Anticholinergic Drugs – Risk of Dementia
A new report published in JAMA Internal Medicine (formerly, Archives of Internal Medicine) indicated that long term use of common anticholinergic drugs and their use in the past 10 years is associated with a significantly increased risk for developing dementia.
Common anticholinergic drugs include tricyclic antidepressants, first-generation antihistamines, and urinary bladder antispasmodics or some anti-vertigo drugs.
In the JAMA Internal Medicine study, the research team from the University of Washington, Seattle, University of Pittsburgh, Pennsylvania, and University of Pennsylvania, Philadelphia used a prospective population-based cohort study from the Adult Changes in Thought study in Group Health, in Seattle, Washington, including 3434 participants, aged 65 years or older.
The conclusion of this study is that “higher cumulative anticholinergic use is associated with an increased risk for dementia”.
Interestingly, a previous British Medical Journal study indicated that there is a dose-effect relation between benzodiazepine use and the increased risk of Alzheimer’s disease.
As per a modvive.com news report, Shelly Gray, the senior author of the JAMA study recommends that
health care providers should regularly review their older patients’ drug regimens – including over-the-counter medications
to look for chances to use fewer anticholinergic medications at lower doses”.
Source: JAMA Intern Med, 2015 Jan 26. doi: 10.1001/jamainternmed.2014.7663. [Epub ahead of print]
Read more: jamanetwork.com
Updates
A 2018 BMJ publication by Kathryn Richardson et al. was based on a nested case-control study using data from the Clinical Practice Research Datalink (CPRD) in the UK. This included anonymized diagnosis, referral, and prescribing records for more than 11.3 million patients from 674 primary care practices.
The study reported a robust association between some classes of anticholinergic drugs and future dementia incidence; i.e., there was a noticeable association between increasing total anticholinergic burden over the previous 4-20 years and incident dementia diagnosis.
Particularly, antidepressants (predominantly amitriptyline, dosulepin, and paroxetine) and urologicals (predominantly oxybutynin and tolterodine) with an ABC score of 3 (definitely anticholinergic) were consistently associated with incident dementia. These relations were seen even for exposures 15-20 years before the diagnosis of dementia, suggesting that reverse causation or confounding with early dementia symptoms are less likely explanations for the effect.
The authors concluded and suggested that
clinicians should continue to be vigilant with respect to the use of anticholinergic drugs, and should consider the risk of long term cognitive effects
as well as short term effects, associated with specific drug classes when performing their risk-benefit analysis.
Briefly, the study suggested:
- Antidepressant, urological, and antiparkinson drugs with definite anticholinergic activity are linked to future dementia incidence, with associations persisting up to 20 years after exposure.
- Gastrointestinal and cardiovascular anticholinergic drugs are not positively associated with later dementia incidence.
A 2019 publication by Carol A C Coupland et al. in the JAMA Internal Medicine used a nested case-control study of 58 769 patients with a diagnosis of dementia and 225 574 matched controls.
This large, nested case-control study found a statistically significant association of dementia risk with exposure to several types of strong anticholinergic drugs. Of note, the associations were stronger in cases diagnosed before the age of 80 years and in cases diagnosed with vascular dementia rather than with Alzheimer disease.
As per the authors, the finding of more pronounced associations for vascular dementia than for other types is novel, and raised questions about the mechanisms by which anticholinergic drugs may increase the risk of subsequent dementia.
These may include vascular and inflammatory changes.
The authors concluded that their study added further evidence of potential risks associated with strong anticholinergic drugs
particularly those that are antidepressants, bladder antimuscarinic drugs, antiparkinson drugs, and epilepsy drugs.
In addition, the authors found greater increases in risk associated with people diagnosed with dementia before the age of 80. Thus, according to these authors, the anticholinergic drugs should be prescribed with more caution in middle-aged and older people.
A 2021 systematic review and meta-analysis by Yong-Bo Zheng et al. concluded that the anticholinergic drug use was associated with an increased risk of all-cause dementia and Alzheimer’s disease. And, moreover, there was a dose-dependent relationship between anticholinergic drugs and risk of dementia.
With respect to the categories of anticholinergic drugs, antiparkinson, urological drugs, and antidepressants increased the risk for dementia; however, cardiovascular and gastrointestinal drugs played potentially protective roles.
Highlights from this systematic review:
- Anticholinergic drug use is an independent risk factor for all-cause dementia and Alzheimer’s disease.
- Heavier anticholinergic drug exposure is associated with a higher risk of dementia.
- Different categories of anticholinergic drugs exert distinct effects on incident dementia.
- It is important to manage and prescribe anticholinergic drugs to help optimize early prevention strategies for dementia.
A 2023 BMC Geriatrics publication by Insiya B. Poonawalla et al. was based on a retrospective cohort study that used the Humana Research Database to identify individuals with at least one anticholinergic (ACH) medication dispensed in 2015. Patients were followed until incidence of dementia/Alzheimer’s disease, death, disenrollment or end of December 2019.
The study reported that as ACH polypharmacy increased (i.e., from no ACH exposure, to one, two, three, and four or more ACH medications), there was a stair-step increase in the incidence rate of dementia/Alzheimer’s disease and in the incidence of mortality. After adjusting for confounders, ACH exposure to one, two, three and four or more ACH medications was associated with a 1.6, 2.1, 2.6, and 2.6 times, respectively, increased risk of a dementia/Alzheimer’s disease diagnosis compared to periods of no ACH exposure.
According to the authors, while the magnitude of effect differed across their results, the directionality was in line with a meta-analysis that documented a 46% increased odds of incident dementia in patients with ≥ 3 months of ACH medication use.
Additionally, as per the authors, reflecting on their results, a Cochrane Database review and meta-analysis with 968,428 participants in total suggested a possible doubling of the risk of dementia with ACH drug exposure and that a greater ACB score increases the risk of dementia.