Depression, not SSRIs, linked to increased mortality in heart-failure patients
NOVEMBER 17, 2008 | Caroline Cassels
From Medscape Medical News—a professional news service of WebMD
Durham, NC - 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 [1].

A large prospective cohort study in HF 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 Dr Christopher M O'Connor (Duke University, Durham, NC) said.

The study is published in the November 10, 2008 issue of 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 two factors in patients with significant heart failure," he said.

The study included 1005 HF patients age 18 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 (BDI), a self-administered questionnaire. Those with a BDI 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 one of four 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 six 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 24.2% were taking antidepressant medications, 80% of which were SSRIs. During an average follow-up of almost three years, 42.7% of patients died.

Unadjusted analyses suggested there was an increased risk of 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?

Interestingly, the investigators found that antidepressants didn't 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 health 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. O'Connor reports receiving funding from Amgen, Astra, Bristol-Myers Squibb, GlaxoSmithKline, Guidant, Medtronic, Merck, Nitrox, Novartis, Otsuka America, Pfizer, ArcaBioPharma, and MedPace. Study investigator Dr Robert M Califf (Duke University) reports receiving funding from Avalere Health, Bayer, Biogen Idec, Brandeis University, Bristol-Myers Squibb/Sanofi, Eli Lilly, Five Prime,, Kowa Research Institute, Merck, Nitrox, Novartis Pharmaceuticals, Sanofi-Aventis, Schering Plough, Scios Pharma, and Vertex and has equity in Nitox.
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O'Connor CM, Jiang W, Kuchibhatla M, et al. Antidepressant use, depression, and survival in patients with heart failure. Arch Intern Med 2008; 168:2232-2237.