There is a strong and possibly irreversible link between
Alzheimer’s disease and many commonly used medications for insomnia, allergies,
and depression, according to a large recent JAMA Internal Medicine study.
Three years of taking either daily Benadryl, Advil PM,
Tylenol PM, or Motrin PM, for example, is associated with about a ten
percentage point increase in the probability of experiencing dementia or
Alzheimer's compared to no use. This risk association is
"significant," claims Malaz Boustani, M.D., M.P.H.
Boustani, director of the Aging Brain Care Program at
Eskenazi Health in Indianapolis, Indiana, was not involved in the study. But he
has done smaller scale work making similar findings. This was the largest study
ever, and utilized the most rigorous standards ever, he said.
“Methodologically, this is the best you can get; it doesn’t get better than
this. This has established a significant link between anticholinergic drugs and
Alzheimer’s." Very few other phenomena have been found to possess such a
strong potential link. “It is rare,” he said.
The new study
Many groups have suggested such links. But for the
current study, the team of senior author Eric Larson, M.D., M.P.H., of the
University of Washington (UW), engaged in longer follow up (over seven years),
and utilized a tighter assessment of use. The study followed some 3,500 Group
Health participants, average age 73, with the Adult Changes in Thought (ACT)
study, which is a Group Health/UW project funded by the National Institute on
Aging.
The group showed for the first time a dose response; that
is, that Alzheimer’s risk may grow with higher use. For instance, it found that
people, taking a minimum of 25 mg of an anticholinergic, called diphenhydramine
(or one Advil PM, Tylenol PM, Motrin PM, or Benadryl pill) a day for three to
12 months, have increased their relative risk for dementia by 19 percent. If
they take it from one to three years, so 23 percent; and for three to seven
years of use, 54 percent compared to no use at all, which represent the
significant statistical difference.
Furthermore, this was the first study to find that
dementias associated with anticholinergics may not be reversible even years
after drug use stops. Wrote Boustani and the Indiana University Center for
Aging Research’s Noll Campbell, Pharm.D., in a JAMA editorial: “The risk for
dementia was consistent when comparing participants with recent and past heavy
use of such medications with nonusers, suggesting that the adverse cognitive
effects are permanent. Other studies have consistently shown similar results.”
Alternatives
Lead author Shelly Gray, who is director of the geriatric
pharmacy program at the UW School of Pharmacy, found the link in a wide range
of anticholinergics, from tricyclic antidepressants like doxepin (Sinequan), to
above-mentioned "PM" products with diphenhydramine, to
first-generation antihistamines like chlorpheniramine (Chlor-Trimeton) and
Benadryl, and antimuscarinics for bladder control like oxybutynin (Ditropan).
The team came to the conclusion, for example, that people taking at least 10
mg/day of doxepin, 4 mg/day of chlorpheniramine, or 5 mg/day of oxybutynin for
more than three years are at greater risk for developing dementia.
Gray herself was truly surprised by such findings. “There
was one prior study that examined this study question, but we thought we might
not find these medications were related to dementia because we had a better
study design, and were able to better adjust for some health conditions that
might be confounders through use of statistical methods,” she told Drug
Discovery & Development. “We know that anticholinergics are related to
impaired cognition acutely when people take these medicines. They feel a little
groggy, less attentive, etc. But these are reversible changes. This study
suggests these medicines are also related to dementia, or irreversible
cognitive changes.”
Substitutes are available for some of the problems
addressed by anticholinergics. Those suffering from depression can take a
selective serotonin re-uptake inhibitor (SSRI) like citalopram (Celexa) or
fluoxitene (Prozac). Those with allergies can take a second-generation
antihistamine like loratadine (Claritin). Behavioral changes can help urinary
incontinence.
Boustani, who is also a professor of medicine at Indiana
University, told Drug Discovery & Development that, when it comes to
insomnia medications, “basically any cold medications that make you sleepy
might contain anticholinergics, so stay away from drugs that make you sleepy.”
NyQuil is an exception, he said. It makes people sleepy, but does not contain
an anti-cholinergic. Still, “if your solution for a sleep problem is a pill, a
quick fix, do you want that?” Any drug taken for a long time could come with
problems. “I tell people, if they have to take any such drug for more than 30
days, they should think about alternatives. Maybe you should just take it easy.
Maybe you should adopt Grandma’s Remedy of hot milk, hot tea, and rest.
Physical fitness is always good. Mindfulness, reflection, physical fitness, tea.”
The cause
The cause of this potential link is unknown and yet to be
discovered. Anticholinergics can block the neurotransmitter acetylcholine. “But
there are many hypotheses” as to why anticholinergics can lead to Alzheimer’s,
Boustani told Drug Discovery & Development. “The current medication for
Alzheimer’s, Aricept, does the opposite of what Benadryl does, for example. We
think that same pathway is involved. So anticholinergics may reduce the
function of acetyl receptors, and may end up killing the brain cells.”
Gray agreed, that “we do not yet know the mechanism by
which anticholinergics may increase risk for dementia. It is possible that long-term
use of these medications leads to changes in the brain similar to those seen
with Alzheimer’s disease, such as neuritic plaques and neurofibrillary tangles.
In animal models, procedures that blocked transmission through these kinds of
pathways increased the concentration of beta-amyloid, a main ingredient in the
plaques found in the brains of patients with Alzheimer’s disease.”
Nothing is likely to be fully nailed down anytime soon as
it would be unethical to do a gold standard clinical trial. Clinical trials can
be done to prove benefit. But to prove a deficit would mean doctors would have
to assign patients to take say, Advil PM, every night for three years to assess
damage.
The recent trial also did not factor in two other classes
of common drugs tapped by the American Geriatrics Society as associated with
cognitive problems: benzodiazapines (recently found to hamper rodent
neurogenesis) and histamine receptor antagonists.
But even given these limitations, this trial, with its
seven years of data, was “very, very good,” Boustani said. Via computerized dispensing, doses and uses
were well established. Potential confounding variables—like people taking
anticholinergics for depression or insomnia precisely because they were in the
grips of an undiagnosed dementia already—were weeded out.
Boustani’s crew is working on a mobile application to help
people figure out what drugs to avoid. In the meantime, he directs clinicians
and patients to a chart by the Aging Brain Care website that lists drugs
containing anticholinergics.
Gray’s group is in the process of “examining whether
these medications are related to changes in the brain of a subsample of this
study cohort that has been autopsied after death,” she told Drug Discovery
& Development. “We will be examining whether those who used
anticholinergics had higher plaques, tangles and other markers of
cerebrovascular disease than those who did not use these medications.”
Do not be scared
easily!
Dr. Alan Manevitz, a clinical psychiatrist at Lenox Hill
Hospital in New York City, noted that occasional use of these medications did
not seem to be tied to a rise in dementia risk. "The risk of dementia was
due to a cumulative total of exposure, not to an acute short course of
treatment," he said.
According to Manevitz, "we need to educate patients
and their families about over-the-counter medicines and alternative therapies.
Also, elderly people in nursing homes tend to have a long list of medicines
that need to be reviewed periodically for need to continue, interactions and
redundancy."
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