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

Chittaranjan Andrade, MD

J Clin Psychiatry 2021;82(3):21f14095

ABSTRACT

β-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.

Continue Reading...

Did you know members enjoy unlimited free PDF downloads as part of their subscription? Subscribe today for instant access to this article and our entire library in your preferred format. Alternatively, you can purchase the PDF of this article individually.

Subscribe Now

Already a member? Login

Download Free PDF

References (28)

Westfall TC, Macarthur H, Westfall DP. Adrenergic agonists and antagonists. In: Brunton LL, Hilal-Dandan R, Knollmann BC, eds. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 13th ed. New York, NY: McGraw Hill; 2018:191–223.
DiNicolantonio JJ, Fares H, Niazi AK, et al. β-Blockers in hypertension, diabetes, heart failure and acute myocardial infarction: a review of the literature. Open Heart. 2015;2(1):e000230. PubMed CrossRef
Dézsi CA, Szentes V. The real role of β-blockers in daily cardiovascular therapy. Am J Cardiovasc Drugs. 2017;17(5):361–373. PubMed CrossRef
Steenen SA, van Wijk AJ, van der Heijden GJMG, et al. Propranolol for the treatment of anxiety disorders: systematic review and meta-analysis. J Psychopharmacol. 2016;30(2):128–139. PubMed CrossRef
Wells BG, Cold JA, Marken PA, et al. A placebo-controlled trial of nadolol in the treatment of neuroleptic-induced akathisia. J Clin Psychiatry. 1991;52(6):255–260. PubMed
Lima AR, Bacalcthuk J, Barnes TR, et al. Central action beta-blockers versus placebo for neuroleptic-induced acute akathisia. Cochrane Database Syst Rev. 2004;(4):CD001946. PubMed
Davidson JRT. Pharmacotherapy of social anxiety disorder: what does the evidence tell us? J Clin Psychiatry. 2006;67(suppl 12):20–26. PubMed
Shanker V. Essential tremor: diagnosis and management. BMJ. 2019;366:l4485. PubMed CrossRef
Silberstein SD, Holland S, Freitag F, et al; Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012;78(17):1337–1345. PubMed CrossRef
Gelenberg AJ, Jefferson JW. Lithium tremor. J Clin Psychiatry. 1995;56(7):283–287. PubMed
Kunik ME, Yudofsky SC, Silver JM, et al. Pharmacologic approach to management of agitation associated with dementia. J Clin Psychiatry. 1994;55(suppl):13–17. PubMed
Allan ER, Alpert M, Sison CE, et al. Adjunctive nadolol in the treatment of acutely aggressive schizophrenic patients. J Clin Psychiatry. 1996;57(10):455–459. PubMed CrossRef
Goedhard LE, Stolker JJ, Heerdink ER, et al. Pharmacotherapy for the treatment of aggressive behavior in general adult psychiatry: a systematic review. J Clin Psychiatry. 2006;67(7):1013–1024. PubMed CrossRef
Portella MJ, de Diego-Adeliño J, Ballesteros J, et al. Can we really accelerate and enhance the selective serotonin reuptake inhibitor antidepressant effect? a randomized clinical trial and a meta-analysis of pindolol in nonresistant depression. J Clin Psychiatry. 2011;72(7):962–969. PubMed CrossRef
Waal HJ. Propranolol-induced depression. BMJ. 1967;2(5543):50. PubMed CrossRef
Luijendijk HJ, Koolman X. The incentive to publish negative studies: how beta-blockers and depression got stuck in the publication cycle. J Clin Epidemiol. 2012;65(5):488–492. PubMed CrossRef
Kessing LV, Rytgaard HC, Ekstrøm CT, et al. Antihypertensive drugs and risk of depression: a nationwide population-based study. Hypertension. 2020;76(4):1263–1279. PubMed CrossRef
Sørensen HT, Mellemkjaer L, Olsen JH. Risk of suicide in users of beta-adrenoceptor blockers, calcium channel blockers and angiotensin converting enzyme inhibitors. Br J Clin Pharmacol. 2001;52(3):313–318. PubMed CrossRef
Callréus T, Agerskov Andersen U, Hallas J, et al. Cardiovascular drugs and the risk of suicide: a nested case-control study. Eur J Clin Pharmacol. 2007;63(6):591–596. PubMed CrossRef
Ko DT, Hebert PR, Coffey CS, et al. Beta-blocker therapy and symptoms of depression, fatigue, and sexual dysfunction. JAMA. 2002;288(3):351–357. PubMed CrossRef
Riemer TG, Villagomez Fuentes LE, Algharably EAE, et al. Do beta-blockers cause depression? systematic review and meta-analysis of psychiatric adverse events during beta-blocker therapy. Hypertension. 2021;77(5):1539–1548. PubMed CrossRef
Glassman AH, Shapiro PA. Depression and the course of coronary artery disease. Am J Psychiatry. 1998;155(1):4–11. PubMed CrossRef
Ziegelstein RC. Depression in patients recovering from a myocardial infarction. JAMA. 2001;286(13):1621–1627. PubMed CrossRef
Patten SB. Propranolol and depression: evidence from the antihypertensive trials. Can J Psychiatry. 1990;35(3):257–259. PubMed CrossRef
Steffensmeier JJ, Ernst ME, Kelly M, et al. Do randomized controlled trials always trump case reports? a second look at propranolol and depression. Pharmacotherapy. 2006;26(2):162–167. PubMed CrossRef
Lipworth B, Wedzicha J, Devereux G, et al. Beta-blockers in COPD: time for reappraisal. Eur Respir J. 2016;48(3):880–888. PubMed CrossRef
Morales DR, Lipworth BJ, Donnan PT, et al. Respiratory effect of beta-blockers in people with asthma and cardiovascular disease: population-based nested case control study. BMC Med. 2017;15(1):18. PubMed CrossRef
Gulea C, Zakeri R, Alderman V, et al. Beta-blocker therapy in patients with COPD: a systematic literature review and meta-analysis with multiple treatment comparison. Respir Res. 2021;22(1):64. PubMed CrossRef