β-Blockers and the Risk of New-Onset Depression: Meta-analysis Reassures, but the Jury Is Still Out.

-Blockers (BBs) are prescribed to a wide range of patients with cardiovascular and neuropsychiatric disorders. For more than half a century, BB treatment has been associated with depression as an adverse effect. The evidence in support of this association includes case reports, observational studies, and randomized controlled trials (RCTs). However, a large number of studies that refute the association have also been published. A very large meta-analysis of the psychiatric adverse effects of BBs, as reported in RCTs, was recently published. This meta-analysis found that BBs were not associated with an increased risk of depression or of withdrawal due to depression in comparison with either placebo or active controls. However, BBs were associated with an increased risk of fatigue/tiredness in comparison with placebo as well as in comparison with some groups of active controls. BBs were additionally associated with an increased risk of unusual dreams, relative to placebo. These findings suggest that fatigue/tiredness and unusual dreams may be misinterpreted by patients and clinicians as depression, explaining why BBs have been associated with depression risk. Furthermore, because BBs are commonly prescribed to patients with ischemic heart disease (IHD), and because IHD patients are at increased risk of depression, confounding by indication may explain why some patients treated with BBs later develop depression. These considerations notwithstanding, there are many reasons why the findings of the meta-analysis cannot be taken as reassurance on the subject. As examples, the RCTs in the meta-analysis mostly ascertained depression as a symptom rather than as a clinical diagnosis; and the meta-analysis did not consider risks with specific BBs such as propranolol, which has been strongly associated with the risk of depression in previous studies. In short, the final word, perhaps, remains to be said.