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

The use of β-blockers after myocardial infarction (MI) reduces mortality by approximately 20%.¹ Long-term β-blocker therapy has also emerged as a valuable treatment in heart failure (HF), resulting in lower mortality and morbidity.² Despite the importance of these agents, they are underused in appropriate patients.³ The reluctance of physicians to prescribe these agents may derive, in part, from concerns about the development of common symptoms, including depression, fatigue, and sexual dysfunction. Although these conditions have been considered to be strongly associated with β-blockers,^4- 7 the evidence supporting these associations is limited.^8- 10

To investigate the association of β-blocker therapy with depressive symptoms, fatigue, and sexual dysfunction, we performed a quantitative review of randomized trials. In addition, we categorized the β-blockers by generation and lipid solubility to determine whether the risks of adverse effects differed by these factors.

Randomized trials of β-blockers used in the treatment of MI, HF, or hypertension were identified by searching the MEDLINE database (January 1966-December 2001, through OVID MEDLINE) using the keywords myocardial infarction, heart failure, or hypertension in combination with adrenergic β- antagonists and trial. In addition, we searched the reference lists of previously published trials and overviews of β-blockers for additional studies. The initial search produced 475 English-language articles. Criteria for inclusion of trials in this 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. This procedure identified 42 trials; of these, 15 reported information on depressive symptoms, fatigue, or sexual dysfunction and were selected for the review.^11- 30

Most of the information on the adverse effects was abstracted from published reports. We also checked the US Food and Drug Administration (FDA) Web site (http://www.fda.gov) for reports of adverse effects in trials of β-blockers. In one instance, we contacted the principal investigator of a trial for information, because it was clear that sexual dysfunction had been assessed but detailed information was not provided.²⁵

For each trial, one author (D.T.K.) abstracted the frequency of adverse events in the β-blocker and placebo groups and the numbers of patients randomized to the treatment groups. Two other authors (J.P.C., A.S.) 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 β-blockers by generation (early vs late) and lipid solubility (high vs low to moderate). Among the β-blockers included in the review, propranolol hydrochloride and timolol maleate are considered as early (first) generation and the remainder as late (second and third) generation.² Bucindolol hydrochloride, carvedilol, and propranolol are classified as highly lipid soluble and the rest as low-to-moderately lipid soluble.^2,4

Most of the trials that assessed symptoms of depression, fatigue, or sexual dysfunction did not report the assessment methods. For depressive symptoms, one trial²⁶ used standardized depression instruments, and one trial²⁰ used the question, "Have you ever felt depressed?" For fatigue, we abstracted the trials that used similar terms to describe the symptom, such as tiredness, lethargy, and asthenia. For sexual dysfunction, one trial²³ used the question, "Have you had a problem with sexual activity?" If the participant answered "yes," more questions relating to erection and orgasm were asked. Another trial²⁶ used 5 different questions to assess sexual dysfunction. We consistently abstracted the more general measures of sexual dysfunction, such as loss of sexual desire as opposed to failure of erection.¹⁵ In addition, we examined impotence as a specific measure of sexual dysfunction in men, including all trials^{15,17- 18,24,26,30} that assessed impotence-related events, such as failure of erection, problems maintaining or obtaining erection, and erectile dysfunction. Although the methods of ascertainment among the trials were not standardized, within each trial they were applied equally to the 2 treatment groups.

We combined information from the trials using the general variance–based method,³¹ which incorporates a fixed-effects model and assumes all the variability is due to random error. However, the assumption of homogeneity was rejected when tested using the χ² statistic, implying the presence of significant variation between studies. To estimate and control for this heterogeneity, we applied a random-effects model to estimate the variance component associated with between-study variation.³² Using this method, the variance for each individual study in the review is the sum of within- and between-study components of the variance. The use of the random-effects method has 2 major implications: (1) the meta-estimate of the relative risk (RR) now represents the mean of observed effect sizes rather than the true effect size in the population, and (2) this method will generally lead to wider confidence intervals (CIs) due to the additional source of variation being considered in the presence of heterogeneity (ie, the random-effects model is generally more conservative).

The combined RR estimate was obtained by computing a weighted average of the individual log RR estimates. The weights correspond to the inverse of the total variance (within and between) for each study. Approximate 95% CIs were formed based on the asymptotic normality of the combined estimates. Final CIs for the RRs were obtained by calculating the exponential of the upper and lower confidence limits for the log RRs. Since CIs from fixed-effects and random-effects models will essentially be equal when there is no heterogeneity (because the additional source of variation is essentially nil), we report results from the random-effects model only throughout this article. In addition to RR estimates, we calculated absolute risks of adverse effects associated with therapy. To account for the wide variation in the duration of follow-up in our trials (6 to 59 months), we calculated pooled incidence risk differences and numbers needed to treat per year to estimate the absolute risks of β-blocker therapy on adverse effects.^1,33

The analyses of the risk estimates were repeated, excluding 3 trials^12,15,30 that tested β-blockers not currently approved for treatment of MI, HF, or hypertension by the FDA. To examine the risks associated with β-blockers of different generations and lipid solubility, we combined the information after stratifying by generation (early vs late) and lipid solubility (high vs low to medium). The combined estimates in each of the strata were compared based on the asymptotic normality of the estimates.³⁴

A total of 15 trials were included in the review, involving more than 35 000 patients, with follow-up periods ranging from 6 to 59 months (Table 1). β-Blockers were evaluated as therapy for MI in 6 trials,^11- 16 HF in 3 trials,^27- 30 and hypertension in 6 trials.^17- 26 Three trials tested the β-blockers oxprenolol hydrochloride,¹² sotalol hydrochloride,¹⁵ and bucindolol,³⁰ which are currently not approved by the FDA for treatment of MI, HF, or hypertension.

Depressive symptoms reported by patients were assessed in 7 trials that included 10 662 patients (Table 2). The overall frequency of depressive symptoms was similar in the β-blocker (20.1%) and the placebo (20.5%) groups. β-Blocker therapy was not associated with a significantly increased RR (RR, 1.12; 95% CI, 0.89-1.41) or absolute risk of reported depressive symptoms (6 per 1000 patients per year; 95% CI, − 7 to 19). The exclusion of trials^15,30 that tested β-blockers not currently FDA approved did not substantially change the risk estimate of reported depressive symptoms associated with therapy (RR, 1.13; 95% CI, 0.95-1.35).

Withdrawal of medication due to symptoms of depression was assessed in 4 trials that included 5803 patients. Only 13 patients (0.4%) were withdrawn from the β-blocker groups and 13 patients (0.5%) from the placebo groups. β-Blocker therapy was not associated with a significantly increased RR (RR, 0.94; 95% CI, 0.44-2.01) or absolute risk of withdrawal (0 per 1000 patients per year; 95% CI, –2 to 2).

Fatigue reported by patients was assessed in 10 trials that included 17 682 patients (Table 3). The frequency of fatigue reported by patients was substantial in both the β-blocker (33.4%) and placebo (30.4%) groups, and β-blockers were associated with a significantly increased RR (RR, 1.15; 95% CI, 1.05-1.26) compared with placebo. The annual increase in risk was also significantly elevated (18 per 1000 patients; 95% CI, 5-30), equivalent to one additional report of fatigue for every 57 patients treated with β-blockers for a year. The exclusion of the trials^15,30 testing non–FDA-approved drugs resulted in an increased risk of reported fatigue (RR, 1.25; 95% CI, 1.07-1.47).

Ten trials that enrolled 29 454 patients reported withdrawal of medication due to fatigue (Table 3). During follow-up, 291 patients (2.4%) were withdrawn from the β-blocker groups and 78 (0.5%) from the placebo groups. β-Blockers were associated with a significantly increased risk of withdrawal due to fatigue (RR, 2.63; 95% CI, 1.16-5.94). The annual increase in withdrawal due to fatigue was 4 per 1000 patients (95% CI, 1-8), equal to 1 withdrawal due to fatigue for every 225 patients treated for a year. The exclusion of 1 trial¹² that tested a non–FDA-approved β-blocker produced similar results for risk of withdrawal due to fatigue attributed to β-blockers (RR, 2.99; 95% CI, 1.29-6.95).

Reported sexual dysfunction was assessed in 6 studies that included 14 897 patients, and the specific measures of sexual dysfunction used in the review are shown in Table 4. When these measures were considered together, the frequency of sexual dysfunction was 21.6% in the β-blocker group and 17.4% in the placebo group. β-Blockers were associated with increased risk of reported sexual dysfunction of borderline statistical significance (RR, 1.10; 95% CI, 0.96-1.25) but a significant annual increase of 5 reports of sexual dysfunction per 1000 patients (95% CI, 2-8), equivalent to one additional report for every 199 patients treated for a year. In addition, β-blockers were associated with significantly increased risk of reported impotence in men (RR, 1.22; 95% CI, 1.05-1.41); however, the absolute risk did not attain statistical significance (3 per 1000 patients per year; 95% CI, –3 to 10). The risk estimates for reported sexual dysfunction were similar when alternative measures from the trial performed by Perez-Stable et al²⁵ were used (Table 4 footnote) and when non–FDA-approved β-blockers were excluded (RR, 1.10; 95% CI, 0.91-1.33).

Sexual dysfunction resulting in withdrawal of study medication was evaluated in 4 trials that included 11 260 patients. In those trials, 57 patients (1.3%) were withdrawn from the β-blocker groups and 20 patients (0.3%) from the placebo groups. The risk of withdrawal of medication due to sexual dysfunction was substantially increased (RR, 4.89; 95% CI, 2.98-8.03). However, the annual absolute increase in risk of withdrawal was only 2 per 1000 patients (95% CI, 0-5), equivalent to 1 withdrawal due to sexual dysfunction for every 438 patients treated for a year.

The risk associated with reported fatigue associated with early-generation β-blocker use (RR, 1.78; 95% CI, 1.08-2.93) was significantly higher than for late-generation β-blocker use (RR, 1.06; 95% CI, 1.00-1.12, P = .04). For reported symptoms of depression and sexual dysfunction, there were no significant differences in the risk estimates between early- and late-generation β-blockers.

None of the risks of the adverse effects examined differed significantly when the β-blockers were categorized by different degrees of lipid solubility. However, for depressive symptoms, there was a nonsignificant trend toward a higher risk in β-blockers with low to moderate lipid solubility (RR, 1.41; 95% CI, 0.91-2.20) compared with β-blockers with high lipid solubility (RR, 0.99; 95% CI, 0.74-1.33, P = .19).

Our quantitative systematic review that combines all available data from randomized trials places the risks of depressive symptoms, fatigue, and sexual dysfunction associated with β-blocker therapy into perspective. We found no significantly increased risk of depressive symptoms associated with β-blocker therapy, although small risks remain plausible. For reported fatigue, sexual dysfunction, and impotence, we found small increases in risks associated with β-blockers. The risks of these reported adverse effects remain modest even at the upper boundaries of the confidence limits. Furthermore, although the RRs were larger for withdrawal due to fatigue and sexual dysfunction, patients rarely required discontinuation of therapy and the absolute risks of withdrawal were small. Depression, fatigue, and sexual dysfunction are adverse effects of β-blockers that have been acknowledged by many authorities^4- 5,7 and are cited in FDA-approved package inserts of β-blockers.³⁵ Concerns about these symptoms may have contributed to the relatively slow adoption of therapy.³⁶ Our findings should alleviate concerns that long-term treatment with β-blockers causes substantial increases in these symptoms that may compromise quality of life, and should encourage the implementation of this life-saving therapy.

The contention that β-blockers cause depression originated when Waal⁸ reported 21 cases of depression among 43 patients treated with propranolol for more than 3 months. Experts have suggested that the inhibitory actions of β-blockers on the β-receptors and serotonin receptors in the central nervous system may play a role in depression.^4,37 However, clinical investigations that examined this association have yielded divergent results,^38- 40 and these studies are limited by many factors, including small sample size, nonrandomized data, confounders, and lack of control groups.

Our results do not support an association between β-blockers and depressive symptoms. We did not find significantly increased risks of depressive symptoms reported by patients or withdrawal associated with therapy. Although increased risks of depressive symptoms associated with β-blocker therapy cannot be definitely excluded, the annual absolute increases in risks at the upper boundaries of the CIs (19 per 1000 patients for reported symptoms and 2 per 1000 patients for withdrawals) were small. Our results, indicating no significant association between β-blockers and depressive symptoms, are consistent with an observational study⁴¹ that controlled for potential confounders and a recent review⁴² that examined all the previous studies qualitatively.

Fatigue has been linked to β-blockers in case series that reported substantial incidence, although such studies are limited by the lack of control groups,^10,43 and some early individual randomized controlled trials have also supported this association.^11,14 Experts have suggested that the development of fatigue with β-blockers may be the result of their central nervous system effects and possibly the decreased cardiac output associated with therapy.⁷ Our results were consistent with earlier reports that β-blockers were associated with increased risk of reported fatigue, but we were also able to quantify that the risks were small (18 additional reports of fatigue per 1000 patients treated for 1 year).

The association of β-blockers with sexual dysfunction was also initially based on case series,^9,44 although further conclusive evidence has been lacking.⁴⁵ Postulated mechanisms for sexual dysfunction include peripheral vasodilation and potentiation of α-adrenergic activity in the penis, resulting in decreased penile blood flow and erectile dysfunction.^5,45 Decreased libido due to central nervous system effects may also play a role; however, none of these proposed mechanisms have been clearly established.

In our review, the largest relative increases in risks associated with β-blockers were the withdrawals due to fatigue and sexual dysfunction. Therapy was associated with a 3-fold increased risk of withdrawal due to fatigue and a 5-fold increased risk of withdrawal due to sexual dysfunction. Nonetheless, the associated absolute risks were small (4 withdrawals due to fatigue and 2 withdrawals due to sexual dysfunction per 1000 per year). The large RRs and small absolute increases in risks of withdrawal are due to the low withdrawal rates from the trials for these symptoms. Our results that show minimal increases in risks of withdrawal are consistent with a review of patients with MI treated with β-blockers that demonstrated an increase in withdrawal from all causes of only 16 per 1000 patients per year (95% CI, 6-18).¹

Experts have hypothesized that β-blockers with low lipid solubility, because of less penetration across the blood-brain barrier, will result in lower frequencies of central nervous system adverse effects such as fatigue and depression.^4,46 However, there was a trend toward a higher risk of depressive symptoms in low to moderatly lipid-soluble β-blockers, and we did not find any significant differences in the risks of fatigue or sexual dysfunction examined according to lipid solubility. In trials testing early-generation (propranolol, timolol) β-blockers, the risks of fatigue, but not depressive symptoms or sexual dysfunction, were higher compared with later-generation β-blockers. Because of the limited number of trials, these risk estimates have relatively wide CIs. Furthermore, we had insufficient data to compare the adverse effects of individual preparations or dosages of β-blockers.

Several issues in this study merit consideration. The rates of depressive symptoms, fatigue, and sexual dysfunction in the reviewed trials were substantial, but we were unable to calculate the true incidence because these symptoms were not assessed at the inception of all the trials. In addition, because a random-effects model was used to account for the heterogeneity in the association of β-blockers with adverse events among the trials, our results likely reflect more conservative risk estimates. However, we performed additional subgroup analyses to eliminate the heterogeneity, which did not substantially change the overall results. Finally, the trials enrolled relatively few elderly patients, and thus the generalizability of these findings, like the trials themselves, may be limited to the groups directly studied.

We found that the conventional wisdom that β-blockers are associated with considerable risks of developing symptoms of depression, fatigue, and sexual dysfunction is not substantiated by randomized trial data. We found no significant increased risk of depressive symptoms and only small increased risks of fatigue and sexual dysfunction associated with β-blocker therapy. We also found that these symptoms were common among patients taking placebo. Therefore, given the survival benefit associated with β-blocker therapy, concerns about the development of these adverse effects should not deter physicians from initiating long-term treatment when indicated, although surveillance for adverse effects remains prudent.