Cleveland Clinic Journal of Medicine

In 2008, the American Heart Association (AHA) published a science advisory on depression and coronary heart disease (CHD).¹ Since its publication, the advisory has evoked substantial commentary. The purpose of this article is threefold: (1) to explain the aims of the AHA science advisory, (2) to briefly discuss its content, and (3) to examine some of the comments it has provoked.

WHAT THE ADVISORY SET OUT TO DO

The purpose of an AHA science advisory is to provide rapid, clear, and consistent AHA positioning on a scientific issue. Advisories are statements on an evolving, prominent scientific issue of great interest to the public and health professionals. All AHA science advisories undergo peer review and are also reviewed and approved by the AHA Science Advisory and Coordinating Committee, AHA’s highest science body. Because this particular advisory addressed the interaction of cardiovascular and mental health, the AHA asked the American Psychiatric Association (APA) to review the document; the APA endorsed the AHA advisory.

Two points are worth emphasizing:

• An AHA science advisory is not a treatment guideline.
• Advisories usually are brief and therefore do not exhaustively discuss their topic.

After discussing epidemiologic studies that elucidated the relationships between depression and CHD, the AHA advisory on depression and CHD focuses on screening, referral, and treatment of depression from a cardiology perspective.

The 1-year prevalence of major depressive disorder in the US general population is 7%, and the lifetime prevalence is about 16%.² Depression in otherwise healthy persons almost doubles the risk of developing CHD.³ About 20% of patients hospitalized for acute coronary syndromes (ACS) have major depressive disorder on admission or within a few weeks thereafter, and these patients have about 2.5 times the mortality rate as patients who are not depressed, after adjusting for infarct severity and cardiovascular risk factors.^4–6

ASSESSMENT OF DEPRESSION AND DEPRESSIVE SYMPTOMS

The AHA advisory discusses use of the 2-question Patient Health Questionnaire (PHQ-2) as the first step in screening for depression.^7,8 The PHQ-2 inquires about the frequency of depressed mood and anhedonia by asking the following:

Over the past 2 weeks, how often have you been bothered by either of the following problems?

(1) Little interest or pleasure in doing things

(2) Feeling down, depressed, or hopeless.

For each item the response options are “not at all” (scored as 0), “several days” (scored as 1), “more than half the days” (scored as 2), and “nearly every day” (scored as 3). Thus, the total PHQ-2 score can range from 0 to 6.

Using a structured psychiatric interview as the standard, a total PHQ-2 score of 3 or greater has been shown to have a sensitivity of 83% and a specificity of 92% for major depression.⁷ A PHQ-2 score of 3 is the optimal cut point for screening purposes. A PHQ-2 score of 0 virtually excludes depression.

If a patient’s PHQ-2 score is 3 or greater, it is recommended that answers be obtained for a full 9-item PHQ. The PHQ-9 provides the sensitivity and specificity suitable for assigning a provisional diagnosis of major depressive disorder and a symptom severity score that can be used to identify patients for further evaluation and to make decisions about therapy.^9–11

Adapted from the 2008 American Heart Association science advisory on depression and coronary heart disease.1 Source: American Heart Association, Inc.

The US Preventive Services Task Force (USPSTF) currently recommends that clinicians screen adults for depression in clinical practices that have systems in place to assure accurate diagnosis, effective treatment, and follow-up.¹² The USPSTF concluded that there is good evidence that screening improves the accurate identification of depressed patients in primary care settings and that treating depressed adults identified in such settings reduces clinical morbidity. Results of trials that have directly evaluated the effect of screening on clinical outcomes depend on follow-up. Limited benefits have been demonstrated in studies that simply feed screening results back to clinicians. Larger benefits have been seen in studies in which the communication of screening results is coordinated with effective follow-up and treatment. The USPSTF concluded that the benefits of screening and treating are likely to outweigh any potential harms.¹²

DEPRESSION TREATMENT

Drug therapy

The safety of fluoxetine, sertraline (SADHART, ENRICHD), citalopram (CREATE), and mirtazapine (MIND-IT) has been evaluated in clinical trials.^4,17–21 By far the strongest evidence of safety is for selective serotonin reuptake inhibitors (SSRIs), especially sertraline.

The Sertraline Antidepressant Heart Attack Randomized Trial (SADHART; N = 369), a randomized study of depression after ACS, found no difference in cardiovascular adverse events between the sertraline and placebo groups after 16 weeks of therapy, and there were no significant differences in left ventricular ejection fraction, heart rate, blood pressure, ventricular premature complexes, or electrocardiogram changes.¹⁷ In the group assigned to sertraline, life-threatening cardiovascular events occurred less frequently (15% vs 22%, P = NS).

The Enhancing Recovery in Coronary Heart Disease study (ENRICHD) was a large trial (N = 2,481) to evaluate the effect of cognitive behavioral therapy (CBT) on depression or low perceived social support in patients enrolled within 28 days of myocardial infarction (MI).⁴ The ENRICHD protocol required patients randomized to CBT with Hamilton Depression Rating Scale (HAM-D) scores greater than 24, or who showed less than 50% reduction in Beck Depression Inventory (BDI) scores after 5 weeks of CBT, to be referred to a study psychiatrist for consideration of pharmacotherapy, usually sertraline. Of the overall ENRICHD population, 1,834 participants (74%) had a diagnosis of depression, and 446 of these participants (24%) were treated with antidepressant drugs, 301 with an SSRI and 145 with other antidepressants.¹⁸ During mean follow-up of 29 months, the SSRI-treated group had a statistically significant 43% reduction in death or MI.⁴

The Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy (CREATE) recruited 284 patients with chronic CHD, major depressive disorder, and a 24-item HAM-D score of 20 or greater and randomly assigned half to citalopram (another SSRI) and half to placebo.¹⁹ Citalopram showed antidepressant efficacy and no evidence of harm.

The Myocardial Infarction and Depression Intervention Trial (MIND-IT) recruited 91 patients within 30 days of hospital admission for MI with depression and randomized them in a 1:1 ratio to mirtazapine or placebo. Mirtazapine showed some evidence of antidepressant efficacy and no evidence of harm.²⁰

Strik et al in the Netherlands recruited 54 patients who had major depression after a first MI and randomized them 1:1 to the SSRI fluoxetine or placebo 3 months after the MI.²¹ The fluoxetine group showed a trend toward antidepressant efficacy, and no cardiovascular safety problems were detected clinically or by either electrocardiogram or echocardiogram.

APA practice guidelines for major depressive disorder indicate that among psycho therapeutic approaches, CBT and interpersonal psychotherapy have the best-documented efficacy for treatment of major depressive disorder.²² CBT aims to solve problems related to dysfunctional emotions, behaviors, and cognition and is an umbrella term for various techniques that share a theoretical basis in behavioristic learning theory and cognitive psychology. Aaron T. Beck proposed that depressed people are quick to make negative evaluations of themselves and the world, and he designed treatment to reduce these negative cognitions.²³ Interpersonal psychotherapy stems from the work of Harry Stack Sullivan, who believed that emotional reactions were triggered by interpersonal behaviors.²⁴ Gerald Klerman and Myrna Weissman used this method to treat adults diagnosed with moderate or severe nondelusional clinical depression.²⁵

CBT was used in ENRICHD,⁴ interpersonal psychotherapy in CREATE,¹⁹ and problem-solving therapy in the Coronary Psychosocial Evaluation Studies (COPES).^26,27 Unintended therapy can also be a confounder in antidepressant drug trials; education and supportive care (eg, frequent visits or telephone calls with monitoring of depressive symptoms and counseling) are often provided for both the intervention and control (placebo) groups. If a study is blinded, education, supportive care, and attention will be identical for both groups and thus may reduce the likelihood of finding a difference between the drug and placebo, if one exists.

Psychotherapy can be helpful for depression, is preferred over antidepressant drugs by some patients, and can be combined with drugs to increase antidepressant efficacy. We still have much to learn about timing and choice of therapy, as well as about sequencing and combination of antidepressant drugs and psychotherapy.

Physical activity and exercise

Aerobic exercise²⁸ and cardiac rehabilitation²⁹ can reduce depressive symptoms in addition to improving cardiovascular fitness. Depression can serve as a barrier to participation in cardiac rehabilitation and exercise programs, but cardiologists can help depressed patients overcome this barrier by offering encouragement and follow-up contacts. Cardiologists also should enlist the help of spouses or other family members and friends to promote adherence. The prescription of exercise needs to be based on the cardiac status and exercise capacity of each individual.³⁰

SUMMARY OF ADVISORY RECOMMENDATIONS

The AHA advisory¹ summarized its recommendations as follows:

1. Routine screening for depression in patients with CHD should be considered in a variety of settings, including the hospital, the physician’s office, clinics, and cardiac rehabilitation centers. The opportunity to screen for and treat depression in cardiac patients should not be missed, as effective depression treatment may improve health outcomes.

2. Patients with positive screening results should be evaluated by a professional qualified in diagnosis and management of depression. Such a clinician can determine whether depression is present and needs treatment, as well as how to connect a patient to an effective care program in the local area.

3. Patients with heart disease who are being treated for depression should undergo careful monitoring for adherence to their medical care and for the efficacy and safety of drug therapy for their medical and mental health conditions.

4. Coordination of care among health care providers is essential for patients with coexisting medical and mental health issues.

COMMENTS ON THE ADVISORY

Since AHA advisories usually address evolving scientific issues, the knowledge base on these issues is constantly growing and a range of opinions and hypotheses are tenable, pending new information. Soon after the AHA science advisory on depression and CHD was issued, a systematic review on depression screening and patient outcomes in cardiac care was published.³¹ This review posed three key questions that are explored below.

Key question 1: What’s the accuracy of screening instruments for depression in cardiovascular care populations? To answer this question, a case-finding method such as a questionnaire (eg, BDI or PHQ) must be compared with a structured interview by mental health personnel as the “gold standard” for diagnosis (ie, the truth).

To estimate the accuracy of clinical diagnosis by general practitioners, Mitchell et al pooled data from 50,371 primary care patients across 41 studies in Europe or the United States to evaluate general practitioners’ ability to make an unassisted diagnosis of depression (ie, without specific help from severity scales, diagnostic instruments, education programs, etc).³² They reported a sensitivity of about 50% and a specificity of 81% when the prevalence of depression was about 20%. In other words, general practitioners missed about half the cases of depression when no case-finding tool was used. These researchers pointed out that a low prevalence of depression favors identification of nondepressed cases (false-positive diagnoses), whereas a high prevalence favors diagnosis of depression (true-positive diagnoses).³²

Cardiologists focused on treatment of ACS are probably less likely to make a clinical diagnosis of depression and may attribute emotional symptoms to rapidly evolving cardiovascular events. The simple 2-question PHQ-2 case-finding instrument takes only a few minutes to administer and is recommended for use by primary care physicians or cardiologists to evaluate patients at high risk for depression or who manifest symptoms suggestive of depression.⁷

In the United States, most patients with depression are cared for in primary care venues. The AHA advisory recommends referring ACS patients who screen positive on a PHQ to a professional qualified in the diagnosis and management of depression.¹ Enhanced care—using outreach, monitoring, adjustment of therapy, and psychiatric backup—produces significant improvement in depression.³³

Key question 2: Is treatment of depression in cardiovascular care patients effective in improving depression? Cardiac outcomes? The evidence for benefit of SSRI therapy for depression detected at the time of ACS is consistent and was discussed above.^4,17–21 However, the antidepressant effect of SSRIs is modest in placebo-controlled trials. Most such trials excluded patients who were taking antidepressant drugs when screened, and many patients recruited for antidepressant clinical trials had no previous episodes of depression, had relatively mild symptoms of short duration, and were recruited by screening (ie, they were not seeking treatment for depression).³⁴ Patients with brief and short episodes are likely to remit spontaneously and to respond to psychotherapy or supportive care.³⁴ Moreover, in most antidepressant trials, both the intervention and “control” groups received elements of enhanced depression care, which will reduce the apparent benefit of antidepressant drugs. For instance, because the primary goal of SADHART was to evaluate the safety of sertraline in patients with ACS, monitoring for adverse effects included six or seven visits during 16 weeks of follow-up plus six or seven phone calls, providing several elements of enhanced depression care, including face-to-face education, frequent follow-up, support by a case manager (research coordinator) with a mental health background, and support from a psychiatrist or psychologist.¹⁷ Randomization to sertraline or placebo in SADHART was blinded, so the frequent contact and support was the same in both groups.

Whether SSRI treatment for depression will improve survival and cardiovascular outcomes is not established by adequately powered randomized trials. Most randomized (SADHART, CREATE) or nonrandomized (ENRICHD) studies suggest that SSRIs reduce cardiovascular events, but only ENRICHD produced a statistically significant result. SSRIs—certainly sertraline and citalopram—are not associated with significant cardiovascular adverse effects, even during ACS, when the cardiovascular system is unstable and multiple drugs are being started and titrated. Patients who do not improve significantly during antidepressant drug therapy or psychotherapy have a two-to threefold increase in cardiovascular events compared with patients who do improve substantially.³⁵

Key question 3: Is systematic screening for depression more effective than usual care for identifying patients with depression? Facilitating treatment of depression? Reducing depressive symptoms? Improving cardiac outcomes? Pignone et al conducted a literature review and meta-analysis on behalf of the USPSTF to clarify whether screening adults for depression in primary care venues improves recognition, treatment, and clinical outcomes.³⁶ They reviewed randomized trials conducted in primary care settings that evaluated the effect of screening for depression on identification, treatment, or health outcomes, including trials that examined integrated, systematic support for treatment after identification of depression. The meta-analysis suggested that screening and feedback of screening results reduced the risk of persistent depression. Stronger effects were observed with programs that integrated interventions to improve recognition and treatment of depressed patients and that incorporated quality improvements into clinic systems as compared with programs that provided only screening and feedback.

Screening patients with CHD, especially those with ACS, is more effective than usual care (no screening). Indeed, many depressed patients go undetected unless identified by screening. Not surprisingly, those identified by screening tend to have milder depression. For example, half the participants in SADHART had a HAM-D score less than 18 (≥ 25 is considered severe). However, a considerable number identified by screening had above-average HAM-D scores but either viewed their symptoms as appropriate for their medical condition or were simply denying their psychiatric illness. If patients had not been screened, their depression would not have been detected or treated. Even among SADHART participants with baseline HAM-D scores less than 18, those whose depression failed to respond to sertraline/placebo had twice the 7-year mortality rate as did those whose depression remitted.¹⁶

The Prevention of Suicide in Primary Care Elderly: Collaborative Trial (PROSPECT) examined the impact of a care management intervention on suicidal ideation and depression in older primary care patients and reported outcomes over a 2-year follow-up.³⁷ PROSPECT screened 9,072 patients in 20 primary care practices to find 599 study participants aged 60 years or older with major or minor depression (not all had cardiovascular disease). Participants were randomly assigned to either usual care or the PROSPECT intervention, which consisted of services rendered by trained care managers who offered algorithm-based recommendations to physicians and helped patients adhere to treatment during the 24-month trial. Compared with patients receiving usual care, those receiving the intervention had a greater likelihood of receiving antidepressant drugs and/or psychotherapy (85%–89% vs 49%–62%) and had a 2.2-fold greater decline in suicidal ideation over 24 months. Treatment response started sooner in the intervention group and continued to improve at 18 and 24 months; no appreciable increase in treatment response was observed in the usual-care group during the same period. Among patients with major depression, a significantly greater percentage of the intervention group achieved remission compared with the usual-care group at 4, 8, and 24 months. Patients with minor depression had favorable mental health outcomes regardless of treatment assignment. Sustained collaborative care maintained high utilization of depression treatment, reduced suicidal ideation, and improved the outcomes of major depression during 2 years of follow-up.³⁷

No randomized trial of SSRIs has been designed to show an effect on mortality or cardiovascular events. ENRICHD has produced the strongest evidence that an SSRI can reduce mortality or cardiovascular outcomes. The study was designed with approximately 85% power to detect a 25% to 30% reduction in the primary end point (death or MI) as a result of CBT; as noted above, 2,481 patients (1,834 with depression) were randomized to usual care or CBT within 28 days of MI.⁴ Depression significantly improved with CBT, but the rate of death or MI did not: during mean follow-up of 29 months, death or MI occurred in 299 patients in the CBT group versus 300 in the usual-care group.⁴ A post hoc analysis specific to the 1,834 ENRICHD participants who had depression aimed to determine the effects of antidepressant drugs on morbidity and mortality.¹⁸ The protocol required patients in the intervention group with scores of 25 or higher on the 17-item HAM-D, or those who had less than a 50% reduction in BDI scores after 5 weeks of treatment, to be referred to study psychiatrists for consideration of pharmacotherapy. Study psychiatrists met with patients who were being treated with antidepressant drugs to monitor medication use. Unless contraindicated or previously ineffective or poorly tolerated, sertraline was the first antidepressant used. Using a time-dependent multivariable Cox proportional hazards regression model to adjust for baseline depression score and cardiac risk factors, the researchers found SSRI use to be associated with a statistically significant 43% lower risk of death or nonfatal MI. Like other SSRI studies, ENRICHD found SSRIs safe for post-MI patients and to possibly, but not certainly, reduce death and MI.¹⁸

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.

In 2008, the American Heart Association (AHA) published a science advisory on depression and coronary heart disease (CHD).¹ Since its publication, the advisory has evoked substantial commentary. The purpose of this article is threefold: (1) to explain the aims of the AHA science advisory, (2) to briefly discuss its content, and (3) to examine some of the comments it has provoked.

WHAT THE ADVISORY SET OUT TO DO

The purpose of an AHA science advisory is to provide rapid, clear, and consistent AHA positioning on a scientific issue. Advisories are statements on an evolving, prominent scientific issue of great interest to the public and health professionals. All AHA science advisories undergo peer review and are also reviewed and approved by the AHA Science Advisory and Coordinating Committee, AHA’s highest science body. Because this particular advisory addressed the interaction of cardiovascular and mental health, the AHA asked the American Psychiatric Association (APA) to review the document; the APA endorsed the AHA advisory.

Two points are worth emphasizing:

• An AHA science advisory is not a treatment guideline.
• Advisories usually are brief and therefore do not exhaustively discuss their topic.

After discussing epidemiologic studies that elucidated the relationships between depression and CHD, the AHA advisory on depression and CHD focuses on screening, referral, and treatment of depression from a cardiology perspective.

The 1-year prevalence of major depressive disorder in the US general population is 7%, and the lifetime prevalence is about 16%.² Depression in otherwise healthy persons almost doubles the risk of developing CHD.³ About 20% of patients hospitalized for acute coronary syndromes (ACS) have major depressive disorder on admission or within a few weeks thereafter, and these patients have about 2.5 times the mortality rate as patients who are not depressed, after adjusting for infarct severity and cardiovascular risk factors.^4–6

ASSESSMENT OF DEPRESSION AND DEPRESSIVE SYMPTOMS

The AHA advisory discusses use of the 2-question Patient Health Questionnaire (PHQ-2) as the first step in screening for depression.^7,8 The PHQ-2 inquires about the frequency of depressed mood and anhedonia by asking the following:

Over the past 2 weeks, how often have you been bothered by either of the following problems?

(1) Little interest or pleasure in doing things

(2) Feeling down, depressed, or hopeless.

For each item the response options are “not at all” (scored as 0), “several days” (scored as 1), “more than half the days” (scored as 2), and “nearly every day” (scored as 3). Thus, the total PHQ-2 score can range from 0 to 6.

Using a structured psychiatric interview as the standard, a total PHQ-2 score of 3 or greater has been shown to have a sensitivity of 83% and a specificity of 92% for major depression.⁷ A PHQ-2 score of 3 is the optimal cut point for screening purposes. A PHQ-2 score of 0 virtually excludes depression.

If a patient’s PHQ-2 score is 3 or greater, it is recommended that answers be obtained for a full 9-item PHQ. The PHQ-9 provides the sensitivity and specificity suitable for assigning a provisional diagnosis of major depressive disorder and a symptom severity score that can be used to identify patients for further evaluation and to make decisions about therapy.^9–11

Adapted from the 2008 American Heart Association science advisory on depression and coronary heart disease.1 Source: American Heart Association, Inc.

The US Preventive Services Task Force (USPSTF) currently recommends that clinicians screen adults for depression in clinical practices that have systems in place to assure accurate diagnosis, effective treatment, and follow-up.¹² The USPSTF concluded that there is good evidence that screening improves the accurate identification of depressed patients in primary care settings and that treating depressed adults identified in such settings reduces clinical morbidity. Results of trials that have directly evaluated the effect of screening on clinical outcomes depend on follow-up. Limited benefits have been demonstrated in studies that simply feed screening results back to clinicians. Larger benefits have been seen in studies in which the communication of screening results is coordinated with effective follow-up and treatment. The USPSTF concluded that the benefits of screening and treating are likely to outweigh any potential harms.¹²

DEPRESSION TREATMENT

Drug therapy

The safety of fluoxetine, sertraline (SADHART, ENRICHD), citalopram (CREATE), and mirtazapine (MIND-IT) has been evaluated in clinical trials.^4,17–21 By far the strongest evidence of safety is for selective serotonin reuptake inhibitors (SSRIs), especially sertraline.

The Sertraline Antidepressant Heart Attack Randomized Trial (SADHART; N = 369), a randomized study of depression after ACS, found no difference in cardiovascular adverse events between the sertraline and placebo groups after 16 weeks of therapy, and there were no significant differences in left ventricular ejection fraction, heart rate, blood pressure, ventricular premature complexes, or electrocardiogram changes.¹⁷ In the group assigned to sertraline, life-threatening cardiovascular events occurred less frequently (15% vs 22%, P = NS).

The Enhancing Recovery in Coronary Heart Disease study (ENRICHD) was a large trial (N = 2,481) to evaluate the effect of cognitive behavioral therapy (CBT) on depression or low perceived social support in patients enrolled within 28 days of myocardial infarction (MI).⁴ The ENRICHD protocol required patients randomized to CBT with Hamilton Depression Rating Scale (HAM-D) scores greater than 24, or who showed less than 50% reduction in Beck Depression Inventory (BDI) scores after 5 weeks of CBT, to be referred to a study psychiatrist for consideration of pharmacotherapy, usually sertraline. Of the overall ENRICHD population, 1,834 participants (74%) had a diagnosis of depression, and 446 of these participants (24%) were treated with antidepressant drugs, 301 with an SSRI and 145 with other antidepressants.¹⁸ During mean follow-up of 29 months, the SSRI-treated group had a statistically significant 43% reduction in death or MI.⁴

The Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy (CREATE) recruited 284 patients with chronic CHD, major depressive disorder, and a 24-item HAM-D score of 20 or greater and randomly assigned half to citalopram (another SSRI) and half to placebo.¹⁹ Citalopram showed antidepressant efficacy and no evidence of harm.

The Myocardial Infarction and Depression Intervention Trial (MIND-IT) recruited 91 patients within 30 days of hospital admission for MI with depression and randomized them in a 1:1 ratio to mirtazapine or placebo. Mirtazapine showed some evidence of antidepressant efficacy and no evidence of harm.²⁰

Strik et al in the Netherlands recruited 54 patients who had major depression after a first MI and randomized them 1:1 to the SSRI fluoxetine or placebo 3 months after the MI.²¹ The fluoxetine group showed a trend toward antidepressant efficacy, and no cardiovascular safety problems were detected clinically or by either electrocardiogram or echocardiogram.

APA practice guidelines for major depressive disorder indicate that among psycho therapeutic approaches, CBT and interpersonal psychotherapy have the best-documented efficacy for treatment of major depressive disorder.²² CBT aims to solve problems related to dysfunctional emotions, behaviors, and cognition and is an umbrella term for various techniques that share a theoretical basis in behavioristic learning theory and cognitive psychology. Aaron T. Beck proposed that depressed people are quick to make negative evaluations of themselves and the world, and he designed treatment to reduce these negative cognitions.²³ Interpersonal psychotherapy stems from the work of Harry Stack Sullivan, who believed that emotional reactions were triggered by interpersonal behaviors.²⁴ Gerald Klerman and Myrna Weissman used this method to treat adults diagnosed with moderate or severe nondelusional clinical depression.²⁵

CBT was used in ENRICHD,⁴ interpersonal psychotherapy in CREATE,¹⁹ and problem-solving therapy in the Coronary Psychosocial Evaluation Studies (COPES).^26,27 Unintended therapy can also be a confounder in antidepressant drug trials; education and supportive care (eg, frequent visits or telephone calls with monitoring of depressive symptoms and counseling) are often provided for both the intervention and control (placebo) groups. If a study is blinded, education, supportive care, and attention will be identical for both groups and thus may reduce the likelihood of finding a difference between the drug and placebo, if one exists.

Psychotherapy can be helpful for depression, is preferred over antidepressant drugs by some patients, and can be combined with drugs to increase antidepressant efficacy. We still have much to learn about timing and choice of therapy, as well as about sequencing and combination of antidepressant drugs and psychotherapy.

Physical activity and exercise

Aerobic exercise²⁸ and cardiac rehabilitation²⁹ can reduce depressive symptoms in addition to improving cardiovascular fitness. Depression can serve as a barrier to participation in cardiac rehabilitation and exercise programs, but cardiologists can help depressed patients overcome this barrier by offering encouragement and follow-up contacts. Cardiologists also should enlist the help of spouses or other family members and friends to promote adherence. The prescription of exercise needs to be based on the cardiac status and exercise capacity of each individual.³⁰

SUMMARY OF ADVISORY RECOMMENDATIONS

The AHA advisory¹ summarized its recommendations as follows:

1. Routine screening for depression in patients with CHD should be considered in a variety of settings, including the hospital, the physician’s office, clinics, and cardiac rehabilitation centers. The opportunity to screen for and treat depression in cardiac patients should not be missed, as effective depression treatment may improve health outcomes.

2. Patients with positive screening results should be evaluated by a professional qualified in diagnosis and management of depression. Such a clinician can determine whether depression is present and needs treatment, as well as how to connect a patient to an effective care program in the local area.

3. Patients with heart disease who are being treated for depression should undergo careful monitoring for adherence to their medical care and for the efficacy and safety of drug therapy for their medical and mental health conditions.

4. Coordination of care among health care providers is essential for patients with coexisting medical and mental health issues.

COMMENTS ON THE ADVISORY

Since AHA advisories usually address evolving scientific issues, the knowledge base on these issues is constantly growing and a range of opinions and hypotheses are tenable, pending new information. Soon after the AHA science advisory on depression and CHD was issued, a systematic review on depression screening and patient outcomes in cardiac care was published.³¹ This review posed three key questions that are explored below.

Key question 1: What’s the accuracy of screening instruments for depression in cardiovascular care populations? To answer this question, a case-finding method such as a questionnaire (eg, BDI or PHQ) must be compared with a structured interview by mental health personnel as the “gold standard” for diagnosis (ie, the truth).

To estimate the accuracy of clinical diagnosis by general practitioners, Mitchell et al pooled data from 50,371 primary care patients across 41 studies in Europe or the United States to evaluate general practitioners’ ability to make an unassisted diagnosis of depression (ie, without specific help from severity scales, diagnostic instruments, education programs, etc).³² They reported a sensitivity of about 50% and a specificity of 81% when the prevalence of depression was about 20%. In other words, general practitioners missed about half the cases of depression when no case-finding tool was used. These researchers pointed out that a low prevalence of depression favors identification of nondepressed cases (false-positive diagnoses), whereas a high prevalence favors diagnosis of depression (true-positive diagnoses).³²

Cardiologists focused on treatment of ACS are probably less likely to make a clinical diagnosis of depression and may attribute emotional symptoms to rapidly evolving cardiovascular events. The simple 2-question PHQ-2 case-finding instrument takes only a few minutes to administer and is recommended for use by primary care physicians or cardiologists to evaluate patients at high risk for depression or who manifest symptoms suggestive of depression.⁷

In the United States, most patients with depression are cared for in primary care venues. The AHA advisory recommends referring ACS patients who screen positive on a PHQ to a professional qualified in the diagnosis and management of depression.¹ Enhanced care—using outreach, monitoring, adjustment of therapy, and psychiatric backup—produces significant improvement in depression.³³

Key question 2: Is treatment of depression in cardiovascular care patients effective in improving depression? Cardiac outcomes? The evidence for benefit of SSRI therapy for depression detected at the time of ACS is consistent and was discussed above.^4,17–21 However, the antidepressant effect of SSRIs is modest in placebo-controlled trials. Most such trials excluded patients who were taking antidepressant drugs when screened, and many patients recruited for antidepressant clinical trials had no previous episodes of depression, had relatively mild symptoms of short duration, and were recruited by screening (ie, they were not seeking treatment for depression).³⁴ Patients with brief and short episodes are likely to remit spontaneously and to respond to psychotherapy or supportive care.³⁴ Moreover, in most antidepressant trials, both the intervention and “control” groups received elements of enhanced depression care, which will reduce the apparent benefit of antidepressant drugs. For instance, because the primary goal of SADHART was to evaluate the safety of sertraline in patients with ACS, monitoring for adverse effects included six or seven visits during 16 weeks of follow-up plus six or seven phone calls, providing several elements of enhanced depression care, including face-to-face education, frequent follow-up, support by a case manager (research coordinator) with a mental health background, and support from a psychiatrist or psychologist.¹⁷ Randomization to sertraline or placebo in SADHART was blinded, so the frequent contact and support was the same in both groups.

Whether SSRI treatment for depression will improve survival and cardiovascular outcomes is not established by adequately powered randomized trials. Most randomized (SADHART, CREATE) or nonrandomized (ENRICHD) studies suggest that SSRIs reduce cardiovascular events, but only ENRICHD produced a statistically significant result. SSRIs—certainly sertraline and citalopram—are not associated with significant cardiovascular adverse effects, even during ACS, when the cardiovascular system is unstable and multiple drugs are being started and titrated. Patients who do not improve significantly during antidepressant drug therapy or psychotherapy have a two-to threefold increase in cardiovascular events compared with patients who do improve substantially.³⁵

Key question 3: Is systematic screening for depression more effective than usual care for identifying patients with depression? Facilitating treatment of depression? Reducing depressive symptoms? Improving cardiac outcomes? Pignone et al conducted a literature review and meta-analysis on behalf of the USPSTF to clarify whether screening adults for depression in primary care venues improves recognition, treatment, and clinical outcomes.³⁶ They reviewed randomized trials conducted in primary care settings that evaluated the effect of screening for depression on identification, treatment, or health outcomes, including trials that examined integrated, systematic support for treatment after identification of depression. The meta-analysis suggested that screening and feedback of screening results reduced the risk of persistent depression. Stronger effects were observed with programs that integrated interventions to improve recognition and treatment of depressed patients and that incorporated quality improvements into clinic systems as compared with programs that provided only screening and feedback.

Screening patients with CHD, especially those with ACS, is more effective than usual care (no screening). Indeed, many depressed patients go undetected unless identified by screening. Not surprisingly, those identified by screening tend to have milder depression. For example, half the participants in SADHART had a HAM-D score less than 18 (≥ 25 is considered severe). However, a considerable number identified by screening had above-average HAM-D scores but either viewed their symptoms as appropriate for their medical condition or were simply denying their psychiatric illness. If patients had not been screened, their depression would not have been detected or treated. Even among SADHART participants with baseline HAM-D scores less than 18, those whose depression failed to respond to sertraline/placebo had twice the 7-year mortality rate as did those whose depression remitted.¹⁶

The Prevention of Suicide in Primary Care Elderly: Collaborative Trial (PROSPECT) examined the impact of a care management intervention on suicidal ideation and depression in older primary care patients and reported outcomes over a 2-year follow-up.³⁷ PROSPECT screened 9,072 patients in 20 primary care practices to find 599 study participants aged 60 years or older with major or minor depression (not all had cardiovascular disease). Participants were randomly assigned to either usual care or the PROSPECT intervention, which consisted of services rendered by trained care managers who offered algorithm-based recommendations to physicians and helped patients adhere to treatment during the 24-month trial. Compared with patients receiving usual care, those receiving the intervention had a greater likelihood of receiving antidepressant drugs and/or psychotherapy (85%–89% vs 49%–62%) and had a 2.2-fold greater decline in suicidal ideation over 24 months. Treatment response started sooner in the intervention group and continued to improve at 18 and 24 months; no appreciable increase in treatment response was observed in the usual-care group during the same period. Among patients with major depression, a significantly greater percentage of the intervention group achieved remission compared with the usual-care group at 4, 8, and 24 months. Patients with minor depression had favorable mental health outcomes regardless of treatment assignment. Sustained collaborative care maintained high utilization of depression treatment, reduced suicidal ideation, and improved the outcomes of major depression during 2 years of follow-up.³⁷

No randomized trial of SSRIs has been designed to show an effect on mortality or cardiovascular events. ENRICHD has produced the strongest evidence that an SSRI can reduce mortality or cardiovascular outcomes. The study was designed with approximately 85% power to detect a 25% to 30% reduction in the primary end point (death or MI) as a result of CBT; as noted above, 2,481 patients (1,834 with depression) were randomized to usual care or CBT within 28 days of MI.⁴ Depression significantly improved with CBT, but the rate of death or MI did not: during mean follow-up of 29 months, death or MI occurred in 299 patients in the CBT group versus 300 in the usual-care group.⁴ A post hoc analysis specific to the 1,834 ENRICHD participants who had depression aimed to determine the effects of antidepressant drugs on morbidity and mortality.¹⁸ The protocol required patients in the intervention group with scores of 25 or higher on the 17-item HAM-D, or those who had less than a 50% reduction in BDI scores after 5 weeks of treatment, to be referred to study psychiatrists for consideration of pharmacotherapy. Study psychiatrists met with patients who were being treated with antidepressant drugs to monitor medication use. Unless contraindicated or previously ineffective or poorly tolerated, sertraline was the first antidepressant used. Using a time-dependent multivariable Cox proportional hazards regression model to adjust for baseline depression score and cardiac risk factors, the researchers found SSRI use to be associated with a statistically significant 43% lower risk of death or nonfatal MI. Like other SSRI studies, ENRICHD found SSRIs safe for post-MI patients and to possibly, but not certainly, reduce death and MI.¹⁸

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.

In 2008, the American Heart Association (AHA) published a science advisory on depression and coronary heart disease (CHD).¹ Since its publication, the advisory has evoked substantial commentary. The purpose of this article is threefold: (1) to explain the aims of the AHA science advisory, (2) to briefly discuss its content, and (3) to examine some of the comments it has provoked.

WHAT THE ADVISORY SET OUT TO DO

The purpose of an AHA science advisory is to provide rapid, clear, and consistent AHA positioning on a scientific issue. Advisories are statements on an evolving, prominent scientific issue of great interest to the public and health professionals. All AHA science advisories undergo peer review and are also reviewed and approved by the AHA Science Advisory and Coordinating Committee, AHA’s highest science body. Because this particular advisory addressed the interaction of cardiovascular and mental health, the AHA asked the American Psychiatric Association (APA) to review the document; the APA endorsed the AHA advisory.

Two points are worth emphasizing:

• An AHA science advisory is not a treatment guideline.
• Advisories usually are brief and therefore do not exhaustively discuss their topic.

After discussing epidemiologic studies that elucidated the relationships between depression and CHD, the AHA advisory on depression and CHD focuses on screening, referral, and treatment of depression from a cardiology perspective.

The 1-year prevalence of major depressive disorder in the US general population is 7%, and the lifetime prevalence is about 16%.² Depression in otherwise healthy persons almost doubles the risk of developing CHD.³ About 20% of patients hospitalized for acute coronary syndromes (ACS) have major depressive disorder on admission or within a few weeks thereafter, and these patients have about 2.5 times the mortality rate as patients who are not depressed, after adjusting for infarct severity and cardiovascular risk factors.^4–6

ASSESSMENT OF DEPRESSION AND DEPRESSIVE SYMPTOMS

The AHA advisory discusses use of the 2-question Patient Health Questionnaire (PHQ-2) as the first step in screening for depression.^7,8 The PHQ-2 inquires about the frequency of depressed mood and anhedonia by asking the following:

Over the past 2 weeks, how often have you been bothered by either of the following problems?

(1) Little interest or pleasure in doing things

(2) Feeling down, depressed, or hopeless.

For each item the response options are “not at all” (scored as 0), “several days” (scored as 1), “more than half the days” (scored as 2), and “nearly every day” (scored as 3). Thus, the total PHQ-2 score can range from 0 to 6.

Using a structured psychiatric interview as the standard, a total PHQ-2 score of 3 or greater has been shown to have a sensitivity of 83% and a specificity of 92% for major depression.⁷ A PHQ-2 score of 3 is the optimal cut point for screening purposes. A PHQ-2 score of 0 virtually excludes depression.

If a patient’s PHQ-2 score is 3 or greater, it is recommended that answers be obtained for a full 9-item PHQ. The PHQ-9 provides the sensitivity and specificity suitable for assigning a provisional diagnosis of major depressive disorder and a symptom severity score that can be used to identify patients for further evaluation and to make decisions about therapy.^9–11

Adapted from the 2008 American Heart Association science advisory on depression and coronary heart disease.1 Source: American Heart Association, Inc.

The US Preventive Services Task Force (USPSTF) currently recommends that clinicians screen adults for depression in clinical practices that have systems in place to assure accurate diagnosis, effective treatment, and follow-up.¹² The USPSTF concluded that there is good evidence that screening improves the accurate identification of depressed patients in primary care settings and that treating depressed adults identified in such settings reduces clinical morbidity. Results of trials that have directly evaluated the effect of screening on clinical outcomes depend on follow-up. Limited benefits have been demonstrated in studies that simply feed screening results back to clinicians. Larger benefits have been seen in studies in which the communication of screening results is coordinated with effective follow-up and treatment. The USPSTF concluded that the benefits of screening and treating are likely to outweigh any potential harms.¹²

DEPRESSION TREATMENT

Drug therapy

The safety of fluoxetine, sertraline (SADHART, ENRICHD), citalopram (CREATE), and mirtazapine (MIND-IT) has been evaluated in clinical trials.^4,17–21 By far the strongest evidence of safety is for selective serotonin reuptake inhibitors (SSRIs), especially sertraline.

The Sertraline Antidepressant Heart Attack Randomized Trial (SADHART; N = 369), a randomized study of depression after ACS, found no difference in cardiovascular adverse events between the sertraline and placebo groups after 16 weeks of therapy, and there were no significant differences in left ventricular ejection fraction, heart rate, blood pressure, ventricular premature complexes, or electrocardiogram changes.¹⁷ In the group assigned to sertraline, life-threatening cardiovascular events occurred less frequently (15% vs 22%, P = NS).

The Enhancing Recovery in Coronary Heart Disease study (ENRICHD) was a large trial (N = 2,481) to evaluate the effect of cognitive behavioral therapy (CBT) on depression or low perceived social support in patients enrolled within 28 days of myocardial infarction (MI).⁴ The ENRICHD protocol required patients randomized to CBT with Hamilton Depression Rating Scale (HAM-D) scores greater than 24, or who showed less than 50% reduction in Beck Depression Inventory (BDI) scores after 5 weeks of CBT, to be referred to a study psychiatrist for consideration of pharmacotherapy, usually sertraline. Of the overall ENRICHD population, 1,834 participants (74%) had a diagnosis of depression, and 446 of these participants (24%) were treated with antidepressant drugs, 301 with an SSRI and 145 with other antidepressants.¹⁸ During mean follow-up of 29 months, the SSRI-treated group had a statistically significant 43% reduction in death or MI.⁴

The Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy (CREATE) recruited 284 patients with chronic CHD, major depressive disorder, and a 24-item HAM-D score of 20 or greater and randomly assigned half to citalopram (another SSRI) and half to placebo.¹⁹ Citalopram showed antidepressant efficacy and no evidence of harm.

The Myocardial Infarction and Depression Intervention Trial (MIND-IT) recruited 91 patients within 30 days of hospital admission for MI with depression and randomized them in a 1:1 ratio to mirtazapine or placebo. Mirtazapine showed some evidence of antidepressant efficacy and no evidence of harm.²⁰

Strik et al in the Netherlands recruited 54 patients who had major depression after a first MI and randomized them 1:1 to the SSRI fluoxetine or placebo 3 months after the MI.²¹ The fluoxetine group showed a trend toward antidepressant efficacy, and no cardiovascular safety problems were detected clinically or by either electrocardiogram or echocardiogram.

APA practice guidelines for major depressive disorder indicate that among psycho therapeutic approaches, CBT and interpersonal psychotherapy have the best-documented efficacy for treatment of major depressive disorder.²² CBT aims to solve problems related to dysfunctional emotions, behaviors, and cognition and is an umbrella term for various techniques that share a theoretical basis in behavioristic learning theory and cognitive psychology. Aaron T. Beck proposed that depressed people are quick to make negative evaluations of themselves and the world, and he designed treatment to reduce these negative cognitions.²³ Interpersonal psychotherapy stems from the work of Harry Stack Sullivan, who believed that emotional reactions were triggered by interpersonal behaviors.²⁴ Gerald Klerman and Myrna Weissman used this method to treat adults diagnosed with moderate or severe nondelusional clinical depression.²⁵

CBT was used in ENRICHD,⁴ interpersonal psychotherapy in CREATE,¹⁹ and problem-solving therapy in the Coronary Psychosocial Evaluation Studies (COPES).^26,27 Unintended therapy can also be a confounder in antidepressant drug trials; education and supportive care (eg, frequent visits or telephone calls with monitoring of depressive symptoms and counseling) are often provided for both the intervention and control (placebo) groups. If a study is blinded, education, supportive care, and attention will be identical for both groups and thus may reduce the likelihood of finding a difference between the drug and placebo, if one exists.

Psychotherapy can be helpful for depression, is preferred over antidepressant drugs by some patients, and can be combined with drugs to increase antidepressant efficacy. We still have much to learn about timing and choice of therapy, as well as about sequencing and combination of antidepressant drugs and psychotherapy.

Physical activity and exercise

Aerobic exercise²⁸ and cardiac rehabilitation²⁹ can reduce depressive symptoms in addition to improving cardiovascular fitness. Depression can serve as a barrier to participation in cardiac rehabilitation and exercise programs, but cardiologists can help depressed patients overcome this barrier by offering encouragement and follow-up contacts. Cardiologists also should enlist the help of spouses or other family members and friends to promote adherence. The prescription of exercise needs to be based on the cardiac status and exercise capacity of each individual.³⁰

SUMMARY OF ADVISORY RECOMMENDATIONS

The AHA advisory¹ summarized its recommendations as follows:

1. Routine screening for depression in patients with CHD should be considered in a variety of settings, including the hospital, the physician’s office, clinics, and cardiac rehabilitation centers. The opportunity to screen for and treat depression in cardiac patients should not be missed, as effective depression treatment may improve health outcomes.

2. Patients with positive screening results should be evaluated by a professional qualified in diagnosis and management of depression. Such a clinician can determine whether depression is present and needs treatment, as well as how to connect a patient to an effective care program in the local area.

3. Patients with heart disease who are being treated for depression should undergo careful monitoring for adherence to their medical care and for the efficacy and safety of drug therapy for their medical and mental health conditions.

4. Coordination of care among health care providers is essential for patients with coexisting medical and mental health issues.

COMMENTS ON THE ADVISORY

Since AHA advisories usually address evolving scientific issues, the knowledge base on these issues is constantly growing and a range of opinions and hypotheses are tenable, pending new information. Soon after the AHA science advisory on depression and CHD was issued, a systematic review on depression screening and patient outcomes in cardiac care was published.³¹ This review posed three key questions that are explored below.

Key question 1: What’s the accuracy of screening instruments for depression in cardiovascular care populations? To answer this question, a case-finding method such as a questionnaire (eg, BDI or PHQ) must be compared with a structured interview by mental health personnel as the “gold standard” for diagnosis (ie, the truth).

To estimate the accuracy of clinical diagnosis by general practitioners, Mitchell et al pooled data from 50,371 primary care patients across 41 studies in Europe or the United States to evaluate general practitioners’ ability to make an unassisted diagnosis of depression (ie, without specific help from severity scales, diagnostic instruments, education programs, etc).³² They reported a sensitivity of about 50% and a specificity of 81% when the prevalence of depression was about 20%. In other words, general practitioners missed about half the cases of depression when no case-finding tool was used. These researchers pointed out that a low prevalence of depression favors identification of nondepressed cases (false-positive diagnoses), whereas a high prevalence favors diagnosis of depression (true-positive diagnoses).³²

Cardiologists focused on treatment of ACS are probably less likely to make a clinical diagnosis of depression and may attribute emotional symptoms to rapidly evolving cardiovascular events. The simple 2-question PHQ-2 case-finding instrument takes only a few minutes to administer and is recommended for use by primary care physicians or cardiologists to evaluate patients at high risk for depression or who manifest symptoms suggestive of depression.⁷

In the United States, most patients with depression are cared for in primary care venues. The AHA advisory recommends referring ACS patients who screen positive on a PHQ to a professional qualified in the diagnosis and management of depression.¹ Enhanced care—using outreach, monitoring, adjustment of therapy, and psychiatric backup—produces significant improvement in depression.³³

Key question 2: Is treatment of depression in cardiovascular care patients effective in improving depression? Cardiac outcomes? The evidence for benefit of SSRI therapy for depression detected at the time of ACS is consistent and was discussed above.^4,17–21 However, the antidepressant effect of SSRIs is modest in placebo-controlled trials. Most such trials excluded patients who were taking antidepressant drugs when screened, and many patients recruited for antidepressant clinical trials had no previous episodes of depression, had relatively mild symptoms of short duration, and were recruited by screening (ie, they were not seeking treatment for depression).³⁴ Patients with brief and short episodes are likely to remit spontaneously and to respond to psychotherapy or supportive care.³⁴ Moreover, in most antidepressant trials, both the intervention and “control” groups received elements of enhanced depression care, which will reduce the apparent benefit of antidepressant drugs. For instance, because the primary goal of SADHART was to evaluate the safety of sertraline in patients with ACS, monitoring for adverse effects included six or seven visits during 16 weeks of follow-up plus six or seven phone calls, providing several elements of enhanced depression care, including face-to-face education, frequent follow-up, support by a case manager (research coordinator) with a mental health background, and support from a psychiatrist or psychologist.¹⁷ Randomization to sertraline or placebo in SADHART was blinded, so the frequent contact and support was the same in both groups.

Whether SSRI treatment for depression will improve survival and cardiovascular outcomes is not established by adequately powered randomized trials. Most randomized (SADHART, CREATE) or nonrandomized (ENRICHD) studies suggest that SSRIs reduce cardiovascular events, but only ENRICHD produced a statistically significant result. SSRIs—certainly sertraline and citalopram—are not associated with significant cardiovascular adverse effects, even during ACS, when the cardiovascular system is unstable and multiple drugs are being started and titrated. Patients who do not improve significantly during antidepressant drug therapy or psychotherapy have a two-to threefold increase in cardiovascular events compared with patients who do improve substantially.³⁵

Key question 3: Is systematic screening for depression more effective than usual care for identifying patients with depression? Facilitating treatment of depression? Reducing depressive symptoms? Improving cardiac outcomes? Pignone et al conducted a literature review and meta-analysis on behalf of the USPSTF to clarify whether screening adults for depression in primary care venues improves recognition, treatment, and clinical outcomes.³⁶ They reviewed randomized trials conducted in primary care settings that evaluated the effect of screening for depression on identification, treatment, or health outcomes, including trials that examined integrated, systematic support for treatment after identification of depression. The meta-analysis suggested that screening and feedback of screening results reduced the risk of persistent depression. Stronger effects were observed with programs that integrated interventions to improve recognition and treatment of depressed patients and that incorporated quality improvements into clinic systems as compared with programs that provided only screening and feedback.

Screening patients with CHD, especially those with ACS, is more effective than usual care (no screening). Indeed, many depressed patients go undetected unless identified by screening. Not surprisingly, those identified by screening tend to have milder depression. For example, half the participants in SADHART had a HAM-D score less than 18 (≥ 25 is considered severe). However, a considerable number identified by screening had above-average HAM-D scores but either viewed their symptoms as appropriate for their medical condition or were simply denying their psychiatric illness. If patients had not been screened, their depression would not have been detected or treated. Even among SADHART participants with baseline HAM-D scores less than 18, those whose depression failed to respond to sertraline/placebo had twice the 7-year mortality rate as did those whose depression remitted.¹⁶

The Prevention of Suicide in Primary Care Elderly: Collaborative Trial (PROSPECT) examined the impact of a care management intervention on suicidal ideation and depression in older primary care patients and reported outcomes over a 2-year follow-up.³⁷ PROSPECT screened 9,072 patients in 20 primary care practices to find 599 study participants aged 60 years or older with major or minor depression (not all had cardiovascular disease). Participants were randomly assigned to either usual care or the PROSPECT intervention, which consisted of services rendered by trained care managers who offered algorithm-based recommendations to physicians and helped patients adhere to treatment during the 24-month trial. Compared with patients receiving usual care, those receiving the intervention had a greater likelihood of receiving antidepressant drugs and/or psychotherapy (85%–89% vs 49%–62%) and had a 2.2-fold greater decline in suicidal ideation over 24 months. Treatment response started sooner in the intervention group and continued to improve at 18 and 24 months; no appreciable increase in treatment response was observed in the usual-care group during the same period. Among patients with major depression, a significantly greater percentage of the intervention group achieved remission compared with the usual-care group at 4, 8, and 24 months. Patients with minor depression had favorable mental health outcomes regardless of treatment assignment. Sustained collaborative care maintained high utilization of depression treatment, reduced suicidal ideation, and improved the outcomes of major depression during 2 years of follow-up.³⁷

No randomized trial of SSRIs has been designed to show an effect on mortality or cardiovascular events. ENRICHD has produced the strongest evidence that an SSRI can reduce mortality or cardiovascular outcomes. The study was designed with approximately 85% power to detect a 25% to 30% reduction in the primary end point (death or MI) as a result of CBT; as noted above, 2,481 patients (1,834 with depression) were randomized to usual care or CBT within 28 days of MI.⁴ Depression significantly improved with CBT, but the rate of death or MI did not: during mean follow-up of 29 months, death or MI occurred in 299 patients in the CBT group versus 300 in the usual-care group.⁴ A post hoc analysis specific to the 1,834 ENRICHD participants who had depression aimed to determine the effects of antidepressant drugs on morbidity and mortality.¹⁸ The protocol required patients in the intervention group with scores of 25 or higher on the 17-item HAM-D, or those who had less than a 50% reduction in BDI scores after 5 weeks of treatment, to be referred to study psychiatrists for consideration of pharmacotherapy. Study psychiatrists met with patients who were being treated with antidepressant drugs to monitor medication use. Unless contraindicated or previously ineffective or poorly tolerated, sertraline was the first antidepressant used. Using a time-dependent multivariable Cox proportional hazards regression model to adjust for baseline depression score and cardiac risk factors, the researchers found SSRI use to be associated with a statistically significant 43% lower risk of death or nonfatal MI. Like other SSRI studies, ENRICHD found SSRIs safe for post-MI patients and to possibly, but not certainly, reduce death and MI.¹⁸

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.

Many advances in the understanding of the relationship between depression and cardiovascular disease (CVD) were reported in 2009. As the study of this relationship encompasses cardiology, psychiatry, behavioral medicine, and many other fields, it is difficult to keep abreast of new developments. Relevant papers are found in a variety of journals. Therefore, we systematically searched the empirical research on depression and CVD published in English in 2009. Our search yielded nearly 500 articles. We review here a few of the most provocative and potentially influential findings. We begin with an overview of the methodology of our systematic review and then summarize the key findings and controversies we identified from the 2009 literature before exploring each key finding in detail.

METHODOLOGY OF OUR SYSTEMATIC SEARCH AND RATIONALE FOR FINDINGS REVIEWED

Previous evidence demonstrated that the presence of depressive symptoms or a diagnosis of a depressive disorder predicts poor prognosis and reduced survival rates after any coronary artery disease diagnosis, including myocardial infarction (MI) and unstable angina, as well as after coronary artery bypass graft surgery (CABG).¹

We aimed to see how this evidence base was expanded in 2009 by using a systematic search strategy to retrieve the most relevant articles about depression and coronary heart disease (CHD) from the MEDLINE and Psyc-INFO (Ovid interface) databases. The most relevant subject headings and free text terms were identified and combined with “or.” The two sets were then combined with “and.” Terms included “depression,” “depressive disorder,” “depress$,” “coronary artery disease” (CAD) “coronary disease,” “acute coronary syndrome” (ACS), “cardiovascular disease” (CVD), “coronary heart disease,” and “heart diseas$.” The final set was limited to the English-language literature and identified 494 unique articles published during 2009.

Closer inspection of titles and abstracts revealed well more than 100 articles directly relevant to the science and management of patients with CVD and depression or pronounced depressive symptoms. In light of this quantity, a thorough review of all new findings, editorials, and reviews is not feasible. Thus, we review here a few exciting articles in several distinct topical areas that could influence views of the relationship between depression and CVD as well as how we screen for and treat depression in patients with CVD. As with any review that is not strictly evidence-based, our choice of articles is subjective and incomplete, but we hope it will stimulate discussion and further exploration.

SUMMARY OF KEY FINDINGS AND CONTROVERSIES

The following numbered topics emerged as common themes or controversies from our survey of the 2009 literature. The remainder of this article will review findings in each of these areas in detail and discuss important clinical implications as appropriate.

1. Antidepressant use and adverse cardiac events. In surprising findings, antidepressant use was associated with increased risk of incident stroke, CVD, and sudden cardiac death in multiple large observational cohort studies. It is not known if the association is caused by unmeasured confounders or depressive symptom severity, although controlling for symptom severity did not reduce this elevated risk in some studies. Another interesting possibility is that the treatment-resistant depressed patient is at particularly high risk of CVD and death.

2. Effects of depression intervention in CVD patients. Four exciting randomized controlled trials on depression intervention in patients with CVD reported important efficacy results and suggested future directions for larger, definitive trials of depression treatment for these patients.

3. Depression screening and treatment in CVD patients. In the absence of large randomized controlled trials, the debate continues on whether depression screening or any type of depression treatment is beneficial, harmless, or harmful to patients with CVD. Continuation of this debate does not serve the health and well-being of patients or the public. Less controversial—and thus less discussed—is the important insight that psychiatric patients with depression should be routinely screened for cardiac disease and risk factors, as they are clearly at risk of CVD. We await clinical trials in this area to ensure that screening leads to improved CVD outcomes.

OBSERVATIONAL EVIDENCE ON ANTIDEPRESSANT USE AND CVD OUTCOMES

In an analysis of the Nurses’ Health Study, Whang et al examined the relationship of depressive symptoms and antidepressant use with sudden cardiac death and adverse cardiac events in 63,469 women without CVD.² Depressive symptoms were assessed using the Mental Health Index, a five-item subscale of the Short Form-36 Health Survey. Among women who reported antidepressant use, most (61%) were taking a selective serotonin reuptake inhibitor (SSRI; sertraline, fluoxetine, paroxetine, or citalopram), while 39% reported use of other antidepressants. Women taking antidepressants were more likely to suffer sudden cardiac death, with a fully adjusted hazard ratio (HR) of 3.34 (95% confidence interval [CI], 2.03–5.50).

Krantz et al examined psychotropic medication use and risk of adverse cardiovascular events in 519 women from the Women’s Ischemia Syndrome Evaluation.³ Enrolled women underwent coronary angiography, were separated into four groups according to their psychotropic medication use (none, anxiolytics only, antidepressants only, or both anxiolytics and antidepressants), and were observed for a median of 5.9 years. Results revealed that women who received both medications had a higher risk for adverse cardiovascular events and higher all-cause mortality compared with those using neither medication, even after controlling for anxious and depressive symptoms. In addition, whereas the use of antidepressant medication was associated with a doubling of risk for subsequent CVD events (HR = 2.16; 95% CI, 1.21–3.93) and all-cause mortality (HR = 2.15; 95% CI, 1.16–3.98), use of anxiolytic medication alone was not. While this study did not examine cause of death, cardiac death is likely to have constituted a large proportion of total mortality in this cohort selected for likelihood of CAD.

Although CVD and death have long been outcomes of interest for those studying the effects of depression, additional end points have recently been investigated as well. In a prospective cohort study of 136,293 community-dwelling postmenopausal women in the Women’s Health Initiative, Smoller et al found that new antidepressant use was significantly associated with increased incidence of stroke and all-cause mortality but not with incidence of CHD.⁴ The rate of stroke per 1,000 person-years was 2.99 for subjects with no antidepressant use versus 4.16 for patients with new SSRI use; the rate of all-cause death was 7.79 versus 12.77, respectively. The rate of all-cause death for subjects with new tricyclic antidepressant use was 14.14 per 1,000 person-years. To address potential confounding by indication, the researchers obtained a propensity score from a logistic regression model to predict any new antidepressant use from demographic, lifestyle, risk factor, and comorbidity variables measured at baseline. New SSRI use was associated with a doubling of the risk of incident hemorrhagic stroke as well as fatal stroke. There were no significant interactions between use of SSRIs and use of statins or aspirin in terms of risk of hemorrhagic stroke.

In an interesting observational study of 7,709 patients with confirmed CAD but without a diagnosis of heart failure or depression (and without current antidepressant use), May et al found that a subsequent diagnosis of depression was associated with a significant 50% increase in the risk of heart failure.⁵ There was no difference, however, between depressed patients who were using antidepressants and those who were not.

Increased risk of bleeding with SSRI use, particularly in patients with CAD, has also been a concern. Kim et al evaluated 1,380 adults who received any anti depressant before CABG for in-hospital mortality or any bleeding events.⁶ After controlling for the percentage of patients taking SSRIs (78%), there were no significant differences between those taking SSRIs and those taking non-SSRIs in the rate of any bleeding events (6.5% vs 7.2%; odds ratio [OR] = 0.93; 95% CI, 0.50–1.76) or in-hospital mortality (3.1% vs 2.3%; OR = 0.88; 95% CI, 0.47–1.65). There was no increased risk of bleeding associated with SSRI use when the analysis was restricted to patients who received antiplatelet and anticoagulant therapy. Thus, compared with patients who received non-SSRI antidepressants, patients who received SSRIs preoperatively had no increased risk of bleeding or in-hospital mortality after CABG; however, this study did not evaluate the effect of no antidepressant use.

Another study hypothesized that the use of any drug with the potential to prolong cardiac repolarization would be associated with an increased risk of sudden death.⁷ Use of individual drugs was analyzed among 1,010 cases of sudden unexplained death and 3,030 living primary care controls, all from the community. SSRI use was associated with a doubling of risk of sudden death (OR = 2.21; 95% CI, 1.61–3.05), and tricyclic antidepressant use was associated with a nonsignificant trend toward increased risk (OR = 1.44; 95% CI, 0.96–2.13). Further analysis that stratified patients according to prior CVD showed that most of the association of SSRIs with sudden death was in those with existing CVD and not in those without CVD. Other drugs found to raise sudden death risk included the typical and atypical antipsychotics.

The Nurses’ Health Study analysis by Whang et al suggested that antidepressant use triples the risk of sudden cardiac death in healthy women, and the authors suggested that the association between fatal ventricular arrhythmias and antidepressant use be examined further. ² The analysis of the Women’s Health Initiative by Smoller et al found that use of SSRIs and tricyclic antidepressants doubled the risk of fatal stroke in healthy women.⁴ The analysis of the Women’s Ischemia Syndrome Evaluation by Krantz et al revealed a doubling of the risk of CVD and death in women taking antidepressants who had been referred for coronary angiography.³ At the same time, May et al found no increase in the risk of heart failure conversion with antidepressant use in patients with CAD,⁵ and Kim et al found no increase in the risk of bleeding with use of SSRIs compared with non-SSRI antidepressants in patients with CAD undergoing CABG.⁶ Finally, in a population- and community-based case-control study, SSRI use was associated with an increased risk of sudden death, particularly in patients with CVD.⁷ So what are we to make of these findings?⁸

In all observational studies (including those reviewed above), unmeasured confounders pose a threat to the validity of any causal conclusions. A study recently tested some of the proposed confounders that might have existed in the above studies. Waldman et al examined racial differences in depressive symptoms and antidepressant treatment among a cohort of 864 consecutive patients with CHD undergoing diagnostic coronary angiography (727 white and 137 African American).⁹ While levels of depression were similar between the white and African American patients, the African Americans were less likely than their white counter-parts to receive antidepressant medications. Patients with only some high school, men, and patients with more severe depressive symptoms were significantly more likely to receive a prescription for antidepressants. Clearly, low education, male sex, and elevated depressive symptoms are related to poor prognosis for CHD, and the simple interpretation that antidepressant use is causing poorer outcomes is problematic.⁸

Two additional interpretations of the observational findings should be considered. First, confounding by indication (depressive symptom severity) might exist in these studies.¹⁰ In other words, patients who are prescribed antidepressant medication may be those with the most severe depressive illness, and it could be this severity, rather than the antidepressant use, that is causally implicated in the CVD incidence.¹¹ However, all of the studies reviewed above either directly controlled for depressive symptom severity (at least as obtained at baseline) or used propensity scores or stratified subjects based on depression severity. The results showed an increased risk among those who were taking antidepressants. However, none of the studies examined depressive symptom severity during or at the end of the study or depression diagnosis and severity before antidepressant use; these data are needed for a clearer understanding of whether the results were confounded by indication.

Second, these findings are also consistent with a treatment-resistant depression phenotype.¹² Krantz et al caution that it is not clear from their observational study³ whether medication use itself or depression refractory to treatment is implicated in the increased risk of CVD events and mortality. Depression that is refractory to treatment may be the type of depression that places patients at risk for sudden death, stroke, or CHD recurrence, so it may not be the antidepressant use per se that is associated with this risk. This phenomenon was documented in a secondary analysis¹³ of the largest-to-date randomized controlled trial of patients with MI undergoing treatment for depression (ENRICHD).¹⁴ It showed that those whose depressive symptoms did not respond to treatment had a higher risk of late mortality (ie, death ≥ 6 months after acute MI). This finding was replicated in 2009 in an important follow-up¹⁵ of the SADHART trial¹⁶; among patients with MI and major depression, treatment-resistant depression (ie, depression that failed to improve substantially during treatment with either sertraline or placebo) was strongly and independently associated with long-term mortality (HR = 2.39; 95% CI, 1.39–2.44; P < .001).¹⁵

What is needed next? Testing the alternative hypothesis— ie, that an unmeasured confounder may exist—is difficult, requiring new observational studies and measurement of the putative third common causes or previously unmeasured confounder. Other putative confounders would then be hypothesized and would need to be included in additional observational studies. To properly test the putative confounding by depressive symptom severity, future observational studies should examine initial depressive symptom severity prior to antidepressant use and then collect data on depressive symptom severity and antidepressant use as time-varying covariates to CVD outcomes. To test whether treatment-resistant depression is the phenotype driving the spurious observational association between antidepressant use and increased risk of CVD, the phenotype and its underlying causal mechanisms need to be better understood. Of course, rigorous and adequately powered randomized controlled trials of antidepressant use in patients with CVD would be a more straightforward way to test the observational association between antidepressant use and increased risk of CVD. We turn now to the recently published randomized controlled trials in this field.

NEW EVIDENCE FROM RANDOMIZED TRIALS IN PATIENTS WITH CVD AND DEPRESSION

Concerns have been voiced for some time about the ability to effectively treat depression and whether an effective depression treatment will affect the risk of CVD recurrence and mortality.⁸ Adding to these concerns is our limited knowledge of the causal pathways and behavioral and biologic mechanisms implicated in this risk association.¹ For these reasons, results from new randomized controlled trials, such as the four summarized below, are important.

Rollman et al compared the effectiveness of telephone-delivered collaborative care (treatment group) and usual physician care (control group) for improving mental health quality of life and reducing depressive symptoms in 302 patients with depression after CABG.¹⁷ Patients were observed for 8 months following randomization. Mental health quality of life and depressive symptoms were both significantly improved in the treatment group relative to the control group. Significantly more patients in the treatment group had a 50% or greater reduction in depressive symptoms (50.0% vs 29.6% in control group, P < .001; number needed to treat = 4.9 [95% CI, 3.2–10.4]). Men particularly benefited from the treatment. This trial suggests that collaborative care can be delivered effectively (and potentially cost-efficiently) over the phone.

Freedland et al also evaluated depression treatment in 123 patients with major or minor depression who underwent CABG.¹⁸ Their primary objective was to determine the efficacy of two behavioral treatments (cognitive behavioral therapy [CBT] or supportive stress management) compared with usual care. Significantly more patients in both the CBT group (71%) and the stress management group (57%) had a low score (indicating less severe depressive symptoms) on the clinician-based Hamilton Rating Scale for Depression compared with the usual care group (33%). These results were maintained 6 months after the end of the trial. Secondary measures of depressive symptoms, anxiety, and quality of life were also significantly improved in the depression treatment groups compared with the usual care group. This trial is important for the following reasons:

• The use of a second control group, the stress management group, represents a strict, high-quality design that controls for professional attention, generic or placebo therapy effect, and time or effort on the part of the patient.
• The second control group also provides treatment options for the patient, as both CBT and stress management were beneficial.
• Outcome assessors were blinded to treatment assignment, an important design feature in behavioral trials.

In a rigorously conducted randomized, double-blind, placebo-controlled trial, Carney et al tested whether 2 g/day of omega-3 acid ethyl esters (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) improved depressive symptoms in 122 patients with major depression and CHD.¹⁹ Patients in both the omega-3 and placebo groups received sertraline (50 mg/day) during the 10-week trial. A deficiency of omega-3 fatty acids has been implicated in both depression and CHD and is a possible causal link between the two diseases. Also, there is some evidence that the efficacy of antidepressants is increased by the addition of omega-3 supplementation. Unfortunately, there were no differences in self-reported or clinician-assessed depressive symptoms or in predefined depression remission at the study’s end. The trial included a 2-week adherence run-in period, ensuring that medication adherence in the trial was excellent (97%), and concluded that omega-3 supplementation, at least at these dosage levels, does not improve depression outcomes.

In the Coronary Psychosocial Evaluation Studies (COPES) randomized controlled trial, Davidson et al compared 6 months of an enhanced care intervention with usual depression care among 157 patients with ACS and persistently elevated depressive symptoms.²⁰ Under the enhanced care intervention, patients received either problem-solving therapy or antidepressant medication, depending on their preference, and then had the option of later augmentation with the other treatment, intensification of the initial treatment, or switching of treatments, if indicated by depressive symptom severity (stepped care). The purpose of the trial was to determine the acceptability and efficacy of depression treatment among patients with ACS, who often neither agree with the diagnosis of depression nor had been seeking treatment for depression. Significantly more patients were satisfied with their depression care in the intervention arm, and depressive symptoms and major adverse cardiac events (nonfatal MI, hospitalization for unstable angina, or all-cause mortality) were significantly reduced in the intervention arm compared with the usual care arm. The absolute numbers were very small; at the end of the trial, 3 patients in the intervention group and 10 patients in the usual care group had major adverse cardiac events (4% and 13%, respectively; log-rank test, χ²₁ = 3.93; P = .047). The results suggested that involving patients in the type of depression care they receive (medication and/or psychotherapy) and stepping treatments aggressively may be methods to improve the treatment of depression in patients with CHD. In addition, persistently depressed patients may be an interesting patient group to select for future trials, as usual care has resulted in large reductions in depressive symptoms in some previous trials but not in this study of patients with persistent depression.

Each of these four efficacy trials adds critical information to the evidence base. Depressed patients who have undergone CABG can be effectively treated in primary care settings with integrative care,¹⁷ and CBT is also extremely effective for these patients.¹⁸ Additional studies of omega-3 supplementation should not be pursued at this time, but using a run-in period to better identify patients who are prepared to engage in treatment is a prudent idea and should be used in future trials in this area.¹⁹ Patients with CHD and persistent depressive symptoms are a promising group to target for depression therapy, and asking patients to choose their type of depression treatment may improve response to therapy for both depression and CHD.²⁰

DEPRESSION SCREENING, REFERRAL, AND TREATMENT IN PATIENTS WITH CVD

We finish with the least evidence-based and most controversial issue in the area of depression and CVD. This controversy started in 2008 when the American Heart Association recommended in an advisory (endorsed by the American Psychiatric Association) that “screening tests for depressive symptoms should be applied to identify patients who may require further assessment and treatment” if appropriate referral for further depression assessment and treatment is available.²¹ Partly in response to this advisory, Thombs et al conducted a systematic review of the evidence on whether screening or treatment improves outcomes of depression or CVD in patients with CVD.²² They found no trial that tested whether depression screening was beneficial in patients with CVD, and the randomized controlled trials of depression treatment provided evidence of only mild improvement of depressive symptoms and no improvement in CVD outcome. Therefore, they questioned whether routine depression screening was appropriate.²²

In at least eight editorials, letters, and reviews published on this subject in 2009, investigators continued to debate this issue.^23–30 Below we provide a simplified list of reasons presented for and against screening and subsequent treatment raised in these articles.

Arguments for depression screening and treatment

The proponents of screening contend that depression is highly prevalent in patients with CVD and is clearly a risk marker for increased adverse events, reduced quality of life, and poorer adherence to treatment.²⁴ They argue that since there are plausible biologic and behavioral mechanisms for this association, and since SSRI use improves depressive symptoms in other patient populations and is safe in patients with CVD, health care providers should not hesitate to screen and refer patients for appropriate depression treatment. At the same time, they have cautioned that SSRIs interact with anti coagulants and that bleeding should be monitored closely in patients with CVD who are taking SSRIs.²⁴

Whooley²⁸ noted that although there are controversial findings in this area, depression screening provided in conjunction with collaborative care depression management is cost-effective and has a documented positive impact on depression, if not on CVD outcomes.^17,31 She observed that there are some costs to screening, such as false-positive findings (resulting in stigma for patients incorrectly diagnosed) and diversion of resources from other health care needs. However, Whooley suggested that primary care providers, rather than cardiologists, should conduct depression screening and that patients should undergo screening only when an established collaborative care treatment protocol exists.²⁸

Carney et al argued that depression, like age, clearly marks CVD risk, and that health care providers should aggressively treat readily modifiable CVD risk factors.²³ They added that because of the strong association between depression and medication nonadherence,³² providers should carefully monitor patient adherence to life-saving therapies.

Taking another tack, Shemesh and colleagues advocated the importance of documenting the prevalence of suicidal ideation and intent if recommendations to screen for depression in CVD patient populations were implemented.²⁵ Using a sample of more than 1,000 patients with CVD, they determined the prevalence of suicidal ideation (12.0%) and the number of patients who required hospitalization for risk of suicide (0.5%) when routine depression screening occurred in a large cardiology clinic. They concluded that identification and stabilization of imminently suicidal patients would be a benefit of universal screening and that there is a high societal cost to neglecting suicidal ideation, intent, and risk in patients with CVD. However, more patients would need immediate thorough psychiatric evaluations for safety, which would affect resource allocation and cost in cardiology clinics.

Arguments against depression screening and treatment

The main argument against screening for and treating depression in patients with CVD is that there are neither randomized controlled trials nor systematic evidence-based reviews showing that screening for depression and/or referring for additional treatment sufficiently improves outcomes for depression or CVD, and that existing evidence does not support the recommendation to screen all patients with CVD.^22,30 Furthermore, antidepressant use is associated with only mild improvement in depressive symptoms, even in other patient populations,³³ and publication bias (“the file-drawer problem”) has prevented the publication of antidepressant trials with null results, thereby skewing the evidence base.³⁴ In addition, considerable health care resources would be needed to mount such a large screening effort, and these resources would come at the expense of other efforts. Finally, the adverse effects of medications and the inevitability of some false-positive screening results must be weighed against any benefit that might occur with universal screening.³⁵

In addition to the arguments above, Ziegelstein et al,²⁹ in commenting on the American Heart Association advisory,²¹ wryly observed that there is far greater observational evidence that depressed patients seen in mental health settings are at risk for incident and recurrent CVD and that there should be universal screening and referral for CVD in patients with depression. They contended as well that the evidence is insufficient to recommend that patients with CVD undergo universal depression screening and referral.

Summary and clinical implications

Although we were hesitant to raise this tense and often emotional issue, we are in favor of routine, algorithm-based depression screening by all cardiologists, with the critical proviso that a nationwide and/or Centers for Medicare and Medicaid Services–coordinated randomized controlled trial be conducted to evaluate this practice. All patients with pronounced depressive symptoms should be referred to the trial, and two depression treatments should be evaluated, such as usual referral versus telephone-based collaborative care¹⁷ or enhanced depression care.²⁰ Such a trial would allow us to ensure that data are collected on the cost,³⁶ the benefit, and even the possible harms associated with routine depression screening for patients with CVD, and we could ascertain if there is an acceptable, beneficial treatment for depression that can be delivered and definitively tested.

Many advances in the understanding of the relationship between depression and cardiovascular disease (CVD) were reported in 2009. As the study of this relationship encompasses cardiology, psychiatry, behavioral medicine, and many other fields, it is difficult to keep abreast of new developments. Relevant papers are found in a variety of journals. Therefore, we systematically searched the empirical research on depression and CVD published in English in 2009. Our search yielded nearly 500 articles. We review here a few of the most provocative and potentially influential findings. We begin with an overview of the methodology of our systematic review and then summarize the key findings and controversies we identified from the 2009 literature before exploring each key finding in detail.

METHODOLOGY OF OUR SYSTEMATIC SEARCH AND RATIONALE FOR FINDINGS REVIEWED

Previous evidence demonstrated that the presence of depressive symptoms or a diagnosis of a depressive disorder predicts poor prognosis and reduced survival rates after any coronary artery disease diagnosis, including myocardial infarction (MI) and unstable angina, as well as after coronary artery bypass graft surgery (CABG).¹

We aimed to see how this evidence base was expanded in 2009 by using a systematic search strategy to retrieve the most relevant articles about depression and coronary heart disease (CHD) from the MEDLINE and Psyc-INFO (Ovid interface) databases. The most relevant subject headings and free text terms were identified and combined with “or.” The two sets were then combined with “and.” Terms included “depression,” “depressive disorder,” “depress$,” “coronary artery disease” (CAD) “coronary disease,” “acute coronary syndrome” (ACS), “cardiovascular disease” (CVD), “coronary heart disease,” and “heart diseas$.” The final set was limited to the English-language literature and identified 494 unique articles published during 2009.

Closer inspection of titles and abstracts revealed well more than 100 articles directly relevant to the science and management of patients with CVD and depression or pronounced depressive symptoms. In light of this quantity, a thorough review of all new findings, editorials, and reviews is not feasible. Thus, we review here a few exciting articles in several distinct topical areas that could influence views of the relationship between depression and CVD as well as how we screen for and treat depression in patients with CVD. As with any review that is not strictly evidence-based, our choice of articles is subjective and incomplete, but we hope it will stimulate discussion and further exploration.

SUMMARY OF KEY FINDINGS AND CONTROVERSIES

The following numbered topics emerged as common themes or controversies from our survey of the 2009 literature. The remainder of this article will review findings in each of these areas in detail and discuss important clinical implications as appropriate.

1. Antidepressant use and adverse cardiac events. In surprising findings, antidepressant use was associated with increased risk of incident stroke, CVD, and sudden cardiac death in multiple large observational cohort studies. It is not known if the association is caused by unmeasured confounders or depressive symptom severity, although controlling for symptom severity did not reduce this elevated risk in some studies. Another interesting possibility is that the treatment-resistant depressed patient is at particularly high risk of CVD and death.

2. Effects of depression intervention in CVD patients. Four exciting randomized controlled trials on depression intervention in patients with CVD reported important efficacy results and suggested future directions for larger, definitive trials of depression treatment for these patients.

3. Depression screening and treatment in CVD patients. In the absence of large randomized controlled trials, the debate continues on whether depression screening or any type of depression treatment is beneficial, harmless, or harmful to patients with CVD. Continuation of this debate does not serve the health and well-being of patients or the public. Less controversial—and thus less discussed—is the important insight that psychiatric patients with depression should be routinely screened for cardiac disease and risk factors, as they are clearly at risk of CVD. We await clinical trials in this area to ensure that screening leads to improved CVD outcomes.

OBSERVATIONAL EVIDENCE ON ANTIDEPRESSANT USE AND CVD OUTCOMES

In an analysis of the Nurses’ Health Study, Whang et al examined the relationship of depressive symptoms and antidepressant use with sudden cardiac death and adverse cardiac events in 63,469 women without CVD.² Depressive symptoms were assessed using the Mental Health Index, a five-item subscale of the Short Form-36 Health Survey. Among women who reported antidepressant use, most (61%) were taking a selective serotonin reuptake inhibitor (SSRI; sertraline, fluoxetine, paroxetine, or citalopram), while 39% reported use of other antidepressants. Women taking antidepressants were more likely to suffer sudden cardiac death, with a fully adjusted hazard ratio (HR) of 3.34 (95% confidence interval [CI], 2.03–5.50).

Krantz et al examined psychotropic medication use and risk of adverse cardiovascular events in 519 women from the Women’s Ischemia Syndrome Evaluation.³ Enrolled women underwent coronary angiography, were separated into four groups according to their psychotropic medication use (none, anxiolytics only, antidepressants only, or both anxiolytics and antidepressants), and were observed for a median of 5.9 years. Results revealed that women who received both medications had a higher risk for adverse cardiovascular events and higher all-cause mortality compared with those using neither medication, even after controlling for anxious and depressive symptoms. In addition, whereas the use of antidepressant medication was associated with a doubling of risk for subsequent CVD events (HR = 2.16; 95% CI, 1.21–3.93) and all-cause mortality (HR = 2.15; 95% CI, 1.16–3.98), use of anxiolytic medication alone was not. While this study did not examine cause of death, cardiac death is likely to have constituted a large proportion of total mortality in this cohort selected for likelihood of CAD.

Although CVD and death have long been outcomes of interest for those studying the effects of depression, additional end points have recently been investigated as well. In a prospective cohort study of 136,293 community-dwelling postmenopausal women in the Women’s Health Initiative, Smoller et al found that new antidepressant use was significantly associated with increased incidence of stroke and all-cause mortality but not with incidence of CHD.⁴ The rate of stroke per 1,000 person-years was 2.99 for subjects with no antidepressant use versus 4.16 for patients with new SSRI use; the rate of all-cause death was 7.79 versus 12.77, respectively. The rate of all-cause death for subjects with new tricyclic antidepressant use was 14.14 per 1,000 person-years. To address potential confounding by indication, the researchers obtained a propensity score from a logistic regression model to predict any new antidepressant use from demographic, lifestyle, risk factor, and comorbidity variables measured at baseline. New SSRI use was associated with a doubling of the risk of incident hemorrhagic stroke as well as fatal stroke. There were no significant interactions between use of SSRIs and use of statins or aspirin in terms of risk of hemorrhagic stroke.

In an interesting observational study of 7,709 patients with confirmed CAD but without a diagnosis of heart failure or depression (and without current antidepressant use), May et al found that a subsequent diagnosis of depression was associated with a significant 50% increase in the risk of heart failure.⁵ There was no difference, however, between depressed patients who were using antidepressants and those who were not.

Increased risk of bleeding with SSRI use, particularly in patients with CAD, has also been a concern. Kim et al evaluated 1,380 adults who received any anti depressant before CABG for in-hospital mortality or any bleeding events.⁶ After controlling for the percentage of patients taking SSRIs (78%), there were no significant differences between those taking SSRIs and those taking non-SSRIs in the rate of any bleeding events (6.5% vs 7.2%; odds ratio [OR] = 0.93; 95% CI, 0.50–1.76) or in-hospital mortality (3.1% vs 2.3%; OR = 0.88; 95% CI, 0.47–1.65). There was no increased risk of bleeding associated with SSRI use when the analysis was restricted to patients who received antiplatelet and anticoagulant therapy. Thus, compared with patients who received non-SSRI antidepressants, patients who received SSRIs preoperatively had no increased risk of bleeding or in-hospital mortality after CABG; however, this study did not evaluate the effect of no antidepressant use.

Another study hypothesized that the use of any drug with the potential to prolong cardiac repolarization would be associated with an increased risk of sudden death.⁷ Use of individual drugs was analyzed among 1,010 cases of sudden unexplained death and 3,030 living primary care controls, all from the community. SSRI use was associated with a doubling of risk of sudden death (OR = 2.21; 95% CI, 1.61–3.05), and tricyclic antidepressant use was associated with a nonsignificant trend toward increased risk (OR = 1.44; 95% CI, 0.96–2.13). Further analysis that stratified patients according to prior CVD showed that most of the association of SSRIs with sudden death was in those with existing CVD and not in those without CVD. Other drugs found to raise sudden death risk included the typical and atypical antipsychotics.

The Nurses’ Health Study analysis by Whang et al suggested that antidepressant use triples the risk of sudden cardiac death in healthy women, and the authors suggested that the association between fatal ventricular arrhythmias and antidepressant use be examined further. ² The analysis of the Women’s Health Initiative by Smoller et al found that use of SSRIs and tricyclic antidepressants doubled the risk of fatal stroke in healthy women.⁴ The analysis of the Women’s Ischemia Syndrome Evaluation by Krantz et al revealed a doubling of the risk of CVD and death in women taking antidepressants who had been referred for coronary angiography.³ At the same time, May et al found no increase in the risk of heart failure conversion with antidepressant use in patients with CAD,⁵ and Kim et al found no increase in the risk of bleeding with use of SSRIs compared with non-SSRI antidepressants in patients with CAD undergoing CABG.⁶ Finally, in a population- and community-based case-control study, SSRI use was associated with an increased risk of sudden death, particularly in patients with CVD.⁷ So what are we to make of these findings?⁸

In all observational studies (including those reviewed above), unmeasured confounders pose a threat to the validity of any causal conclusions. A study recently tested some of the proposed confounders that might have existed in the above studies. Waldman et al examined racial differences in depressive symptoms and antidepressant treatment among a cohort of 864 consecutive patients with CHD undergoing diagnostic coronary angiography (727 white and 137 African American).⁹ While levels of depression were similar between the white and African American patients, the African Americans were less likely than their white counter-parts to receive antidepressant medications. Patients with only some high school, men, and patients with more severe depressive symptoms were significantly more likely to receive a prescription for antidepressants. Clearly, low education, male sex, and elevated depressive symptoms are related to poor prognosis for CHD, and the simple interpretation that antidepressant use is causing poorer outcomes is problematic.⁸

Two additional interpretations of the observational findings should be considered. First, confounding by indication (depressive symptom severity) might exist in these studies.¹⁰ In other words, patients who are prescribed antidepressant medication may be those with the most severe depressive illness, and it could be this severity, rather than the antidepressant use, that is causally implicated in the CVD incidence.¹¹ However, all of the studies reviewed above either directly controlled for depressive symptom severity (at least as obtained at baseline) or used propensity scores or stratified subjects based on depression severity. The results showed an increased risk among those who were taking antidepressants. However, none of the studies examined depressive symptom severity during or at the end of the study or depression diagnosis and severity before antidepressant use; these data are needed for a clearer understanding of whether the results were confounded by indication.

Second, these findings are also consistent with a treatment-resistant depression phenotype.¹² Krantz et al caution that it is not clear from their observational study³ whether medication use itself or depression refractory to treatment is implicated in the increased risk of CVD events and mortality. Depression that is refractory to treatment may be the type of depression that places patients at risk for sudden death, stroke, or CHD recurrence, so it may not be the antidepressant use per se that is associated with this risk. This phenomenon was documented in a secondary analysis¹³ of the largest-to-date randomized controlled trial of patients with MI undergoing treatment for depression (ENRICHD).¹⁴ It showed that those whose depressive symptoms did not respond to treatment had a higher risk of late mortality (ie, death ≥ 6 months after acute MI). This finding was replicated in 2009 in an important follow-up¹⁵ of the SADHART trial¹⁶; among patients with MI and major depression, treatment-resistant depression (ie, depression that failed to improve substantially during treatment with either sertraline or placebo) was strongly and independently associated with long-term mortality (HR = 2.39; 95% CI, 1.39–2.44; P < .001).¹⁵

What is needed next? Testing the alternative hypothesis— ie, that an unmeasured confounder may exist—is difficult, requiring new observational studies and measurement of the putative third common causes or previously unmeasured confounder. Other putative confounders would then be hypothesized and would need to be included in additional observational studies. To properly test the putative confounding by depressive symptom severity, future observational studies should examine initial depressive symptom severity prior to antidepressant use and then collect data on depressive symptom severity and antidepressant use as time-varying covariates to CVD outcomes. To test whether treatment-resistant depression is the phenotype driving the spurious observational association between antidepressant use and increased risk of CVD, the phenotype and its underlying causal mechanisms need to be better understood. Of course, rigorous and adequately powered randomized controlled trials of antidepressant use in patients with CVD would be a more straightforward way to test the observational association between antidepressant use and increased risk of CVD. We turn now to the recently published randomized controlled trials in this field.

NEW EVIDENCE FROM RANDOMIZED TRIALS IN PATIENTS WITH CVD AND DEPRESSION

Concerns have been voiced for some time about the ability to effectively treat depression and whether an effective depression treatment will affect the risk of CVD recurrence and mortality.⁸ Adding to these concerns is our limited knowledge of the causal pathways and behavioral and biologic mechanisms implicated in this risk association.¹ For these reasons, results from new randomized controlled trials, such as the four summarized below, are important.

Rollman et al compared the effectiveness of telephone-delivered collaborative care (treatment group) and usual physician care (control group) for improving mental health quality of life and reducing depressive symptoms in 302 patients with depression after CABG.¹⁷ Patients were observed for 8 months following randomization. Mental health quality of life and depressive symptoms were both significantly improved in the treatment group relative to the control group. Significantly more patients in the treatment group had a 50% or greater reduction in depressive symptoms (50.0% vs 29.6% in control group, P < .001; number needed to treat = 4.9 [95% CI, 3.2–10.4]). Men particularly benefited from the treatment. This trial suggests that collaborative care can be delivered effectively (and potentially cost-efficiently) over the phone.

Freedland et al also evaluated depression treatment in 123 patients with major or minor depression who underwent CABG.¹⁸ Their primary objective was to determine the efficacy of two behavioral treatments (cognitive behavioral therapy [CBT] or supportive stress management) compared with usual care. Significantly more patients in both the CBT group (71%) and the stress management group (57%) had a low score (indicating less severe depressive symptoms) on the clinician-based Hamilton Rating Scale for Depression compared with the usual care group (33%). These results were maintained 6 months after the end of the trial. Secondary measures of depressive symptoms, anxiety, and quality of life were also significantly improved in the depression treatment groups compared with the usual care group. This trial is important for the following reasons:

• The use of a second control group, the stress management group, represents a strict, high-quality design that controls for professional attention, generic or placebo therapy effect, and time or effort on the part of the patient.
• The second control group also provides treatment options for the patient, as both CBT and stress management were beneficial.
• Outcome assessors were blinded to treatment assignment, an important design feature in behavioral trials.

In a rigorously conducted randomized, double-blind, placebo-controlled trial, Carney et al tested whether 2 g/day of omega-3 acid ethyl esters (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) improved depressive symptoms in 122 patients with major depression and CHD.¹⁹ Patients in both the omega-3 and placebo groups received sertraline (50 mg/day) during the 10-week trial. A deficiency of omega-3 fatty acids has been implicated in both depression and CHD and is a possible causal link between the two diseases. Also, there is some evidence that the efficacy of antidepressants is increased by the addition of omega-3 supplementation. Unfortunately, there were no differences in self-reported or clinician-assessed depressive symptoms or in predefined depression remission at the study’s end. The trial included a 2-week adherence run-in period, ensuring that medication adherence in the trial was excellent (97%), and concluded that omega-3 supplementation, at least at these dosage levels, does not improve depression outcomes.

In the Coronary Psychosocial Evaluation Studies (COPES) randomized controlled trial, Davidson et al compared 6 months of an enhanced care intervention with usual depression care among 157 patients with ACS and persistently elevated depressive symptoms.²⁰ Under the enhanced care intervention, patients received either problem-solving therapy or antidepressant medication, depending on their preference, and then had the option of later augmentation with the other treatment, intensification of the initial treatment, or switching of treatments, if indicated by depressive symptom severity (stepped care). The purpose of the trial was to determine the acceptability and efficacy of depression treatment among patients with ACS, who often neither agree with the diagnosis of depression nor had been seeking treatment for depression. Significantly more patients were satisfied with their depression care in the intervention arm, and depressive symptoms and major adverse cardiac events (nonfatal MI, hospitalization for unstable angina, or all-cause mortality) were significantly reduced in the intervention arm compared with the usual care arm. The absolute numbers were very small; at the end of the trial, 3 patients in the intervention group and 10 patients in the usual care group had major adverse cardiac events (4% and 13%, respectively; log-rank test, χ²₁ = 3.93; P = .047). The results suggested that involving patients in the type of depression care they receive (medication and/or psychotherapy) and stepping treatments aggressively may be methods to improve the treatment of depression in patients with CHD. In addition, persistently depressed patients may be an interesting patient group to select for future trials, as usual care has resulted in large reductions in depressive symptoms in some previous trials but not in this study of patients with persistent depression.

Each of these four efficacy trials adds critical information to the evidence base. Depressed patients who have undergone CABG can be effectively treated in primary care settings with integrative care,¹⁷ and CBT is also extremely effective for these patients.¹⁸ Additional studies of omega-3 supplementation should not be pursued at this time, but using a run-in period to better identify patients who are prepared to engage in treatment is a prudent idea and should be used in future trials in this area.¹⁹ Patients with CHD and persistent depressive symptoms are a promising group to target for depression therapy, and asking patients to choose their type of depression treatment may improve response to therapy for both depression and CHD.²⁰

DEPRESSION SCREENING, REFERRAL, AND TREATMENT IN PATIENTS WITH CVD

We finish with the least evidence-based and most controversial issue in the area of depression and CVD. This controversy started in 2008 when the American Heart Association recommended in an advisory (endorsed by the American Psychiatric Association) that “screening tests for depressive symptoms should be applied to identify patients who may require further assessment and treatment” if appropriate referral for further depression assessment and treatment is available.²¹ Partly in response to this advisory, Thombs et al conducted a systematic review of the evidence on whether screening or treatment improves outcomes of depression or CVD in patients with CVD.²² They found no trial that tested whether depression screening was beneficial in patients with CVD, and the randomized controlled trials of depression treatment provided evidence of only mild improvement of depressive symptoms and no improvement in CVD outcome. Therefore, they questioned whether routine depression screening was appropriate.²²

In at least eight editorials, letters, and reviews published on this subject in 2009, investigators continued to debate this issue.^23–30 Below we provide a simplified list of reasons presented for and against screening and subsequent treatment raised in these articles.

Arguments for depression screening and treatment

The proponents of screening contend that depression is highly prevalent in patients with CVD and is clearly a risk marker for increased adverse events, reduced quality of life, and poorer adherence to treatment.²⁴ They argue that since there are plausible biologic and behavioral mechanisms for this association, and since SSRI use improves depressive symptoms in other patient populations and is safe in patients with CVD, health care providers should not hesitate to screen and refer patients for appropriate depression treatment. At the same time, they have cautioned that SSRIs interact with anti coagulants and that bleeding should be monitored closely in patients with CVD who are taking SSRIs.²⁴

Whooley²⁸ noted that although there are controversial findings in this area, depression screening provided in conjunction with collaborative care depression management is cost-effective and has a documented positive impact on depression, if not on CVD outcomes.^17,31 She observed that there are some costs to screening, such as false-positive findings (resulting in stigma for patients incorrectly diagnosed) and diversion of resources from other health care needs. However, Whooley suggested that primary care providers, rather than cardiologists, should conduct depression screening and that patients should undergo screening only when an established collaborative care treatment protocol exists.²⁸

Carney et al argued that depression, like age, clearly marks CVD risk, and that health care providers should aggressively treat readily modifiable CVD risk factors.²³ They added that because of the strong association between depression and medication nonadherence,³² providers should carefully monitor patient adherence to life-saving therapies.

Taking another tack, Shemesh and colleagues advocated the importance of documenting the prevalence of suicidal ideation and intent if recommendations to screen for depression in CVD patient populations were implemented.²⁵ Using a sample of more than 1,000 patients with CVD, they determined the prevalence of suicidal ideation (12.0%) and the number of patients who required hospitalization for risk of suicide (0.5%) when routine depression screening occurred in a large cardiology clinic. They concluded that identification and stabilization of imminently suicidal patients would be a benefit of universal screening and that there is a high societal cost to neglecting suicidal ideation, intent, and risk in patients with CVD. However, more patients would need immediate thorough psychiatric evaluations for safety, which would affect resource allocation and cost in cardiology clinics.

Arguments against depression screening and treatment

The main argument against screening for and treating depression in patients with CVD is that there are neither randomized controlled trials nor systematic evidence-based reviews showing that screening for depression and/or referring for additional treatment sufficiently improves outcomes for depression or CVD, and that existing evidence does not support the recommendation to screen all patients with CVD.^22,30 Furthermore, antidepressant use is associated with only mild improvement in depressive symptoms, even in other patient populations,³³ and publication bias (“the file-drawer problem”) has prevented the publication of antidepressant trials with null results, thereby skewing the evidence base.³⁴ In addition, considerable health care resources would be needed to mount such a large screening effort, and these resources would come at the expense of other efforts. Finally, the adverse effects of medications and the inevitability of some false-positive screening results must be weighed against any benefit that might occur with universal screening.³⁵

In addition to the arguments above, Ziegelstein et al,²⁹ in commenting on the American Heart Association advisory,²¹ wryly observed that there is far greater observational evidence that depressed patients seen in mental health settings are at risk for incident and recurrent CVD and that there should be universal screening and referral for CVD in patients with depression. They contended as well that the evidence is insufficient to recommend that patients with CVD undergo universal depression screening and referral.

Summary and clinical implications

Although we were hesitant to raise this tense and often emotional issue, we are in favor of routine, algorithm-based depression screening by all cardiologists, with the critical proviso that a nationwide and/or Centers for Medicare and Medicaid Services–coordinated randomized controlled trial be conducted to evaluate this practice. All patients with pronounced depressive symptoms should be referred to the trial, and two depression treatments should be evaluated, such as usual referral versus telephone-based collaborative care¹⁷ or enhanced depression care.²⁰ Such a trial would allow us to ensure that data are collected on the cost,³⁶ the benefit, and even the possible harms associated with routine depression screening for patients with CVD, and we could ascertain if there is an acceptable, beneficial treatment for depression that can be delivered and definitively tested.

Many advances in the understanding of the relationship between depression and cardiovascular disease (CVD) were reported in 2009. As the study of this relationship encompasses cardiology, psychiatry, behavioral medicine, and many other fields, it is difficult to keep abreast of new developments. Relevant papers are found in a variety of journals. Therefore, we systematically searched the empirical research on depression and CVD published in English in 2009. Our search yielded nearly 500 articles. We review here a few of the most provocative and potentially influential findings. We begin with an overview of the methodology of our systematic review and then summarize the key findings and controversies we identified from the 2009 literature before exploring each key finding in detail.

METHODOLOGY OF OUR SYSTEMATIC SEARCH AND RATIONALE FOR FINDINGS REVIEWED

Previous evidence demonstrated that the presence of depressive symptoms or a diagnosis of a depressive disorder predicts poor prognosis and reduced survival rates after any coronary artery disease diagnosis, including myocardial infarction (MI) and unstable angina, as well as after coronary artery bypass graft surgery (CABG).¹

We aimed to see how this evidence base was expanded in 2009 by using a systematic search strategy to retrieve the most relevant articles about depression and coronary heart disease (CHD) from the MEDLINE and Psyc-INFO (Ovid interface) databases. The most relevant subject headings and free text terms were identified and combined with “or.” The two sets were then combined with “and.” Terms included “depression,” “depressive disorder,” “depress$,” “coronary artery disease” (CAD) “coronary disease,” “acute coronary syndrome” (ACS), “cardiovascular disease” (CVD), “coronary heart disease,” and “heart diseas$.” The final set was limited to the English-language literature and identified 494 unique articles published during 2009.

Closer inspection of titles and abstracts revealed well more than 100 articles directly relevant to the science and management of patients with CVD and depression or pronounced depressive symptoms. In light of this quantity, a thorough review of all new findings, editorials, and reviews is not feasible. Thus, we review here a few exciting articles in several distinct topical areas that could influence views of the relationship between depression and CVD as well as how we screen for and treat depression in patients with CVD. As with any review that is not strictly evidence-based, our choice of articles is subjective and incomplete, but we hope it will stimulate discussion and further exploration.

SUMMARY OF KEY FINDINGS AND CONTROVERSIES

The following numbered topics emerged as common themes or controversies from our survey of the 2009 literature. The remainder of this article will review findings in each of these areas in detail and discuss important clinical implications as appropriate.

1. Antidepressant use and adverse cardiac events. In surprising findings, antidepressant use was associated with increased risk of incident stroke, CVD, and sudden cardiac death in multiple large observational cohort studies. It is not known if the association is caused by unmeasured confounders or depressive symptom severity, although controlling for symptom severity did not reduce this elevated risk in some studies. Another interesting possibility is that the treatment-resistant depressed patient is at particularly high risk of CVD and death.

2. Effects of depression intervention in CVD patients. Four exciting randomized controlled trials on depression intervention in patients with CVD reported important efficacy results and suggested future directions for larger, definitive trials of depression treatment for these patients.

3. Depression screening and treatment in CVD patients. In the absence of large randomized controlled trials, the debate continues on whether depression screening or any type of depression treatment is beneficial, harmless, or harmful to patients with CVD. Continuation of this debate does not serve the health and well-being of patients or the public. Less controversial—and thus less discussed—is the important insight that psychiatric patients with depression should be routinely screened for cardiac disease and risk factors, as they are clearly at risk of CVD. We await clinical trials in this area to ensure that screening leads to improved CVD outcomes.

OBSERVATIONAL EVIDENCE ON ANTIDEPRESSANT USE AND CVD OUTCOMES

In an analysis of the Nurses’ Health Study, Whang et al examined the relationship of depressive symptoms and antidepressant use with sudden cardiac death and adverse cardiac events in 63,469 women without CVD.² Depressive symptoms were assessed using the Mental Health Index, a five-item subscale of the Short Form-36 Health Survey. Among women who reported antidepressant use, most (61%) were taking a selective serotonin reuptake inhibitor (SSRI; sertraline, fluoxetine, paroxetine, or citalopram), while 39% reported use of other antidepressants. Women taking antidepressants were more likely to suffer sudden cardiac death, with a fully adjusted hazard ratio (HR) of 3.34 (95% confidence interval [CI], 2.03–5.50).

Krantz et al examined psychotropic medication use and risk of adverse cardiovascular events in 519 women from the Women’s Ischemia Syndrome Evaluation.³ Enrolled women underwent coronary angiography, were separated into four groups according to their psychotropic medication use (none, anxiolytics only, antidepressants only, or both anxiolytics and antidepressants), and were observed for a median of 5.9 years. Results revealed that women who received both medications had a higher risk for adverse cardiovascular events and higher all-cause mortality compared with those using neither medication, even after controlling for anxious and depressive symptoms. In addition, whereas the use of antidepressant medication was associated with a doubling of risk for subsequent CVD events (HR = 2.16; 95% CI, 1.21–3.93) and all-cause mortality (HR = 2.15; 95% CI, 1.16–3.98), use of anxiolytic medication alone was not. While this study did not examine cause of death, cardiac death is likely to have constituted a large proportion of total mortality in this cohort selected for likelihood of CAD.

Although CVD and death have long been outcomes of interest for those studying the effects of depression, additional end points have recently been investigated as well. In a prospective cohort study of 136,293 community-dwelling postmenopausal women in the Women’s Health Initiative, Smoller et al found that new antidepressant use was significantly associated with increased incidence of stroke and all-cause mortality but not with incidence of CHD.⁴ The rate of stroke per 1,000 person-years was 2.99 for subjects with no antidepressant use versus 4.16 for patients with new SSRI use; the rate of all-cause death was 7.79 versus 12.77, respectively. The rate of all-cause death for subjects with new tricyclic antidepressant use was 14.14 per 1,000 person-years. To address potential confounding by indication, the researchers obtained a propensity score from a logistic regression model to predict any new antidepressant use from demographic, lifestyle, risk factor, and comorbidity variables measured at baseline. New SSRI use was associated with a doubling of the risk of incident hemorrhagic stroke as well as fatal stroke. There were no significant interactions between use of SSRIs and use of statins or aspirin in terms of risk of hemorrhagic stroke.

In an interesting observational study of 7,709 patients with confirmed CAD but without a diagnosis of heart failure or depression (and without current antidepressant use), May et al found that a subsequent diagnosis of depression was associated with a significant 50% increase in the risk of heart failure.⁵ There was no difference, however, between depressed patients who were using antidepressants and those who were not.

Increased risk of bleeding with SSRI use, particularly in patients with CAD, has also been a concern. Kim et al evaluated 1,380 adults who received any anti depressant before CABG for in-hospital mortality or any bleeding events.⁶ After controlling for the percentage of patients taking SSRIs (78%), there were no significant differences between those taking SSRIs and those taking non-SSRIs in the rate of any bleeding events (6.5% vs 7.2%; odds ratio [OR] = 0.93; 95% CI, 0.50–1.76) or in-hospital mortality (3.1% vs 2.3%; OR = 0.88; 95% CI, 0.47–1.65). There was no increased risk of bleeding associated with SSRI use when the analysis was restricted to patients who received antiplatelet and anticoagulant therapy. Thus, compared with patients who received non-SSRI antidepressants, patients who received SSRIs preoperatively had no increased risk of bleeding or in-hospital mortality after CABG; however, this study did not evaluate the effect of no antidepressant use.

Another study hypothesized that the use of any drug with the potential to prolong cardiac repolarization would be associated with an increased risk of sudden death.⁷ Use of individual drugs was analyzed among 1,010 cases of sudden unexplained death and 3,030 living primary care controls, all from the community. SSRI use was associated with a doubling of risk of sudden death (OR = 2.21; 95% CI, 1.61–3.05), and tricyclic antidepressant use was associated with a nonsignificant trend toward increased risk (OR = 1.44; 95% CI, 0.96–2.13). Further analysis that stratified patients according to prior CVD showed that most of the association of SSRIs with sudden death was in those with existing CVD and not in those without CVD. Other drugs found to raise sudden death risk included the typical and atypical antipsychotics.

The Nurses’ Health Study analysis by Whang et al suggested that antidepressant use triples the risk of sudden cardiac death in healthy women, and the authors suggested that the association between fatal ventricular arrhythmias and antidepressant use be examined further. ² The analysis of the Women’s Health Initiative by Smoller et al found that use of SSRIs and tricyclic antidepressants doubled the risk of fatal stroke in healthy women.⁴ The analysis of the Women’s Ischemia Syndrome Evaluation by Krantz et al revealed a doubling of the risk of CVD and death in women taking antidepressants who had been referred for coronary angiography.³ At the same time, May et al found no increase in the risk of heart failure conversion with antidepressant use in patients with CAD,⁵ and Kim et al found no increase in the risk of bleeding with use of SSRIs compared with non-SSRI antidepressants in patients with CAD undergoing CABG.⁶ Finally, in a population- and community-based case-control study, SSRI use was associated with an increased risk of sudden death, particularly in patients with CVD.⁷ So what are we to make of these findings?⁸

In all observational studies (including those reviewed above), unmeasured confounders pose a threat to the validity of any causal conclusions. A study recently tested some of the proposed confounders that might have existed in the above studies. Waldman et al examined racial differences in depressive symptoms and antidepressant treatment among a cohort of 864 consecutive patients with CHD undergoing diagnostic coronary angiography (727 white and 137 African American).⁹ While levels of depression were similar between the white and African American patients, the African Americans were less likely than their white counter-parts to receive antidepressant medications. Patients with only some high school, men, and patients with more severe depressive symptoms were significantly more likely to receive a prescription for antidepressants. Clearly, low education, male sex, and elevated depressive symptoms are related to poor prognosis for CHD, and the simple interpretation that antidepressant use is causing poorer outcomes is problematic.⁸

Two additional interpretations of the observational findings should be considered. First, confounding by indication (depressive symptom severity) might exist in these studies.¹⁰ In other words, patients who are prescribed antidepressant medication may be those with the most severe depressive illness, and it could be this severity, rather than the antidepressant use, that is causally implicated in the CVD incidence.¹¹ However, all of the studies reviewed above either directly controlled for depressive symptom severity (at least as obtained at baseline) or used propensity scores or stratified subjects based on depression severity. The results showed an increased risk among those who were taking antidepressants. However, none of the studies examined depressive symptom severity during or at the end of the study or depression diagnosis and severity before antidepressant use; these data are needed for a clearer understanding of whether the results were confounded by indication.

Second, these findings are also consistent with a treatment-resistant depression phenotype.¹² Krantz et al caution that it is not clear from their observational study³ whether medication use itself or depression refractory to treatment is implicated in the increased risk of CVD events and mortality. Depression that is refractory to treatment may be the type of depression that places patients at risk for sudden death, stroke, or CHD recurrence, so it may not be the antidepressant use per se that is associated with this risk. This phenomenon was documented in a secondary analysis¹³ of the largest-to-date randomized controlled trial of patients with MI undergoing treatment for depression (ENRICHD).¹⁴ It showed that those whose depressive symptoms did not respond to treatment had a higher risk of late mortality (ie, death ≥ 6 months after acute MI). This finding was replicated in 2009 in an important follow-up¹⁵ of the SADHART trial¹⁶; among patients with MI and major depression, treatment-resistant depression (ie, depression that failed to improve substantially during treatment with either sertraline or placebo) was strongly and independently associated with long-term mortality (HR = 2.39; 95% CI, 1.39–2.44; P < .001).¹⁵

What is needed next? Testing the alternative hypothesis— ie, that an unmeasured confounder may exist—is difficult, requiring new observational studies and measurement of the putative third common causes or previously unmeasured confounder. Other putative confounders would then be hypothesized and would need to be included in additional observational studies. To properly test the putative confounding by depressive symptom severity, future observational studies should examine initial depressive symptom severity prior to antidepressant use and then collect data on depressive symptom severity and antidepressant use as time-varying covariates to CVD outcomes. To test whether treatment-resistant depression is the phenotype driving the spurious observational association between antidepressant use and increased risk of CVD, the phenotype and its underlying causal mechanisms need to be better understood. Of course, rigorous and adequately powered randomized controlled trials of antidepressant use in patients with CVD would be a more straightforward way to test the observational association between antidepressant use and increased risk of CVD. We turn now to the recently published randomized controlled trials in this field.

NEW EVIDENCE FROM RANDOMIZED TRIALS IN PATIENTS WITH CVD AND DEPRESSION

Concerns have been voiced for some time about the ability to effectively treat depression and whether an effective depression treatment will affect the risk of CVD recurrence and mortality.⁸ Adding to these concerns is our limited knowledge of the causal pathways and behavioral and biologic mechanisms implicated in this risk association.¹ For these reasons, results from new randomized controlled trials, such as the four summarized below, are important.

Rollman et al compared the effectiveness of telephone-delivered collaborative care (treatment group) and usual physician care (control group) for improving mental health quality of life and reducing depressive symptoms in 302 patients with depression after CABG.¹⁷ Patients were observed for 8 months following randomization. Mental health quality of life and depressive symptoms were both significantly improved in the treatment group relative to the control group. Significantly more patients in the treatment group had a 50% or greater reduction in depressive symptoms (50.0% vs 29.6% in control group, P < .001; number needed to treat = 4.9 [95% CI, 3.2–10.4]). Men particularly benefited from the treatment. This trial suggests that collaborative care can be delivered effectively (and potentially cost-efficiently) over the phone.

Freedland et al also evaluated depression treatment in 123 patients with major or minor depression who underwent CABG.¹⁸ Their primary objective was to determine the efficacy of two behavioral treatments (cognitive behavioral therapy [CBT] or supportive stress management) compared with usual care. Significantly more patients in both the CBT group (71%) and the stress management group (57%) had a low score (indicating less severe depressive symptoms) on the clinician-based Hamilton Rating Scale for Depression compared with the usual care group (33%). These results were maintained 6 months after the end of the trial. Secondary measures of depressive symptoms, anxiety, and quality of life were also significantly improved in the depression treatment groups compared with the usual care group. This trial is important for the following reasons:

• The use of a second control group, the stress management group, represents a strict, high-quality design that controls for professional attention, generic or placebo therapy effect, and time or effort on the part of the patient.
• The second control group also provides treatment options for the patient, as both CBT and stress management were beneficial.
• Outcome assessors were blinded to treatment assignment, an important design feature in behavioral trials.

In a rigorously conducted randomized, double-blind, placebo-controlled trial, Carney et al tested whether 2 g/day of omega-3 acid ethyl esters (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) improved depressive symptoms in 122 patients with major depression and CHD.¹⁹ Patients in both the omega-3 and placebo groups received sertraline (50 mg/day) during the 10-week trial. A deficiency of omega-3 fatty acids has been implicated in both depression and CHD and is a possible causal link between the two diseases. Also, there is some evidence that the efficacy of antidepressants is increased by the addition of omega-3 supplementation. Unfortunately, there were no differences in self-reported or clinician-assessed depressive symptoms or in predefined depression remission at the study’s end. The trial included a 2-week adherence run-in period, ensuring that medication adherence in the trial was excellent (97%), and concluded that omega-3 supplementation, at least at these dosage levels, does not improve depression outcomes.

In the Coronary Psychosocial Evaluation Studies (COPES) randomized controlled trial, Davidson et al compared 6 months of an enhanced care intervention with usual depression care among 157 patients with ACS and persistently elevated depressive symptoms.²⁰ Under the enhanced care intervention, patients received either problem-solving therapy or antidepressant medication, depending on their preference, and then had the option of later augmentation with the other treatment, intensification of the initial treatment, or switching of treatments, if indicated by depressive symptom severity (stepped care). The purpose of the trial was to determine the acceptability and efficacy of depression treatment among patients with ACS, who often neither agree with the diagnosis of depression nor had been seeking treatment for depression. Significantly more patients were satisfied with their depression care in the intervention arm, and depressive symptoms and major adverse cardiac events (nonfatal MI, hospitalization for unstable angina, or all-cause mortality) were significantly reduced in the intervention arm compared with the usual care arm. The absolute numbers were very small; at the end of the trial, 3 patients in the intervention group and 10 patients in the usual care group had major adverse cardiac events (4% and 13%, respectively; log-rank test, χ²₁ = 3.93; P = .047). The results suggested that involving patients in the type of depression care they receive (medication and/or psychotherapy) and stepping treatments aggressively may be methods to improve the treatment of depression in patients with CHD. In addition, persistently depressed patients may be an interesting patient group to select for future trials, as usual care has resulted in large reductions in depressive symptoms in some previous trials but not in this study of patients with persistent depression.

Each of these four efficacy trials adds critical information to the evidence base. Depressed patients who have undergone CABG can be effectively treated in primary care settings with integrative care,¹⁷ and CBT is also extremely effective for these patients.¹⁸ Additional studies of omega-3 supplementation should not be pursued at this time, but using a run-in period to better identify patients who are prepared to engage in treatment is a prudent idea and should be used in future trials in this area.¹⁹ Patients with CHD and persistent depressive symptoms are a promising group to target for depression therapy, and asking patients to choose their type of depression treatment may improve response to therapy for both depression and CHD.²⁰

DEPRESSION SCREENING, REFERRAL, AND TREATMENT IN PATIENTS WITH CVD

We finish with the least evidence-based and most controversial issue in the area of depression and CVD. This controversy started in 2008 when the American Heart Association recommended in an advisory (endorsed by the American Psychiatric Association) that “screening tests for depressive symptoms should be applied to identify patients who may require further assessment and treatment” if appropriate referral for further depression assessment and treatment is available.²¹ Partly in response to this advisory, Thombs et al conducted a systematic review of the evidence on whether screening or treatment improves outcomes of depression or CVD in patients with CVD.²² They found no trial that tested whether depression screening was beneficial in patients with CVD, and the randomized controlled trials of depression treatment provided evidence of only mild improvement of depressive symptoms and no improvement in CVD outcome. Therefore, they questioned whether routine depression screening was appropriate.²²

In at least eight editorials, letters, and reviews published on this subject in 2009, investigators continued to debate this issue.^23–30 Below we provide a simplified list of reasons presented for and against screening and subsequent treatment raised in these articles.

Arguments for depression screening and treatment

The proponents of screening contend that depression is highly prevalent in patients with CVD and is clearly a risk marker for increased adverse events, reduced quality of life, and poorer adherence to treatment.²⁴ They argue that since there are plausible biologic and behavioral mechanisms for this association, and since SSRI use improves depressive symptoms in other patient populations and is safe in patients with CVD, health care providers should not hesitate to screen and refer patients for appropriate depression treatment. At the same time, they have cautioned that SSRIs interact with anti coagulants and that bleeding should be monitored closely in patients with CVD who are taking SSRIs.²⁴

Whooley²⁸ noted that although there are controversial findings in this area, depression screening provided in conjunction with collaborative care depression management is cost-effective and has a documented positive impact on depression, if not on CVD outcomes.^17,31 She observed that there are some costs to screening, such as false-positive findings (resulting in stigma for patients incorrectly diagnosed) and diversion of resources from other health care needs. However, Whooley suggested that primary care providers, rather than cardiologists, should conduct depression screening and that patients should undergo screening only when an established collaborative care treatment protocol exists.²⁸

Carney et al argued that depression, like age, clearly marks CVD risk, and that health care providers should aggressively treat readily modifiable CVD risk factors.²³ They added that because of the strong association between depression and medication nonadherence,³² providers should carefully monitor patient adherence to life-saving therapies.

Taking another tack, Shemesh and colleagues advocated the importance of documenting the prevalence of suicidal ideation and intent if recommendations to screen for depression in CVD patient populations were implemented.²⁵ Using a sample of more than 1,000 patients with CVD, they determined the prevalence of suicidal ideation (12.0%) and the number of patients who required hospitalization for risk of suicide (0.5%) when routine depression screening occurred in a large cardiology clinic. They concluded that identification and stabilization of imminently suicidal patients would be a benefit of universal screening and that there is a high societal cost to neglecting suicidal ideation, intent, and risk in patients with CVD. However, more patients would need immediate thorough psychiatric evaluations for safety, which would affect resource allocation and cost in cardiology clinics.

Arguments against depression screening and treatment

The main argument against screening for and treating depression in patients with CVD is that there are neither randomized controlled trials nor systematic evidence-based reviews showing that screening for depression and/or referring for additional treatment sufficiently improves outcomes for depression or CVD, and that existing evidence does not support the recommendation to screen all patients with CVD.^22,30 Furthermore, antidepressant use is associated with only mild improvement in depressive symptoms, even in other patient populations,³³ and publication bias (“the file-drawer problem”) has prevented the publication of antidepressant trials with null results, thereby skewing the evidence base.³⁴ In addition, considerable health care resources would be needed to mount such a large screening effort, and these resources would come at the expense of other efforts. Finally, the adverse effects of medications and the inevitability of some false-positive screening results must be weighed against any benefit that might occur with universal screening.³⁵

In addition to the arguments above, Ziegelstein et al,²⁹ in commenting on the American Heart Association advisory,²¹ wryly observed that there is far greater observational evidence that depressed patients seen in mental health settings are at risk for incident and recurrent CVD and that there should be universal screening and referral for CVD in patients with depression. They contended as well that the evidence is insufficient to recommend that patients with CVD undergo universal depression screening and referral.

Summary and clinical implications

Although we were hesitant to raise this tense and often emotional issue, we are in favor of routine, algorithm-based depression screening by all cardiologists, with the critical proviso that a nationwide and/or Centers for Medicare and Medicaid Services–coordinated randomized controlled trial be conducted to evaluate this practice. All patients with pronounced depressive symptoms should be referred to the trial, and two depression treatments should be evaluated, such as usual referral versus telephone-based collaborative care¹⁷ or enhanced depression care.²⁰ Such a trial would allow us to ensure that data are collected on the cost,³⁶ the benefit, and even the possible harms associated with routine depression screening for patients with CVD, and we could ascertain if there is an acceptable, beneficial treatment for depression that can be delivered and definitively tested.