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Anticholinergic Drug Exposure Is Associated with Dementia Risk in a Nested Case-Control Study

Article In Brief

In a large study, researchers found anticholinergic medicines were associated with an increased risk of dementia. They suggest that physicians should be cautious when prescribing these drugs to middle-aged and older people.

Long-term cumulative use of anticholinergic medicines is associated with an elevated risk of dementia, according to a nested case-control study published online in JAMA Internal Medicine on June 24.

The findings suggest that physicians should exercise caution when prescribing these drugs to middle-aged and older people.

After adjusting for confounding variables in a large and representative British cohort, the investigators found varying but statistically significant associations of dementia risk with exposure to different types of anticholinergic medications.

The research team analyzed outcomes from a database in England of prescriptions up to two decades prior to diagnosis; they included anticholinergic antidepressants, anti-Parkinson's agents, bladder antimuscarinics, and antipsychotic and antiepileptic medications.

Anticholinergic drugs share a common mechanism of action: they block the neurotransmitter acetylcholine in the central and peripheral nervous system. Although these medicines pose a risk of short-term side effects, including confusion and memory loss in older people, it is less clear whether long-term use heightens the risk of dementia.

Until now, however, observational studies of anticholinergic drugs and dementia risk typically have been relatively small, only evaluated short-term exposure, or were affected by recall bias, the authors indicated.

The new study “adds to previous evidence that prescribing drugs with anticholinergic properties may increase the risk of developing dementia in the future,” Tom Dening, MA, MD, FRCPsych, a study co-author and professor of dementia research at the University of Nottingham's Institute of Mental Health in Nottingham, United Kingdom, told Neurology Today.

“We have also shown that the risk only applies to certain types of drugs with anticholinergic properties, not all of them,” Dr. Dening said. “The risk is related to the length of exposure and the dosage received.”

Modifiable risk factors “are really important when we consider possible approaches to dementia prevention,” Dr. Dening added.

Dr. Dening cautioned that the study's major limitation is its inability to prove that these drugs cause dementia. “Even though we looked at different time periods as far back as 20 years before the diagnosis of dementia, it is difficult to exclude the possibility that there may be some other mechanism that actually causes the dementia,” he said.

As a result, he would advise neurologists to review all of a patient's prescribed medications—particularly antidepressants, antipsychotics, anti-epileptic drugs, and anticholinergic medicines for incontinence. Clinicians should carefully consider whether patients need to take the drugs and/or can be switched to alternatives without anticholinergic properties.

Study Methodology, Results

The study authors analyzed data from the QResearch primary care database culled from general practices in England. Researchers evaluated whether exposure to anticholinergic drugs was associated with dementia risk in 58,769 patients with a diagnosis of dementia and 225,574 controls 55 years or older matched by age, sex, general practice, and calendar time.

Extracting information on prescriptions for 56 drugs with strong anticholinergic properties, they calculated measures of cumulative anticholinergic drug exposure. Data analysis spanned from May 2016 to June 2018.

The primary exposure consisted of the total standardized daily doses of anticholinergic drugs prescribed in the one to 11 years before the diagnosis date of dementia or a parallel date in matched controls (index date).

Among the findings, the adjusted odds ratio for dementia rose from 1.06 (95% CI, 1.03-1.09) in the lowest overall anticholinergic exposure category to 1.49 (95% CI, 1.44-1.54) in the highest category, compared with no anticholinergic drug prescriptions in the one to 11 years before the index date.

Researchers observed significant increases in dementia risk for the anticholinergic antidepressants (adjusted odds ratio [AOR],1.29; 95% CI, 1.24-1.34), anti-Parkinson's drugs (AOR,1.52; 95% CI, 1.16-2.00), antipsychotics (AOR, 1.70; 95% CI, 1.53-1.90), bladder antimuscarinic drugs (AOR,1.65; 95%CI, 1.56-1.75), and antiepileptic drugs (AOR, 1.39; 95% CI, 1.22-1.57).

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“Until these benefits and risks are better understood, clinicians should primarily focus on prioritizing safer medications when managing these symptoms.”—DR. TOM DENING

Expert Commentary

An editorial accompanying the study commended the study authors for adding to the literature chronicling the connection between strong anticholinergic medications and Alzheimer's disease and related dementias. However, the editorial noted that such studies “provide only incremental new knowledge and require additional research to clarify whether anticholinergic medications truly represent a reversible risk factor.”

The editorial pointed out that “causation has not been established.”

Testing the causal hypothesis between anticholinergic medication use and the diagnosis of Alzheimer's disease and related dementias could be performed in well-designed prospective randomized clinical trials focused on deprescribing interventions, they wrote.

These trials could evaluate the potential harms of halting anticholinergic medications, which may include exacerbating the symptoms of depression, incontinence, or pain, as well as the possible inadvertent increase in acute health care utilization, the authors of the editorial wrote.

“The benefits of deprescribing anticholinergics on cognitive health are certainly worth studying, but we also know that there could be risks from deprescribing,” said Noll Linden Campbell, PharmD, MSc, the editorial's lead author and assistant professor for pharmacy practice at Purdue University in West Lafayette, Indiana.

“Until these benefits and risks are better understood, clinicians should primarily focus on prioritizing safer medications when managing these symptoms,” Dr. Campbell, faculty associate in the university's Center on Aging and the Life Course, told Neurology Today.

For instance, neurologists could consider managing neuropathic pain with medicines that do not have anticholinergic properties. Such an alternative approach “would be quite reasonable” when the medicine is equally effective, he said.

With funding from the National Institute on Aging, Dr. Campbell and his research colleagues are implementing two parallel five-year deprescribing trials—using a pharmacist-driven protocol or mobile application—to support patients and physicians in this endeavor. Recruitment is expected to begin this fall, said Dr. Campbell, also an investigator with the Regenstrief Institute and the Indiana University Center for Aging Research in Indianapolis, where he studies the adverse cognitive effects of medications related to delirium and dementia.

Anticholinergic drugs have long been associated with acute and chronic adverse events, such as falls, in older adults, said Raj C. Shah, MD, associate professor in the family medicine and Rush Alzheimer's Disease Center at Rush University Medical Center in Chicago. And guidelines have endorsed limiting their use for decades, he said.

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“One of the key difficulties in examining medication exposure as a risk factor is untangling the effects of the medication from the reason why the medication was prescribed. Observational data cannot determine whether anticholinergic medications or the conditions, such as depression, parkinsonism, and urge incontinence are leading to the increased risk of dementia.”—DR. RAJ C. SHAH

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“Its well within the realm of possibilities and likelihood that very strong anticholinergics used to treat other conditions will exacerbate the dementia symptoms. Quite early in the disease process, it has been shown that the cholinergic neurons in the brain are particularly susceptible to the Alzheimers process.”—DR. DONNA M. WILCOCK

Neurologists and other physicians should continue to look for ways to limit patients' exposure to medications with anticholinergic properties by initiating other treatment options or re-evaluating whether continued treatment with these drugs is needed, Dr. Shah said.

“One of the key difficulties in examining medication exposure as a risk factor is untangling the effects of the medication from the reason why the medication was prescribed,” Dr. Shah noted, citing indication bias. “Observational data cannot determine whether anticholinergic medications or the conditions, such as depression, parkinsonism, and urge incontinence are leading to the increased risk of dementia.”

In some cases, it is possible to delay initiating medication, said Sanjay Asthana, MD, professor of medicine and director of the Wisconsin Alzheimer's Disease Research Center at the University of Wisconsin School of Medicine and Public Health in Madison, WI.

For example, in early stages of depression, cognitive behavioral therapy may work, he said. Some patients with mild Parkinson's disease can tolerate a bit of slowness or rigidity and can compensate by strengthening muscles. And for bladder incontinence, newer medications with minimal to no anticholinergic effects may be an option.

On the other hand, withdrawing someone with severe depression from a particular antidepressant could have severe consequences, including worsening of depression and increased risk of suicide. A patient with progressive Parkinson's disease is likely to experience worsening of the condition, and an individual with epilepsy can't safely postpone treatment, said Dr. Asthana, who hailed the study as being “the first of its kind” and for including a “phenomenal” number of subjects.

However, he cautioned that the data consisted of people evaluated by general internists. “The odds of making a wrong diagnosis of dementia are not insignificant in a primary care setting,” Dr. Asthana said. “Without known referrals to neurologists, this study may have falsely accepted the diagnosis of dementia, which would weaken the associations. Underdiagnosis of dementia was also a possibility.”

“Alzheimer's is a complex disease,” Dr. Asthana said. Sometimes differentiating Alzheimer's from other causes of dementia, such as frontal temporal dementia, vascular dementia, and Lewy body dementia, can be difficult. “The diagnosis can be pretty tricky.”

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“Without known referrals to neurologists, this study may have falsely accepted the diagnosis of dementia, which would weaken the associations. Underdiagnosis of dementia was also a possibility.”—DR. SANJAY ASTHANA

Proving causation would require follow-up research, even though the biological mechanisms in Alzheimer's are believed to involve the cholinergic system, said Donna M. Wilcock, PhD, professor in the Sanders-Brown Center on Aging at the University of Kentucky College of Medicine in Lexington.

“It's well within the realm of possibilities and likelihood that very strong anticholinergics used to treat other conditions will exacerbate the dementia symptoms,” Dr. Wilcock said. “Quite early in the disease process, it has been shown that the cholinergic neurons in the brain are particularly susceptible to the Alzheimer's process.”

Disclosures

Drs. Dening, Campbell, and Asthana reported no conflicts. Dr. Wilcock has received consulting fees from Alector and Eisai, Inc., and has also received travel expenses from Eisai. Dr. Shah is the principal investigator or sub-investigator for clinical trials for which Rush University Medical Center is compensated for from Amylyx Pharmaceuticals, Inc., Ely Lilly and Company, Inc., Genentech Inc., Merck & Company, Inc., Navidea Biopharmaceuticals, Novartis Pharmaceuticals, Roche Holdings AG, and Takeda Development Center Americas, Inc.

Link Up for More Information

• Coupland CAC, Hill T, Dening T, et al. Anticholinergic drug exposure and the risk of dementia: A nested case-control study https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2736353. JAMA Intern Med 2019; Epub 2019 Jun 24.
    • Campbell NL, Holden R, Boustani MA. Invited Commentary. Preventing Alzheimer disease by prescribing anticholinergic medications https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/2736349. JAMA Intern Med 2019; Epub 2019 Jun 24.