes for patients with CHD. Two early meta-analyses (34, 35) pooled data from trials of cardiac rehabilitation programs that included exercise, among other interventions, for post-MI patients. Although most of the individual trials failed to show a statistically significant benefit to these interventions, both meta-analyses, which allowed for the analysis of substantially more patients, reported about a 25% decrease in all-cause mortality for patients in intervention groups. Because some studies tested multimodal interventions of which exercise was one component, it was not possible to determine the independent effect of exercise from the other elements such as stress reduction, counseling, dietary modifications, smoking cessation, and weight reduction. More recently, however, Jolliffe et al. (36) conducted a meta-analysis comparing exercise-only interventions, comprehensive rehabilitation, and usual care. Exercise only interventions were associated with a decrease in both all-cause and cardiac mortality, a difference of 31% and 27%, respectively. Comprehensive rehabilitation, on the other hand, was not associated with statistically significant reductions in all-cause mortality but was associated with a decreased risk for cardiac mortality, to a slightly lesser extent than exercise only interventions. Recent data from the ENRICHD trial suggest that exercise may reduce the rates of mortality and nonfatal reinfarction in depressed or socially isolated post-MI patients (37). After controlling for medical and demographic variables, the magnitude of reduction in risk associated with exercise was nearly 40% for nonfatal reinfarction and 30% for mortality. The evidence that exercise affects depression, CHD risk factors, and CHD outcomes suggests that exercise is a particularly promising intervention for depression in this population.

	BOTANICAL, DIETARY, AND ENERGY-BASED TREATMENTS

TOP ABSTRACT INTRODUCTION PSYCHOLOGICAL TREATMENTS EXERCISE BOTANICAL, DIETARY, AND ENERGY... SUMMARY NOTES REFERENCES

 
A variety of botanical, dietary, and energy-based approaches have been studied under controlled, and often double-blind, conditions in depression. These are summarized in Table 1. The evidence is solid for SJW as being superior to placebo, although a recent review (38) found declining strength of effect in more recent trials. An unpublished analysis by Davidson and Wagner (J. Davidson, personal communication) of the largest available database (n = 26 trials, including unpublished studies) finds a substantial decline in relative risk (RR) ratio for SJW over PBO, when the original cohort of 14 published studies (39) was compared with 12 more recently published and unpublished placebo-controlled, double-blind trials (RR = 2.48 (95% CI = 1.84, 3.33) versus RR = 1.36 (95% CI = 1.08, 1.70).

For SAMe, the evidence is reasonably compelling, but for three other treatments (omega-3 EFA, chromium and acupuncture) there are minimal data from well-controlled trials, although they remain promising approaches. In the context of this review, it is important to emphasize that none of the five treatments has been adequately evaluated in patients with CHD.

	SUMMARY

TOP ABSTRACT INTRODUCTION PSYCHOLOGICAL TREATMENTS EXERCISE BOTANICAL, DIETARY, AND ENERGY... SUMMARY NOTES REFERENCES

 
In summary, although depression has emerged as an important risk factor for CHD, there is no concensus on the optimal way to treat depression in CHD patients. The only RCT to date to test a nonpharmacologic treatment for depression in CHD patients with clinical depression is the ENRICHD trial. The results of the ENRICHD trial indicate that while CBT may reduce depression in patients with a recent MI, the magnitude of change in depressive symptoms compared with controls was relatively modest (2 points on the HAM-D). More importantly, the primary analysis revealed that CBT did not reduce rates of mortality or cardiac events. Secondary analyses did indicate that the intervention was effective in reducing event rates in specific subgroups (i.e., white males) (14) and that group therapy may be particularly effective. It is possible that other psychosocial interventions, such as IPT, may prove to be effective. Further research is needed to address these questions.

There are other emerging nonpharmacologic treatments for depression, including exercise, SJW, EFAs, SAMe, acupuncture, and CP. SJW may have potentially harmful interactions with medications, a risk that warrants further scrutiny, particularly in cardiac populations. Exercise, EFAs, SAMe, and CP may be particularly helpful as they have been shown to effect both depression and cardiovascular risk factors.

Research on patient treatment match might improve treatment efficacy. Ultimately, it may be possible to identify patients based on demographic, disease, and psychological characteristics that are most likely to respond to particular treatments. A greater understanding of the timing of treatment might also improve efficacy. For example, the ENRICHD trial was designed to intervene with depression detected shortly after an AMI. This might not have been the optimal time to assess and intervene with depression as the chance of detecting an adjustment disorder or transient depressed mood is high and some patients may be unwilling to address psychological issues at the time of cardiac surgery or after an AMI. At such times, patients may be more amenable to passive interventions, such as antidepressants, or herbal therapies. Future research might also begin to determine if nonpharmacologic treatments in combination with antidepressant medication offer added benefit (40). Although it is not possible at this point to recommend any treatment for depression over another to reduce cardiac risk, depression is common in this population and certainly warrants treatment due to quality of life concerns alone. Psychotherapy (particularly CBT and IPT) has the most empirical support of nonpharmacologic treatments. Because behavioral activation is a key ingredient of CBT and exercise has known CHD benefits, exercise combined with CBT may prove most effective in reducing depression and improving overall health in patients with CHD.

	NOTES

TOP ABSTRACT INTRODUCTION PSYCHOLOGICAL TREATMENTS EXERCISE BOTANICAL, DIETARY, AND ENERGY... SUMMARY NOTES REFERENCES

 

In accordance with CME accreditation guidelines, author Jonathan Davidson disclosed that he has received research support or speaker fees, and/or has served as a scientific advisor for Solvay, Pfizer, GlaxoSmithKline, Wyeth-Ayerst, Forest, Eli Lilly, Ancile, Roche, Novartis, Organon, Boehringer Ingelheim, UCB-Pharma, Pharmacia, Johnson and Johnson, Boots, Bristol-Myers-Squibb, Cephalon, Nutrition 21, Sanofi-Synthelabo, PureWorld, and Allergan. The other authors of this article disclosed no real or potential conflicts of interest.

DOI:10.1097/01.psy.0000163453.24417.97

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