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-Blocker Therapy and Symptoms of Depression, Fatigue, and Sexual Dysfunction

Dennis T. Ko, MD; Patricia R. Hebert, PhD; Christopher S. Coffey, PhD; Artyom Sedrakyan, MD; Jeptha P. Curtis, MD; Harlan M. Krumholz, MD

JAMA. 2002;288:351-357.

Context  -Blocker therapy remains substantially underused in cardiac patients despite its proven mortality benefits. Reluctance to prescribe these agents may derive from concerns about their association with symptoms of depression, fatigue, and sexual dysfunction.

Objective  To determine the association of -blockers with depressive symptoms, fatigue, and sexual dysfunction by performing a quantitative review of randomized trials that tested -blockers in myocardial infarction, heart failure, and hypertension.

Data Sources  Randomized trials of -blockers used in the treatment of myocardial infarction, heart failure, or hypertension were identified by searching the MEDLINE database for English-language articles (1966-2001). In addition, we searched the reference lists of previously published trials and reviews of -blockers for additional studies.

Study Selection  Criteria for inclusion of trials in the review were: random allocation of study treatments, placebo control, noncrossover design, enrollment of at least 100 patients, and a minimum of 6 months of follow-up. The initial search produced 475 articles, 42 of which met these criteria. Fifteen of these trials reported on depressive symptoms, fatigue, or sexual dysfunction and were selected for inclusion.

Data Extraction  For each trial, 1 author abstracted the frequency of adverse events in the -blocker and placebo groups and the numbers of patients randomized to the treatment groups. Two other authors verified the counts of events, and all authors adjudicated any discrepancies. Two different types of information on adverse events were abstracted: patient-reported symptoms and withdrawal of therapy due to a specified symptom. We categorized the tested -blockers by generation (early vs late) and lipid solubility (high vs low to moderate).

Data Synthesis  The 15 trials involved more than 35 000 subjects. -Blocker therapy was not associated with a significant absolute annual increase in risk of reported depressive symptoms (6 per 1000 patients; 95% confidence interval [CI], –7 to 19). -Blockers were associated with a small significant annual increase in risk of reported fatigue (18 per 1000 patients; 95% CI, 5-30), equivalent to 1 additional report of fatigue for every 57 patients treated per year with -blockers. -Blockers were also associated with a small, significant annual increase in risk of reported sexual dysfunction (5 per 1000 patients; 95% CI, 2-8), equivalent to one additional report for every 199 patients treated per year. None of the risks of adverse effects differed significantly by degree of -blocker lipid solubility. The risk associated with reported fatigue was significantly higher for early-generation than for late-generation -blockers (P = .04).

Conclusion  The conventional wisdom that -blocker therapy is associated with substantial risks of depressive symptoms, fatigue, and sexual dysfunction is not supported by data from clinical trials. There is no significant increased risk of depressive symptoms and only small increased risks of fatigue and sexual dysfunction. The risks of these adverse effects should be put in the context of the documented benefits of these medications.

Author Affiliations: Section of Cardiovascular Medicine, Department of Medicine (Drs Ko, Hebert, Curtis, and Krumholz), and Section of Health Policy and Administration, Department of Epidemiology and Public Health (Drs Sedrakyan and Krumholz), Yale University School of Medicine, and Yale–New Haven Hospital Center for Outcomes Research and Evaluation (Dr Krumholz), New Haven, Conn; and Department of Biostatistics, University of Alabama at Birmingham (Dr Coffey).

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