Although anticholinergic-induced cognitive impairment has been considered reversible on discontinuation of anticholinergic therapy, a few studies suggest it may be associated with an increased risk for dementia. The objective of this study therefore was to examine the association between 10-year cumulative anticholinergic use and the risk for dementia. It involved 3434 participants enrolled in the Adult Changes in Thought (ACT study) who had at least 10 years of health plan enrolment, to permit sufficient and equal ascertainment of cumulative anticholinergic exposure. Participants underwent assessment at study entry and returned biennially for evaluation of cognitive function, medical history, health behaviours and health status and collection of demographic characteristics.
Medication use was ascertained from computerised pharmacy dispensing records, and the primary measure of anticholinergic use was the 10-year cumulative exposure. This was categorised in terms of cumulative total standardised daily dose (TSDD; based on all anticholinergic pharmacy fills during the exposure period). As an example, the highest category (>1095 TSDD) was equal to >3 years of exposure to oxybutynin chloride 5mg, chlorpheniramine maleate 4mg or olanzapine 2.5mg.
A total of 23.2% of the study population developed dementia during a mean follow-up of 7.3 years; a cumulative dose-response relationship was observed for anticholinergic use and both dementia and Alzheimer disease (test for trend, P<0.001). Participants in the highest exposure category (TSDD >1095) had a statistically significant increased risk for dementia (adjusted HR 1.54; 95% CI 1.21-1.96]) or Alzheimer’s (1.63; 95% CI 1.24-2.14) compared with those with no use. Participants with primarily past use had a dementia risk similar to those with greater recent or continuous use, which suggests the risk may persist despite discontinuation of therapy.
The researchers note the strengths of their study, including the large community-based sample, the mean follow-up of more than 7 years, and the use of standard definitions for dementia and AD ascertainment. They do however acknowledge a number of potential limitations, including possible misclassification of exposure (several first-generation antihistamines are available as over-the-counter medications), the possibility of unmeasured or residual confounding, and the reliance of the exposure measure on prescription fills (the medication was not necessarily taken). Additional studies are needed to confirm these findings.
The authors advise prescribers to be aware of this potential complication when considering prescribing anticholinergics for older patients and to consider alternatives where possible. Where necessary, the lowest dose should be used and treatment should be stopped if ineffective.
An accompanying Commentary states that translation of these findings into clinical interventions to minimise the adverse cognitive effects of medications is an important next step, and calls for an RCT to examine whether discontinuing anticholinergics improves cognition (and whether this is associated with any unintended consequences in older patients). As the approach to discontinuing such a wide array of medications depends on the dose, duration, and indication, the intervention must be designed with the ability to tailor the deprescribing and monitoring approach to each individual to optimize safe and effective medication changes.