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Medically Clear: The Anticholinergic Connection to Dementia

Ballard, Dustin MD

doi: 10.1097/01.EEM.0000465948.25980.6e
Medically Clear

Dr. Ballardis an emergency physician at San Rafael Kaiser and the medical director for Marin County Emergency Medical Services.

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If you have patients over age 65 who are concerned about developing dementia, this is a column you might want to read. And not forget.

Here's why. A new study has revealed a possible connection between a commonly used class of medications and the early onset of dementia.

The drugs in question are anticholinergics, which, as we recall from our first year in medical school, block the action of acetylcholine. Acetylcholine is, of course, a key player in the autonomic nervous system, and is involved in mediating learning and memory in the brain.

Anticholinergics have a wide range of indications in clinical practice, including depression, vertigo, bladder spasm, benign prostatic hypertrophy, and seasonal allergies. (Let's recall that Benadryl is an anticholinergic!) Suffice it to say, many people take anticholinergics, and some depend on them. Indeed, data show that between eight percent and 37 percent of older adults use at least one of these medications.

That may soon change.

A study by Gray et al., “Cumulative Use of Strong Anticholinergics and Incident Dementia: A Prospective Cohort Study,” suggested that long-term use of anticholinergics in people over age 65 may harm cognitive function. (JAMA Intern Med 2015;175[3]:401.) This makes sense from an external validity standpoint. We know the elderly are more sensitive to medications for a number of reasons, including those related to muscle mass and renal function, and the blood-brain barrier becomes leakier as it ages. Previous work has also suggested a possible link between leaks in the blood-brain barrier and developing dementia. So, what about this particular study?

The authors followed nearly 3,500 dementia-free patients over age 65 longitudinally, assessing for new diagnoses of dementia and Alzheimer's disease. They matched these subjects to detailed pharmacy records within the Group Health system, an integrated delivery system in the northwest United States, to determine all the prescription and over-the-counter medications that study participants took before (up to 10 years prior) and during the study period. The most commonly prescribed anticholinergics were tricyclic antidepressants, antihistamines (such as those used to treat allergies), and bladder antimuscarinics.

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Twenty-three percent of study participants were given a dementia diagnosis using standard diagnostic criteria over a mean study period of 7.3 years, and those with the highest level of anticholinergic exposure in cumulative dosing were 1.5 times more likely to develop dementia than those who had had no exposure to anticholinergics. The data also indicated that the risk for dementia from anticholinergic therapy persisted even after patients stopped taking the medications. Subjects with lower levels of anticholinergic use did not have hazard ratios consistent with significantly increased risk.

You may be wondering what type of dosing was classified as the highest exposure. That category, at least in this study, would have included individuals who took any of the following medications daily for more than three years: 5 mg oxybutynin chloride (Ditropan), 4 mg chlorpheniramine maleate (Chlor-Trimeton), 2.5 mg olanzapine (Zyprexa), 25 mg meclizine hydrochloride (Dramamine), and 10 mg doxepin hydrochloride (Sinequan).

Before we brush anticholinergics off the pharmacy shelf, however, we should consider that this study was a prospective observational study relying on electronic pharmacy data to define the predictive variable. We know that dementia can be a tricky diagnosis in its early stages; conditions such as depression may be caused by early dementia symptoms. The authors of this study attempt to relieve the concern about this protopathic bias in several ways, including by excluding all anticholinergics prescribed in the 12 months prior to dementia diagnosis from analysis and running two separate sensitivity analyses that churned up similar results.

Nonetheless, we should approach these results with caution, especially considering that prior work in Europe found that the deleterious cognitive effects of anticholinergics might be reversible with cessation of the drug. (Arch Intern Med 2009;169[14]:1317.) This topic is ripe for a randomized trial, but we shouldn't hold our breath.

In the meantime, what are physicians and elderly patients to do? Gray et al. suggest that prescribers “should be aware of this potential association when considering anticholinergics for their older patients and should consider alternatives when possible. For conditions with no therapeutic alternatives, prescribers should use the lowest effective dose and discontinue therapy if ineffective.”

Going forward, it seems reasonable that physicians discuss this topic with their at-risk patients and weigh factors such as age (age 65 or not), how long the anticholinergic therapy may be expected to last, and whether other treatment options could manage the patient's condition with fewer risks.

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