Depression in Patients with Heart Failure: Clinical Implications and Management

Depression in Patients with Heart Failure:Clinical Implications and Management

Kristin Watson, Pharm.D., and Kelly M. Summers, Pharm.D.

Mortality and morbidity rates remain high in patients with heart failuredespite advances in medical therapy. Heart failure can also significantlyworsen quality of life. Attention has been paid to evaluating the effects ofpsychological disease in patients with heart failure. Depression rates arehigher in patients with heart failure than in the general population.Depression has been associated with worse outcomes in patients with heartfailure. Those at highest risk for depression include patients with implantablecardioverter-defibrillators, alcohol abuse, history of depression, and multiplecomorbidities. Depression may be underdiagnosed in the heart failurepopulation, as symptoms can often be similar in the two disease states.Evidence is limited on the effects of pharmacologic and nonpharmacologictherapy for depression, specifically in patients with heart failure. Based on theavailable literature, patients with heart failure should be screened routinely fordepression. Treatment is known to improve quality of life, but its effect onoutcomes such as mortality and hospital admissions for heart failure remainsunknown. If treatment includes pharmacologic strategies, selective serotoninreuptake inhibitors (especially paroxetine and sertraline), mirtazapine, andnefazodone have the strongest efficacy evidence in this population. Based onsafety data of these agents and after consideration of comorbid conditions andthe potential for drug interactions, a selective serotonin reuptake inhibitorshould be used as first-line therapy. Finally, clinicians should not avoid �-blockers in those with a diagnosis of depression, as recent evidencedemonstrates that these agents are not associated with inducing or worseningdepressive symptoms.Keys Words: �-adrenergic antagonists, antidepressants, defibrillators,depression, heart failure.(Pharmacotherapy 2009;29(1):49–63)

OUTLINE

Impact of Depression on the Heart Failure PopulationManagement of Depression

Clinical TrialsSafety of AntidepressantsNonpharmacologic Interventions

Screening for DepressionImplantable Cardioverter-Defibrillators and

DepressionEffects of �-Blockers on Symptoms of DepressionFuture DirectionsConclusion

Heart failure affects more than 5 millionAmericans, and the estimated direct and indirectcost for 2008 was $34.8 billion.1 Despiteimprovements in medical therapy, the mortalityrate from heart failure increased by 28% from1994 to 2004.2 More than 3 million hospital-izations each year are related to heart failure,with mortality rates after discharge of 11.3% at30 days and 33.1% at 1 year.1 Numerous factors

From the Department of Pharmacy Practice and Sciences,School of Pharmacy, University of Maryland, Baltimore,Maryland (both authors).

Address reprint requests to Kristin Watson, Pharm.D.,BCPS, 20 North Pine Street, Room 430, Baltimore, MD21201; e-mail: [email protected].

PHARMACOTHERAPY Volume 29, Number 1, 2009

can contribute to disease complications includingnonadherence to diet and drug therapy, age, andserum sodium concentrations.3, 4 Research iscontinually being conducted to determineadditional risk factors that can affect diseaseprogression and/or complications in this patientpopulation. In the past few years, attention hasbeen paid to evaluating the effect of psycho-logical disease in patients with heart failure.There is now evidence that supports arelationship between depression and pooreroutcomes in these patients, including increasedfrequency of hospitalizations, worsening qualityof life (QOL), and increased mortality.5–9

Depression can easily be unrecognized in patientswith heart failure, as depressive symptoms suchas fatigue and anorexia or loss of appetite aresimilar to symptoms seen in patients withadvanced heart failure, potentially leading tounderdiagnosis.

To better understand the relationship betweendepression and heart failure and to reviewmanagement strategies for depression in thispatient population, we conducted a search of theMEDLINE database (1950–May 2008) using thefollowing key words: heart failure, depression,implantable cardioverter-defibrillators, and �-adrenergic antagonists. We also used variousantidepressant agents and nonpharmacologictreatment strategies (e.g., meditation) as searchterms. All identified available published trials,case reports, and abstracts were reviewed.

Impact of Depression on the Heart FailurePopulation

Major depressive disorder occurs in up to 6.5%of the general population in the United States ina given year, and the prevalence is estimated tobe 21.5% in patients with heart failure.10, 11

Therefore, the impact of depression may be animportant contributor to less than optimaloutcomes in patients with heart failure. In onestudy, 374 patients who were hospitalized forheart failure with New York Heart Association(NYHA) classes II–IV symptoms and a leftventricular ejection fraction (LVEF) of 35% orless were screened for depression.8 All-causemortality and readmission rates were evaluated at3 months and 1 year. Mild depression (based onthe Beck Depression Inventory [BDI]) wasdiagnosed in 54 (15.1%) of 357 patients andmajor depression (based on the BDI and modifiedNational Institute of Mental Health DiagnosticInterview Schedule) was diagnosed in 46 (13.9%)

of 331 patients. All-cause mortality rates weresignificantly increased in patients with majordepression compared with those withoutdepression at 1 year (26.1% vs 13.7%, odds ratio[OR] 2.23, p=0.04). No significant differencewas noted in mortality rates at 1 year in patientswith no depression compared with those whohad mild depression (13.7% vs 11.1%, p=0.62).In addition, patients with major depression had asignificant increase in hospital readmission ratescompared with those without depression at 3months (52.2% vs 36.5%, OR 1.09, p=0.04) andat 1 year (80.4% vs 52.3%, OR 3.07, p=0.005).

Another group of investigators evaluated therelationship between depressive symptoms anddeath or cardiovascular hospitalizations over amean follow-up of 3 years (range 2–5 yrs) in 204outpatients with heart failure.12 Those with aBDI score of 10 or higher (which indicatesdepression) had a significant increase in death orcardiovascular hospitalization compared withthose with a score less than 10 (hazard ratio 1.56,95% confidence interval [CI] 1.07–2.29, p=0.02).Others have suggested that a history ofdepression in patients admitted to the hospitalfor decompensated heart failure may increase thelikelihood of in-hospital mortality or the need forcardiopulmonary resuscitation (OR 3.3, 95% CI1.01–10.6, p<0.05).9

Heart failure alone can significantly impairpatients’ QOL.13, 14 In a study conducted todetermine the relationship between depressionand QOL among patients with heart failure, 155patients were screened, of whom more than halfwere classified as NYHA class III or IV.15 Seventy-five patients (48%) were considered to havedepression (BDI score ≥ 10). Patients withdepression scored significantly worse on allcomponents of the Medical Outcomes Study 36-item Short Form Health Survey (SF-36) (p<0.001for all subscales except the bodily pain (p=0.016)and role-emotional subscales (p=0.001) and onthe Minnesota Living with Heart FailureQuestionnaire (MLWHFQ) (p<0.001). Inanother study, the effect of depressive symptomson heart failure–associated health status in 460outpatients was evaluated.16 Depressivesymptoms, measured by the Medical OutcomesStudy–Depression questionnaire, were associatedwith lower scores on all health status measures ofthe Kansas City Cardiomyopathy Questionnaire(p<0.001). In this study, depression was thestrongest predictor of decline in heartfailure–specific health status over 6 ± 2 weeks.These two studies demonstrate the need to

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HEART FAILURE AND DEPRESSION Watson and Summers

recognize the link between depression anddiminished QOL in patients with heart failure.

Finally, depression in patients with heartfailure can lead to increased costs. A retro-spective 3-year cohort study of adult patientsfollowed after hospitalization for heart failurerevealed that there is a significantly higher cost ofcare in patients with depression.17 The medianadjusted cost ratio for total health care costs(including inpatient, outpatient, mental health,ambulance, long-term care, and equipment costs)for patients diagnosed and treated for depressionwas 29% higher than that in patients withoutdepression (95% CI 1.12–1.47, p<0.001). Themedian annualized cost (in 1998 dollars) was$9550 in patients with depression and $7474 inthose without depression.

Management of Depression

No guidelines exist specific to the treatment ofdepression in patients with cardiac conditions.Therefore, clinicians must rely on limitedliterature published in such populations andextrapolate from general population–basedguidelines. Current treatment recommendationsfor depression support the use of pharmacotherapyalone or in combination with psychotherapy,such as cognitive behavioral therapy andinterpersonal therapy, and electroconvulsivetherapy.18, 19 Pharmacotherapy includes selectiveserotonin reuptake inhibitors (SSRIs), selectivenorepinephrine reuptake inhibitors, tricyclicantidepressants, monoamine oxidase inhibitors,and mixed-neurohormone reuptake inhibitors.Psychotherapy, electroconvulsive therapy, andpharmacotherapy have all led to symptomimprovement in approximately 50% of thosetreated in the general population.20, 21

Clinical Trials

Heart Failure Population

Although antidepressant use has consistentlybeen proven efficacious, it is important toexamine efficacy in a heart failure–specificpopulation. Literature focusing on patients withheart failure, however, is extremely limited. Thefirst trial to target depression in a studypopulation with heart failure was the SerzoneAntidepressant Remedy in Congestive HeartFailure (SEARCH) trial.22 This 12-week, open-label trial studied nefazodone treatment inpatients with NYHA class II or III heart failure(LVEF < 40%) and a Hamilton Rating Scale for

Depression (HAM-D) score of 15 (moderatedepression) or greater. The mean dose ofnefazodone was 276 mg/day. Twenty-eightsubjects were enrolled, 19 of whom had a firstdiagnosis of depression. Twenty were male, andmean age of the population was 59 years. MeanLVEF was 29%, with 36% (10 patients) classifiedas having NYHA class III. Only 23 patientsfinished the 4 weeks of treatment required forefficacy analysis. At 12 weeks, the primaryoutcome of mean ± SD HAM-D score haddecreased from 25.2 ± 5.9 at baseline (very severedepression) to 9.2 ± 8.4 (mild depression;p<0.0001). Seventeen patients had at least a 50%decrease in their HAM-D score and wereclassified as responders, which corresponds toreported rates in the general population.Significant decreases from baseline were also seenin the secondary end points of BDI, ClinicalGlobal Impression, and MLWHFQ score changes(p≤0.006 for all); however, like the 12-weekHAM-D score classification, a BDI score of 11.1would still be considered mild depression.Although the authors report half of the subjectsbeing in “remission” at 12 weeks, the fact thatmany subjects remained depressed at the end oftreatment is most likely due to the shorttreatment duration overall and the baseline statusof severe depression for most patients. Triallimitations include its extremely small population,open-label design, and high dropout rate. Nine(32%) of the 28 patients enrolled dropped out,primarily for noncompliance and adverse effects,before week 12. Despite these limitations, thisstudy provides preliminary efficacy data fornefazodone indicating an acceptable responserate when used specifically in a fairly sick heartfailure population.

To our knowledge, results from the firstrandomized, placebo-controlled trial conductedin depressed patients with heart failure waspublished in 2007; the study’s goals were toexamine efficacy and QOL measures associatedwith use of paroxetine controlled release (CR) inpatients with depression and NYHA class II or IIIheart failure who were receiving optimal andstable heart failure regimens.23 Paroxetine CRdosages started at 12.5 mg/day and increased to25 mg/day at 2 weeks if tolerated. Depressionremission, classified as BDI scores less than 10 at12 weeks, constituted the primary end point.Twenty-eight patients were enrolled from aVeterans Affairs facility and equally distributedbetween groups. Mean LVEF was 26%, about68% of patients were NYHA class III, and 86% of

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patients were male. At baseline, over 85% inboth groups were taking an angiotensin-converting enzyme (ACE) inhibitor, 93% weretaking �-blockers, and 39% were takingspironolactone. The mean ± SD baseline BDIscore was 23.4 ± 9.4 in the placebo group and21.1 ± 9.9 in the paroxetine CR group, but thedifference was not significant. Fifteen and eightpatients had diagnoses of recurrent and new-onset major depression, respectively. Ninepatients receiving paroxetine CR reached theprimary end point compared with three receivingplacebo (p=0.018). This correlates to approxi-mately 69% in the paroxetine CR group versusapproximately 23% in the placebo group(p=0.018) who were considered responders,exceeding nefazodone’s response rate in theSEARCH study.22 The mean BDI score at 12weeks was 9 in the paroxetine CR group versus18 in the placebo group (p=0.054); the compara-tive BDI score lowering at weeks 4 and 8significantly favored paroxetine CR (p<0.05 forboth). However, analysis of variance ofcontinuous BDI score change throughout theentire intervention indicated paroxetine CR to besignificantly superior in lowering BDI scorecompared with placebo (p=0.024). It is likelythat a type II statistical error is responsible forthe lack of significance seen at week 12, as aprevious power calculation was not performed inthe study. The results did not change whenadjusted for multiple analyses. When examiningthe occurrence of any worsening depressionwhile randomized, the results indicated thatsignificantly fewer patients receiving paroxetineCR had increases in BDI scores compared withthose taking placebo (p=0.029). Although bothgroups had similar SF-36 scores at baseline, onlythe paroxetine CR group had significantly highermental health and social functioning componentscores at 12 weeks (p<0.05). Although bothgroups had significant decreases in MLWHFQemotional dysfunction scores compared withbaseline (p<0.05 for both groups), no significantdifferences were seen in total MLWHFQ scores;however, this failure to show a significantdifference in total scores may be due to highplacebo effects, small sample size, or instrumentvalidity in this population.23 These findingscould be clinically important as improved QOLhas been proposed to enhance drug adherence.24

Overall, this study was the first, to ourknowledge, to prove that paroxetine CR wassignificantly superior to placebo in treatingdepression of various classifications in patients

with heart failure who were already receivingrecommended, survival-enhancing heart failuretherapies. Until further studies are conducted,however, extrapolations from this trial should beapplied with caution to immediate-releaseparoxetine. The study’s patients were fairlyrepresentative of those one might encounterclinically, with the exception of a relatively lowpercentage of women. This limited femalepopulation component could be important, assome data have shown a lower treatmentresponse rate in women.25, 26

We found one other study focusing on heartfailure and depression that assessed therelationship of depression to cognitive function.27

This prospective, case-control study had twoprimary objectives: the first was to demonstrategreater cognitive dysfunction in patients withheart failure compared with healthy controls, andthe second was to prove that antidepressant useleads to less cognitive impairment. Patients wereexcluded if they were receiving psychoactivetreatment or if they had a personal or familyhistory of neurodegenerative, nondepressivepsychiatric or anxiety disorders. A total of 20patients with heart failure and depression, 23with heart failure but without depression, and 18elderly controls were enrolled. The average agewas 74 years, and average LVEF was 37.4%, withan equal distribution of NYHA classes II and IIIin both heart failure groups. Mean baselineHAM-D scores were 27.4 for the depressed heartfailure group, 7.0 for the nondepressed group,and 3.3 for the control group. Thirteen patientsin the depressed group completed treatment withcitalopram, which was started at 20 mg/day, andseven completed treatment with sertraline,started at 50 mg/day, for 8 weeks. The other twogroups did not receive any antidepressants.Treatment decreased mean HAM-D scores a mean± SD of 64.9 ± 4.2%. Although this treatmentresponse is similar to that seen in other heartfailure populations with depression,7, 22 the actualmean end-treatment HAM-D scores and corre-sponding statistical analysis were not reported.

Other main findings of this trial support theauthors’ primary objectives. Significantly lowerCambridge Mental Disorders of the ElderlyExamination (CAMCOG) scores (indicatingworse performance in a range of cognitivefunctioning abilities) were seen in depressedpatients with heart failure at baseline (mean ± SD52.4 ± 10.9) versus nondepressed patients (70.2± 12.3) and controls (83.2 ± 3.6) (p<0.001 for allcomparisons). Overall mean ± SD CAMCOG

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scores after treatment were significantly higherthan baseline values (61.8 ± 14.3, p<0.001).Considering statistically significant increasesseen in components such as remote memory,language comprehension, abstract reasoning, andattention, the authors theorized that SSRItreatment could result in clinically improvedQOL and adherence to heart failure treatmentplans. Indeed this theory is appealing as heartfailure drug therapy and self-care measureadherence are estimated to be only 70%.28

However, until trials are conducted in which theprimary outcome is improved adherence to heartfailure regimens with SSRI use and results are notlimited to secondary component outcomes, thislink to improved cognition must be consideredpreliminary. The results of this study do providefurther support for the efficacy of SSRIs inpatients with heart failure, although the studywas not designed to answer this question withstatistical clarity. In addition, whereas thecomprehensive exclusion criteria were necessaryto help isolate the cognitive deficits seen specificto patients with heart failure, they also limitedthe external validity of its treatment effects.

To our knowledge, no studies have assessedpsychotherapy interventions in a heart failure–only population.29

Other Cardiac Populations

Since outcome data for patients with heartfailure are lacking, it is useful to extrapolatesafety and efficacy data from the more extensivecadre of studies conducted in patients withcoronary artery disease, especially as thiscomorbidity is present in many patients withheart failure. The first landmark trial in patientswith acute coronary syndromes and depressionwas the Sertraline Treatment of Major Depressionin Patients with Acute MI or Unstable Angina(SADHART) study, which compared sertralinewith placebo for its effects on LVEF (primaryoutcome) and depression (secondary outcome).30

In this study of 369 patients enrolled within 30days of hospitalization for acute coronarysyndromes and whose mean LVEF was 53%, nosignificant changes were noted in HAM-D scoresat 24 weeks in sertraline-treated patients.However, the percentage of patients classified asresponders was 67% (125/186 patients) in thesertraline group compared with 53% (97/183patients) in the placebo group (p=0.01).

The Myocardial Infarction and Depression-Intervention Trial (MIND-IT) was a nested drugstudy of mirtazapine treatment versus placebo in

patients who had myocardial infarction in aparent study that compared a usual care groupwith an active intervention group.31, 32 Of the 91patients enrolled, approximately 27% and 14%had an LVEF of 30–45% and less than 30%,respectively. At the end of the study, althoughnumerically there was a greater improvement inscore with mirtazapine, no significant differenceswere seen in the primary outcome of change inHAM-D score between the two groups or in thesecondary outcome of change in BDI score. Also,no significant differences were shown in thosewith response or remission over the 24 weeks.Limitations of these trials include theconfounders of high response rates in the placebogroups, close proximity of depression diagnosisto an acute medical event, and, in the case ofMIND-IT, a high dropout rate. Also, all trialsfound significant interventional improvement insubgroups with recurrent depression, whichcomplicates interpretation of results for thosewith a new diagnosis.

Considering the established ways in whichdepression adversely affects outcomes in patientswith heart failure, it is useful to go beyondsymptomatic treatment of depression to examinethe potential role of antidepressant therapy inpreventing future cardiac events. One of themost often subscribed pathophysiologic reasonsbehind the association between the presence ofdepression and increased cardiac mortality is theenhanced platelet reactivity seen in patients withdepression.33 Accordingly, studies of antidepres-sant efficacy for effecting cardiac disease–freesurvival in patients with depression have oftenfocused on drugs shown to affect this mechanism.Because serotonin is such a potent stimulus forplatelet aggregation, drugs affecting synapticserotonin concentrations such as the SSRIs wereamong the first to be studied in cardiac disease.The SSRIs have been shown to prevent both therelease of serotonin from platelets and anyfurther reuptake of serotonin, thus impairinghemostasis.34–37 Indeed, in a SADHART substudy,patients receiving sertraline had lower releasedconcentrations of platelet-related biomarkerscompared with the placebo group, despite the useof antiplatelet agents in both arms of the study.38

Paroxetine has been shown to decrease plateletreactivity as well in patients with coronary arterydisease.39, 40 Mirtazapine, however, has only shownnonsignificant decreases in platelet reactivity.41

In the Enhancing Recovery in Coronary HeartDisease (ENRICHD) trial,25 for example, after amean follow-up of 29 months, no significant

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differences were observed between groupsassigned to cognitive behavioral therapy or usualcare in the primary end point of death or nonfatalmyocardial infarction, although the cognitivebehavioral therapy groups had significantlyhigher BDI scores. In this post–myocardialinfarction population (2481 patients), 334patients had heart failure. Of note, up to 28%overall used concomitant antidepressants(median duration of use 12 mo), which likely

contributed to the nonsignificant results seen.The most recent trial including a primary

outcome of any cardiac event occurrence was theparent MIND-IT study42 (of the nested MIND-ITtrial discussed previously). Patients who hadexperienced a myocardial infarction, of whom16% had an LVEF less than 30%, were randomlyassigned to receive either treatment of depression(drug or placebo, psychiatrist-directed treatment,or patient-elected no treatment [122 patients]) or

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Table 1. Efficacy Trials of Treatment of Depression in Patients with Heart Failure

Study Design Intervention Patient Characteristics Primary Outcome ResultsOpen-label Nefazodone x 12 wks 71% male; mean age 59 yrs; 100% had Decrease in mean ± SD HAM-D(n=28)22 (mean dose 276 mg/day) heart failure, 36% NYHA class III score from baseline to

Mean ± SD baseline HAM-D score 9.2 ± 8.4 (p<0.0001)25.2 ± 5.9

Randomized, Paroxetine CR 12.5–25 86% male; mean age 62 yrs; 100% had BDI score < 10: 69.2%placebo- mg/day x 12 wks vs heart failure, 68% NYHA class III paroxetine vs 23.1% placebocontrolled placebo Mean ± SD baseline BDI scores: 21.1 ± 9.9 (p=0.018)(n=28)23 paroxetine vs 2.34 ± 9.4 placebo

Prospective, Sertraline (mean dose 44% male; mean age 74 yrs; 100% had Improvement in mean ± SDcase-control 70 mg/day) or heart failure, 44% NYHA class III CAMCOG score from baseline(n=61)27 citalopram (mean dose Mean ± SD baseline HAM-D score: to 61.8 ±14.3 (p<0.001) in

5 mg/day) x 8 wks 27.4 ± 6.7 in depressed patients vs depressed patients7.0 ± 4.8 in nondepressed patients vs3.3 ± 1.8 in controls

Mean ± SD baseline CAMCOG score:52.4 ± 10.9 in depressed patients vs70.2 ± 12.3 in nondepressed patients vs83.2 ± 3.6 in controls

Randomized, Sertraline (mean dose 63% male; mean age 57 yrs; 14% had heart Change in LVEF: no significantplacebo- 68 mg/day) vs placebo failure, 7% > Killip class II; enrolled within difference between groupscontrolled x 24 wks 30 days of acute coronary syndromes(n=369)30 Mean ± SD baseline HAM-D score:

19.6 ± 5.3 sertraline and placebo

Randomized, Mirtazapine 15–45 84% male; mean age 57 yrs; 14% had LVEF Change in mean HAM-D scoresplacebo- mg/day vs placebo < 30%, 2% Killip class III or IV; enrolled from baseline: -8.0controlled x 24 wks within 3–12 mo after myocardial infarction mirtazapine vs -5.56 placebo(n=91)31 Mean baseline HAM-D score: (p=NS)

18.66 mirtazapine vs 16.1 placebo

Randomized, Weekly cognitive 56% male; mean age 61 yrs; 14% had heart Recurrent myocardial infarctioncontrolled behavioral therapy vs failure, 7% Killip class III or IV; enrolled or all-cause mortality at mean(n=2481)25 usual careb x 6 mo within 30 days after myocardial infarction 29-mo follow-up: 24.2%

Mean ± SD baseline BDI score: cognitive behavioral therapy vs18.0 ± 7.6 usual care vs 17.7 ± 8.1 24.1% usual care (p=NS)cognitive behavioral therapy

Randomized, Antidepressant therapyc 75% male; mean age 58 yrs; 16% had LVEF Any significant cardiac event atcontrolled vs usual care x 6 mo < 30%, 14% Killip class ≥ II; enrolled 18 mo after myocardial(n=331)42 within 3–12 mo after myocardial infarction infarction: 27 events with

Mean ± SD baseline BDI score: 11.9 ± 7.2 intervention vs 15 eventsintervention vs 11.7 ± 6.4 usual care with usual care (p=NS)

BDI = Beck Depression Index; CAMCOG = Cambridge Mental Disorders of the Elderly Examination; CGI = Clinical Global ImpressionImprovement; CR = controlled release; LVEF = left ventricular ejection fraction; HAM-D = Hamilton Rating Scale for Depression; MLWHFQ =Minnesota Living with Heart Failure Questionnaire; NS = not significant; NYHA = New York Heart Association; SF = Medical Outcomes Study36-item Short Form Health Survey.aResponse was defined as a 50% or greater reduction in HAM-D score from baseline, or a total HAM-D score of 9 or lower at end of treatment.bUsual care included education materials on cardiac risk factors.cAntidepressant therapy could include mirtazapine alone; mirtazapine for 8 wks, then citalopram if insufficient response; placebo for 8 wks,then citalopram if insufficient response; or individualized treatment with drugs and /or psychotherapy under the care of a psychiatrist.


usual care (209 patients). No significantdifferences were seen 18 months after myocardialinfarction in BDI scores or cardiac events,although the frequency of overall cardiac eventswas low. It is probable that lack of consistency intreatment duration and timing of event recordingin the study’s complicated trial design affectedthe end results, and thus any conclusiveinterpretations of the effects of treating versusnot treating depression in such patients awaitscompletion of more rigorously conducted trials.

Table 1 provides a summary of the efficacytrials.

Safety of Antidepressants

Although proven efficacy is essential in deter-

mining how to treat patients with depression,confirming the safety of antidepressants in acardiac-specific population is also crucial. Safetydata must be extrapolated from the fewrandomized controlled trials conducted in thesepatients, from randomized controlled trialsperformed in patients with coronary arterydisease or in the elderly, and from small safetydata–focused studies in various cardiac popula-tions. Reviewing the noncardiovascular-relatedsafety of antidepressants in patients with heartfailure is beyond the scope of this article. One ofthe primary aims of the SEARCH study was toassess the impact of nefazodone on cardiacindexes.22 In the 19 patients included in thesafety analyses, the mean pulse at study end was64.8 beats/minute compared with 69.7beats/minute at baseline (p=0.011). Heart rate,as measured by electrocardiogram (ECG),demonstrated a nearly identical decrease (from71.4 to 64.6 beats/min, p=0.004). Mean plasmanorepinephrine levels decreased from 332.9 to275.5 pg/ml (p=0.071). Standing and supinesystolic and diastolic blood pressures were alsonot significantly different from baseline, althoughit is unknown if statistical adjustments weremade for concomitant blood pressure–loweringagents. No significant differences were seen inheart rate variability. A small but significantincrease was seen in QT intervals, with a meanbaseline value of 423.3 msec and a mean 12-weekvalue of 444.0 msec (p=0.006). As neithertorsade de pointes nor any other drug-inducedcardiovascular-related outcome was reported, thisis likely of little clinical significance. Theauthors theorized that the observed decrease innorepinephrine level could be of particularbenefit to patients with heart failure if confirmedin other studies.22 Likewise, the observeddecrease in heart rate could have clinicalimplications for patients with heart failure inwhom target �-blocker doses known to reducemortality are trying to be achieved. The onlyother study, to our knowledge, that focused onpatients with heart failure does not discussadverse events except for the death of one patientat 8 weeks due to heart failure and one patient’sreport of lightheadedness with an increase indosage.23

Although the SADHART trial had primarily acoronary artery disease population, its primaryend point was actually the safety measure ofchange in LVEF during treatment as measured bymultiple gated acquisition scan.30 No significantdifferences in LVEF were seen between placebo-

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Table 1. continued

Secondary Outcome ResultsMean ± SD BDI score decreased from 23.0 ± 9.1 to11.1 ± 6.0 (p<0.0001)

Mean ± SD MLWHFQ score decreased from 56.6 ± 17.8 to46.1 ± 20.1 (p=0.006)

Mean ± SD SF-36 score: 38 ± 10 paroxetine vs 30 ± 6placebo (p<0.05)

Mean ± SD MLWHFQ score: 36 ± 27 paroxetine vs 51 ± 27placebo (p=NS)

Mean HAM-D reduction from baseline: 64.9%(p value not reported)

Mean ± SD CGI-I score at 24 wks: 2.51 ± 0.06 sertraline vs2.75 ± 0.07 placebo (p=NS)

Mean ± SD change in HAM-D score at 16 wks: -8.4 ± 0.41sertraline vs -7.6 ± 0.41 placebo (p=NS)

% of patients who respondeda: no significant differencebetween groups

Change in BDI scores from baseline: -4.82 mirtazapine vs-1.97 placebo (p=0.07)

Mean ± SD change in BDI score at 6 mo: -8.6 ± 9.2 cognitivebehavioral therapy vs -5.8 ± 8.9 usual care (p<0.001)

Mean ± SD change in HAM-D score: -10.1 ± 7.8 cognitivebehavioral therapy vs -8.4 ± 7.7 usual care (p<0.001)

Mean ± SD BDI score at 18 mo after myocardial infarction:11.0 ± 7.0 intervention vs 10.2 ± 5.1 usual care (p=NS)


and sertraline-treated patients, even specificallyin those with an LVEF less than 30% (18patients), nor were significant differencesobserved for measurements of blood pressure,ventricular premature complex count, or ECGcomponent, including heart rate. Sertralineresulted in fewer instances of total cardiovascularadverse effects compared with placebo, but thedifference was not significant.

Another group compared the cardiovascularsafety of fluoxetine in 27 patients with that ofnortriptyline in 60 patients, all of whom hadheart disease, including 45 with decreased LVEF(mean LVEF 34%).43 Fluoxetine led to asignificantly decreased 24-hour heart rate(change of 5 beats/min) and significantlyincreased supine systolic blood pressure (changeof 3 mm Hg), whereas nortriptyline caused asignificant increase in standing systolic bloodpressure (change of 7 mm Hg) and increase inheart rate (change of 7 beats/min). No significantchanges were seen in ECG intervals, although QTinterval was not reported for nortriptyline. Asignificant absolute decrease from baseline of 2%in LVEF was reported with nortriptyline;however, this is likely not clinically relevant andcould merely represent variations in operator-dependent LVEF interpretations, especially asother studies have not reported such changeswith tricyclic antidepressant use.43–46

Nortriptyline-treated patients experienced farmore cardiac-related adverse events, includingorthostatic hypotension, proarrhythmias, new-onset heart failure, and conduction problems,compared with fluoxetine-treated patients.

These studies suggest that SSRIs have fewerconcerning cardiac effects than tricyclic anti-depressants and thus are a safer option inpatients with heart failure. Indeed, with theirinherent sodium-channel–blocking activity,tricyclic antidepressants present a concern foruse in patients with cardiac disease because oftheir potential for causing conduction delays andprolonged QT interval. Due to their effects on�1-adrenergic receptors, orthostatic hypotensionis also well documented in patients with heartfailure who use tricyclic antidepressants,46–48 andincreases in basal norepinephrine concentrationsresulting in sinus tachycardia have also beenreported.49

Cardiovascular safety data for other antidepres-sants not already discussed are limited for theheart failure population. In a study of 10 patientswith depression who had decreased LVEF,bupropion was not shown to affect LVEF or to

cause orthostatic hypotension.44 In a mixedcardiac population including those with heartfailure, trazodone was shown to have little effecton cardiac functioning beyond some slowing ofresting heart rate.49, 50 In the selective norepi-nephrine reuptake inhibitor antidepressantcategory, no data have been published on the useof duloxetine specifically in a cardiac or elderlypopulation, but some data exist for venlafaxine inthe elderly population showing no alarmingchanges in heart rate, ECG parameters, or bloodpressure with its use compared to baseline orsertraline.51, 52 Mirtazapine safety data arecorrelatively drawn from the 24-week MIND-ITnested trial.31 No significant differences wereobserved in heart rate, blood pressure, ECGvalues, number of hospitalizations, or identifiedcardiovascular-related events with mirtazapinecompared with placebo, although as expectedfrom the general population, mirtazapine led tosignificantly more weight gain.

The sum of the limited cardiovascular system–specific safety evidence available for antidepressantuse in patients with heart failure seems to clearlyindicate that tricyclic antidepressants pose thelargest risk for adverse cardiac effects, whereasSSRIs, bupropion, and mirtazapine appear tohave a relatively benign adverse-effect profile.The lowering of heart rate seen with fluoxetine,nefazodone, and trazodone and the variable effecton blood pressure seen with venlafaxine maycause concern in patients with heart failure,although the clinical relevance of these adverseeffects is uncertain. When considering safety, itis also crucial to consider potential drug inter-actions with concomitant heart failure therapy.For example, with cytochrome P450 (CYP) 3A4inhibition, potentially dangerous increases inlevels of 3-hydroxy-3-methylglutaryl coenzyme Ainhibitors (statins), amiodarone, calcium channelblockers, lidocaine, and digoxin could occur.Inhibition of the CYP2D6 enzyme could result inhigher plasma levels of metoprolol, carvedilol,and lidocaine. Increased bleeding is possible dueto the interaction of CYP2C19 substrate warfarinand some SSRIs, such as fluoxetine andparoxetine. Venlafaxine has relatively weakCYP2D6 inhibition properties, whereas duloxetineinhibits CYP2D6 to a moderate degree.Citalopram, escitalopram, and sertraline are theleast potent CYP3A4 inhibitors, whereasparoxetine and fluoxetine are the most potentCYP2D6 inhibitors. Nefazodone, fluoxetine, andfluvoxamine inhibit CYP3A4 to a high degree aswell. Tricyclic antidepressants, although weak in

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their inhibition of CYP enzymes, shouldgenerally be avoided in patients with heart failureand should be used only if patients are resistantto other therapies. In patients with heart failurewho are elderly or who have hepatic impairment,SSRIs should be started at lower dosages due topotential for accumu-lation. Also, in patientswith decompensated heart failure and livercongestion, SSRI use should be monitoredcarefully to prevent toxicity.35, 53, 54

Nonpharmacologic Interventions

Interventions other than pharmacotherapy andpsychotherapy have long been advocated fortreating depression, with or without evidentiarysupport, for their various effects on mood. Inpatients with coronary artery disease, interven-tions such as cardiac rehabilitation, stressmanagement, educational formats, music therapy,and psychosocial counseling have all been shownto have positive effects on depression.55 To ourknowledge, no studies of the efficacy of herbalproducts to treat depression in patients withheart failure exist.

Exercise frequently is recommended for patientswith depression for its documented effects onmood enhancement.56 Although many patientswith heart failure are limited in their ability toexercise, they should still be encouraged toattempt what they can as studies have shown thatcontrolled exercise has no adverse hemodynamicconsequences.57, 58 In a 12-week study of 20patients with heart failure with a mean baselineLVEF of 34%, patients were randomly assigned tostructured exercise 3–5 times/week, dietarymodifications, and twice-weekly cognitivebehavioral therapy (seven patients); digoxin(seven patients); or placebo (six patients).58 Ofnote, whereas patients had mild depression bybaseline HAM-D scores (range 8.3–13.5), BDIscores (range 7.8–9.6) did not qualify them asdepressed. Regardless, only the nonpharmaco-logic-treatment group showed a significantdecrease in both BDI and HAM-D scorescompared with placebo (p=0.04 and 0.01,respectively), although it is impossible toseparate out the relative benefits of exercise inthe intervention.

Relaxation and other stress managementtechniques have been promoted for their benefitsin depression as well. One group assessed theimpact of 12-week, twice-daily progressivemuscle relaxation therapy (PMRT), which focuseson coordinated breathing and systemic muscle

contraction, in 59 Chinese patients with heartfailure.59 All patients practiced PMRT and werecompared with 62 controls receiving usual care.At the 14-week follow-up, the Hospital Anxietyand Depression Scale (HADS) score of the PMRTgroup decreased from 15.57 to 8.71, which wassignificantly more than the reduction from 16.56to 12.52 in the control group (p<0.001). Ofinterest, in a subsequent nonrandomizedinvestigation comparing these same two patientgroups with 32 patients given weekly exercisetraining,60 exercise decreased depression at 12weeks but not significantly. However, thepatients assigned to exercise began with a lowerbaseline HADS score.59

Several trials exist in which patients were notdepressed at enrollment; however, the resultsdemonstrated significantly improved psychologicalwell-being after interventions such as tran-scendental meditation and Tai Chi Chuanexercise.61–64 Although exercise and relaxationtechniques have potential for benefitingdepressed patients, before adopting them asroutine practice larger studies and feasibilityanalyses should be done. Results may not bereplicable when extensive training on theintervention is unavailable or in populations ofdifferent culture-specific health beliefs.

By far, the nonpharmacologic intervention withthe most supporting literature and the onerecommended in the American PsychologicalAssociation guidelines is electroconvulsivetherapy, which has been documented to improvepatient symptoms in up to 80% of users.65 Itspotential benefit, however, must be tempered bythe knowledge of a rare but real risk of cardio-vascular-related death, as well as demonstratedelevations in blood pressure and heart rate anddecreases in LVEF after therapy in patientswithout cardiac conditions.66, 67

Screening for Depression

An equal challenge to evaluating the besttherapies to use for depression in the heart failurepopulation is determining with clarity whichpatients are more likely to become depressed andthen who should be treated. No evidence hasbeen proposed that symptoms of depression inpatients with heart failure differ substantiallyfrom those seen in the general population. Themost commonly cited reasons for difficulties inmaking an appropriate diagnosis in patients withheart failure are the commonalities seen withtypical depressive symptoms and heart failure

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symptoms, which can confuse clinical presen-tations.54, 68 Symptoms such as weight gain,fatigue, malaise, loss of interest in previouslyenjoyed activities, and depressed mood couldeasily be attributed to either disease state. Inmany cases, practitioners inadvertently ascribedepressive symptoms to a nonoptimized heartfailure status without formally screening theirpatients for depression or assume the symptomswill naturally remit with time. However, evidenceexists that including any patient-exhibiteddepression-related somatic symptoms as positiveresponses in screening instruments results insimilar numbers of depression diagnoses comparedwith excluding such symptoms.54 Cliniciansshould primarily focus on determining if theirpatients have anhedonia or depressed moodalong with asking the standard recom-mendedidentifying questions about guilt, worthlessness,suicidal ideation, and changes in weight, sleep,and concentration.20 Although in the ENRICHDtrial,25 depression was diagnosed based on only 1week of symptoms, all other intervention trialsused the standard 2-week criterion. Practitionersalso should not dismiss diagnosing milddepression, as its presence is well documented inthe heart failure intervention trials.

Several epidemiologic studies have attemptedto isolate predictive factors for depression inpatients with heart failure, both ones that forecastthe patients who will at some point screenpositive for depression and ones predicting long-term continuation of depression after diagnosis.Studies have identified comorbid psychiatricdisorder, depression history, impaired activities ofdaily living, higher economic health care burden,alcohol abuse, and baseline increased illnessseverity score as significant predictive factors fordeveloping major or minor depression. Of note,NYHA class, income level, and LVEF were notpredictors.69–72 One group also provided dataindicating that the factors predictive of shorterremission time after diagnosis were severity ofdepression for major and minor depression andpresence of medical comorbidity for minordepression.73 Although patients with predictivecharacteristics should be screened routinely,knowing which patients have higher likelihoodsof remaining depressed over time can also helpone decide in whom aggressive treatment isindicated immediately versus those who may notdeteriorate with a watch-and-wait strategy.

Determining the most effective screeningapproach, including what instrument to use andhow often to screen, is important. Besides the

general recommendation of the United StatesPreventive Services Task Force to provide routinescreening in primary care settings for all patienttypes,74 no guidelines exist on screening the heartfailure population, so clinical judgment must beused. It would seem prudent to screen allpatients at least quarterly for the presence ofdepressive symptoms and at least monthly inpatients who have high predictive risk factors fordeveloping depression. Screening can take theform of routine screening of all patients (casefinding) or screening only when symptomssuggest diagnosis (symptom triggered). Due tothe predilection of clinicians to miss depressivesymptoms in patients with heart failure, symptom-triggered screening can lead to underdiagnosis,although it does save time. Case-finding screeningcan be more laborious with complex self- orpersonnel-administered instruments; however,using a simpler form of case-finding screeningsuch as the yes-or-no two-item test with a highsensitivity and moderate specificity has been bothadvocated and successfully implemented intopractice.53, 54, 68, 75 Then, cases identified canundergo confirmatory testing.

As with all survey questionnaires, appropriatepsychometric testing should be performed toensure validity in a specific population. The onlyinstruments validated in populations includingthose with heart failure (ranging from 10–100%)have been the HADS, Cardiac Depression Scale,Depression in the Medically Ill-10 and -18,Patient Health Questionnaire-2 and -9, and theyes-or-no two-item test. Sensitivities and specifi-cities on these have exceeded 75% and 72.2%,respectively.76–78 The most sensitive test was theHADS-Depression subscale at 100% in a hyper-trophic cardiomyopathy population (115 patients),and the most specific were the Patient HealthQuestionnaire Scales at 90% in a coronary arterydisease population with 60% having classes II–IVheart failure (1024 patients).76, 79 Of note, thetwo-item yes-or-no instrument discussed previ-ously had 90% sensitivity and 69% specificity,79

thus providing additional proof that such asimple and quick tool could be an effectivemethod of implementing routine screening. Inpractice, therefore, this tool or any one studied ina cardiac population would be preferred.

Implantable Cardioverter-Defibrillators andDepression

Sudden cardiac death accounts for 50% ofdeaths in patients with heart failure. The risk of

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sudden cardiac death is 6–9 times higher inpatients with heart failure compared with thegeneral population.2 This risk can be signifi-cantly decreased with an implantable cardio-verter-defibrillator (ICD) in patients withischemic and nonischemic cardiomyopathy. Thedecrease in sudden cardiac death with ICDs issignificantly higher compared with the use ofprophylactic antiarrhythmic therapy.80, 81 Unlikeadverse drug reactions with antiarrhythmictherapy, the potential consequences of an ICD arenot as readily recognized. It is estimated that22–66% of patients with an ICD have clinicallysignificant levels of depression.82, 83 The effect ofan ICD implantation on depression and anxietylevels specifically in patients with heart failure isnot available; these psychological disturbanceshave been reported in only general cardiac andother subsets of cardiac populations. Questionshave been raised if heightened depression is aresult of the implantation or the actual shockreceived.

One group of authors surveyed 143 ICD recip-ients, and 55% reported at least 1 non–medicallyrecommended avoidance behavior afterimplantation of their device.84 Patients in thisstudy reported avoiding varying levels ofexercise, the gym, and telephones. However, theauthors reported that there was no relationshipbetween receiving a shock and avoidancebehaviors. Another group evaluated the changesin QOL, psychological well-being, depression,and anxiety in cardiac arrest survivors amongpatients who did or did not receive a shock fromtheir ICD.83 No significant change in depressionon the Center for Epidemiologic Studies-Depression (CES-D) scale was noted in patientswho did and those who did not receive a shockover 12 months after ICD implantation.

The Antiarrhythmics versus ImplantableDefibrillators (AVID) trial, which includedpatients with an LVEF of 40% or less and ventric-ular fibrillation or symptomatic ventriculartachycardia, evaluated the effect of ICD shocksand adverse symptoms on QOL by using the SF-36.85 In the 905 patients surveyed, there weresimilar changes in SF-36 scores in patients whoreceived an ICD or antiarrhythmic therapy over 1year. There was a significant worsening inmental well-being (p=0.04) and physicalfunctioning (p=0.03) in patients who received anICD shock compared with those who were notshocked. A QOL assessment from the CanadianImplantable Defibrillator Study (CIDS) revealed

that psychological distress and well-being on theMental Health Inventory and five of the sevenQOL assessments on the Nottingham HealthProfile improved in patients randomly assignedto ICD therapy.86 The scores on the QOL assess-ments either declined or remained the same inpatients treated with amiodarone. The QOLeffects were not sustained in ICD recipients whoreceived five or more shocks. Quality of life wasevaluated by using the SF-36 in a substudy of theCoronary Artery Bypass Graft (CABG) PatchTrial, which randomly assigned patients whounderwent coronary bypass graft surgery andwho had an LVEF less than 36% to prophylacticdefibrillators or no antiarrhythmic therapy.87

Patients who were randomized to the ICD grouphad lower levels of physiologic well-being at the6 month follow-up.87

Recent evidence demonstrates that depressionmay precipitate ventricular tachycardia or ventric-ular fibrillation.88, 89 One group evaluated therelationship between depressive symptoms andthe risk of ventricular tachycardia or fibrillationleading to an ICD discharge among 645 patientswith an ICD.89 Moderate-to-severe depression,determined by the CES-D scale, was associatedwith a significant increase in time to first shockfor ventricular tachycardia or fibrillation (hazardratio 3.2, 95% CI 1.1–9.9, p=0.04) and for allshocks for ventricular tachycardia or fibrillation(hazard ratio 3.2, 95% CI 1.2–8.6, p=0.02).

The ICDs have been reported to inappro-priately fire in 13–22% of patients, usually inresponse to supraventricular tachycardias.90, 91

Steps should be taken to reduce this frequency, asdelivery of a shock can potentially worsen QOL.Examples of strategies to reduce shocks are toprescribe antiarrhythmic drugs and performroutine monitoring of potassium and magnesiumlevels. Clinicians need to be aware of thepotential psychological implications of ICDtherapy such as avoidance behaviors, alterationsin QOL, and new or worsening anxiety anddepression.

There is promising yet limited data supportingthe use of repetitive cognitive behavioral therapyor comprehensive cardiac rehabilitation inlimiting depressive and anxiety symptoms afterICD implantation.92 It is prudent to counselpatients on what is to be expected when a shockis delivered. Also, health care providers shouldboth explain the cause of a shock and addressany concerns of the patient after a shock isdelivered.

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Effects of �-Blockers on Symptoms ofDepression

Standard therapy for heart failure includes theuse of a �-blocker, specifically bisoprolol,carvedilol, or sustained-release metoprololsuccinate, in all patients with a decreased LVEF(< 40%) who are stable unless contraindicationsare present or patients are unable to toleratetherapy.93 These agents have been consistentlyshown to improve mortality and hospitalizationrates, slow disease progression, and improvesymptoms in patients with heart failure with areduced LVEF.94–96 �-Blockers are associated withcentral nervous system adverse effects includingfatigue, generalized weakness, and sexualdysfunction.97 Dating back to the late 1960s,concern has existed based on case reports,specifically with propranolol, that �-blockersmay induce depression.39, 98 The potential forthis adverse effect has been shown to limit �-blocker prescription use in patients with heartfailure.99, 100

Based on conflicting results from case reportsand reviews as well as limitations of evaluationsgeared to answer whether �-blockers can causedepression, more recent analyses have beenconducted to resolve these inconsistent reports.101,

102 In 2002, cardiac trials were reviewed todetermine the association of �-blockers withdepressive symptoms, fatigue, and sexualdysfunction.97 In the 15 trials reviewed, the rateof depression was 20.1% (1094 patients) of the5450 patients receiving �-blocker therapy and20.5% (1070 patients) of the 5212 patientsreceiving placebo. �-Blocker therapy was notassociated with an increased relative risk ofdepressive symptoms (relative risk 1.12, 95% CI0.89–1.41). They also evaluated withdrawal ratesdue to depressive symptoms in these trials.Again, the rates were similar in those whoreceived �-blocker therapy (0.4%) and those whoreceived placebo (0.5%, relative risk with �-blocker 0.94, 95% CI 0.44–2.01). Another groupevaluated the relationship between �-blocker useand depression in 1246 patients who had amyocardial infarction.103 No significant differ-ences in mean ± SD BDI scores between the �-blocker and non–�-blocker groups were presentat the 3-month (6.4 ± 5.4 vs 7.4 ± 6.5, p=0.14), 6-month (6.4 ± 5.7 vs 6.8 ± 6.4, p=0.54), or 12-month(6.5 ± 6.0 vs 6.8 ± 6.9, p=0.7) follow-up periods.

Based on these findings, clinicians should notavoid prescribing because of the concern that the

addition of �-blocker therapy may significantlyincrease the risk of depression or worsendepression in their patients. Clinicians need toremember that the prevalence of depression inthe heart failure population is increased over thatin patients in the general population104; therefore,a depression diagnosis can be common in thispopulation. The overwhelming morbidity andmortality benefits of �-blockers make theseagents critical in the management of heart failure,and they should not be withheld from patients inthe fear that this therapy could worsen or precip-itate depression. All patients with heart failureshould be monitored closely for symptoms ofdepression, and clinicians should ensure thatpatients with depression have adequate supportfor such diagnoses especially in those who are athigh risk.

Future Directions

Although depression has been clearly linked tooutcomes in heart failure, research on optimaltreatment strategies has lagged. More extensiveresearch needs to be conducted to prove efficacyand safety in individuals with heart failure.Specifically, trials need to be conducted withother SSRIs and antidepressant classes as well asin the area of psychotherapy and other non-pharmacologic interventions. Studies should useinstruments validated for screening andtreatment effect and should include not only endpoints on depression status but also measures ofheart failure status. We appear to be on the brinkof the availability of much more data ondepression in patients with heart failure. Trialsare in progress evaluating both pharmacologicand nonpharmacologic therapies in this patientpopulation. For instance, following the exampleof the SADHART trial, which was the first majorpublished trial in a cardiac population withdepression, the most exciting trial ongoing isSADHART-CHF, in which investigators arefollowing cardiac morbidity and mortalityoutcomes, including rehospitalization, in patientswith heart failure assigned to either sertraline orplacebo for 12 weeks. In addition, other ongoingtrials are assessing the impact of interpersonaltherapy and coping strategies as well as intensivepatient education on depression in patients withheart failure.105 These upcoming results willundoubtedly provide much needed guidance onthe most appropriate treatment of depressedpatients with heart failure.

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Conclusion

Patients with heart failure, especially thosewith ICDs, multiple comorbidities, and alcoholabuse, should be routinely screened fordepression. Based on the recent data available, �-blockers should not be avoided in patients withheart failure because of concerns of causing orworsening depression or considered as acausative factor in patients with heart failure anddepression.

Once depression is appropriately diagnosed, afew crucial considerations exist when planningtreatment and monitoring. It is important toconsider patient preference and previous treat-ment use when choosing the right plan of care.When choosing a drug, paroxetine, sertraline,nefazodone, and mirtazapine appear to have thebest antidepressant efficacy. Regarding safety, theSSRIs appear to have the best safety profile,although they have been shown to cause lowerheart rates in some cases. Likewise, trazodoneand nefazodone can lower heart rate, whereasvenlafaxine may cause idiosyncratic changes inblood pressure. It is also important to considerthe potential drug interactions with concurrentheart failure drugs as well as any resultingadverse effects from antidepressants that mayaugment heart failure–associated symptoms suchas weight gain, fatigue, and decreased libido.Psychotherapy, although not proven to decreasefuture cardiac events, nevertheless is effective fordepression and should be encouraged when thepatient is amenable. Finally, treating cliniciansshould remember to enforce frequent monitoringand long-term follow-up of patients with heartfailure and depression.

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Depression in Patients with Heart Failure: Clinical Implications and Management