Use of Beta-Blockers and Risk of Dementia in Elderly Patients

To the Editor: Dementia is a syndrome that can be caused by a number of progressive disorders that affect memory, thinking, behavior, and the ability to perform everyday activities. Dementia mainly affects older people, although there is a growing awareness of cases that start before the age of 65. After age 65, the likelihood of developing dementia roughly doubles every 5 years. It is estimated that the number of dementia sufferers worldwide will increase from 35.6 million today to 65.7 million by 2030 and 115.4 million by 2050.¹ Decline in cognitive functioning is a core feature of dementias.

However, other symptoms of the disease are also crucial. These symptoms are the behavioral and psychological manifestations of dementia, including symptoms such as delusions, hallucinations, illusions, anxiety, aggression, depression, personality changes, disinhibition–impulsivity, violation of social and moral norms, changes in dietary or eating behavior, and repetitive behaviors.² It is well documented that beta-adrenoceptor blocking agents in elderly patients frequently cause mild-to-moderate cognitive deficits, with manifestations that look like dementia on psychometric tests. There is some evidence that use of beta-blockers may be a risk factor for the expression of dementia in later life, and cognitive impairment may occur as a prodrome for dementia.³ Moreover, cognitive impairment often complicates the course of dementing disorders. However, there is no evidence that use of beta-blockers causes dementia without coexisting factors. There is increasing controversy regarding the long-term cognitive effects of beta-blockers on elderly people. Rogers and Bowman,⁴ in a three-case report of older patients, demonstrated that subjects using beta-blockers (propranolol or atenolol) had insidious cognitive impairment. In each case, marked improvement occurred on drug withdrawal. Similarly, impaired memory caused by the beta-blocker agent atenelol has been reported in a 54-year-old man, and he made a complete recovery on withdrawal of the beta-blocker.⁵ In another, two-case report, visual hallucinations were reported in a 78-year-old woman and a 57-year-old man after 1 day of beta-blocker use.⁶ Furthermore, acute delirium has been reported in an 89-year-old Caucasian man with acute coronary syndrome, who had no psychiatric history, after two small doses of metoprolol (25 mg). The delirium disappeared within 20 hours after metoprolol was ceased, despite continuing all other medications.⁷

The mechanism of beta-blocker–induced cognitive impairment is unclear. It could be due to impairment of hepatic metabolism (especially in the aging liver) and complex neurotransmitter-related effects on brain beta-adrenoceptors and serotonin (5-HT) receptors.⁷ Moreover, beta-blockers have been shown to reduce the production of melatonin via specific inhibition of adrenergic beta₁-receptors. Result from two placebo-controlled studies of hypertensive patients investigating the relationship between beta-blocker–induced CNS side effects and the nightly urinary secretion of melatonin demonstrated that the CNS side effects during beta-blockade are related to a reduction of melatonin levels.⁸ Short-term beta-blocker therapy does not appear to be associated with long-term cognitive impairment, whereas long-term use could lead to a generalized effect on cognition. In a large, population-based study, over a 3-year follow-up, the rates of conversion to dementia were 46% among those with cognitive impairment at baseline. By comparison, 3.3% without impairment converted to dementia in the interval. Among converters, Alzheimer’s disease (AD) was the most common type of dementia.⁹ These results are largely consistent with those previously reported for mild cognitive impairment.¹⁰ Similarly, a prospective clinical study of community-living elderly volunteers, both without dementia and minimally cognitively impaired, over a 9.5-year follow-up, showed a rate of 60.5% conversion to dementia at 5 years.¹¹ The etiology of cognitive impairment is multifactorial; however, drugs are an important cause of delirium and dementia in elderly hospital patients. Several factors may increase the risk of drug-induced cognition disorders in elderly persons; these include imbalances in neurotransmitters (e.g., acetylcholine), age-related alterations in pharmacokinetics and pharmacodynamics, and high levels of medication use. In some cases, CNS toxicity occurs in a dose-dependent manner, often as a result of interference with neurotransmitter functioning.¹²

However, beta-blockers are widely used to treat hypertension and heart disease, and it is necessary to screen elderly patients on these agents from time to time for possible cerebral side effects. If there is any suspicion of cognitive impairment, then one should withdraw the beta-blocker. Also, the validity and reliability of the confusion assessment method for elderly patients on beta-blockers needs to be re-evaluated. The possible relationship between beta-blocker and reduced production of melatonin suggests the possibility that the night-time dose of beta-blocker could be responsible to the CNS side effects. There is insufficient evidence for this assertion currently, but further studies should investigate the effects of beta-blockers in patients with cognitive impairment or dementia.