Popular drugs raise dementia risk

Every drug that brings a benefit also carries a risk. And while the FDA’s review process is designed to uncover as many risks as possible, some inevitably slip through the cracks undetected. That could be the case with two long-standing classes of drugs—benzodiazepines and anticholinergic drugs. Even though benzodiazepines were first discovered in the 1950s and anticholinergic drugs have been used since ancient times (there’s a reference to one in Homer’s The Odyssey), mounting evidence suggests that these two drugs classes are associated with an increased risk of dementia, and possibly Alzheimer's disease, in people who used them for more than a few months.

Drug usage

Benzodiazepines are a class of agents that attach to receptors of the inhibitory neurotransmitter gamma-aminobutyric acid-A (GABA-A), making the nerves and brain less sensitive to stimulation and causing a calming effect. Taken by up to 37% of older people, “benzos” are most often used to treat anxiety and insomnia. Because they’re highly addictive and pose a serious withdrawal threat, benzos are only intended to be used for a few weeks. But many people continue to take benzodiazepines for years. 

Anticholinergics block the neurotransmitter acetylcholine in the central and peripheral nervous systems. Anticholinergic properties can be found in a huge number of drugs used to treat a variety of conditions that affect the gastrointestinal, genitourinary, respiratory, and nervous systems, like seasonal allergies, depression, overactive bladder, chronic obstructive pulmonary disease, and Parkinson’s disease. Side effects are as numerous as the conditions anticholinergics can treat, and include dry mouth, low blood pressure, urinary retention, constipation, tachycardia, confusion, difficulty concentrating, agitation, and memory problems. Until recently, these side effects were thought to be temporary.

Two separate, large population studies have suggested that both types of medications are associated with an increased risk of dementia in people who used them for longer than a few months. It’s important to note that neither of these studies was a randomized controlled clinical trial, so further research is needed to prove a causal link between the drugs and dementia. Still, the findings remain concerning, warranting both additional investigation from researchers and consideration from physicians and patients.

The anticholinergic study

In the first study, researchers at the University of Washington and at Group Health, a Seattle healthcare system, tracked 3,434 men and women aged 65 years or older who had no dementia at baseline. Pharmacy records were used to determine the prescription and over-the-counter drugs that each participant took in the decade before starting the study. 

Participants were followed for an average of 7.3 years. During that time, 797 (23%) developed dementia. The researchers found that people who used anticholinergic drugs were more likely to have developed dementia than those who didn't use them, and dementia risk increased with the cumulative dose. Taking an anticholinergic for the equivalent of 3 years or more was associated with a 54% higher dementia risk than taking the same dose for 3 months or less.

The study was the first to include nonprescription drugs and the first to eliminate the possibility that people were taking the drugs to alleviate early symptoms of undiagnosed dementia.

The benzodiazepine study

Using a database maintained by the Quebec health insurance program, a team of researchers from France and Canada not only linked benzodiazepine use to an increased risk of being diagnosed with Alzheimer's disease, but also found that increasing the cumulative dose of benzodiazepines raised that risk as well.

In a case-control study published in BMJ, investigators identified nearly 1,800 men and women over age 66 who had been diagnosed with Alzheimer's disease, and randomly selected more than 7,000 others without Alzheimer's who were matched for age and sex to those with the disease. The researchers looked at participants’ drug prescriptions during the 5 to 6 years before the Alzheimer's diagnosis.

People who had taken a benzodiazepine for 3 consecutive months or less had about the same dementia risk as those who had never taken one. But those who had taken a benzodiazepine for 3 to 6 months had a 32% greater risk of developing Alzheimer's, and those taking one for more than 6 months had an 84% higher risk than those who had never taken one.

The type of benzodiazepine made a difference, too. People who were on long-acting benzodiazepines, such as diazepam or flurazepam, had a greater risk than people on a short-acting one, like lorazepam, alprazolam, triazolam, or temazepam.

Other benzodiazepine and anticholinergic research 

A team in China scoured PubMed and Embase databases for observational studies analyzing the relationship between the long-term use of benzodiazepine and dementia risk. They included ten studies in their meta-analysis: six case-control and four cohort studies. 

Across these studies, the pooled risk ratio for developing dementia was 1.51 in patients taking a benzodiazepine. Similar to the BMJ study of benzodiazepines, this meta-analysis found that the risk of dementia was 16% higher in patients taking benzodiazepines with a longer half-life and 21% higher in those taking benzodiazepines for a longer time period.

On the other hand, more recent research published in the British Journal of Clinical Pharmacology found no significant association between anticholinergic exposure and cognitive decline in older adults, highlighting the need for more studies on this drug class’s effects on cognitive health.

Investigations continue 

Researchers at the University of East Anglia, Norwich, England, are currently investigating the links between benzodiazepines, anticholinergic drugs, and dementia, focusing on the ways these drugs are associated with increased incidence of dementia and cognitive decline.

The researchers say that the cognitive harms of anticholinergics remain uncertain, and benzodiazepines are widely used despite the known harms of their prolonged use. In fact, studies consistently find that 10% or more American adults aged 50 and over regularly use a benzodiazepine or a medication with anticholinergic activity, and nearly half of older people are using one or more medications that may be anticholinergic.

The goal of the East Anglia study is to confirm what research thus far has alluded to—that there is substantial cognitive decline associated with anticholinergic medications and that benzodiazepines lead to increased dementia risk. If links are established, patients and doctors can begin exploring safer alternatives, like the ones in this table from Harvard Health Publishing.

If no effect is found in the studies, this will provide reassurance that anticholinergic medications—which are effective treatments for many medical conditions despite their adverse effects—can be used safely, and will inform further guidance on the use of benzodiazepines.