What is known about the association between beta-blockers and depression.

Fråga: What is known about the association between beta-blockers and depression.

Sammanfattning: The question of depression as a side-effect to beta-blocker treatment has been widely discussed in the literature, both in case-reports and in epidemiological studies, and the results are still contradictory. Interpretation of the data is hampered by a variability in the definition of depression and differences in methods used. Double-blind, placebo-controlled studies are lacking. The strongest evidence in favour of an association is found for propranolol, and it is also possible that other lipophilic beta-blockers may have negative mood-effects in predisposed individuals.

Svar: Among cardiac medications, beta-blockers have probably most frequently been associated with depression as a side-effect (1).

The Swedish adverse drug reaction register contains 63 reports on depression linked to the use of beta-blockers (2). The WHO adverse drug reaction database contains hundreds of similar reports, involving both selective and non-selective beta-blockers (3).

The relation between propranolol and depression has been discussed most actively. This drug was introduced into the market earlier than others, and the first report linking it to depression appeared in 1967 (4). Since that time, at least 8 additional case-reports linking propranolol to depression have been published (2). Other beta-blockers that has been reported to be linked to depression are timolol (3 case-reports), betaxolol (1 case-report), nadolol (2 case-reports) and metoprolol (1 case-report). Some evidence appeared in the early 1980s, suggesting that the incidence and severity of side-effects in the central nervous system may be less pronounced with hydrophilic beta-blockers (eg atenolol), which are less likely to cross the blood-brain barrier, than with lipophilic beta-blockers (eg propranolol) (2). However, it has been noted that the assessment of the case-reports is hampered in part by the variability in the definition of depression and the fact that the diagnostic criteria for depression has changed several times since 1967, when the first report appeared (6).

The case-reports gave rise to a number of epidemiological studies, conducted in late 1980s and early 1990s. Two studies that strongly supported the association between depression and the use of beta-blockers were both based on record linkage of health care databases and used antidepressant prescriptions as proxy markers for the existence of clinically relevant depressive disorders among patients on beta-blockers (7,8). The volume of antidepressant prescriptions in propranolol users (9.5 % was almost 3-fold higher than in users of other lipophilic beta-blockers (3.9 %) or hydrophilic substances (2.5 %). The incidence of antidepressive treatment was equal in users of hydrophilic beta-blockers and a control group, consisting of patients without beta-blocker use (7). The role of propranolol in depression was also confirmed in a reevaluation of two prospective trials (11).

There is also a number of studies not showing an association between beta-blockers and depression. Two retrospective epidemiological studies (10, 11) did not reveal a higher prevalence of beta-blocker treatment in patients with clinically diagnosed depression, compared to non-depressed patients.

We can assume, based on available data, that beta-blockers in general are not likely to be associated with major depression. We cannot conclude anything about minor depression in relation to use of beta-blockers since it is frequently undiagnosed in cardiology and hence not reflected in the medical databases used in the epidemiological studies mentioned above (13).

In the 1990s, more negative results were published, which may be due to the more extensive use of beta-blockers, other than propranolol. Seiner SJ, Mallya G. Treating depression in patients with cardiovascular disease. Harv Rev Psychiatry 1999;7(2):85-93.

Swedis (The Swedish Drug Information System) (2004-03-22)
Vigibase: WHO:s adverse drug reactions database (2004-03-22)
Waal HJ. Propranolol-induced depression. Br Med J 1967;2(543):50.

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