Higher dementia risk linked to more use of common drugs

January 27, 2015

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A large study links a significantly increased risk for developing dementia, including Alzheimer’s disease, to taking commonly used medications with anticholinergic effects at higher doses or for a longer time.

Many older people take these medications, which include nonprescription diphenhydramine (Benadryl) and related drugs.

JAMA Internal Medicine published the report, called “Cumulative Use of Strong Anticholinergic Medications and Incident Dementia.”

It’s been known for some time that memory or concentration problems in the elderly might be caused by common medications used to treat insomnia, anxiety, itching or allergies, according to a 2012 study reported by KurzweilAI.

The study, however, used more rigorous methods, longer follow-up (more than seven years), and better assessment of medication use via pharmacy records (including substantial nonprescription use) to confirm this previously reported link.

It is the first study to show a dose response: linking more risk for developing dementia to higher use of anticholinergic medications. And it is also the first to suggest that dementia risk linked to anticholinergic medications may persist and may not be reversible — even years after people stop taking these drugs.

The most common anticholinergic classes used by subjects in the study were tricyclic antidepressants, first-generation antihistamines, and bladder antimuscarinics.

Anticholinergic effects happen because some medications block the neurotransmitter called acetylcholine in the brain and body, causing many side effects, including drowsiness, constipation, retaining urine, and dry mouth and eyes, said Shelly Gray, PharmD, MS, the first author of the report, which tracks nearly 3,500 Group Health seniors participating in the long-running Adult Changes in Thought (ACT).

ACT is a joint Group Health–University of Washington (UW) study funded by the National Institute on Aging.

Medications with strong anticholinergic effects

“Older adults should be aware that many medications — including some available without a prescription, such as over-the-counter sleep aids — have strong anticholinergic effects,” she said.  Seniors should “tell their health care providers about all their over-the-counter use,” she added.

“But of course, no one should stop taking any therapy without consulting their health care provider,” said Dr. Gray, who is a professor, the vice chair of curriculum and instruction, and director of the geriatric pharmacy program at the UW School of Pharmacy.

At KurzweilAI’s request,  Cara Tannenbaum, MD, Research Chair at the Institut universitaire de gériatrie de Montréal (IUGM, Montreal Geriatric University Institute) and Associate Professor of Medicine and Pharmacy at the University of Montreal (UdeM), provided the following list of the most dangerous drugs shown to affect memory (generic names) in the 2012 study mentioned above.:

Benzodiazepines and non-benzodiazepine sedative hypnotics:


Tricyclic antidepressants


First-generation antihistamines


“Health care providers should regularly review their older patients’ drug regimens—including over-the-counter medications—to look for chances to use fewer anticholinergic medications at lower doses.”

The most commonly used medications in the study were tricyclic antidepressants like doxepin (Sinequan), first-generation antihistamines like chlorpheniramine (Chlor-Trimeton), and antimuscarinics for bladder control like oxybutynin (Ditropan).

The study estimated that people taking at least 10 mg/day of doxepin, 4 mg/day of chlorpheniramine, or 5 mg/day of oxybutynin for more than three years would be at greater risk for developing dementia.


Gray said substitutes are available for the first two: a selective serotonin re-uptake inhibitor (SSRI) like citalopram (Celexa) or fluoxitene (Prozac) for depression and a second-generation antihistamine like loratadine (Claritin) for allergies. It’s harder to find alternative medications for urinary incontinence, but some behavioral changes can reduce this problem.

“If providers need to prescribe a medication with anticholinergic effects because it is the best therapy for their patient,” Dr. Gray said, “they should use the lowest effective dose, monitor the therapy regularly to ensure it’s working, and stop the therapy if it’s ineffective.”

“With detailed information on thousands of patients for many years, the ACT study is a living laboratory for exploring risk factors for conditions like dementia,” said Dr. Gray’s coauthor Eric B. Larson, MD, MPH. “This latest study is a prime example of that work and has important implications for people taking medications—and for those prescribing medications for older patients.”

Some ACT participants agree to have their brains autopsied after they die. That will make it possible to follow up this research by examining whether participants who took anticholinergic medications have more Alzheimer’s-related pathology in their brains compared to nonusers.

Larson is the ACT principal investigator, vice president for research at Group Health, and executive director of Group Health Research Institute (GHRI). He is also a clinical professor of medicine at the UW School of Medicine and of health services at the UW School of Public Health.

This work was supported by National Institute on Aging NIH grants and by the Branta Foundation.

Abstract of Cumulative Use of Strong Anticholinergics and Incident Dementia

Importance  Many medications have anticholinergic effects. In general, anticholinergic-induced cognitive impairment is considered reversible on discontinuation of anticholinergic therapy. However, a few studies suggest that anticholinergics may be associated with an increased risk for dementia.

Objective  To examine whether cumulative anticholinergic use is associated with a higher risk for incident dementia.

Design, Setting, and Participants  Prospective population-based cohort study using data from the Adult Changes in Thought study in Group Health, an integrated health care delivery system in Seattle, Washington. We included 3434 participants 65 years or older with no dementia at study entry. Initial recruitment occurred from 1994 through 1996 and from 2000 through 2003. Beginning in 2004, continuous replacement for deaths occurred. All participants were followed up every 2 years. Data through September 30, 2012, were included in these analyses.

Exposures  Computerized pharmacy dispensing data were used to ascertain cumulative anticholinergic exposure, which was defined as the total standardized daily doses (TSDDs) dispensed in the past 10 years. The most recent 12 months of use was excluded to avoid use related to prodromal symptoms. Cumulative exposure was updated as participants were followed up over time.

Main Outcomes and Measures  Incident dementia and Alzheimer disease using standard diagnostic criteria. Statistical analysis used Cox proportional hazards regression models adjusted for demographic characteristics, health behaviors, and health status, including comorbidities.

Results  The most common anticholinergic classes used were tricyclic antidepressants, first-generation antihistamines, and bladder antimuscarinics. During a mean follow-up of 7.3 years, 797 participants (23.2%) developed dementia (637 of these [79.9%] developed Alzheimer disease). A 10-year cumulative dose-response relationship was observed for dementia and Alzheimer disease (test for trend, P < .001). For dementia, adjusted hazard ratios for cumulative anticholinergic use compared with nonuse were 0.92 (95% CI, 0.74-1.16) for TSDDs of 1 to 90; 1.19 (95% CI, 0.94-1.51) for TSDDs of 91 to 365; 1.23 (95% CI, 0.94-1.62) for TSDDs of 366 to 1095; and 1.54 (95% CI, 1.21-1.96) for TSDDs greater than 1095. A similar pattern of results was noted for Alzheimer disease. Results were robust in secondary, sensitivity, and post hoc analyses.

Conclusions and Relevance  Higher cumulative anticholinergic use is associated with an increased risk for dementia. Efforts to increase awareness among health care professionals and older adults about this potential medication-related risk are important to minimize anticholinergic use over time.