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Depression, Not SSRIs, Linked to Increased Mortality in Heart-Failure Patients

  • Authors: News Author: Caroline Cassels
    CME Author: Charles Vega, MD, FAAFP
  • CME Released: 11/18/2008
  • Valid for credit through: 11/18/2009
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Target Audience and Goal Statement

This article is intended for primary care clinicians, cardiologists, psychiatrists, and other specialists who care for patients with heart failure.

The goal of this activity is to provide medical news to primary care clinicians and other healthcare professionals in order to enhance patient care.

Upon completion of this activity, participants will be able to:

  1. Describe previous research into the association between the use of antidepressants and cardiovascular outcomes.
  2. Identify the effect of depression and treatment with antidepressants on the survival of patients with heart failure.


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  • Caroline Cassels

    Caroline Cassels is News Editor for Medscape Psychiatry. A medical and health journalist for 20 years, she has written extensively for both physician and consumer audiences. She is the recipient of the 2008 American Academy of Neurology Journalism Fellowship Award. She can be contacted at [email protected]


    Disclosure: Caroline Cassels has disclosed no relevant financial relationships.


  • Brande Nicole Martin

    Brande Nicole Martin is the News CME editor for Medscape Medical News.


    Disclosure: Brande Nicole Martin has disclosed no relevant financial information.

CME Author(s)

  • Charles P. Vega, MD, FAAFP

    Associate Professor; Residency Director, Department of Family Medicine, University of California, Irvine


    Disclosure: Charles Vega, MD, FAAFP, has disclosed an advisor/consultant relationship to Novartis, Inc.

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Depression, Not SSRIs, Linked to Increased Mortality in Heart-Failure Patients

Authors: News Author: Caroline Cassels CME Author: Charles Vega, MD, FAAFPFaculty and Disclosures

CME Released: 11/18/2008

Valid for credit through: 11/18/2009


November 18, 2008 — Contrary to recent research suggesting antidepressants increase mortality in heart-disease patients, a new study suggests that, at least when it comes to selective serotonin-reuptake inhibitors (SSRIs), this is not the case.

A large prospective cohort study in heart-failure patients shows that depression, but not antidepressant use, was associated with a 33% increased mortality risk.

"It's well established that depression increases morbidity and mortality risk in patients with ischemic heart disease. There have also been some smaller studies demonstrating that this also applies to heart failure. But the interaction between depression, antidepressant use, and how this influences the whole landscape of risk in heart patients has not been well studied," principal investigator Christopher M. O'Connor, MD, from Duke University in Durham, North Carolina, said.

The study is published in the November 10 issue of the Archives of Internal Medicine.

Reluctance to Treat

Although the efficacy of antidepressant therapy for depression is generally well recognized, the safety of these medications in patients with heart disease has raised concerns.

According to O'Connor, older-generation tricyclic antidepressants (TCAs) have been linked to increased mortality risk in cardiac patients, and this has fueled concern about treating depression with antidepressants.

"Even though we know depression is a major risk factor in heart patients that is on par with smoking and high cholesterol, there's been a reluctance to treat depression in this patient population—even with SSRIs, which, generally speaking, have a much better safety profile—because of this treacherous history with tricyclics," he said.

He added that previous studies examining the potential impact of SSRIs on morbidity and mortality in this patient group have been underpowered to tease out the effect of depression vs medication.

Large Cohort

"Our objective was to look at the impact of depression and antidepressant use on long-term mortality in patients with heart failure in a cohort that was large enough and had sufficient power to look at depression, antidepressant use, and the interaction of these 2 factors in patients with significant heart failure," he said.

The study included 1005 heart-failure patients age 18 years and older admitted to a single center between March 1997 and June 2003. All patients had heart failure and a left ventricular ejection fraction of 35% or less.

During hospitalization, study participants completed the Beck Depression Inventory, a self-administered questionnaire. Those with a Beck Depression Inventory score of 10 or more were considered to be clinically depressed. Antidepressant drug use was prospectively collected from inpatient pharmacy records and discharge summaries.

Study subjects were categorized into 1 of 4 possible groups:

  • No antidepressant use.
  • SSRI only.
  • TCA group (this group included patients who took TCAs with or without SSRIs or other antidepressant drugs).
  • Other group (this group included patients who took other antidepressant drugs with or without SSRIs or TCAs).

Careful Analysis

Patients were contacted 6 months after hospital discharge and annually thereafter to obtain vital status.

The investigators found that of the total study group, 30% had clinical depression and 24.5% were taking antidepressant medications, 79.6% of which were SSRIs. During an average follow-up of almost 3 years (972 days), 42.7% of patients died.

Unadjusted analyses suggested there was an increased risk for mortality associated with antidepressant use. However, after researchers controlled for various risk factors, including depression, this association disappeared, but depression remained associated with a 33% increased mortality risk.

"This study shows that if you don't conduct a careful analysis you might mistakenly conclude that antidepressants are associated with an increased risk of death. We believe this is what has occurred in some of the previous studies—that investigators simply looked at antidepressants along with other cardiac risk factors and found a correlation with death.

"We also demonstrated this but found when you control for depression, the mortality risk associated with antidepressant use goes away, but the depression risk remains," said O'Connor.

Suboptimal Management?

The investigators found that antidepressants did not have a therapeutic impact on the depression. O'Connor speculated that this may be due to suboptimal follow-up.

"I think what may be happening is that heart-failure patients with depression are being identified and started on an SSRI but are not receiving optimal management. In my experience, nonpsychiatrists are very comfortable diagnosing depression and initiating an SSRI at a low dose. But when it comes to follow-up—monitoring drug response and adherence to therapy and titrating the medication—they may be falling short," he said.

Based on these results, O'Connor said, all patients hospitalized for heart failure should be screened for depression at discharge and, if positive, should be followed up by healthcare professionals who are adept at and comfortable with surveillance and titration of antidepressant medications.

The study was supported by the Duke Clinical Research Institute and the National Institutes of Mental Health. Dr. O'Connor has received funding from Amgen, Astra, Bristol-Myers Squibb, GlaxoSmithKline, Guidant, Medtronic, Merck Nitrox LLC, Novartis, Otsuka America, Pfizer, ArcaBioPharma, and MedPace. Study investigator Robert M. Califf, MD, has received funding from Avalere Health, Bayer, Biogen Idec, Brandeis University, Bristol-Myers Squibb/Sanofi, Eli Lilly, Five Prime,, Kowa Research Institute, Merck, Nitrox LLC, Novartis Pharmaceuticals, Sanofi-Aventis, Schering Plough, Scios Pharma, and Vertex and has equity in Nitox LLC.

Arch Intern Med. 2008;168:2232-2237.

Clinical Context

The relationship between depression and cardiovascular disease is complex. Although depression appears to increase the risk for cardiovascular events, research into the effects of antidepressants on cardiovascular outcomes has been mixed. In a study by Monster and colleagues, which was published in the November 15, 2004, issue of the American Medical Journal, researchers demonstrated that the risk for myocardial infarction was lower in patients with a history of cardiovascular disease who received antidepressant medications vs adults not treated with antidepressants. SSRIs, non-SSRIs, and other antidepressants all appeared effective in this regard. However, antidepressants were not effective in reducing the rate of myocardial infarction in patients who did not have a history of cardiovascular disease.

The current study examines the effects of antidepressants on survival in patients with heart failure, and the researchers adjust this result to account for the presence of depression.

Study Highlights

  • Patients eligible for study participation were at least 18 years old and were admitted to the cardiology service for heart failure, as defined by a New York Heart Association classification of II or more. Study participants had a left ventricular ejection fraction of 35% or more.
  • All participants completed the Beck Depression Inventory during hospitalization. Subjects with a score of 10 or more were considered to have depression.
  • Participants were contacted at 6 months after admission and annually thereafter to assess vital status.
  • The main outcome of the study was the relationship between depression, the use of antidepressants at the baseline admission, and survival.
  • 1005 patients provided data for study analysis. The average age of participants was nearly 70 years, and most subjects were men and were white.
  • 16.1% of participants were receiving antidepressants during the index hospitalization. Among these patients, 79.6% took only SSRIs, 7.4% took TCAs, and 7.4% took other antidepressants.
  • Patients taking antidepressants were more likely to be white and married.
  • 30% of the total study cohort met study criteria for depression; 24.5% of these patients with depression were receiving antidepressants, as were 12.5% of nondepressed individuals.
  • The average duration of follow-up was 972 days, with a median follow-up of 801 days. During this period, a total of 429 participants (42.7%) died, including 53.3% of the depressed cohort and 38.1% of the nondepressed group. Both depression and worsened heart failure were associated with a higher risk for mortality.
  • Univariate analysis revealed that the use of all antidepressants as well as SSRIs specifically increased the risk for death (hazard ratio for both variables, 1.32).
  • However, after adjustment for depression, neither all antidepressant use nor SSRI use was associated with a significant effect on survival.
  • Depression itself increased the risk for death in all study analyses (multivariate hazard ratio, 1.34).
  • There were no differences in the main conclusions of the study based on the sex of the participants.

Pearls for Practice

  • In a previous study, the use of different types of antidepressant medication was associated with a reduced risk for myocardial infarction, but only in patients with a history of cardiovascular disease.
  • In the current study, depression independently increased the risk for mortality in patients with heart failure, but the use of any antidepressant or SSRIs specifically did not.


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