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Anticholinergic drugs and risk of dementia: case-control study

BMJ 2018; 361 doi: (Published 25 April 2018) Cite this as: BMJ 2018;361:k1315

Rapid Response:

Re: Anticholinergic drugs and risk of dementia: case-control study

Inappropriate media coverage

The study aimed to assess the evidence for a causal association between anticholinergic drug exposure and an increased dementia risk. This hypothesis may be biologically plausible, because these drugs block the neurotransmitter acetylcholine, which in turn could lead to Alzheimer’s disease-like pathology(1) and these drugs also have short-term effects on cognition.

The authors concluded that, “…there was a noticeable association between increasing total anticholinergic burden over the previous 4-20 years and incident dementia diagnosis”, while acknowledging that a dose-response effect was only seen for antidepressants, anti-parkinsonian drugs and urological drugs with high anticholinergic burden.

This was a well-conducted study and addressed an important research question considering the lack of modifiable risk factors for dementia. We recently reviewed the paper in our departmental Journal Club and although the authors were cautious about their interpretation, we are concerned about the lay media’s somewhat less cautious reporting.

We believe these results suggest a non-causal relationship between anticholinergic burden and dementia risk. If the association were causal, the increased risk of dementia with exposure to antidepressants with an ACB score of 3 (OR: 1.11 (95%CI 1.08-1.14) would have been observed for all drugs with an ACB score of 3; however, gastrointestinal and respiratory drugs with a high anticholinergic burden were not associated with dementia. Small odds ratios seen in observational studies can be due to bias, even if highly statistically significant Giving a “Number needed to harm”, based on 15 years use is certainly non-standard, and gives an impression of an absolute number when it is highly dependent on the period of time considered.

Despite the fact that authors excluded anticholinergic prescriptions in the four years prior to the index date, it is still possible that the associations observed reflect reverse causality, given the long asymptomatic and symptomatic pre-diagnostic phases of dementia. Parkinson’s disease(2) and lower urinary tract symptoms(3) are known to be associated with an increased risk of subsequent dementia. Late-life depression is strongly associated with a greater risk of dementia, with some evidence suggesting this condition is a prodrome of early pre-clinical dementia.(4, 5) A non-causal association is further supported by the study’s findings that the magnitude of association between antidepressants with an ACB score of 1 and dementia became stronger the closer drug prescription was to the dementia diagnosis (table 4). The authors did aim to address the issue of confounding by depression severity in a sensitivity analysis; however, deriving depression severity from Read codes recorded in primary care is challenging and there is likely to be substantial misclassification.

This article garnered a great deal of media attention, some of which went as far as saying, “Scientists say doctors should consider weaning patients with depression, Parkinson’s or bladder problems off anticholinergic drugs”,(6) which went well beyond the authors’ conclusions. While we agree that combinations of drugs with anticholinergic activity should be prescribed with caution in older adults, we do not believe the results of this study support the interpretation put on the findings by the lay media. Stopping treatments that are providing benefits to patients can have unintended harmful consequences.

1. Kolisnyk B, Al-Onaizi M, Soreq L, et al. Cholinergic Surveillance over Hippocampal RNA Metabolism and Alzheimer's-Like Pathology. Cerebral Cortex. 2017;27(7):3553-67.
2. Breteler MMB, de Groot RRM, van Romunde LKJ, Hofman A. Risk of Dementia in Patients with Parkinson's Disease, Epilepsy, and Severe Head Trauma: A Register-based Follow-up Study. American Journal of Epidemiology. 1995;142(12):1300-5.
3. Chiang C-H, Wu M-P, Ho C-H, et al. Lower Urinary Tract Symptoms Are Associated with Increased Risk of Dementia among the Elderly: A Nationwide Study. BioMed Research International. 2015;2015:187819.
4. Singh-Manoux A, Dugravot A, Fournier A, et al. Trajectories of Depressive Symptoms Before Diagnosis of Dementia: A 28-Year Follow-up Study. JAMA Psychiatry. 2017 Jul 1;74(7):712-8.
5. Mirza SS, Wolters FJ, Swanson SA, et al. 10-year trajectories of depressive symptoms and risk of dementia: a population-based study. Lancet Psychiatry. 2016 Jul;3(7):628-35.
6. Boseley S. Some antidepressants linked to dementia risk. Guardian. 2018.

Competing interests: No competing interests

23 July 2018
Harriet Forbes
UKRI Innovation Fellow
Ian Douglas, Stephen Evans, Liam Smeeth, Laurie Tomlinson, Charlotte Warren-Gash.
London School of Hygiene and Tropical Medicine
Keppel Street, London, WC1e7HT