Epidemiology ofDepression inHeart Failure

Gowrishankar Gnanasekaran, MD, MPH

KEYWORDS

� Epidemiology � Depression � Heart failure � Pathogenesis

ics.com

Congestive heart failure (CHF) and depressionhave become increasingly rampant in the growingUS population.1e5 Depression in CHF has beenextensively studied recently, because of the highprevalence of the diseases and their tendency toworsen medical prognosis. More recently, therehas been an exponential growth of patients withheart failure (HF). According to the National Heart,Lung and Blood Institute, an estimated 4.8 millionAmericans have CHF and about 400,000 newcases are diagnosed each year. CHF is also themost frequent cause of hospitalization in olderadults and has accounted for more than 1 millionannual hospital admissions in the past 10 years,resulting in $60 billion in health-care expenses.6e8

Almost $5 billion of the total cost of HF has beenattributed to depression.7

Major advances in treatment of HF have pro-longed survival, provoking considerable interestin identifying methodologies to improve quality oflife (QOL) and functional capacity of patients.QOL encompasses physical, mental, emotional,social, and functional health of the individual.Depression is a major public health problem,which has significant impact on all componentsof QOL by increasing mortality and frequency ofreadmissions in patients with HF.9,10 The WorldHealth Organization report ranked depression asthe fourth-most common medical condition, pre-dicting that it is to become the second majordisease with disease burden worldwide by 2020.It is estimated to cause more disabilities thanmany other chronic conditions, including diabetesand osteoarthritis.11,12 In a multicenter trial of48,612 patients from 259 hospitals, the investiga-tors reported increased mortality and morbidity

Division of General Internal Medicine & Geriatrics, DepMedical Center, 2050 Kenny Road, Suite 2335, ColumbusE-mail address: gowrishankar.gnanasekaran@osumc.edu

Heart Failure Clin 7 (2011) 1e10doi:10.1016/j.hfc.2010.08.0021551-7136/11/$ e see front matter � 2011 Elsevier Inc. Al

associated with patients diagnosed with depres-sion and HF.13 In their meta-analysis of depressionin HF, Rutledge and colleagues14 have been ableto quantify the precise magnitude of increasedrisk of cardiac events in depressed patients. Inaddition to CHF, many chronic medical problemshave been linked with depression, including dia-betes mellitus (DM).15,16 Fava and colleagues17

have observed depression to manifest as a life-threatening complication of endocrine diseases,like Cushing and thyroid disease andhyperprolactinemia.

Growing evidence supports this comorbid asso-ciation, if left unchecked, posing a significantthreat to the health of patients. Better under-standing of the epidemiology and etiology ofdepression in HF becomes critically important,providing a better insight in understanding thisassociation to improve QOL and regain functionin patients.

EPIDEMIOLOGY

The incidence of depression in HF has been citedby fewer studies than prevalence. In their study of4538 patients aged 60 years and older who wereenrolled in the Systolic Hypertension in the ElderlyProgram (SHEP), Abramson and colleagues18

found a covariate-adjusted hazard ratio of 2.82after adjusting for occurrence of myocardial infarc-tion (MI). They concluded that depression is inde-pendently associated with a substantiallyincreased risk of HF among older patients with iso-lated systolic hypertension.

A study using theCenter for Epidemiologic StudyDepressive Symptomatology Questionnaire, a

artment of Internal Medicine, Ohio State University, OH 43210, USA

l rights reserved. heartfailure.th

eclin

Gnanasekaran2

self-reporting depression questionnaire, assessedemotional support before a hospital admission tobe an independent predictor of fatal and nonfatalcardiac events.19 Apparently, the researchersmade the assessment of depression well beforethe diagnosis of HF, making it difficult to establisha positive correlation between these diseases.On the other hand, the prevalence of depression

in HF has been observed by multiple studies. Intheir study of 204 outpatients with HF, Sherwoodand colleagues20 reported that symptoms ofdepression were associated with increased riskof death or hospitalization during a median3-year follow-up. In their prospective study of374 hospitalized patients with HF, Jiang andcolleagues21 investigated the prevalence ofdepression and the significant mortality andmorbidity associated in terms of readmissionrates. They identified that patients with HF anddepression had 13% and 26% mortality at 3months and 1 year, respectively. Furthermore,depressed patients were twice as likely to behospitalized compared with nondepressedpatients. Jiang and colleagues have used BeckDepression Inventory (BDI) as a tool to assessthe severity of depression. In their subgroup anal-ysis on depressive symptoms and long-termmortality, 30% of subjects were found to bedepressed and were found to be younger or withmuch more severe HF as classified by the NewYork Heart Association (NYHA).In their study on 155 outpatients with HF,

Gottlieb and colleagues22 examined the influenceof race, sex, NYHA classification, and age onQOL and frequency of depression. Almost 50%of the study population, 79% of whom were menand 21%, women, were found to be depressedusing the BDI scale. QOL was assessed usingthe Medical Outcome Study Short Form (SF-36)and the Minnesota Living with Heart Failure Ques-tionnaire. The younger population was found to bemore depressed compared with the older; 64% ofwomen were found to be depressed comparedwith 44% of men. Among men, blacks wereobserved to be more depressed than whites, andthere was no significant difference seen in womenbased on ethnic classifications. Almost 68% ofpeople had severe HF classified as NYHA 111 orhigher, and the rate of depression was almostdouble in patients with class 111 HF comparedwith class 11.In their study of depression and risk of HF in the

elderly, Williams and colleagues23 examineda community sample and reported depression asan independent risk factor of HF, mostly in elderlywomen. In their report on gender difference in thedepression cardiovascular link, Naqvi and

colleagues24 identified depression to be twice ashigh in women as in men.Freedland and colleagues2 examined the preva-

lence of depression in a sample of 682 hospital-ized patients with HF and found more than half(55%) at least met the criteria for depression usingthe BDI scale. The strongest correlates identifiedwere greater functional impairments and youngerage.Koenig5 found the prevalence of depression to

be 36.5% in inpatients aged 60 years and olderadmitted in a tertiary care hospital. Frasure-Smith and colleagues25 reported a higher inci-dence of depression in patients with a recent MIin the previous 1 to 3 weeks, with an ejection frac-tion (EF) of 35% or less or Kilip class 11 or greaterHF.Havranek and colleagues3 used the Medical

Outcomes Study Depression Tool to identify inde-pendent predictors like living alone, alcohol abuse,and financial burden frommedical care associatedwith development of depressive symptoms amongoutpatients with HF. The incidence of thesepredictors at 1 year was 16%, 36%, and 69%,respectively. Furthermore, they used the KansasCity Cardiomyopathy Questionnaire and identifiedpatients with worse HF developed significantdepressive symptoms at year one.The Organized Program to Initiate Life Saving

Treatment in Hospitalized Patients (OPTIMIZE-HF)evaluated the association of depression withhospital treatments and postdischarge mortality.In their analysis of 48,612 patients from 259 hospi-tals, depression was found more commonly in thefemale gender, in whites, and in patients withassociated comorbidities of HF, including DM,chronic obstructive pulmonary disease, andanemia. Furthermore, investigators found a signifi-cant increase in 60- to 90-day mortality in patientswith a history of depression, and these patientswere less likely to receive cardiac interventionsand referral to outpatient rehabilitationprograms.13 Fig. 1 shows the Kaplan-Meir curvefor postdischarge mortality in patients hospitalizedwith HF and history of depression.Rohyans and colleagues26 analyzed the socio-

demographic variables associated with depres-sive symptoms in patients with HF. Theyobserved that depression was more prevalent inyounger patients, women, and patients withmore severe HF based on NYHA classification.The researchers used the Personal Health Ques-tionnaire (PHQ 9) for their depression evaluation,whereas many other studies have used BDI asthe screening scale. Furthermore, in their regres-sion analysis of elderly patients with HF, theyfound that patients who had functional impairment

Fig. 1. Kaplan-Meir curve for postdischarge mortality was increased in patients hospitalized with HF and historyof depression. (Reproduced from Albert NM, Fonarow GC, Abraham WT, et al. Depression and clinical outcomesin heart failure: an OPTIMIZE-HF analysis. Am J Med 2009;122:366; with permission.)

Epidemiology of Depression in Heart Failure 3

and lacked problem-focused coping mechanismstended to be more depressed compared withthose who did not.

In their study on depressive symptoms withrespect to long-termmortality in patients with atrialfibrillation and CHF. Nancy Frasure-Smith andcolleagues25 reported that elevated depressivesymptoms significantly predicted cardiovascular(CV) mortality in rate- and rhythm-controlled treat-ment groups. The covariate-adjusted depression-related increase in CV death was similar to theincrease with not taking anticoagulants or beingprescribed aldosterone antagonists, importanttreatment factors for the disease. The CanadianAmiodarone Myocardial Infarction Arrhythmia Trial(CAMIAT) found that depression significantly pre-dicted sudden cardiac death in placebo-treatedpatients but not in those receiving amiodarone.27

Fig. 2 shows the prevalence rates of clinicallysignificant depression among patients with HF inthe meta-analytic review of Rutledge andcolleagues14.

Wide heterogeneity has been observed in the re-ported prevalence of depression in HF across thevarious studies done, ranging from 11% to 25%for outpatients and 35% to 70% for inpatients. Intheir meta-analysis of depression in HF, Rutledgeand colleagues14 have examined at least 36 publi-cations and have calculated an overall point esti-mate prevalence rate of 21.6%. The variationobserved can be attributed to several factors,including the assessment methods used in diag-nosing depression, the severity of HF, and thedifferent characteristics of the patient populationenrolled in these studies. Of these, the different

assessment tools of depression and severity ofHF seem to have a greater impact on the variationsobserved. In their systematic review, Delville andcolleagues28 analyzed the most common instru-ments used for evaluating depression in adultswith HF. In the 16 articles that met the inclusioncriteria, 6 self-reporting instruments and 2 diag-nostic interviews were identified. Depressivesymptoms were reported in 14% to 60% of adultswith HF. Self-reporting questionnaires provideda higher incidence of depressive symptoms, 21%to 60%, compared with diagnostic interviews,which ranged from 14% to 39%. A possible expla-nation would be the perception of lower QOL inpatients with depression and subsequent report-ing of diminished functional status. Based on theNYHA classification, a fourfold increase in depres-sion was observed in patients with class 4 HFcompared with class 1 HF. Furthermore, the prev-alence of depression in Caucasian patients wasfound to be 9% to 54% with an aggregate of25% compared with 7% to 44%with an aggregateof 18.7% in the minority group.

Inconsistencies in the use of depression assess-ment methodologies in these various studies havebeen a limiting factor in systematic analysis of theprevalence of these comorbid diseases. Probably,the use of standardized psychiatric measureswould make the measurement more equitable infuture studies.

Depression is annotated to be a behavioraldisease manifesting biologic changes, whichmakes it constantly change over time. Althoughthese studies provide compelling evidence ofincreased prevalence of depression in HF, there

Fig. 2. Shows the prevalence rates of clinically significant depression among patients with HF in the meta-analyticreview of Rutledge and colleagues. The prevalence rate widely varied, ranging from 9% to 60% and the aggre-gated point estimate was 21.5%. (Reproduced from Rutledge T, Reis VA, Linke SE, et al. Depression in heartfailure: a meta-analytic review of prevalence, intervention effects, and associations with clinical outcomes.J Am Coll Cardiol 2006;48:1527e37; with permission.)

Gnanasekaran4

is a lack of information on changes in depressionover time and their influence on patients with HF.More outcome studies are necessary to systemat-ically analyze the diseases, taking into consider-ation the heterogeneity observed. This study triesto draw the attention of future investigators tothe further research needed to address thispaucity of knowledge. Furthermore, a betterunderstanding on the areas of incidence ofdepression in HF and associated health-carecosts is important.

DEPRESSION IN CHF IN THE ELDERLY

Depression and cardiovascular diseases areamong the top 5 chronic disorders leading todisability worldwide in the elderly population.12

Aging is considered a byproduct of an interactionbetween genetic, environmental, and lifestylefactors, which predisposes the elderly to multiplevascular abnormalities. Elderly people haveheightened levels of oxidative stress and inflam-mation, which in combination with other abnormal-ities, such as cellular senescence, can conspire toinduce proatherosclerotic changes.29 In theirstudy of prevalence of CV diseases involvingcentenarians, Cicconetti and colleagues30 re-ported a prevalence of 16.7%, of which 8% wasdue to HF. Vascular disease enhances functionaldecline and has a major impact on QOL in theelderly population.10 In patients with HF, the asso-ciation of depression has led to poorer QOL,increased hospitalization, and mortality.31 Asregards physical functioning, depressed patients

Epidemiology of Depression in Heart Failure 5

with cardiac disease scored, on average, 77.6% ofnormal functioning compared with controls.32 Inacutely ill hospitalized older adults, the functionalcapacity of the patient deteriorates morecompared with the rest of population.33 Koenigh5

reported a high prevalence of 36.5% of majordepression by Diagnostic and Statistical Manualof Mental Disorders fourth edition (DSM-IV) criteriain 107 elderly patients admitted with CHF. Therewas no difference in mortality reported, but mostpatients (57.5%) met the criteria for depression.Data from the Hispanic Established Populationfor the Epidemiologic Study of the Elderly indi-cated higher death rates in patients with a highlevel of depressive symptoms and DM.34 Further-more, under-recognition of depression in this pop-ulation has been associated with increased risk ofrecurrent falls.34 In a study that used the 2001 to2003 National Hospital Discharge Survey datasets, the investigators found that ambulatory olderadults who were discharged with a primary diag-nosis of HF and a secondary diagnosis of depres-sion had a significant increase in nursing homeadmissions.35

Carels10 study found a positive correlationbetween depression and QOL indices like phys-ical, emotional, and social support; mood; andcoping behaviors in patients with CHF. Chungand colleagues36 further analyzed the effects ofdepressive symptoms and anxiety on QOL inpatients with CHF and their spouses. QOL was as-sessed using the Minnesota Living with HeartFailure Questionnaire and the investigators re-ported that patients and their spouses had poorerQOL with higher depressive symptoms.

Fulop and colleagues6 analyzed the course ofdepression and economic consequences in olderpatients with CHF. Almost 36% of the study pop-ulation of 203 subjects were found to bedepressed using the geriatric depression scale,and 22% were depressed according to the Struc-tured Clinical Interview of the DSM-IIIeR nonpa-tient edition. They also found that depressedpatients were using more medical resourcescompared with the nondepressed population.

In their study of major depression and disabilityin older primary-care patients with HF, Friedmanand colleagues37 examined the associationbetween depression and dependence on activitiesof daily living and instrumental activities in anelderly population. A progressive increase in prev-alence of depression to about 40% was reportedin patients with increased dependency on instru-mental activities of daily living.

Gottlieb and colleagues22 reported that forevery 10 years more than mean age 64 years,the likelihood of depressive symptoms tends to

decrease by 26%. Although their observation issurprising, it would be prudent to understandthat subclinical depression is widely prevalentand left underdiagnosed in this population.Recent National Institute of Mental Health studiesshow that 13% to 27% of elderly patients mighthave subclinical depression, and most would notmeet the diagnostic criteria for major depressionusing standard screening questionnaires. Further-more, cognitive capability in the country’s elderlypopulation would limit the utility of thesescreening questionnaires. Using more structuredscales for the geriatric population and diagnosticinterviews would improve understanding of theepidemic in this age group.

BIOLOGY OF THE EPIDEMIC

Mounting evidence of this perilous association hasnot prompted significant interventions. Similarityof symptoms, like fatigue, malaise, weight gain,and insomnia, shared by these diseases increasesthe difficulty of delineating the 2 diseaseprocesses. Superficially, depression can bethought of as a somatic outcome of the CVchanges that happen in HF. If this is considereda plausible explanation, treatment of HF wouldhave remitted depression and the associationwould have been nullified effortlessly.

An analogous way to identify the etiology is tounderstand the biology of the disease processes.Common pathophysiology includes biologicreasons, like neurohumoral activation, sympa-thoadrenal activation, and hypercoagulability.Psychosocial reasons, including medicationnoncompliance, lower social support, and concernfor medical stigmata, have also been associatedwith worse outcomes.38 Gottlieb and colleagues22

point out that only 7% of patients in their studywere taking antidepressants.

Medication noncompliance is a potential mech-anism documented to produce adverse outcomein these diseases.39e41 Studies have shown thatmedication noncompliance causes 125,000deaths annually in the United States and leads to10% of hospital admission and 23% of nursinghome admissions.42 In their study, Casey andcolleagues43 reported elevated levels of depres-sion predicting failure to complete a 12-weekphase 2 cardiac rehabilitation program. Further-more, patients with a history of depression wereless likely to receive coronary interventions andcardiac devices or be referred to outpatientdisease management programs. Depressiontends to produce more noncompliance, whichcould instigate a vicious cycle of worseningdepression and HF.

Gnanasekaran6

Grippo and Johnson44 have hypothesized sym-pathoadrenal activation as a possible mechanismof this epidemic. Hypersecretion of norepinephrinein unipolar depression has been reported inprevious studies.45e47 Benedict and colleagues48

found an independent relation of neurohumoralactivation and severity of left ventricular (LV) func-tion in a subgroup of patients enrolled in theStudies of Left Ventricular Dysfunction (SOLVD)registry. The 2 central components of stressresponse are the hypothalamic pituitary adreno-cortical axis and sympathoadrenal system. Ina depressive state, escalated stress responsedoes not react to the counter-regulatory response,resulting in hyperactivity of the adrenocortical axisand sympathoadrenal axis. This results inincreased cortisol levels, which predisposespatients to enhanced CV disease. Depressioncauses dysregulation of the autonomic nervouscontrol in HF, resulting in increased sympathetictone, thereby increasing resting heart rate anddecreasing heart-rate variability (HRV). Augmentedsympathetic tone further increases levels ofplasma cortisol, serotonin, rennin, aldosterone,

Fig. 3. Hypothetical schema of the various pathophysiol(Reproduced from Musselman DL, Evans DL, Nemeroffdisease, epidemiology, biology and treatment. Arch Gen P�1998 American Medical Association. All rights reserved.)

and free radicals that worsen the diseaseprocesses. Hypothetical schema of the variouspathophysiological changes found in depressionand CV diseases are shown in Fig. 3.Elevated levels of inflammatory cytokines have

also been proposed as a possible mechanism forworsening depression and HF.49 The VesnarinoneMulticenter Trial (VEST) revealed that proinflam-matory cytokines, like tumor necrosis factor(TNF) and IL-6, and their receptors sTNFR1 andsTNFR2 independently predicted increasedmortality in patients with advanced HF.49 Sliwaand colleagues50 found that pentoxifylline,a platelet antiagrregant, significantly lowered thecytokine levels and improved LVEF in patientswith idiopathic cardiomyopathy. Smith51 in 1991postulated the macrophage theory of depressionin which he reported excessive secretion of IL-1and other macrophage products in the pathogen-esis of depression. In their meta-analysis, Zorillaand colleagues52 found an association betweenmajor depression and immune activation reminis-cent of an acute-phase response. Any acutecardiac event activates the immune system, which

ogical changes found in depression and CV diseases.CB. The relationship of depression to cardiovascularsychiatry 1998;55:580e92; with permission. Copyright

Epidemiology of Depression in Heart Failure 7

triggers the cytokine cascade. The failing heartthen becomes the source for production ofTNF-a, which secondarily activates the immunesystem. Decreased tissue perfusion in CHF leadsto production of inflammatory cytokines in thesystemic tissues, which further accelerates thevicious cycle.

HRV has been studied as another potentialmechanism contributing to diminished survival indepressed patients with CV disease. HRV, whichis measured as the standard deviation of succes-sive intervals between two successive R waves,has been a valid way of measuring the functioningof the sympathetic, parasympathetic, and rennin-angiotensin mechanism. CV homeostasis is main-tained by these nervous systems that alter theheart rate. A higher degree of HRV predicts a bettercardiac outcome, and HRV is significantlydepressed in patients with severe HF and indepressed patients, which reflects the decreasedparasympathetic tone associated with these co-morbid diseases.53

In their study of 10,294 patients 65 years andolder, Markovitz and colleagues54 were able topropose platelet activation as a possible cause inthe proposed link. Platelets contain adrenergic,serotonergic, and dopaminergic receptors. Activa-tion of the a-adrenoreceptors increase the level ofcatecholamines and initiate platelet response. Thisresults in activation of the arachidonate pathway,causing thrombus formation and vasculardamage. Serotonin-induced platelet activationcan cause thrombosis and vascular constriction.

Other mechanisms leading to poorer outcomesinclude the severity of HF noted in depressedpatients compared with the nondepressed. Onepossible explanation would be the deteriorationin the cardiopulmonary reserve in patients withsevere HF and their diminished perception ofQOL. McCaffrey and colleagues55 have hypothe-sized a genetic vulnerability in both thesediseases. Sociodemographic indicators, likeyounger age and female sex, and psychologicalindicators, like comorbid psychiatric disorder,situational stressors, and coping sources, are validpredictors of depression, and better under-standing them would add value in better under-standing this association.

ANTIDEPRESSANTS IN HF

Little is known about the effectiveness of antide-pressant therapy in patients with CHF. Studieshave found that 16% to 26% of depressedpatients with CHF receive antidepressants.5,56e60

Three trials have been published so far on theutility of treatment of depression in HF. It is crucial

to understand that depression is more than justa somatic reaction to CHF and that prompt evalu-ation and treatment would be of benefit in terms ofmortality and morbidity. The recent EnhancingRecovery in Coronary Heart Disease (ENRICHD)trial, which enrolled 2481 patients hospitalizedfor MI in the previous 30 days, reported lack of effi-cacy of nonpharmacologic strategies in treatmentof depression in patients who had had an MI.However, a post hoc analysis of participants inthe ENRICHD trial found that the use of a selectiveserotonin reuptake inhibitor (SSRI) was associatedwith 40% reduction in recurrent MI and death afteradjustments for demographic and CV variables.61

The Montreal Heart Attack Readjustment Trial(M-HART), which randomized 1376 patients whohad had an MI to telephone monitoring, foundhigher cardiac and all-cause mortality, especiallyin women who had received the nonpharmaco-logic intervention for depression. The studyconcluded, cautioning that nonpharmacologictreatment can potentially be harmful to patientswho have had a recent MI.62,63 A possible expla-nation may be that the intervention reminded thepatients of their disease state and increaseddistress in this population. Pharmacologic treat-ments for depression are controversial in HF,because of the potential side effects associatedwith psychiatric medications. Tricyclics affect thecardiac system. SSRIs like sertraline and citalo-pram are found to be safe in heart disease,because they are the least likely to inhibit the cyto-chrome P450 enzymes. However, there is norandomized study that is evaluating the safetyand efficacy of antidepressants in HF.

The Sertraline Antidepressant Heart AttackRandomization Trial (SADHART) evaluated theuse of antidepressants in patients with heartdisease and demonstrated that depression canbe treated without increasing the complicationsof CV events in patient with coronary arterydisease. The investigators also found a nonsignifi-cant reduction in the composite endpoint of MI ordeath from coronary heart disease.64 Whethertherapy for depression would improve CVoutcome remains undetermined. The ongoingSADHART-HF study will provide important datato address this paucity of knowledge. Morbidity,Mortality and Mood in Depressed Heart Failurepatients (MOOD-HF), a large randomizedplacebo-controlled trial, is investigating the utilityof the drug escitalopram, an SSRI, to improveoutcomes in depressed patients with CHF ofNYHA class II to IV and impaired LV systolic func-tion. The Interpersonal Theory and Citalopram forDepression in Coronary Disease (CREATE) trial iscomparing the efficacy and safety of interpersonal

Gnanasekaran8

therapy and SSRI in the treatment of depression inpatients with heart disease. Currently, cognitivebehavioral therapy is the only known safe andeffective treatment of depression in patients withheart disease.65 The Myocardial Infarction andDepression Intervention Trial (MIND IT) comparedthe efficacy of antidepressants like mirtazapineand citalopram (Celexa) to improve cardiacoutcomes in an 18-month trial in patients whohad had a recent MI and had reported no differ-ence in cardiac prognosis. A post hoc analysiscomparing responders to medication with nonre-sponders to treatment reported that the nonre-sponse group may be associated with anincreased cardiac event rate.66

SUMMARY

Increasing evidence supports the occurrence ofdepression in CHF. The impact of the disease isstill under-recognized and standard protocols toaddress this serious occurrence have not been es-tablished. This article intends to refresh ourmemory on the health-care burden associatedwith this occurrence. Updated literature on theepidemiology of the disease provides the knowl-edge and insight needed to understand thecomplex burden of the disease in terms ofmortality, morbidity, health-care costs, and QOL.Accounting for sociodemographic predictors ofdepression, like female gender; comorbid psychi-atric disorders; situational stressors; and copingsources, including social support; play an impor-tant role in ameliorating the disease process. Theauthor has found wide heterogeneity in the preva-lence of depression in HF across the variousstudies conducted, partly because of the assess-ment methods used to diagnose depression.This study directs future research in directions toaddress these gaps. Use of standardizeddepression assessment measures that involvea self-reported screening followed by a structuredinterview would better validate the diagnosis.Furthermore, “elder-friendly” screening toolswould add more value in unraveling subclinicaldepression in our elderly population. A conscien-tious effort to understand the shared pathophysi-ology in these diseases highlights the importanceof their early recognition to appropriate interven-tions. Furthermore, this knowledge would lead toidentification of potential biologic markers,including markers of systemic inflammation,inflammatory cytokines, and changes in HRV, forearly interventions.Future studies need to be conducted to investi-

gate the utility of treatments for depression inreducing CV mortality and their safety profile. Early

detection and treatment is important to improvingQOL. Depression is associated with poor medica-tion compliance, and interventional efforts shouldtarget a broad range of clinical outcomes to effec-tively assess potential benefits. This becomesincreasingly important in our elderly population inwhom drug-drug interaction and medicationcompliance is a challenge. Health-care providerknowledge and awareness of this association iswarranted and becomes crucially important togive patients and caregivers the necessary toolsand methods to develop better coping strategiesduring distress.

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