July 01, 2019

The Dirt on Drugs

Several months ago, in writing about Katy Butler’s generally admirable new book, The Art of Dying Well,I questioned her uncritical acceptance of claims that certain drugs, the anticholinergics, caused dementia. That drugs such as antihistamines and some antidepressants cause delirium, or acute confusion, is well-established. But dementia? A large, well-conceived study just published in JAMA Internal Medicine provides additional evidence that they may well result in dementia. Previous studies were tainted because they tended to be small, observational studies that lumped many different anticholinergic drugs together, some of which are known to be far more potent than others. So how does the new study fare by comparison?
The recent analysis is still an observational study—it is impossible to randomize patients into those who receive anticholinergics and those who do not and then follow them for years—but it is very large, it analyzes different classes of anticholinergics separately, and it focuses on the cumulative anticholinergic exposure over a period of many years. While not perfect, it is probably the best we are going to get and it provides strong, although not definitive, evidence that anticholinergics are a risk factor for dementia.
This “nested case control study” allowed the authors to identify just under 59,000 people over age 55 with dementia from a British data base of 30 million. For each case, they found 5 controls matched along four discrete dimensions. The main variable of interest was the total, cumulative anticholinergic exposure which they calculated according to a well-established protocol that allows standardization across drugs with different dosage regimens. The authors also decided in advance to study the association between the total standardized daily dose (TSDD) for each type of anticholinergic: antihistamines, antidepressants, antipsychotics, antiparkinsonian drugs were considered both separately and collectively. Finally, the study repeated the analysis for patients diagnosed with Alzheimer’s disease, those diagnosed with vascular dementia, and those with some other form of dementia. So what did they find?
The main finding was that the adjusted odds ratio associated with low anticholinergic exposure was 1.06, while the ratio associated with the highest degree of anticholinergic exposure was 1.49, a highly significant difference. Also interesting was the observation that only certain groups of anticholinergics increased the risk of developing dementia. In particular, antidepressants, antipsychotics, antiepileptics, and drugs used to treat Parkinson’s and incontinence were the main offenders (and antihistamines, which geriatric physicians inveigh against as potential causes of delirium, had no effect). Curiously, the effects were more dramatic in patients with vascular dementia than in those with Alzheimer’s disease, a novel finding. Finally, the strongest association was found in people diagnosed before age 80.
As the authors are quick to point out, associations do not demonstrate causality. They can’t. Researchers simply cannot exclude the possibility that some of the drug use in fact reflected early, preclinical effects of as yet undiagnosed dementia. For example, many people with dementia are depressed; it is entirely possible that the depression manifests itself before a formal diagnosis is made, at a time when patients are beginning to detect subtle but disturbing changes in their memory and problem-solving ability. But if anticholinergics are causative, then they may well be responsible for as much as 10 percent of all dementia. The evidence is sufficiently suggestive and the magnitude of the danger sufficiently great that it’s time to be very wary of these drugs, especially in people under age 80.