Anticholinergic drugs that are commonly prescribed as antidepressants or for treating incontinence are linked with an increased risk of dementia, even when taken 20 years before cognitive impairment is diagnosed, according to data from what researchers claim is the largest and most detailed study of this class of drug.

Results from the nested case-control study, including more than 40,000 patients with dementia, showed a significant correlation between the use of anticholinergic drugs and dementia, but only for certain types of this class of drugs. Nevertheless, the team claims, the findings are significant enough to warrant reduced prescribing anticholinergics, where possible. “With many medicines having some anticholinergic activity, one key focus should be deprescribing,” states study co-researcher Ian Maidment, Ph.D., senior lecturer in clinical pharmacy at Aston University in the U.K. “Clinical staff, patients and carers need to work together collaboratively to limit the potential harm associated with anticholinergics.”

The study, led by a team at the University of East Anglia in the U.K., involved a collaboration between teams in the U.K., U.S., and Ireland. “These findings make it clear that clinicians need to carefully consider the anticholinergic burden of their patients and weigh other options,” claims Malaz Boustani, M.D., MPH, a Regenstrief Institute and Indiana University (IU) Center for Aging Research investigator, and co-author of the researchers’ published paper in the BMJ. Boustani added that “Physicians should review all the anticholinergic medications—including over-the-counter drugs—that patients of all ages are taking and determine safe ways to take individuals off anticholinergic medications in the interest of preserving brain health.” Dr. Boustani is the founder of the Indiana Clinical and Translational Science Institute’s IU Center for Health Innovation and Implementation Science and the Richard M. Fairbanks Professor of Aging Research at IU School of Medicine. The researchers’ study is published in a paper entitled, “Anticholinergic Drugs and Risk of Dementia: Case-Control Study.”

Anticholinergic drugs are designed to block the neurotransmitter acetylcholine in the central or peripheral nervous system, and have diverse actions, dependent on the site, the researchers explain. Different classes of anticholinergic drugs have been developed to treat diseases, including depression, gastrointestinal disorders, Parkinson’s disease, urinary incontinence, epilepsy, and to manage allergies.

However, “it is well known that anticholinergics affect cognition, and guidelines suggest they are to be avoided among frail, older people,” they state. Studies involving community-living residents or those in nursing homes have also suggested that anticholinergic drugs are linked with long-term cognitive decline or dementia. Despite this evidence, studies haven’t been able to determine if the increased risk is specifically caused by the anticholinergic activity, or “whether or not the association is owing to the drugs or the underlying conditions for which they were prescribed,” the authors note. In addition, “many studies have linked anticholinergic drug use with concurrent or short-term cognitive effects, but few have examined associations of long-term anticholinergic exposure; the latter tend to report positive associations.”

To try and answer outstanding questions about the link between anticholinergic drug use and dementia risk, the researchers analyzed the anonymized prescribing records of more than 40,000 older adult patients, aged 65–99 years, held in the U.K.’s Clinical Practice Research Datalink (CPRD), who were diagnosed with dementia, and another 283,993 older adults without dementia. The analysis included a comparison of dementia patients’ anticholinergic drug prescription 4–20 years before their dementia diagnosis, with prescriptions in a matched group of control patients without dementia.

The results showed a “noticeable association” between increasing total anticholinergic use over the prior 4–20 years and incident dementia diagnosis. However, the dose-response link was only seen for certain classes of anticholinergic drugs, including the antidepressants amitriptyline, dosulepin, and paroxetine, and urologicals, including oxybutynin and tolterodine. More broadly, there was a link between the use of any prescribed antidepressant, antiparkinson, or urologic drug with an anticholinergic activity burden (ACB) score of 3 (i.e., they can cross the blood-brain barrier and have definite anticholinergic activity). The association between anticholinergic drug use and dementia was even evident for drug exposure 15–20 years before diagnosis, “suggesting that reverse causation or confounding with early dementia symptoms are less likely explanations for the effect,” the team writes.

“This study is large enough to evaluate the long-term effect and determine that harm may be experienced years before a diagnosis of dementia is made,” comments co-author Noll Campbell, PharmD, MS., a Regenstrief Institute and Indiana University Center for Aging Research investigator. Dr. Campbell is also an assistant professor of pharmacy practice at Purdue University College of Pharmacy.

In contrast, there was no association between dementia risk and the historical use of antispasmodic, antipsychotic, antihistamine, or other drugs with a similar ACB score of 3. Neither was there any dose-response effect seen for cumulative use of drugs with an ACB score of 1 (possibly anticholinergic).

The researchers say that while the associations appear “moderate,” they still reflect an “appreciable risk to patients,” given the high incidence of dementia. And while evidence for a mechanistic link between anticholinergic drugs and dementia incidence is limited, “neuropathological studies in humans and mice do support a role of anticholinergics affecting neurodegenerative pathology,” they write.

Interestingly, anticholinergic drugs, and particularly oxybutynin, have been consistently associated with a short-term cognitive decline in randomized controlled studies, so a long-term risk of dementia is “plausible,” they write. And while patients with Parkinson’s disease are at a higher risk of dementia irrespective of drug use, anticholinergic antiparkinson drugs have also previously been linked with greater cognitive decline. “This study provides further evidence that anticholinergic drugs should be avoided when treating patients with Parkinson’s disease.”

“This research is really important because there are an estimated 350 million people affected globally by depression,” comments lead researcher George Savva, Ph.D., a visiting researcher at the University of East Anglia’s School of Health Sciences. “Bladder conditions requiring treatment are estimated to affect over 13% of men and 30% of women in the U.K. and U.S.”

The researchers do stress that patients prescribed anticholinergic drugs shouldn’t just stop taking their medicines. “We don’t know exactly how anticholinergics might cause dementia,” acknowledges study co-author Chris Fox, M.D., professor of clinical psychiatry at the University of East Anglia’s Norwich Medical School and a consultant psychiatrist. “Further research is needed to understand possible reasons for this link. In the meantime, I strongly advise patients with any concerns to continue taking their medicines until they have consulted their doctor or pharmacist.”