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Anticholinergic-Drug Exposure Tied to Increased Dementia Risk

June 25, 2019

By Will Boggs MD

NEW YORK—Exposure to anticholinergic drugs in middle age is associated with an increased risk of dementia, according to a database study.

"It was unexpected that the association with anticholinergic drug use was stronger in people diagnosed with dementia before the age of 80," said Dr. Carol A. C. Coupland of the University of Nottingham, in England.

"We were also interested in our finding that around 10% of dementia diagnoses could be due to anticholinergic drug exposure if the association is causal," she told Reuters Health by email. "This is similar to or higher than estimates for several other risk factors for dementia, such as physical inactivity and smoking."

Anticholinergic drugs, which include some antihistamines, antidepressants, and medications for gastrointestinal and bladder disorders, have short-term adverse effects that include confusion and memory loss in older people. Whether long-term use increases the risk of dementia remains unclear.

Dr. Coupland's team used data from QResearch, a research database of more than 30 million individuals in over 1,500 general practices, to assess the association between cumulative anticholinergic drug use and the risk of dementia up to 20 years later.

In their analysis of more than 58,000 case patients and 225,000 matched controls, the adjusted odds of dementia associated with total cumulative anticholinergic exposure in the one to 11 years before diagnosis increased from 6% higher for one to 90 total standardized daily doses (TSDDs) to 49% higher for more than 1,095 TSDDs, compared with nonuse.

In the highest exposure category (>1095 TSDDs, equivalent to three years' daily use of a single strong anticholinergic medication at the minimum effective dose recommended for older people), there were significant increases in dementia odds associated with antidepressants (29% higher), antiparkinsonian drugs (52% higher), antipsychotics (70% higher), bladder antimuscarinics (65% higher), and antiepileptic drugs (39% higher), compared with nonuse.

If these associations are causal, the population-attributable fractions indicate that around 10% of dementia diagnoses are attributable to anticholinergic drug exposure, the researchers write in JAMA Internal Medicine, online June 24.

The associations for most exposures were stronger among case patients diagnosed before age 80 years, and adjusted odds ratios were generally higher for vascular dementia than for Alzheimer disease.

"This study provides further evidence that doctors should be careful when prescribing certain drugs that have anticholinergic properties," Dr. Coupland said. "The risks should be carefully considered alongside the benefits when the drugs are prescribed, and alternative treatments should be considered where possible, such as other types of antidepressants or alternative treatments for bladder conditions."

"These findings also highlight the importance of carrying out regular medication reviews, so that patients don't take these drugs for longer than necessary," she said.

Dr. Coupland added, "This is an observational study, so no firm conclusions can be drawn about whether these anticholinergic drugs actually cause dementia. Also it's important to emphasize that patients taking these types of medications shouldn't stop them abruptly, as this could be harmful. If they have concerns, then they should discuss them with their doctor."

Dr. Noll L. Campbell of Purdue University College of Pharmacy, in West Lafayette, Indiana, who co-authored an invited commentary, told Reuters Health by email, "Findings that the relationship between anticholinergics and dementia remain when including exposure up to 20 years prior to the diagnosis of dementia are of particular interest. This implies that each dose contributes to the risk, and if a causal relationship is eventually confirmed, requires interventions far earlier in life to prevent the anticholinergic-attributable risk of dementia."

"Based on the data available, prescribers and pharmacists should focus on preventing exposure to anticholinergics when alternative treatments are available," he said. "However, interventions targeting both prescribers and patients may be necessary to accomplish a reduction in anticholinergic use. Deprescribing trials that are currently under way will inform us whether stopping anticholinergics among current users will result in expected improvements in brain health, and what, if any safety risks should be monitored as a result of deprescribing."

"Clinicians should be cautious about deprescribing many of the anticholinergics too quickly, since adverse withdrawal reactions can occur and can reduce the success of future deprescribing trials," Dr. Campbell said. "To avoid withdrawal reactions, slow titrations either off or to an alternative should be conducted over weeks and sometimes months."

Dr. Rajender R. Aparasu of the University of Houston College of Pharmacy, who studies the risks associated with anticholinergics, told Reuters Health by email, "Most of the previous research focused on short-term effects of anticholinergics; this study found that long-term anticholinergic use is associated with dementia risk in older adults."

"These findings are particularly important for those who are at risk for dementia, such as those with family history, genetics, and specific comorbidities such as diabetes and depression," he said.


JAMA Intern Med 2019.

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