ARTICLE IN BRIEF
In a new study, researchers reported that that long-term use of anticholinergic drugs, including allergy and sleep aids, older antidepressants, and bladder medications, could increase the risk of incident dementia.
Doctors have long known that anticholinergic drugs like non-prescription diphenhydramine (Benadryl, Nytol) can have immediate cognitive side effects — particularly drowsiness and memory loss. But a new study found that long-term use of these drugs, including allergy and sleep aids, older antidepressants, and bladder medications, could increase the risk of incident dementia.
The study, published in the Jan. 26 online edition of JAMA Internal Medicine, looked at 3,434 participants, all of whom had no signs of dementia at the study's start. Researchers followed up by administering neuropsychological tests to participants every two years.
The researchers found that 78 percent of these participants had been prescribed anticholinergics at least once over 10 years.
The most commonly prescribed anticholinergics were tricyclic antidepressants, first-generation antihistamines, and bladder antimuscarinics. People taking at least 10 mg per day of doxepin, 4 mg per day of chlorpheniramine, or 5 mg per day of oxybutynin for more than three years were among those at the highest risk of developing dementia, the researchers reported.
During a mean follow-up of 7.3 years, 797 participants (23.2 percent) developed dementia; 67 percent of them, or 79.9 percent, developed Alzheimer's disease.
A 10-year cumulative dose-response reltionship was observed for dementia and Alzheimer's disease (p<0.001).
Using pharmacological claims data, researchers were able to specifically analyze anticholinergic use as prescribed, and not base their analysis on interview information. They were also able to capture some over-the-counter use information because group health pharmacies entered that information as well as prescriptions.
When they tracked use of anticholinergics, they found that those who used these drugs were more likely to develop dementia compared with those who weren't taking these drugs. In the group that was anticholinergic drugs over 10 years, there were 136 dementia cases for 5618 person-years of follow-up. For the highest group, there were 184 cases of dementia in 4022 person years of follow-up.
“We know these drugs cause acute changes in cognition. You wake up a little groggy if you've taken a drug like Benadryl, for example,” said lead study author Shelly L. Gray, PharmD, a professor, vice chair of curriculum and instruction, and director of the geriatric pharmacy program at the University of Washington School of Pharmacy in Seattle. “What was a bit surprising was the link to increased risk for dementia.”
For those taking the highest doses of anticholinergic drugs over the study period, the relative risk of dementia was increased by a statistically significant 54 percent compared with no use. The risk of Alzheimer's alone was raised by 63 percent, Dr. Gray said.
“Most other studies would simply ask participants to bring their pill bottles and count the pills to get a sense of the exposure,” said David S. Knopman, MD, FAAN, a professor of neurology at the Mayo Clinic in Rochester, MN. “This gives a genuinely better view because it can go back in time and access the drug use in the years before the dementia is diagnosed.”
Malaz A. Boustani, MD, MPH, a coauthor of an accompanying editorial in JAMA Internal Medicine, said he was surprised the dementia signals did not start appearing sooner and that it took three years of exposure.
“Based on earlier data, I expected problems to arise within 90 days to a year of use,” said Dr. Boustani, who is a professor of aging research and chief innovation and implementation officer for Indiana University Health.
Dr. Knopman said that it was “highly unlikely” that the drugs themselves were the direct cause of the dementia, adding that the ultimate underpinnings of the article have a strong biologic basis.
Anticholinergic drugs “affect the area of the brain that facilitates learning and memory, and that's the basis of the cholinergic model of Alzheimer's,” he said. “That pharmacologic profile probably has negligible impact on people under 60, but with people with incipient dementia, the drug probably exacerbates the symptoms.”
Dr. Knopman said the main limitation with a prospective study is an indication bias. He suggested that the use of these drugs might be because of incipient dementia, rather than the drugs themselves causing the dementia. But he added that the researchers did split off those taking antidepressants, and they still found the same associations with the anticholinergic drugs.
Dr. Gray said that with any observational study, there is the risk of not being able to adjust for all the differences that occur between participants.
“It could be that the reasons people take these medications that are leading to the increased risk for dementia,” she said. “You can never completely rule out the chance that there are other reasons that might be explaining our findings.”
Larry Tune, MD, Emory Clinic Professor of Psychiatry at Emory Healthcare, conducted similar studies focusing on exposure to anticholinergic medications in small groups of people with Alzheimer's disease. He found that those on anticholinergic drugs deteriorated more rapidly than those who were not.
“You realize there's a cognitive reserve, there's acetylcholine decrease in those with Alzheimer's, so maybe the anticholinergics provoke that threshold and tip them over the top,” he said.
The study brought up two main challenges, both for research and for practicing neurologists: Will stopping the medication reverse the cognitive decline? And how should doctors address the risks of using these drugs with current patients?
In an accompanying commentary, Noll L. Campbell, PharmD, and Dr. Boustani focused on the next step — determining whether there is a possibility of reversing the adverse cognitive effects and determining the safety risks of discontinuing the medications.
“If we go after this reversibility, find people who are on this medication and stop it, are we modifying their future risk? That's the big question,” said Dr. Boustani.
“We also need to develop better methods to determine when to stop these medications, a good tool to use to reduce their exposure.”
He said that ultimately, the goal should be to create a greater public awareness of cognitive side effects and encourage pharmaceutical companies to develop new medications.
“Over-the-counter drugs and prescribed drugs come with a price,” he said. “We need people to push their doctors to explain the side effects. We talk about the effects on the kidneys, the liver, the heart, but in our semantic lexicon we don't go above the neck.”
Dr. Gray said the researchers will next look at postmortem studies of a subset of the group. She hopes that by looking at the brain pathology, researchers can identify a process in the brain that's changed between those who used anticholinergic medications and those who did not.
She said one of the main hopes of the study is that it will encourage physicians to talk about the risk/benefit ratio with their patients and help them make informed decisions, including discussing non-drug therapies.
For prescribers, it's a matter of periodically reviewing the medication regime and coordinating with primary care physicians.
“The key point is for neurologists to ask about anticholinergic medications, particularly over-the-counter medications, so that they're aware of what the patient is taking, said Dr. Gray. “Particularly OTC drugs to help sleep and for allergies — those are the two main products with anticholinergic properties.”
EXPERTS: ON ANTICHOLINERGICS AND DEMENTIA