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Available online at www.sciencedirect.com
www.elsevier.com/locate/tcm
Depression and cardiovascular disease Steven M. Bradleya,b,c,n, and John S. Rumsfelda,b,c a
Department of Veterans Affairs, VA Eastern Colorado Health Care System, 1055 Clermont Street (111B), Denver, CO 80220-3808 b Department of Medicine, Division of Cardiology, University of Colorado School of Medicine, Aurora, CO c Colorado Cardiovascular Outcomes Research Consortium, Denver, CO
abstra ct There is a wealth of evidence linking depression to increased risk for cardiovascular disease (CVD) and worse outcomes among patients with known CVD. In addition, there are safe and effective treatments for depression. Despite this, depression remains under-recognized and undertreated in patients at risk for or living with CVD. In this review, we first summarize the evidence linking depression to increased risk of CVD and worse patient outcomes. We then review the mechanisms by which depression may contribute to cardiovascular risk and poor cardiovascular outcomes. We then summarize prior studies of depression treatment on cardiovascular outcomes. Finally, we offer guidance in the identification and management of depression among CVD populations. Given that 1 in 4 CVD patients has concurrent depression, application of these best-practices will assist providers in achieving optimal outcomes for their CVD patients. Published by Elsevier Inc.
Introduction More than 1 in 10 general medical patients has major depression, making the disorder among the most common chronic conditions encountered in general practice [1]. Furthermore, the prevalence of depression in patients with cardiovascular disease (CVD) is double that of general medical populations [2]. As such, depression is exceptionally common in patients at risk for or with known CVD. Depression results in worse quality of life, functional status, and increased mortality. The mechanisms by which depression contributes to worse patient outcomes include an increased risk of incident CVD and poor outcomes among patients with known CVD. As such, identification and appropriate management of depression is critical to optimal CVD outcomes. Yet,
most cases of depression remain unrecognized or undertreated. In this review article, we analyze the epidemiologic evidence linking depression to increased CVD risk and worse CVD outcomes, proposed mechanisms by which depression contributes to CVD risk and outcomes, and optimal approaches to the diagnosis and management of depression in CVD patients.
The relationship between depression and cardiovascular risk A number of studies have demonstrated that depression increases the risk of incident coronary artery disease (CAD) by at least 1.5 times that of otherwise physically healthy
Dr. Bradley is supported by a Career Development Award (HSR&D-CDA2 10-199) from VA Health Services Research & Development. The authors report no relevant relationships with industry or other disclosures. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the United States government. The authors have indicated there are no conflicts of interest. n Corresponding author at: Department of Veterans Affairs, VA Eastern Colorado Health Care System, 1055 Clermont Street (111B), Denver, CO 80220-3808. Tel.: þ1 720 857 5120; fax: þ1 720 857 5992. E-mail addresses: [email protected], [email protected] (S.M. Bradley). http://dx.doi.org/10.1016/j.tcm.2015.02.002 1050-1738/Published by Elsevier Inc.
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individuals [3–11]. Among the largest of these studies was a prospective evaluation of 20,000 patients without prior heart disease that found patients with depression were 2.7 times more likely to die from ischemic heart disease over a median follow-up of 8.5 years [11]. In addition to ischemic heart disease, depression has been associated with an increased risk of stroke and peripheral arterial disease [12,13]. The implications of depression on cardiovascular risk and global health are far from minor. In a comparative risk assessment conducted by Charlson et al. [14], the authors estimated that depression accounts for 3% of worldwide disability-adjusted life years due to ischemic heart disease . Thus, depression may account for 3.5 million years of life lost and 250,000 years of life lived with disability due to ischemic heart disease alone. These findings suggest significant promise in reducing the global burden of CVD by addressing the role of depression in cardiovascular risk.
The relationship between depression and cardiovascular outcomes In addition to increasing CV risk, depression is highly prevalent in patients with underlying CVD. While depression exists as a comorbid condition in less than 10% of general medical patients, depression is found in 20–30% of cardiovascular patients (Fig.) [2]. Given that depression is twice as common in cardiovascular populations as the general medical population, the impact of depression on cardiovascular outcomes is all the more pertinent. A large number of studies have shown that depression predicts worse outcomes following hospitalization for cardiovascular events. One of the first studies to demonstrate this relationship evaluated outcomes following an acute myocardial infarction (MI) in depressed and non-depressed patients. Among patients with major depression, the 6-month mortality following an MI was 17% as compared with 3% among non-depressed patients, corresponding to a risk-adjusted hazard ratio of 3.44 (95% confidence interval, 2.25–4.63) [15]. Subsequent studies have demonstrated similar findings in larger cohorts of MI and ACS patients [16,17], in evaluation of
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longer term outcomes [18], as it relates to cardiac-specific mortality [19], and in other ischemic heart disease patient cohorts (i.e., stable ischemic heart disease, post-CABG, and post-PCI) [20,21]. Furthermore, a dose–response relationship has been observed between the severity of depression and cardiovascular outcomes. After hospital discharge for MI, Lespérance et al. [18] found a stepwise relationship between the severity of depression and mortality outcomes . Although not all published studies suggest depression is associated with worse outcomes after ACS, the preponderance of evidence has led to a scientific statement from the American Heart Association supporting depression as a formal risk factor for adverse outcomes in patients with ACS [22]. Depression is also associated with an increased risk of recurrent and fatal stroke among patients with prior stoke [12] and an increased risk of heart failure readmission and death among CHF patients [23–25]. In addition to being associated with worse survival and an increased risk of recurrent cardiovascular events, depression is strongly associated with worse patient health status (i.e., symptom burden, functional status, and quality of life). Among patients with stable ischemic heart disease, Ruo et al. [26] found that more severe depression is associated with worse measures of ischemic heart disease-specific health status as assessed by the Seattle Angina Questionnaire . Similar results have been observed in post-ACS [27] and post-MI [28] patient populations. In addition to being associated with worse cardiovascular-specific health status measures, depression has been shown to predict declines in health status. In a study of 460 outpatients with a history of heart failure and left ventricular ejection fraction o0.40, depression was the strongest predictor of decline in health status over a 6-week period of follow-up [29]. These findings are consistent with a study by Vaccarino et al. [30] that found a graded relation between the severity of depressive symptoms and a combined end-point of functional decline or death among heart failure patients. Finally, a number of studies have demonstrated that depression is associated with higher costs of care. In a cohort of patients with acute MI, Frasure-Smith et al. [31] demonstrated that 1-year post-MI costs were 41% higher for patients
Prevalence of Depression, %
45 40 35 30 25 20 15 10 5 0 General Medical Stable Heart Post-CABG Post-ACS Population Outpatients Coronary Failure Disease Outpatients Fig – The prevalence of depression across the patient spectrum. Prevalence estimates taken from Whooley [2].
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with depressive symptoms. Similarly, Sullivan et al. [32] found that 3-year costs of care were 29% higher for heart failure patients with depression. Together, these studies implicate a strong relationship between depression, increased cardiovascular risk, and poor cardiovascular outcomes. Understanding the mechanisms that drive these relationships may guide opportunities to intervene and disrupt the impact of depression on cardiovascular outcomes. We next review the possible mechanisms by which depression leads to increased cardiovascular risk and worse clinical outcomes.
Depression's mechanistic path to increased cardiovascular risk and poor cardiovascular outcomes For nearly 3 decades, it has been appreciated that depression is associated with physiological derangements. These derangements include (1) autonomic dysfunction in the form of excessive sympathetic and/or reduced parasympathetic modulation [33–36], (2) elevated cortisol related to a blunted inhibitory feedback loop on corticotropin-releasing hormone [36–38], (3) platelet activation as demonstrated through elevated levels of platelet factor 4 and β-thromboglobulin [39–42], (4) endothelial dysfunction [42–47], and (5) inflammation as evidenced by elevated C-reactive protein and cytokines including tumor necrosis factor-α and interleukins [47–53]. The result of these derangements may include increased sympathetic tone resulting in higher blood pressure, reduced heart rate variability [47,54,55], increased ventricular arrhythmias [56–58], and accentuation of atherosclerosis progression with associated risk for cardiovascular events and cardiovascular death. One proposed pathway by which depression may exert these physiologic derangements relates to hyperactivity of the hypothalamic–pituitary–adrenal (HPA) axis [59,60] and defective serotonin signaling that results in dysfunction of the amygdala [61,62]. These abnormalities subsequently result in autonomic dysfunction, hypercortisolemia, elevation in catecholamines and inflammatory markers, endothelial dysfunction, and platelet activation. Although these physiologic derangements may contribute to cardiovascular risk and outcomes among depressed patients, behavioral mechanisms may play an even larger role in explaining the link between depression and cardiovascular disease. Depressed patients are 2–4 times less likely to adhere to their medication regimen [63–68], follow lifestyle recommendations (e.g., low-fat diet and smoking cessation) [63,66,69–71], and practice self-management [72]. In addition, depressed patients are more inactive, and several studies have suggested this lack of physical activity may be a major driver of worse cardiovascular outcomes. In the Cardiovascular Health Study of 5888 individuals followed for an average of 10.3 years, physical inactivity accounted for about 25% of the risk of cardiovascular mortality due to depressive symptoms in older adults [73]. Similarly, in a study of outpatients with stable coronary disease, Whooley et al. [74] found the association between depressive symptoms and risk of adverse cardiovascular events was predominantly explained by physical inactivity.
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These findings on the health behaviors of depressed patients have led some to question whether depression itself causes increased cardiovascular risk and worse outcomes, or whether depression is simply a risk marker for health behaviors that lead to worse cardiovascular risk and outcomes. Unfortunately, this dichotomization has little merit in guiding optimal patient care as the management of both depression and associated health behaviors is necessary to achieve ideal health. In the next section, we review prior studies of depression treatment as it relates to cardiovascular risk and outcomes to guide an understanding of the bestpractices in clinical care.
Treatment of depression and cardiovascular outcomes Pharmacologic-based approaches to depression treatment Treatment of depression with pharmacologic therapies has been shown to improve the physiologic derangements associated with depression. This includes significant decreases in platelet/endothelial activation markers (e.g., platelet factor 4 and β-thromboglobulin) [75–77], reduced inflammatory markers (e.g., tumor necrosis factor-α and C-reactive protein) [78], improved heart rate variability [79,80], and normalized brain serotonin turnover [81]. Thus, these studies suggest promise in the potential for mitigating the impact of depression on cardiovascular risk and outcomes related to physiologic derangements. Subsequently, studies have tested the impact of antidepressant pharmacology on outcomes in patients with cardiovascular disease. Among the first randomized controlled trials of pharmacologic therapy for depression in cardiovascular patients was the Sertraline Antidepressant heart Attack Randomized Trial (SADHEART). In this study, 369 patients with depression after ACS were randomized to sertraline (a selective serotonin reuptake inhibitor) versus placebo. This trial demonstrated that sertraline was safe in ACS patients and resulted in improvements in depressive symptoms and quality of life [82,83]. Although not powered for cardiovascular outcomes, the effect of sertraline on cardiovascular events was indeterminate with point-estimates suggesting benefit for sertraline but failing to achieve statistical significance [82]. The Myocardial INfarction and Depression—Intervention Trial (MIND–IT) trial randomized 331 patients with depression after an AMI to pharmacologic therapy for depression (with mirtazapine specified as first-line therapy) versus placebo. This trial found no difference in cardiac event rates between treatment arms at 18 months of follow-up [84]. However, nearly a full 25% of patients in the intervention arm did not receive pharmacologic antidepressant therapy, and no reduction in depressive symptoms was observed in the intervention group, raising questions about the efficacy of the treatment arm in this trial. More recently, the Improving Mood-Promoting Access to Collaborative Treatment (IMPACT) trial randomized 235 primary care patients with depression to a 12-month collaborative care program involving antidepressants and psychotherapy. In this study, intervention patients without baseline
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CVD had a dramatic 48% lower risk of a CVD event over 5 years of follow-up [85]. Similar benefit was not observed among patients with baseline CVD. Cause of death was only available for 65% of deaths in the study, raising questions about the validity of the primary findings. Although these findings warrant replication, this study suggests the promise of antidepressants and psychotherapy as a component of primary prevention for CVD among depressed patients. In addition to these randomized trials, there have been several observational studies that suggest pharmacologic therapy for depression reduces future cardiovascular risk. A secondary analysis of depressed patients with CVD who participated in a randomized controlled trial of cognitive behavioral therapy found a significant reduction in CV events with use of SSRIs and a non-significant benefit with non-SSRI medications [86]. Similarly, observational studies have suggested that the use of SSRIs is associated with reduced risk of first MI [87] and cardiovascular- or cerebrovascular-related deaths [88]. Taken together, the weight of evidence suggests cardiovascular benefit is achieved with pharmacologic depression management. A corollary concern in the management of CVD is the perceived risk of inducing depression as a side effect of cardiovascular risk-modifying therapies. In particular, β-blockers have been implicated as resulting in depression. However, studies have conclusively demonstrated that cardioprotective β-blockers do not cause depression [89]. As such, these therapies should be implemented for risk modification among patients with CVD conditions that warrant their use.
Non-pharmacologic and collaborative care-based approached to depression treatment The ENRICHED trial is the largest study of a nonpharmacologic-based treatment approach for depressed patients with cardiovascular disease [90]. This trial compared cardiovascular outcomes after myocardial infarction among 2481 patients with low perceived social support and depression who were randomized to cognitive behavior therapy supplemented with a selective serotonin reuptake inhibitor antidepressant when indicated. Although the intervention improved depression and social isolation, it did not reduce cardiovascular events in 6 months of follow-up [90]. In contrast, several studies have suggested the promise of collaborative care models for depression treatment and improved CV outcomes among patients with CVD. The Coronary Psychosocial Evaluation Studies (COPES) intervention trial randomized 157 patients with persistent depression after ACS to enhanced care by a treatment team with a stepped-care approach in treatment. This approach demonstrated significant reductions in depressive symptoms and major cardiac events [91]. A trial of 183 patients randomized to a telephone-based collaborative care treatment model that used care managers to coordinate stepped treatment recommendations was effective in reducing depression symptoms, though rates of cardiac admission were unchanged [92]. In the MoodCare study of 121 post-ACS patients randomized to a telehealth intervention targeting depression and other cardiovascular risk factors, the intervention improved
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depression measures with effect sizes exceeding those of some face-to-face psychotherapeutic interventions and pharmacotherapy [93]. Similarly, a randomized controlled trial of telephone-delivered collaborative care for treatment of postCABG depression resulted in improvements in health-related quality of life, functional status, and mood symptoms at 8 months [94]. Similar findings were observed among 175 depressed cardiac inpatients randomized to a collaborative care intervention with resultant improvements in depression and mental health status, medication adherence, and fewer cardiac symptoms [95]. A collaborative care model has also been shown effective in improving cholesterol and blood pressure control in patients with coronary disease [96]. In summary, prior studies suggest we can improve the outcomes of patients with depression and cardiovascular disease through the use of pharmacologic, psychotherapy, and collaborative care interventions. In particular, depression treatment results in better physiologic markers, lower depression severity, and higher quality of life. It is less clear if depression treatment reduces cardiovascular event rates or costs of care among patients with known CVD. However, the point-estimates from the SADHEART study, combined with the large effect size in the IMPACT trial and several collaborative care model studies suggest the promise of depression treatment to improve CV outcomes in addition to quality-oflife measures.
Depression management in the clinical care of cardiovascular patients Treatment of depression is first dependent on making the diagnosis. Unfortunately, depression is grossly underrecognized. Less than 25% of patients with depressive symptoms are recognized by their providers [97]. As a result, a large number of CVD patients may suffer from depressive symptoms, worse quality of life, and potentially worse CV outcomes due to a failure to recognize concurrent depression. Although we lack randomized controlled trials that demonstrate definitive benefit of depression screening in CVD patients [98], clinical practice guidelines recommend routine depression screening in CVD patients [99]. Screening for depression in CVD patients can be as simple as asking 2 questions (Box). Responding “yes” to 1 of these 2
Box–Two-item screening for depression. (1). During the past month, have you often been bothered by feeling down, depressed, or hopeless? (2). During the past month, have you often been bothered by little interest or pleasure in doing things? Answering “yes” to one of these questions has a 90% sensitivity and 69% specificity for depression. The negative likelihood ratio for answering “no” to both questions is 0.14, essentially ruling out depression.
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Table – Pharmacologic treatment options for depression in cardiovascular disease patients. Drug name
Class
Common side effects
Considerations for CVD patients
Sexual dysfunction
Preferred first-line therapy
Citalopram Escitalopram Paroxetine
Selective serotonin reuptake inhibitor (SSRI) SSRI SSRI SSRI
QTc prolongation; preferred first-line therapy QTc prolongation; preferred first-line therapy Inhibits 2D6 of P-450 resulting in drug–drug interactions
Fluoxetine
SSRI
Sexual dysfunction Sexual dysfunction Sexual dysfunction, weight gain Sexual dysfunction
Atypical
Insomnia
Mirtazapine
Atypical
Venlafaxine
Serotonin– norepinephrine reuptake inhibitor (SNRI) SNRI
Weight gain and drowsiness Insomnia and gastrointestinal
First-line therapies Sertraline
Second-line therapies Bupropion
Duloxetine
Use cautioned St. John's wort Contraindicated Amitriptyline, Clomipramine, Doxepin, Imipramine, etc. Phenelzine, Isocarboxazid, and Tranylcypromine
Insomnia and gastrointestinal
Inhibits 2D6 of P-450 resulting in drug–drug interactions Long half-life (3–4 weeks), increased by heart failure Consider first line if (1) sexual dysfunction of SSRI not tolerated or (2) concurrent smoking cessation considered Potential for increased blood pressure Hypertensive urgency when administered with clonidine Unstudied in CVD patients
Unstudied in CVD patients
Herbal supplement
Potential interactions with cardiac medications
Tricyclic antidepressants
Adverse cardiovascular events
Monoamine oxidase inhibitors
Adverse cardiovascular events
questions is 90% sensitive and 70% specific for a diagnosis of depression, while a “no” response to both questions effectively rules out depression [100]. Alternately, patients can be surveyed prior to clinic as part of routine vital sign gathering to screen for depression using instruments like the depression module of the Patient Health Questionnaire (PHQ-9). In this instrument, a score of Z10 is 88% sensitive and 88% specific for major depression [101]. However, identification of the diagnosis is just the first step in optimal care of depressed CVD patients, and screening that is not linked to a treatment plan for depression likely offers no patient benefit. Initiation of treatment is necessary to mitigate the effects of depression on cardiovascular and mental health outcomes (Table). Among available pharmacologic therapies for depression, selective serotonin reuptake inhibitors (SSRIs) (i.e., sertraline, citalopram, and escitalopram) are considered first line given their effectiveness, safety profile, cost-effectiveness, and best supporting data among CVD populations. For all SSRIs, sexual dysfunction is the most common side effect. Among the SSRIs, it is important to note that fluoxetine, and paroxetine to a lesser extent, inhibit the 2D6 isoenzyme of the cytochrome P-450 system resulting in greater potential for drug interactions. In
addition, fluoxetine has a long half-life of 3–4 weeks that can be increased further by heart failure, while paroxetine is associated with weight gain of approximately 10 pounds in 20–25% of patients. Finally, citalopram and escitalopram each demonstrate a dose-dependent effect on QTc prolongation [102]. This has resulted in recommendations to monitor the QT interval and avoid use of these medications in settings of underlying QT prolongation [103]. Despite this concern, citalopram, escitalopram, and sertraline are preferred among the SSRIs for first-line pharmacologic therapy. Second-line pharmacologic therapies for depression include buproprion, mirtazapine, and serotonin–norepinephrine reuptake inhibitors (e.g., venlafaxine and duloxetine). Considerations in these alternate therapies include side effects of hypertension with buproprion and orthostatic hypotension and weight gain with mirtazapine. The serotonin–norepinephrine reuptake inhibitors should be used with caution as they remain unstudied in settings of CVD. Caution should be used with St. John's wort given the interactions with a number of cardiac medications while tricyclic antidepressants and monoamine oxidase inhibitors are contraindicated in CVD patients due to an increased risk of adverse cardiovascular events.
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Initiation of pharmacologic treatment for depression must be coupled with patient education, review of concurrent medications, and structured follow-up [2]. Patient education includes a discussion of treatment expectations, with clarification that depressive symptoms generally take 2–4 weeks to improve with antidepressant medications. Structured follow-up allows the opportunity to assess the response to therapy, uptitrate dosing, or trial alternate therapies as needed.
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A team approach to depression care in CVD patients [9]
Although 75% of depressed patients can be managed without the input of mental health specialists, it is important to note that prior data suggests the importance of a team approach to achieve optimal outcomes for patients with depression. For example, a large number of successful trials have applied a model in which patients receive coordinated care with stepped treatment recommendations [91,93–96]. Access to specialist input or a similar collaborative care model may be important to ensure high-quality depression care in clinical practice. Furthermore, specialized providers should always be involved in the care of complicated depressed patients (such as those with a history of mania or manic symptoms or suicidal thoughts) or patient's with depression that is refractory to initial therapies [2].
Summary Depression is exceedingly common in CVD patients and contributes to worse patient outcomes, including mortality, recurrent CVD events, and health status. Although the mechanism by which depression exerts these negative effects can be debated, what is no longer in doubt is the need to recognize and treat this common disorder for the optimal health of our patients.
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Available online at www.sciencedirect.com
www.elsevier.com/locate/tcm
Depression and cardiovascular disease Steven M. Bradleya,b,c,n, and John S. Rumsfelda,b,c a
Department of Veterans Affairs, VA Eastern Colorado Health Care System, 1055 Clermont Street (111B), Denver, CO 80220-3808 b Department of Medicine, Division of Cardiology, University of Colorado School of Medicine, Aurora, CO c Colorado Cardiovascular Outcomes Research Consortium, Denver, CO
abstra ct There is a wealth of evidence linking depression to increased risk for cardiovascular disease (CVD) and worse outcomes among patients with known CVD. In addition, there are safe and effective treatments for depression. Despite this, depression remains under-recognized and undertreated in patients at risk for or living with CVD. In this review, we first summarize the evidence linking depression to increased risk of CVD and worse patient outcomes. We then review the mechanisms by which depression may contribute to cardiovascular risk and poor cardiovascular outcomes. We then summarize prior studies of depression treatment on cardiovascular outcomes. Finally, we offer guidance in the identification and management of depression among CVD populations. Given that 1 in 4 CVD patients has concurrent depression, application of these best-practices will assist providers in achieving optimal outcomes for their CVD patients. Published by Elsevier Inc.
Introduction More than 1 in 10 general medical patients has major depression, making the disorder among the most common chronic conditions encountered in general practice [1]. Furthermore, the prevalence of depression in patients with cardiovascular disease (CVD) is double that of general medical populations [2]. As such, depression is exceptionally common in patients at risk for or with known CVD. Depression results in worse quality of life, functional status, and increased mortality. The mechanisms by which depression contributes to worse patient outcomes include an increased risk of incident CVD and poor outcomes among patients with known CVD. As such, identification and appropriate management of depression is critical to optimal CVD outcomes. Yet,
most cases of depression remain unrecognized or undertreated. In this review article, we analyze the epidemiologic evidence linking depression to increased CVD risk and worse CVD outcomes, proposed mechanisms by which depression contributes to CVD risk and outcomes, and optimal approaches to the diagnosis and management of depression in CVD patients.
The relationship between depression and cardiovascular risk A number of studies have demonstrated that depression increases the risk of incident coronary artery disease (CAD) by at least 1.5 times that of otherwise physically healthy
Dr. Bradley is supported by a Career Development Award (HSR&D-CDA2 10-199) from VA Health Services Research & Development. The authors report no relevant relationships with industry or other disclosures. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the United States government. The authors have indicated there are no conflicts of interest. n Corresponding author at: Department of Veterans Affairs, VA Eastern Colorado Health Care System, 1055 Clermont Street (111B), Denver, CO 80220-3808. Tel.: þ1 720 857 5120; fax: þ1 720 857 5992. E-mail addresses: [email protected], [email protected] (S.M. Bradley). http://dx.doi.org/10.1016/j.tcm.2015.02.002 1050-1738/Published by Elsevier Inc.
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individuals [3–11]. Among the largest of these studies was a prospective evaluation of 20,000 patients without prior heart disease that found patients with depression were 2.7 times more likely to die from ischemic heart disease over a median follow-up of 8.5 years [11]. In addition to ischemic heart disease, depression has been associated with an increased risk of stroke and peripheral arterial disease [12,13]. The implications of depression on cardiovascular risk and global health are far from minor. In a comparative risk assessment conducted by Charlson et al. [14], the authors estimated that depression accounts for 3% of worldwide disability-adjusted life years due to ischemic heart disease . Thus, depression may account for 3.5 million years of life lost and 250,000 years of life lived with disability due to ischemic heart disease alone. These findings suggest significant promise in reducing the global burden of CVD by addressing the role of depression in cardiovascular risk.
The relationship between depression and cardiovascular outcomes In addition to increasing CV risk, depression is highly prevalent in patients with underlying CVD. While depression exists as a comorbid condition in less than 10% of general medical patients, depression is found in 20–30% of cardiovascular patients (Fig.) [2]. Given that depression is twice as common in cardiovascular populations as the general medical population, the impact of depression on cardiovascular outcomes is all the more pertinent. A large number of studies have shown that depression predicts worse outcomes following hospitalization for cardiovascular events. One of the first studies to demonstrate this relationship evaluated outcomes following an acute myocardial infarction (MI) in depressed and non-depressed patients. Among patients with major depression, the 6-month mortality following an MI was 17% as compared with 3% among non-depressed patients, corresponding to a risk-adjusted hazard ratio of 3.44 (95% confidence interval, 2.25–4.63) [15]. Subsequent studies have demonstrated similar findings in larger cohorts of MI and ACS patients [16,17], in evaluation of
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longer term outcomes [18], as it relates to cardiac-specific mortality [19], and in other ischemic heart disease patient cohorts (i.e., stable ischemic heart disease, post-CABG, and post-PCI) [20,21]. Furthermore, a dose–response relationship has been observed between the severity of depression and cardiovascular outcomes. After hospital discharge for MI, Lespérance et al. [18] found a stepwise relationship between the severity of depression and mortality outcomes . Although not all published studies suggest depression is associated with worse outcomes after ACS, the preponderance of evidence has led to a scientific statement from the American Heart Association supporting depression as a formal risk factor for adverse outcomes in patients with ACS [22]. Depression is also associated with an increased risk of recurrent and fatal stroke among patients with prior stoke [12] and an increased risk of heart failure readmission and death among CHF patients [23–25]. In addition to being associated with worse survival and an increased risk of recurrent cardiovascular events, depression is strongly associated with worse patient health status (i.e., symptom burden, functional status, and quality of life). Among patients with stable ischemic heart disease, Ruo et al. [26] found that more severe depression is associated with worse measures of ischemic heart disease-specific health status as assessed by the Seattle Angina Questionnaire . Similar results have been observed in post-ACS [27] and post-MI [28] patient populations. In addition to being associated with worse cardiovascular-specific health status measures, depression has been shown to predict declines in health status. In a study of 460 outpatients with a history of heart failure and left ventricular ejection fraction o0.40, depression was the strongest predictor of decline in health status over a 6-week period of follow-up [29]. These findings are consistent with a study by Vaccarino et al. [30] that found a graded relation between the severity of depressive symptoms and a combined end-point of functional decline or death among heart failure patients. Finally, a number of studies have demonstrated that depression is associated with higher costs of care. In a cohort of patients with acute MI, Frasure-Smith et al. [31] demonstrated that 1-year post-MI costs were 41% higher for patients
Prevalence of Depression, %
45 40 35 30 25 20 15 10 5 0 General Medical Stable Heart Post-CABG Post-ACS Population Outpatients Coronary Failure Disease Outpatients Fig – The prevalence of depression across the patient spectrum. Prevalence estimates taken from Whooley [2].
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with depressive symptoms. Similarly, Sullivan et al. [32] found that 3-year costs of care were 29% higher for heart failure patients with depression. Together, these studies implicate a strong relationship between depression, increased cardiovascular risk, and poor cardiovascular outcomes. Understanding the mechanisms that drive these relationships may guide opportunities to intervene and disrupt the impact of depression on cardiovascular outcomes. We next review the possible mechanisms by which depression leads to increased cardiovascular risk and worse clinical outcomes.
Depression's mechanistic path to increased cardiovascular risk and poor cardiovascular outcomes For nearly 3 decades, it has been appreciated that depression is associated with physiological derangements. These derangements include (1) autonomic dysfunction in the form of excessive sympathetic and/or reduced parasympathetic modulation [33–36], (2) elevated cortisol related to a blunted inhibitory feedback loop on corticotropin-releasing hormone [36–38], (3) platelet activation as demonstrated through elevated levels of platelet factor 4 and β-thromboglobulin [39–42], (4) endothelial dysfunction [42–47], and (5) inflammation as evidenced by elevated C-reactive protein and cytokines including tumor necrosis factor-α and interleukins [47–53]. The result of these derangements may include increased sympathetic tone resulting in higher blood pressure, reduced heart rate variability [47,54,55], increased ventricular arrhythmias [56–58], and accentuation of atherosclerosis progression with associated risk for cardiovascular events and cardiovascular death. One proposed pathway by which depression may exert these physiologic derangements relates to hyperactivity of the hypothalamic–pituitary–adrenal (HPA) axis [59,60] and defective serotonin signaling that results in dysfunction of the amygdala [61,62]. These abnormalities subsequently result in autonomic dysfunction, hypercortisolemia, elevation in catecholamines and inflammatory markers, endothelial dysfunction, and platelet activation. Although these physiologic derangements may contribute to cardiovascular risk and outcomes among depressed patients, behavioral mechanisms may play an even larger role in explaining the link between depression and cardiovascular disease. Depressed patients are 2–4 times less likely to adhere to their medication regimen [63–68], follow lifestyle recommendations (e.g., low-fat diet and smoking cessation) [63,66,69–71], and practice self-management [72]. In addition, depressed patients are more inactive, and several studies have suggested this lack of physical activity may be a major driver of worse cardiovascular outcomes. In the Cardiovascular Health Study of 5888 individuals followed for an average of 10.3 years, physical inactivity accounted for about 25% of the risk of cardiovascular mortality due to depressive symptoms in older adults [73]. Similarly, in a study of outpatients with stable coronary disease, Whooley et al. [74] found the association between depressive symptoms and risk of adverse cardiovascular events was predominantly explained by physical inactivity.
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These findings on the health behaviors of depressed patients have led some to question whether depression itself causes increased cardiovascular risk and worse outcomes, or whether depression is simply a risk marker for health behaviors that lead to worse cardiovascular risk and outcomes. Unfortunately, this dichotomization has little merit in guiding optimal patient care as the management of both depression and associated health behaviors is necessary to achieve ideal health. In the next section, we review prior studies of depression treatment as it relates to cardiovascular risk and outcomes to guide an understanding of the bestpractices in clinical care.
Treatment of depression and cardiovascular outcomes Pharmacologic-based approaches to depression treatment Treatment of depression with pharmacologic therapies has been shown to improve the physiologic derangements associated with depression. This includes significant decreases in platelet/endothelial activation markers (e.g., platelet factor 4 and β-thromboglobulin) [75–77], reduced inflammatory markers (e.g., tumor necrosis factor-α and C-reactive protein) [78], improved heart rate variability [79,80], and normalized brain serotonin turnover [81]. Thus, these studies suggest promise in the potential for mitigating the impact of depression on cardiovascular risk and outcomes related to physiologic derangements. Subsequently, studies have tested the impact of antidepressant pharmacology on outcomes in patients with cardiovascular disease. Among the first randomized controlled trials of pharmacologic therapy for depression in cardiovascular patients was the Sertraline Antidepressant heart Attack Randomized Trial (SADHEART). In this study, 369 patients with depression after ACS were randomized to sertraline (a selective serotonin reuptake inhibitor) versus placebo. This trial demonstrated that sertraline was safe in ACS patients and resulted in improvements in depressive symptoms and quality of life [82,83]. Although not powered for cardiovascular outcomes, the effect of sertraline on cardiovascular events was indeterminate with point-estimates suggesting benefit for sertraline but failing to achieve statistical significance [82]. The Myocardial INfarction and Depression—Intervention Trial (MIND–IT) trial randomized 331 patients with depression after an AMI to pharmacologic therapy for depression (with mirtazapine specified as first-line therapy) versus placebo. This trial found no difference in cardiac event rates between treatment arms at 18 months of follow-up [84]. However, nearly a full 25% of patients in the intervention arm did not receive pharmacologic antidepressant therapy, and no reduction in depressive symptoms was observed in the intervention group, raising questions about the efficacy of the treatment arm in this trial. More recently, the Improving Mood-Promoting Access to Collaborative Treatment (IMPACT) trial randomized 235 primary care patients with depression to a 12-month collaborative care program involving antidepressants and psychotherapy. In this study, intervention patients without baseline
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CVD had a dramatic 48% lower risk of a CVD event over 5 years of follow-up [85]. Similar benefit was not observed among patients with baseline CVD. Cause of death was only available for 65% of deaths in the study, raising questions about the validity of the primary findings. Although these findings warrant replication, this study suggests the promise of antidepressants and psychotherapy as a component of primary prevention for CVD among depressed patients. In addition to these randomized trials, there have been several observational studies that suggest pharmacologic therapy for depression reduces future cardiovascular risk. A secondary analysis of depressed patients with CVD who participated in a randomized controlled trial of cognitive behavioral therapy found a significant reduction in CV events with use of SSRIs and a non-significant benefit with non-SSRI medications [86]. Similarly, observational studies have suggested that the use of SSRIs is associated with reduced risk of first MI [87] and cardiovascular- or cerebrovascular-related deaths [88]. Taken together, the weight of evidence suggests cardiovascular benefit is achieved with pharmacologic depression management. A corollary concern in the management of CVD is the perceived risk of inducing depression as a side effect of cardiovascular risk-modifying therapies. In particular, β-blockers have been implicated as resulting in depression. However, studies have conclusively demonstrated that cardioprotective β-blockers do not cause depression [89]. As such, these therapies should be implemented for risk modification among patients with CVD conditions that warrant their use.
Non-pharmacologic and collaborative care-based approached to depression treatment The ENRICHED trial is the largest study of a nonpharmacologic-based treatment approach for depressed patients with cardiovascular disease [90]. This trial compared cardiovascular outcomes after myocardial infarction among 2481 patients with low perceived social support and depression who were randomized to cognitive behavior therapy supplemented with a selective serotonin reuptake inhibitor antidepressant when indicated. Although the intervention improved depression and social isolation, it did not reduce cardiovascular events in 6 months of follow-up [90]. In contrast, several studies have suggested the promise of collaborative care models for depression treatment and improved CV outcomes among patients with CVD. The Coronary Psychosocial Evaluation Studies (COPES) intervention trial randomized 157 patients with persistent depression after ACS to enhanced care by a treatment team with a stepped-care approach in treatment. This approach demonstrated significant reductions in depressive symptoms and major cardiac events [91]. A trial of 183 patients randomized to a telephone-based collaborative care treatment model that used care managers to coordinate stepped treatment recommendations was effective in reducing depression symptoms, though rates of cardiac admission were unchanged [92]. In the MoodCare study of 121 post-ACS patients randomized to a telehealth intervention targeting depression and other cardiovascular risk factors, the intervention improved
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depression measures with effect sizes exceeding those of some face-to-face psychotherapeutic interventions and pharmacotherapy [93]. Similarly, a randomized controlled trial of telephone-delivered collaborative care for treatment of postCABG depression resulted in improvements in health-related quality of life, functional status, and mood symptoms at 8 months [94]. Similar findings were observed among 175 depressed cardiac inpatients randomized to a collaborative care intervention with resultant improvements in depression and mental health status, medication adherence, and fewer cardiac symptoms [95]. A collaborative care model has also been shown effective in improving cholesterol and blood pressure control in patients with coronary disease [96]. In summary, prior studies suggest we can improve the outcomes of patients with depression and cardiovascular disease through the use of pharmacologic, psychotherapy, and collaborative care interventions. In particular, depression treatment results in better physiologic markers, lower depression severity, and higher quality of life. It is less clear if depression treatment reduces cardiovascular event rates or costs of care among patients with known CVD. However, the point-estimates from the SADHEART study, combined with the large effect size in the IMPACT trial and several collaborative care model studies suggest the promise of depression treatment to improve CV outcomes in addition to quality-oflife measures.
Depression management in the clinical care of cardiovascular patients Treatment of depression is first dependent on making the diagnosis. Unfortunately, depression is grossly underrecognized. Less than 25% of patients with depressive symptoms are recognized by their providers [97]. As a result, a large number of CVD patients may suffer from depressive symptoms, worse quality of life, and potentially worse CV outcomes due to a failure to recognize concurrent depression. Although we lack randomized controlled trials that demonstrate definitive benefit of depression screening in CVD patients [98], clinical practice guidelines recommend routine depression screening in CVD patients [99]. Screening for depression in CVD patients can be as simple as asking 2 questions (Box). Responding “yes” to 1 of these 2
Box–Two-item screening for depression. (1). During the past month, have you often been bothered by feeling down, depressed, or hopeless? (2). During the past month, have you often been bothered by little interest or pleasure in doing things? Answering “yes” to one of these questions has a 90% sensitivity and 69% specificity for depression. The negative likelihood ratio for answering “no” to both questions is 0.14, essentially ruling out depression.
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Table – Pharmacologic treatment options for depression in cardiovascular disease patients. Drug name
Class
Common side effects
Considerations for CVD patients
Sexual dysfunction
Preferred first-line therapy
Citalopram Escitalopram Paroxetine
Selective serotonin reuptake inhibitor (SSRI) SSRI SSRI SSRI
QTc prolongation; preferred first-line therapy QTc prolongation; preferred first-line therapy Inhibits 2D6 of P-450 resulting in drug–drug interactions
Fluoxetine
SSRI
Sexual dysfunction Sexual dysfunction Sexual dysfunction, weight gain Sexual dysfunction
Atypical
Insomnia
Mirtazapine
Atypical
Venlafaxine
Serotonin– norepinephrine reuptake inhibitor (SNRI) SNRI
Weight gain and drowsiness Insomnia and gastrointestinal
First-line therapies Sertraline
Second-line therapies Bupropion
Duloxetine
Use cautioned St. John's wort Contraindicated Amitriptyline, Clomipramine, Doxepin, Imipramine, etc. Phenelzine, Isocarboxazid, and Tranylcypromine
Insomnia and gastrointestinal
Inhibits 2D6 of P-450 resulting in drug–drug interactions Long half-life (3–4 weeks), increased by heart failure Consider first line if (1) sexual dysfunction of SSRI not tolerated or (2) concurrent smoking cessation considered Potential for increased blood pressure Hypertensive urgency when administered with clonidine Unstudied in CVD patients
Unstudied in CVD patients
Herbal supplement
Potential interactions with cardiac medications
Tricyclic antidepressants
Adverse cardiovascular events
Monoamine oxidase inhibitors
Adverse cardiovascular events
questions is 90% sensitive and 70% specific for a diagnosis of depression, while a “no” response to both questions effectively rules out depression [100]. Alternately, patients can be surveyed prior to clinic as part of routine vital sign gathering to screen for depression using instruments like the depression module of the Patient Health Questionnaire (PHQ-9). In this instrument, a score of Z10 is 88% sensitive and 88% specific for major depression [101]. However, identification of the diagnosis is just the first step in optimal care of depressed CVD patients, and screening that is not linked to a treatment plan for depression likely offers no patient benefit. Initiation of treatment is necessary to mitigate the effects of depression on cardiovascular and mental health outcomes (Table). Among available pharmacologic therapies for depression, selective serotonin reuptake inhibitors (SSRIs) (i.e., sertraline, citalopram, and escitalopram) are considered first line given their effectiveness, safety profile, cost-effectiveness, and best supporting data among CVD populations. For all SSRIs, sexual dysfunction is the most common side effect. Among the SSRIs, it is important to note that fluoxetine, and paroxetine to a lesser extent, inhibit the 2D6 isoenzyme of the cytochrome P-450 system resulting in greater potential for drug interactions. In
addition, fluoxetine has a long half-life of 3–4 weeks that can be increased further by heart failure, while paroxetine is associated with weight gain of approximately 10 pounds in 20–25% of patients. Finally, citalopram and escitalopram each demonstrate a dose-dependent effect on QTc prolongation [102]. This has resulted in recommendations to monitor the QT interval and avoid use of these medications in settings of underlying QT prolongation [103]. Despite this concern, citalopram, escitalopram, and sertraline are preferred among the SSRIs for first-line pharmacologic therapy. Second-line pharmacologic therapies for depression include buproprion, mirtazapine, and serotonin–norepinephrine reuptake inhibitors (e.g., venlafaxine and duloxetine). Considerations in these alternate therapies include side effects of hypertension with buproprion and orthostatic hypotension and weight gain with mirtazapine. The serotonin–norepinephrine reuptake inhibitors should be used with caution as they remain unstudied in settings of CVD. Caution should be used with St. John's wort given the interactions with a number of cardiac medications while tricyclic antidepressants and monoamine oxidase inhibitors are contraindicated in CVD patients due to an increased risk of adverse cardiovascular events.
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Initiation of pharmacologic treatment for depression must be coupled with patient education, review of concurrent medications, and structured follow-up [2]. Patient education includes a discussion of treatment expectations, with clarification that depressive symptoms generally take 2–4 weeks to improve with antidepressant medications. Structured follow-up allows the opportunity to assess the response to therapy, uptitrate dosing, or trial alternate therapies as needed.
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A team approach to depression care in CVD patients [9]
Although 75% of depressed patients can be managed without the input of mental health specialists, it is important to note that prior data suggests the importance of a team approach to achieve optimal outcomes for patients with depression. For example, a large number of successful trials have applied a model in which patients receive coordinated care with stepped treatment recommendations [91,93–96]. Access to specialist input or a similar collaborative care model may be important to ensure high-quality depression care in clinical practice. Furthermore, specialized providers should always be involved in the care of complicated depressed patients (such as those with a history of mania or manic symptoms or suicidal thoughts) or patient's with depression that is refractory to initial therapies [2].
Summary Depression is exceedingly common in CVD patients and contributes to worse patient outcomes, including mortality, recurrent CVD events, and health status. Although the mechanism by which depression exerts these negative effects can be debated, what is no longer in doubt is the need to recognize and treat this common disorder for the optimal health of our patients.
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