A case-control study published in the BMJ has shown a 'noticeable' association between increasing anticholinergic exposure and development of dementia up to 20 years later.
The risk of dementia was specifically linked to prescriptions for drugs with a high anticholinergic burden used for antidepressant, urological, and antiparkinson's indications.
Using the Clinical Practice Research Datalink, the researchers looked at the medical records of 40,770 patients aged 65–99 years with a diagnosis of dementia between April 2006 and July 2015 and compared prescriptions of anticholinergic drugs in this group 4–20 years earlier with prescriptions in 283,933 controls without dementia.
Anticholinergic drugs were classified according to the Anticholinergic Cognitive Burden (ACB) scale, whereby:
- Drugs with anticholinergic activity but with no known clinically relevant negative cognitive effects are assigned a score of 1 (possibly anticholinergic)
- Drugs with established and clinically relevant anticholinergic effects are assigned a score of 2 (definitely anticholinergic)
- Drugs with a score of 2 that also have reported associations with delirium are assigned a score of 3 (definitely anticholinergic).
In total 14,453 (35%) cases and 86,403 (30%) controls were prescribed at least one anticholinergic drug with an ACB score of 3 during the exposure period.
The researchers' analysis showed there was a positive and significant association between the prescription of any drug with an ACB score of 1, 2, or 3 and dementia with odds ratios of 1.10 (95% CI 1.06–1.15), 1.10 (95% CI 1.03–1.16), and 1.11 (95% CI 1.08–1.14), respectively.
A dose-response effect was evident for prescribed doses of drugs with an ACB score of 2 or 3.
When analysed by class, there was a significant association between dementia incidence and any prescription of antidepressant, antiparkinson, or urological drugs with an ACB score of 3, but no association with antispasmodic, antipsychotic, antihistamine, or other drugs with an ACB score of 3. Antidepressants were predominantly amitriptyline, dosulepin, and paroxetine; urological drugs were predominantly oxybutynin and tolterodine.
Associations with dementia were seen for drugs with an ACB score of 3 prescribed 4–10, 10–15, and 15–20 years before diagnosis. In particular, the prescription of any drug with an ACB score of 3 15–20 years before a diagnosis of dementia was significantly associated with greater dementia incidence with an odds ratio of 1.17 (95% CI 1.10–1.24) adjusted for covariates at the start of the exposure period.
Cause or correlation
It is unclear from the study whether anticholinergic agents contribute to the development of dementia or whether the association reflects use of these drugs to treat very early symptoms of dementia. The authors suggest that early dementia symptoms are less likely explanations for the effect given the association seen with anticholinergic exposure 15–20 years before the diagnosis of dementia.
The researchers advise clinicians to be vigilant with the use of anticholinergic drugs, and to consider the risk of long-term cognitive effects associated with specific classes when performing their risk-benefit analysis.
'These findings make it clear that clinicians need to carefully consider the anticholinergic burden of their patients and weigh other options,' said co-author Malaz Boustani, Professor of Ageing Research at the University of Indiana.
'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,' he said.