Ann. N.Y. Acad. Sci. ISSN 0077-8923

A N N A L S O F T H E N E W Y O R K A C A D E M Y O F SC I E N C E S Issue: Qatar Clinical Neuroscience Conference

The interface of depression and cardiovascular disease: therapeutic implications Fred Seligman and Charles B. Nemeroff Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, Florida Address for correspondence: Charles B. Nemeroff, M.D., Ph.D., Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, 1120 NW 14 St., Miami, FL 33136. [email protected]

Patients with major depression are at an increased risk for developing cardiovascular disease, respond more poorly to treatment, and exhibit worse outcomes, including increased morbidity and mortality. This article reviews the relationship between depression and heart disease, with an emphasis on epidemiology, biological substrates that likely underlie this relationship, and implications for treatment. Keywords: depression; mood disorders; cardiovascular disease; platelets; antidepressants

Introduction Although a two-way association between depression and cardiovascular disease is now well established, it is only recently that the consequences of this association—originally noted in Maltzberg’s seminal work in 1937 documenting increased mortality in depressed patients—have become meaningfully integrated into mainstream medical thinking.1,2 We review some of the evidence that has led to the current state of thinking and that expands the traditional list of coronary artery disease (CAD) risk factors, which, in the past, included genetic factors, diabetes, hypertension, thrombocyte dysfunction, hyperlipemia, smoking, and obesity. To highlight key relationships between depression and cardiovascular disease, we arbitrarily divide our discussion into four major areas: (1) depression and the development of coronary heart disease (CHD); (2) depression and already-established CHD; (3) mechanistic links between depression and CHD; and (4) treatment considerations, especially regarding the use of selective serotonin reuptake inhibitors (SSRIs) as effective antidepressants (Table 1). Depression and the development of coronary heart disease Weeke, in 1979, was one of the first investigators to note an increase (on the order of 40%) in

cardiovascular deaths in patients with major depression and manic-depressive disease (P < 0.001).3 The National Health Examination follow-up study, using the General Well-Being Schedule as a measure of depression, looked at the relationship between depression and ischemic heart disease (IHD) in 2832 participants, aged 45–77 years. At baseline, 11.5% of the participants reported depressed affect. At follow-up (mean = 12.4 years), depressed affect was significantly related to fatal IHD (relative risk (RR) = 1.5).4 In addition, a systematic review of 10 studies conducted between 1993 and 2000 found that the RR of depression for the onset of CAD ranged from 0.98 to 3.5, with a combined overall risk of 1.64 (95% CI, 1.41–1.90).5 This risk lies intermediate to that of passive smoking (RR = 1.25) and active smoking (RR = 2.5). Similar findings emerged from the Baltimore cohort of the Epidemiological Catchment Area (ECA) study, which prospectively followed 1551 respondents who, in 1981, were free of heart disease and were assessed for a history of major depressive disorder (MDD) and dysphoria. In 1994, 64 myocardial infarctions (MIs) were self-reported by this group. The odds ratio (OR) for MI was 4.54 in patients with MDD, compared to an OR of 2.07 in patients with dysphoria. These data suggest that a history of dysphoria and major depressive episodes increases the risk for MI.6

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Table 1. Key relationships in depression and coronary heart disease

Relational topic Depression and development of CHD Depression and established CHD Mechanistic links in depression and coexisting CHD Treatment considerations

Finding Depression is a risk factor for developing CHD Depression is a risk factor for morbidity/mortality post-MI Depression is associated with increased platelet activation, platelet reactivity, and cardiac events. Inflammation, heart rate variability, and compliance issues are important considerations SSRIs are effective antidepressants in CHD without many of the adverse effects of TCAs

Abbreviations: CHD, coronary heart disease; MI, myocardial infarction; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant.

In a 1996 Danish study that followed a community sample of 409 men and 321 women born in 1914, it was reported that depressed patients have an RR of 1.71 (P = 0.005) for MI and 1.59 (P < 0.001) for death from all causes. The graded relationships between depression scores and risk, the long-standing nature of the effect, and the stability of depression across time suggest that depression as a risk factor can be viewed as a trait marker, rather than a state marker.7 The idea that depression can be considered a continuous risk factor variable was further supported by work showing that the severity of depression over time in elderly patients predicted subsequent cardiovascular events (death, stroke, or MI). An increase in the Center for Epidemiology Studies Depression (CES-D) score was an independent predictor in both placebo and active drug groups, and it was strongest as a risk factor for stroke among women (RR = 1.29; 95% CI, 1.07–1.34). Clinically, this finding supports the opinion that physicians should pay more attention to mood changes in their patients.7,8 A British study found that the risk of IHD was three times higher among men with a diagnosis of depression than among same-age controls (OR = 3.09; 95% CI, 1.33–7.21; P = 0.009), supporting the hypothesis that depression may be an independent risk factor for the development of IHD in men but not in women.9 Ford et al. analyzed data from the Johns Hopkins Precursors Study, a prospective, observational study of 1190 male medical students enrolled between 1948 and 1964. The cumulative incidence of depression was 12%, and men who reported experiencing clinical depression were at significantly greater risk for subsequent CHD (RR = 2.12; 95% CI,

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1.11–4.06). This increased statistical risk persisted even for those in whom an MI occurred 10 years or more after the onset of the first depressive episode, supporting the hypothesis that clinical depression appears to be an independent risk factor for CAD.10 Several investigators have prospectively followed subjects without CAD and have shown that depression is a significant independent risk factor for CAD morbidity and mortality, with an adjusted RR showing an increase in the range of 1.5- to 2-fold.4,7,8,10–13 Another report showed the same effect using hopelessness as the dependent variable.14 Furthermore, a review of 13 studies in five different countries, prospectively following 40,000 healthy subjects over a mean of 10 years (range, 4–37 years), found depression to be a significant independent risk factor for the development of CAD morbidity and mortality. The adjusted RR for major depression showed a 4- to 4.5-fold increase.15 The Systolic Hypertension in the Elderly Program (SHEP) followed 4538 patients aged over 60 years with isolated systolic hypertension for 4.5 years. After taking into consideration 12 potential confounding factors, including, for example, age, sex, and history of MI, depressed patients had more than a twofold higher risk of developing heart failure compared with nondepressed patients (hazard ratio (HR), 2.59; 95% CI, 1.57–4.27; P < 0.001). After additional adjustments for patients who developed MI during follow-up, depressed patients still remained at an elevated risk for heart failure (HR, 2.82; 95% CI, 1.71–4.67; P < 0.001).16 These results are consistent with an earlier 6-month study analysis of the same (SHEP) cohort.17 In a retrospective analysis of 17,337 adult health plan members from 1995 to 1997, a dose–response

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relationship was found between adverse childhood experiences (ACE) and IHD, which was mediated more strongly by individual psychological risk factors, such as depressed affect and anger, than by traditional risk factors, such as smoking, physical inactivity, obesity, diabetes, and hypertension. These findings provide further insights into the potential pathways by which stressful childhood experiences, such as abuse, neglect, and household dysfunction, may increase the risk of IHD in adulthood.18 The nature of the association between depression and cardiovascular disease is complex and may not only involve bidirectional causation but may involve common pathophysiology. This notion is supported by a 2013 study of 45 young people at an increased risk of depression, which showed evidence of an altered cardiovascular risk profile in young adulthood even in the absence of depressive symptoms. Such vulnerability may precede or follow the onset of depression and may share common risk factors.19 Depression is thus a significant risk factor in the development of CHD; this risk is independent, continuous, and relatively stable over time, with up to a 4.5-fold increase. Gender differences were noted in one study, which showed a greater gender effect for IHD in males, and in a second study, which showed a greater gender effect for stroke in women. Depression in established CHD In order to determine the effect of depression on 6month survival, the Montreal Heart Study followed 222 post-MI hospitalized patients (mean age = 60 years; males = 78%) and found that the cumulative mortality rate for depressed patients post-MI was significantly higher than the rate in nondepressed patients, with the greatest effect occurring in the first 6 months.20 A regression analysis showed that both premature ventricular contractions (PVCs) and elevated Beck Depression Inventory (BDI) scores were significantly related to mortality at 18 months.21 The Montreal group also examined longer-term survival and measured BDI scores of 892 postMI patients at admission and again at 1 year. They found a significant dose–response relationship between BDI scores and cardiac mortality, using Quebec Medicare (RAMQ) survival data, and these results remained significant even after controlling for multiple measures of cardiac disease severity. Patients with the highest initial BDI scores had the worst prognosis, and an improvement in depressive

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symptoms lessened cardiac mortality only for patients with mild depression. In the authors’ opinion, the link between depression and cardiac mortality may be a relatively permanent marker for long-term survival, especially in patients with moderate or severe depression.22 In spite of strong evidence that much of the post-MI risk in mortality appears during the first 6 months and that the risk of death is positively correlated to depression severity, a low left ventricular ejection fraction (LVEF) and an age of over 64 years, coupled with even minor symptoms of depression (BDI < 10), contribute significant additional mortality risk. This is important because as many as one-third of patients will show some stigmata of depression soon after an MI. Unfortunately, the healthcare system and patients alike appear to minimize the potential increased risk of an adverse cardiac event.15,23,24 Indeed, despite the increased risk, depressed patients with CAD are less likely to be diagnosed with depression than patients without heart disease.15 Moreover, depression is clearly associated with nonadherence to risk-reducing behavioral recommendations.23 A study of 817 patients who underwent coronary artery bypass surgery (CABG) revealed that, during the mean follow-up of 5.2 years, there were 122 deaths (15%), 38% of the patients had mild depression (CES-D score, 16–26), and 12% had moderate to severe depression (CES-D score ࣙ 27). A survival analysis, which controlled for age, gender, number of grafts, diabetes, smoking, LVEF, and previous MI, showed that patients with moderate to severe depression at baseline (adjusted HR = 2.4; P = 0.001) and patients with mild, moderate, or severe depression persisting from baseline for 6 months (HR = 2.2; P = 0.015), had higher rates of death than those who had no depression.25 A study that explored the rate of depression in CAD, found that 23% of 99 inpatients with CAD had a current Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV diagnosis of major depression, and that the risk of depression increased with the severity of cardiovascular disease and a family history of psychopathology.26 Furthermore, a 2-year follow-up inquiry of 804 patients (649 men) with stable CAD at the Montreal Heart Institute found that 27.4% had elevated BDIII scores (ࣙ14), and 41.4% had elevated Hospital Anxiety and Depression Scale (HADS) scores (ࣙ8),

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with 21.1% overlap. The Montreal group specifically scrutinized the percentage of major adverse cardiac events (MACEs) (cardiac death, MI, cardiac arrest, or nonelective revascularization) during a 2-year period after baseline assessment. After covariate control, only the P value associated with the continuous BDI-II symptom severity scores was significant. Most of the risk associated with elevated symptoms occurred in patients with syndromal psychiatric disorders. Interestingly, patients with comorbid MDD and generalized anxiety disorder, or elevated anxiety and depression symptoms, were not at greater MACE risk than those with only a single risk factor. Anxiety and depression thus predict greater MACE risk in patients with stable CAD.27 Another study sought to determine whether the use of antidepressants is associated with increased mortality in patients with cardiac disease. This study annually followed 1006 patients, aged 18 years or older with congestive heart failure and an ejection fraction of 35% or less, between March 1997 and June 2003 for depression symptom severity (BDI) and the prospective use of antidepressants. It was found that 30% were depressed and 24.2% were receiving antidepressants (79.6% of this group was being treated with SSRIs only). The average followup time was a mean of 972 days, and 42.7% of the patients died during this period. Although the use of antidepressants and SSRIs were associated with increased mortality, this connection no longer existed after other confounders were controlled. After such adjustment, depression (HR, 1.33; 95% Cl, 1.07–1.66) rather than SSRI use (HR, 1.10; 95% Cl, 0.81–1.50) was independently associated with increased mortality. These findings suggest that depression (defined by a BDI score ࣙ 10), but not antidepressant use, is associated with increased mortality in patients with CAD.28 A prospective study of 648 patients at 14 Veterans Affairs (VA) hospitals found preoperative depression to be an independent risk factor for mortality following cardiac valve surgery. Of note in this study was the finding that 29.2% of patients were depressed at baseline and that depressed patients were more likely to be younger, more frequently had more severe cardiac symptoms, and more likely required emergent surgery. The OR for 6-month mortality following cardiac valve surgery was 1.90 for depression, nearly identical to that of hypertension (1.89). The authors advocated that depression 28

screening should be incorporated into preoperative risk stratification, and that future studies are warranted to determine if preoperative or postoperative depression treatment interventions can improve outcomes.29 Depression is a risk factor for morbidity/ mortality post-MI. Once CHD coexists with depression, the clinical picture worsens dramatically. The incidence of depression in CHD is as high as 23%, with the risk of depression highest in the most severe CHD. Mortality is related to depression scores, hopelessness, and premature ventricular contractions and is highest in the first 6 months post-MI. Once depression is severe with coexisting CHD, the disorder is very difficult to remit. Mechanistic factors in depression and coexisting CHD Progress has been made toward a better understanding of the pathophysiology of depression through advances in immunology and neuroendocrine interconnections, particularly those of the hypothalamic–pituitary–adrenal (HPA) axis.30,31 Inflammatory factors During the past 25 years there has been a paradigm shift from thinking of depression as an immunosuppressive disorder to more recent theories emphasizing immune overactivation, particularly hyperactivity of inflammatory processes.30 Such a theoretical construct would help explain the comorbidity that often occurs between depression and certain medical illnesses. There is an increasingly rich literature showing relationships between depression and inflammation and, more specifically, proinflammatory cytokines and their signaling pathways. Depressed patients have shown increased concentrations of certain proinflammatory cytokines, including interleukin (IL)-6 and C-reactive protein (CRP). Additionally, psychosocial stressors (such as early adversity, interpersonal conflict, and social isolation) activate central nervous system processes, including corticotropinreleasing hormone (CRH), which acts through various pathways to promote inflammation.31–35 A study that measured plasma IL-6, lymphocyte subsets, and DNA binding of nuclear factor (NF)-␬B in peripheral blood mononuclear cells, revealed that depressed men with a history of early-life stress exhibited exaggerated inflammatory

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responses to psychosocial stress. The authors suggested that the findings provide preliminary indication of a link between major depression, early-life stress, and adverse health outcomes in diseases associated with inflammation.36 In a Danish study following 73,367 individuals from the general population, in cross-sectional studies, and in prospective studies of depressed inpatients, it was found that elevated levels of fibrinogen were associated with psychological distress, use of antidepressant medication, and hospitalization for depression, suggesting that low-grade systemic inflammation may contribute to the development of depression.37 Platelet pathways In a double-blind, placebo-controlled randomized trial of 2099 high-risk patients undergoing coronary angioplasty in 56 academic and community hospitals in the United States, abciximab (a monoclonal antibody against the platelet receptor ␣IIb ␤3 integrin) given as an infusion at the time of coronary angioplasty, improved cardiac outcomes for as long as 3 years following the procedure. For example, among those with refractory unstable angina or evolving MI, death occurred by 3 years in 5.1% of patients receiving abciximab bolus, in 9.2% of those receiving bolus plus infusion, and in 12.7% of the placebo group (P = 0.01).38 Several studies support the hypothesis that depression is associated with increased platelet activation, platelet reactivity, and cardiac events. By measuring in vivo platelet activation, secretion, and dose–response aggregation in 12 depressed patients and eight normal comparison subjects after overnight bed rest and following orthostatic challenge, depressed patients exhibited enhanced baseline platelet activation and responsiveness compared to normal subjects.39 Another study demonstrated that platelet factor 4 (PF4) and ␤-thromboglobulin (␤-TG) plasma concentrations were significantly higher in patients with IHD and depression than in nondepressed IHD controls and healthy controls. This finding suggests that, in depressed patients with IHD, there is greater platelet activation, and may indicate an increased risk of thrombotic complications.40 The finding was also duplicated in 12 depressed post-MI patients compared with a matched nondepressed post-MI patient group for PF4, but not for ␤-TG.41 Because the sample sizes in these studies were not large, we

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cannot definitely conclude that enhanced platelet reactivity in depressed patients with IHD is the cause of increased mortality risk. Pollock evaluated the therapeutic effect of antidepressants in patients with IHD and depression by measuring the magnitude of platelet activation using PF4 and ␤-TG concentrations. The levels of both PF4 and ␤-TG were significantly higher in patients with IHD and depression than in patients with IHD without depression and in controls. Treatment with paroxetine returned PF4 levels back to the levels of patients with IHD who are not depressed, suggesting that paroxetine has a significant effect on reducing platelet activation in patients who have IHD and depression. In contrast, nortriptyline showed no such effect. Similar results were also observed with ␤-TG as the index of platelet activation.42 Before treatment, platelet antiligand-induced binding site (LIBS)1 levels of patients with major depression are significantly increased (P = 0.0007) compared with normal controls. After 6 weeks of open-label paroxetine treatment, anti-LIBS1 binding is not significantly elevated compared to normal controls (P = 0.56), supporting the notion that paroxetine is effective in reducing platelet activation in patients with IHD and depression. Behavioral mechanisms In addition to the direct impact of depression on the cardiac conditions previously described, depression has a significant negative impact on how patients seem to self-manage chronic medical illness, with major adverse cardiac implications. For example, depressed post-MI patients are more likely to drop out of exercise programs, depressed smokers are 40% less likely to quit smoking over a 9-year period, and depressed CAD patients are less likely to adhere to low-dose aspirin therapy.4,25,43 Although depressive symptoms are associated with increased morbidity and mortality in individuals with CHD, the degree to which behavioral mechanisms contribute to this association is unclear. In the REGARDS study, four behavioral mechanisms (alcohol use, smoking, physical inactivity, and lack of medication adherence) were added to prior incremental proportional hazard models in 4676 participants with a history of CHD. These four behavioral factors together significantly increased the risk for MI or death conveyed by elevated

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depressive symptoms, with smoking and physical activity having the largest explanatory roles. These findings suggest potential roles for behavioral interventions targeting smoking and physical inactivity in patients with CHD and comorbid depression.44 Heart rate variability Decreased heart rate (HR) variability is a known independent risk factor for cardiac mortality. In one study, 19 CAD patients with depression were compared with 19 CAD patients without depression. Patients were followed by Holter monitoring. It was found that HR variability was significantly lower in depressed patients compared to nondepressed patients even after adjusting for relevant covariates (90 ± 35 ms vs. 117 ± 26 ms; P ࣘ 0.01). Thus, the increased risk of cardiac mortality and morbidity that is seen in patients with CAD may be explained, in part, by decreased HR variability.45 Similar results were found by comparing HR variability in patients with major depression, heart transplant recipients, and healthy comparison subjects. Using both nonlinear and conventional measures of HR variability, no significant differences in cardiac variability were noted between the depressive group and the transplant recipients. However, both groups had significantly lower mean HR variability values compared to healthy subjects. These results support the notion that reduced vagal modulation is present in depression.46 Another HR variability study compared 32 nonmedicated depressed patients with 32 normal controls matched for age and gender and who were tested for HR variability at rest and during deep breathing. During treatment with either amitriptyline (150 mg/day) or doxepin (150 mg/day), the coefficients of variation at rest and during deep breathing, which are largely independent of HR, significantly decreased after 14 days (P = 0.012), whereas patients treated with fluvoxamine (150 mg/day) and paroxetine (20 mg/day) showed no significant changes.47 This finding is consistent with a lack of adverse effects of SSRIs on autonomic function.48 In this section, we have discussed aspects of putative biological mechanisms, which play an increasingly important role in our understanding of the interrelationship of depression and CHD. Considerations regarding inflammation, and platelet activation and reactivity, will, going 30

forward, likely affect our treatment strategies. The preliminary links between depression, early-life stress, and adverse health outcomes offer additional directions for therapeutic success. Compliance with medical prescriptions and positive health behaviors markedly improve outcomes. Antidepressants need to be noninflammatory friendly, if not outright anti-inflammatory, with minimal effects on autonomic function. Additional studies to more fully elucidate these mechanisms are necessary. Treatment considerations Patients with treatment-responsive depression following MI have a better prognosis than those with treatment-resistant depression. A follow-up of 4037 patients with MDD who had a subsequent MI showed a percentage death rate of 2.4%, 5%, and 6.9% in those with treated depression, treatment-resistant depression, and insufficiently treated depression, respectively. Undertreated or nontreated patients were 3.04 times more likely, and patients with treatment resistant depression were 1.71 times more likely, to die when compared to (successfully) treated patients.49 Adherence by the patient and persistence by the practitioner are therefore important treatment considerations. In the Sertraline Antidepressant Heart Attack Trial (SADHAT) substudy, 55 acute coronary syndrome (ACS) patients with depression were randomly assigned to receive sertraline (n = 23) or placebo (n = 32). A strong, mostly time-dependent negative correlation between PF4 and plasma levels of sertraline and N-dexmethylsertraline (the primary metabolite of sertraline) was seen at 6 and 16 weeks in ACS patients receiving SSRI treatment for depression. The authors note this finding to be the first documented evidence that plasma release of platelet/endothelial biomarkers is directly related to levels of sertraline and N-desmethylsertraline in ACS patients receiving SSRI treatment for depression.50 Another study determined the effect of sertraline on the recovery rate of cardiac autonomic function in 38 depressed patients postacute MI who were randomized to receive either sertraline (50 mg/day) or placebo for 6 months. Twenty-seven patients completed the randomization. Although there was a trend toward a more rapid rate of recovery in the sertraline group, the differences did not attain statistical significance. The authors concluded that,

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in depressed patients who have survived the acute phase of an MI, sertraline facilitates the rate of recovery of HR variability.51 Furthermore, antidepressant efficacy has been assessed in patients with comorbid cardiovascular disease and depression. In a study of 54 patients with major depression after MI who were randomly assigned to receive a flexible dosage regimen of fluoxetine or placebo, there was a trend (not statistically significant) favoring fluoxetine. The authors note that fluoxetine seemed to be particularly effective in patients with mild depression and was associated with a statistically significant reduction in hostility.52 The effectiveness of paxoxetine and nortriptyline was compared in 81 depressed outpatients with IHD, in a 2-week placebo lead-in study followed by a double-blind randomized 6-week medication trial conducted at four university centers. Sixty-one percent of 41 patients responded (a decline in Hamilton Rating Scale for Depression (HAM-D) scores by ࣙ50% and final score ࣘ8) with paroxetine treatment compared with 55% of 41 patients with nortriptyline treatment; both drugs can be considered as effective treatments for depressed patients with IHD. However, nortriptyline was associated with a significantly higher rate of serious adverse cardiac events compared to paroxetine.53 A multicenter, open-label, pilot study of sertraline (part of the SADHAT trial) in 26 patients showed that sertraline treatment was associated with clinical improvement and was well tolerated in greater than 85% of patients with major depression postMI.54 The SADHART study, a randomized, doubleblind, placebo-controlled sertraline treatment trial for major depression in 369 patients post-MI or with unstable angina, was conducted at 40 sites in seven countries between April 1997 and April 2001. Sertraline had no significant effect on mean (SD) LVEF or other cardiac measures; however, the incidence of adverse cardiac events was lower in the sertraline group. In the total sample, scores on the Clinical Global Impression of Improvement (CGII) scale favored sertraline (P = 0.049), but HAM-D (P = 0.14) scores were not significantly different than controls. It is important to note that, in the more severely ill MDD group (24-week responder rates for sertraline (78%) versus placebo (45%); P = 0.001), both CGI-I and HAM-D assessments were significantly better for the sertraline treatment

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group than the controls. The authors suggest that sertraline is a safe and effective treatment for recurrent depression in patients with recent MI or unstable angina and without other life-threatening conditions.55 In the Enhancing Recovery in Coronary Heart Disease (ENRICHD) randomized trial, 2481 patients were randomized into a usual-care group or into a treatment group for depression and low perceived social support (LPSS) and were treated with cognitive behavioral therapy (CBT), supplemented when indicated by an SSRI. Although the intervention improved depression and social isolation at an average follow-up time of 29 months, there was no increase in event-free survival.56 More convincing treatment findings were found in a randomized controlled trial of 123 patients in the treatment of depression after coronary bypass surgery using CBT, supportive stress management, and usual care. For example, at 9 months, remission rates were 73%, 57%, and 35%, respectively (chi(2)(2) = 12.2, P = 0.003). The authors concluded that both CBT and supportive stress management are effective in treating depression following coronary artery bypass, in comparison to usual care.57 A case-control study of the first MI in smokers (30–65 years of age), in 68 hospitals in an eightcounty area during a 28-month period, examined 653 first-MI patients and 2990 controls. The OR for MI among current SSRI users was 0.35 (95% CI, 0.18–0.68; P < 0.01). The authors speculated that SSRIs may confer a protective effect against MI, possibly due to the inhibitory effects of SSRIs on platelet activation.58 An observational secondary analysis of 1834 depressed patients post-MI who were followed for 29 months found that the risk of death, recurrent MI, or all-cause mortality was significantly lower in patients treated with SSRIs compared to untreated patients (adjusted HRs, 0.53–0.59). Since this study did not include a control group, a controlled study is needed to further examine this issue.59 The Korean Depression in Acute Coronary study (K-DEPACS) is a well-designed prospective naturalistic study, in which 300 patients with ACS were randomized to a 24-week double-blind trial of escitalopram or placebo. Depression was significantly associated with worse quality of life (QoL) even in patients with recently developed ACS. Depression treatment with escitalopram was associated

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with significant QoL improvement over the 24-week treatment period, the effect of which extended to 1 year.60 Using a U.K. general-practice research database, 1651 cases of upper gastrointestinal (GI) bleeding and 248 cases of ulcer perforation were found between April 1993 and September 1997 among patients aged 40–70 years and 10,000 matched controls. Exposure to SSRIs was observed in 3.1% of patients with GI bleeding but in only 1% of controls, with an adjusted RR = 3 (95% CI, 2.1–4.4). Although the absolute effect is only moderate (approximately equivalent to low-dose ibuprofen), the use of nonsteroidal anti-inflammatory drugs or aspirin with SSRIs greatly increases the risk of GI bleeding.61,62 Even short-term (for as little as 7 days) SSRI usage with high and intermediate (but not low) affinity for the serotonin transporter elevates the risk of upper GI bleeding, especially in male patients.63 A 2011 review of 3253 topic references led the authors to conclude that psychological interventions and pharmacological interventions with SSRIs may have a small yet clinically meaningful effect on depression outcomes in CAD patients. No beneficial effects on the reduction of mortality rates and cardiac events were found. The authors do state, however, that the evidence for this conclusion is weak due to the low number of high-quality trials per outcome and the heterogeneity of examined populations and interventions.64 Work is emerging in identifying biomarkers to improve treatment outcomes in depression. For example, one research group has identified biomarkers associated with inflammation or metabolism and genomic markers that may identify patients with SSRI-resistant depression who are responsive to adjunctive therapy with l-methylfolate.65 Another biomarker study adds substantial support for the role of the inflammatory cytokine pathway in mediating the response to the SSRI escitalopram and identifies tumor necrosis factor (TNF)-␣ and its targets as putative transcriptomic predictors of clinical response.66 Furthermore, Hashimoto discusses the low levels of brain-derived neurotrophic factor (BDNF) observed in both MDD and cardiovascular disease along with decreased levels of sigma-1 chaperone levels in the mouse brain, which contributes to the association between heart failure and depression, as 32

an emerging link between depression and cardiovascular disease.67 The clinical significance of such findings call for confirmatory studies and additional research for other shared biomarkers in MDD and cardiovascular disease. In this section, we have noted that the main therapeutic approach to depression with comorbid cardiovascular disease is pharmacological, mostly using SSRIs (which have fewer side effects) or secondgeneration tricyclics. Results in relevant studies range from insignificant to significant, depending on the outcome variable. SSRIs have fewer side effects and are favored over tricyclics but are associated with a risk for GI bleeding. Results have been more positive with respect to the improvement of QoL parameters than in the reduction of morbidity and mortality. Behavioral approaches, such as CBT, can also be effective, but better therapeutic agents are needed. Finally, biomarker identification is an emerging field that holds promise in improving treatment outcomes in depression and cardiovascular disease. While we have concentrated on the interrelations of depression and cardiovascular disease, there is mounting recognition in the literature that there are even broader interrelations between mood disorders and comorbid medical conditions.68 The Latin aphorism “a sound body in a sound mind” is true, and there are still mountains to climb in untangling these relationships. Conclusions We have reviewed evidence that depression is a risk factor for cardiovascular disease, both in otherwise healthy subjects and in those with known CHD. In 2008, the scientific advisory committee on Depression and Coronary Heart Disease of the American Heart Association (AHA) recommended screening for depression in patients with established CHD.69 In March 2014, an AHA scientific statement recommended that depression be elevated to the status of a risk factor for adverse medical outcomes in patients with ACS.70 In spite of the wisdom of this recommendation, further research is needed, especially on those risk factors shared by ACS and depression, such as chronic stress, adverse life events, and social and geopolitical catastrophes, as well as genetic and pathophysiological pathways. Treatments have shown success primarily in the improvement of QoL

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issues but have so far been much less effective in reducing morbidity and mortality.

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9.

Conflicts of interest Dr. Nemeroff has received research grants from the National Institutes of Health (NIH); has served as a consultant (over the last 3 years) for Xhale, Takeda, SK Pharma, Shire, Roche, Lilly, Allergan, Mitsubishi Tanabe Pharma Development America, Taisho Pharmaceutical Inc., Lundbeck, Prismic Pharmaceuticals, Clintara LLC, and Total Pain Solutions (TPS); is a stockholder in Xhale, Celgene, Seattle Genetics, Abbvie, and Titan Pharmaceuticals; serves on the scientific advisory boards for the American Foundation for Suicide Prevention (AFSP), Brain and Behavior Research Foundation (BBRF) (formerly named National Alliance for Research on Schizophrenia and Depression (NARSAD)), Xhale, Anxiety Disorders Association of America (ADAA), Skyland Trail, and Clintara LLC; is on the board of directors for AFSP, Gratitude America, and ADAA; has income sources or equity of $10,000 or more in American Psychiatric Publishing, Xhale, and Clintara; and has the following patents: Method and devices for transdermal delivery of lithium (US 6375990B1) and Method of assessing antidepressant drug therapy via transport inhibition of monoamine neurotransmitters by ex vivo assay (US 7148027B2). References 1. Maltzberg, B. 1937. Mortality among patients with involutional melancholia. Am. J. Psychiatr. 93: 1231–1238. 2. Mavrides, N., & C.B. Nemeroff. 2013. Treatment of depression in cardiovascular disease. Depress. Anx. 30: 328–341. 3. Weeke, A. 1979. Prevention and Treatment of Affective Disorders. Schou, M., Stromgen, E., Eds.: 289–299. London: Academic Press. 4. Anda, R., D. Williamson, D. Jones, et al. 1993. Depressed affect, hopelessness, and the risk of ischemic heart disease in a cohort of US adults. Epidemiology 4: 285–294. 5. Wulsin, L.R., & B.M. Singal. 2003. Do depressive symptoms increase the risk for the onset of coronary disease? A systematic quantitative review. Psychosom. Med. 65: 201–210. 6. Pratt, L.A., D.E. Ford, R.M. Crum, et al. 1996. Depression, psychotropic medication, and risk of myocardial infarction. Prospective data from the Baltimore ECA follow-up. Circulation 94: 3123–3129. 7. Barefoot, J.C., & M. Schroll. 1996. Symptoms of depression, acute myocardial infarction, and total mortality in a community sample. Circulation 93: 1776–1780. 8. Schulz, R., S.R. Beach, D.G. Ives, et al. 2000. Association between depression and mortality in older adults: the

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