Dose-dependent risk of dementia with anticholinergics: study

Last Updated: 2015-01-26

By Megan Brooks

NEW YORK (Reuters Health) - Anticholinergic drugs raise the risk of dementia in older adults in a dose-dependent manner, and the adverse cognitive effects may be permanent, researchers say.

Using pharmacy data, the researchers were able to examine dose and use over a long period of time, said first author Dr. Shelly Gray, from the School of Pharmacy, University of Washington in Seattle, in email to Reuters Health.

The research team assessed cumulative use of strong anticholinertic medications and incident dementia in 3434 adults aged 65 and older and free of dementia when they enrolled in the longitudinal Adult Changes in Thought (ACT) study, a joint Group Health-University of Washington study funded by the National Institute on Aging.

Overall, 78.3% of participants filled at least one prescription for an anticholinergic in the 10 years before entering the study. The most commonly used anticholinergic classes were tricyclic antidepressants, first-generation antihistamines and bladder antimuscarinics, which together accounted for more than 90% of all anticholinergic exposure. The most common individual agents from these three classes were doxepin, chlorpheniramine and oxybutynin.

Over an average of 7.3 years, 797 people (23.2%) developed dementia, of whom 637 (79.9%) were thought to have Alzheimer's disease.

A clear dose-response relationship was evident for dementia and Alzheimer disease (test for trend p< 0.001), the researchers reported online January 26 in JAMA Internal Medicine.

Adults with the highest exposure (total standardized daily dose, TSDD >1095) had a statistically significant increased risk for dementia (adjusted HR 1.54) or AD (adjusted HR, 1.63) compared with those with no use.

Adults with the next highest exposure level (TSDD, 366-1095) had a slightly elevated risk for dementia (adjusted HR 1.23) and AD (adjusted HR 1.30) compared with no use.

"Our findings suggest that a person taking an anticholinergic, such as oxybutynin chloride, 5 mg/d, or doxepin hydrochloride, 10mg/d, for more than three years would have a greater risk for dementia," the investigators say.

The risk for dementia was similar when comparing adults with recent and past heavy use with nonusers, suggesting that the risk for dementia with anticholinergic use may persist despite discontinuation of therapy, they note.

"Our findings were robust in secondary and sensitivity analyses, including those performed to take into account the potential use of anticholinergics (e.g., antidepressants) for prodromal symptoms of dementia," they add.

The findings support two other cohort studies that have looked at anticholinergic use and the development of dementia. In a population-based study of French adults aged 65 and older, long-term anticholinergic drug use yielded an adjusted HR for dementia and Alzheimer's disease of 1.65 and 1.94, respectively, over four years of follow up. A study from Germany of adults aged 75 or older found that any anticholinergic drug use over 4.5 years was associated with a greater than twofold increased risk of dementia compared with no use (adjusted HR 2.08).

In email to Reuters Health, Dr. Eric Larson, executive director of the Group Health Research Institute, who worked on the study, noted that the original French study "showing that the risk of a permanent progressive brain disease like Alzheimer's was associated with these drugs was extremely surprising as the anticholinergic drugs were felt to only have effects that were time limited - no structural brain changes were felt to be a consequence. Because of the surprising nature of the findings, there was a lot of skepticism, especially since drugs with these features are very commonly used. The study published in JAMA Internal Medicine confirms the results and in a much more rigorous design and in a second population. The findings confirming the earlier study make this a much more convincing and concerning finding."

"Older adults should be aware that many medications, including some available over-the-counter such as sleep aids, have strong anticholinergic effects," Dr. Gray told Reuters Health. "For most conditions there are alternatives to anticholinergics. Trying nondrug therapy for insomnia and urinary incontinence is prudent."

"However, if nondrug therapy is not effective for urinary incontinence and anticholinergic therapy is warranted, healthcare providers should use the lowest effective dose, monitor the therapy regularly to ensure it's working, and stop the therapy if it's ineffective," Dr. Gray said.

"Many doctors are already reluctant to prescribe medications with these side effects but there is certainly demand both from patients and other caregivers. Our findings reinforce the value of seeking other adaptive or medication strategies," Dr. Larson added.

The coauthors of an invited commentary note that the American Geriatrics Society has recognized anticholinergics, benzodiazepines, and histamine H2 receptor antagonists as potentially inappropriate for older adults owing to their adverse cognitive effects. Yet more than three quarters of the current cohort had been dispensed at least one strong anticholinergic in the 10-year study period.

"It makes clinical sense to minimize exposure to these medications among older adults," write Dr. Noll Campbell and Malaz Boustani of Indiana University in Indianapolis.

They applaud the researchers for "the novel approach of describing the cumulative risk for dementia among users of medications with adverse cognitive effects," and say "translation of these findings into clinical interventions is an important next step with the potential for a meaningful effect on the quality of care of older adults and the global burden of dementia. Results from observational studies heighten the need to develop interventions to identify and attenuate potentially reversible risk factors for dementia among older adults."

The study was supported by the National Institute on Aging and the Branta Foundation.

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JAMA Intern Med 2015.