This investigation is believed to be the "largest and most detailed" study to date into long-term anticholinergic use and dementia risk.
Anticholinergics work by blocking a chemical messenger, or neurotransmitter, called acetylcholine that carries brain signals for controlling muscles.
Anticholinergics for depression, such as amitriptyline, dosulepin, and paroxetine, have previously been linked to higher risk of dementia, even when they were used up to 20 years beforehand.
Some studies have also suggested that use of any anticholinergic is linked to raised risk of dementia.
Long-term use of certain anticholinergics
But the new study — which was led by the University of East Anglia (UEA) in the United Kingdom and is now published in The BMJ — discovered that long-term use of only certain types of anticholinergics is linked to higher dementia risk.
It confirms the link to long-term use of anticholinergics for depression, and also for Parkinson's disease (such as procyclidine) and loss of bladder control (for example, oxybutynin, solifenacin, and tolterodine).
However, the study found no link between increased dementia risk and other anticholinergic drugs, such as antihistamines and medications for abdominal cramps.
For their investigation, the researchers used data from the Clinical Practice Research Database, which contains anonymized records for more than 11 million people across the U.K.
Anticholinergic Cognitive Burden
The dataset used in the analysis included 40,770 dementia patients between the ages of 65 and 99 who were diagnosed during 2006–2015. Each of these was matched to up to seven people who did not have dementia but who were of the same sex and similar age.
The researchers used a system called the Anticholinergic Cognitive Burden (ACB) scale to score the anticholinergic effect of the drugs that the patients had been prescribed.
An ACB score of 1 meant that a drug was "possibly anticholinergic," whereas a score of 2 or 3 meant that it was "definitely anticholinergic." Altogether, they analyzed more than 27 million prescriptions.
The team reviewed the records of the patients and their matched controls to count all prescriptions and doses for drugs with an ACB score of 1–3 during the period covering 4–20 years before dementia diagnosis.
They found that 35 percent of the dementia patients and 30 percent of the controls had been prescribed at least one drug with a score of 3 on the ACB scale during that period.
The researchers then carried out a further analysis to take out the effect of factors that might influence the results.
The further analysis revealed that drugs with an ACB score of 3 that had been prescribed for depression, Parkinson's disease, and loss of bladder control were linked to higher risk of dementia up to 20 years "after exposure."
No such link was found, however, for drugs that scored 1 on the ACB scale, nor for respiratory and gastrointestinal drugs that scored 3.
Clinicians should 'be vigilant'
The researchers point out that due to the limitations of their study design, they cannot say whether the anticholinergics directly cause dementia or not.
One possibility is that the people taking the drugs are already in the very early stages of dementia.
But, because the link was present even when exposure took place 15–20 years before dementia was diagnosed, the authors argue that "reverse causation or confounding with early dementia symptoms are less likely explanations."
They advise clinicians to "continue to be vigilant with respect to the use of anticholinergic drugs," and to take into account possible long-term, and short-term, effects when they weigh up risks versus benefits.
Importance of the research
Dementia affects around 50 million people worldwide, and every year, 10 million more find out that they have the disease, which will eventually rob them of their ability to remember, think, hold a conversation, and live independently.
"This research is really important," explains study leader Dr. George Savva, who works in the School of Health Sciences at UEA, "because there are an estimated 350 million people affected globally by depression, and bladder conditions requiring treatment are estimated to affect over 13 percent of men and 30 percent of women in the U.K. and [United States]."
"Many of the treatment options for these conditions," he continues, "involve medication with anticholinergic effects."
"Developing strategies to prevent dementia is therefore a global priority."
Dr. George Savva
In an editorial article that is linked to the study, Prof. Shelly Gray, from the University of Washington in Seattle, and Prof. Joseph Hanlon, from the University of Pittsburgh in Pennsylvania, say that the authors did a good job of addressing the problem of how best to "summarize anticholinergic burden for future research."
They also agree that, in the meantime, "As suggested by guidelines, anticholinergics in general should be avoided in older adults."