Pauline Anderson May 22, 2013

Older adults using anticholinergic (AC) medications for just 2 months to manage sleep problems, urinary incontinence, and other ailments could be at increased risk of developing mild cognitive impairment (MCI), a new study suggests.

The association between AC medication use and cognition appears to depend not only on the length of exposure but also on the strength of the medication burden. The study showed that the risk for cognitive impairment was increased by 50% in adults receiving at least 3 mild ACs for more than 90 days and by 100% in those receiving 1 or more severe ACs for more than 60 days.

The results highlight the importance of limiting prescriptions for ACs in older adults and helps fill some research gaps, said study author Malaz Boustani, MD, associate director, Indiana University Center for Aging Research, and associate professor, medicine, Indiana University School of Medicine, Indianapolis.

"Before, we didn't know if you would have a problem with cognition if you were exposed to ACs for just 1 day, or if it had to be 2 days, 3 days, 5 days, 6 days," he said. "Now, we know that if you've been exposed to stronger ACs, you need 60 days, and if you were exposed to a little bit milder ACs, you need 90 days."

The study was published online in the journal Alzheimer's & Dementia.

Cognitive Impairment

Participants were from the Indianapolis Dementia Screening and Diagnosis (IDSD) study, which targeted patients aged 65 years and older receiving primary care within the Wishard Health Services (WHS) system from January 2002 to October 2003.

They received a formal diagnostic assessment that included standardized neuropsychological testing, a neurologic examination, medical record review, and a structured interview. A team consisting of a psychologist, neuropsychologist, geriatrician, and geriatric psychiatrist made the final diagnosis of MCI or dementia.

Of the 3690 eligible participants, 562 were considered to have cognitive impairment requiring further evaluation, after they made at least 1 mistake on the 6-item screener that measures temporal orientation and new learning ability and then scored 24 or below on the abbreviated version of the Community Screening Instrument for Dementia, which evaluates multiple cognitive domains (language, memory, attention, and calculation, among others).

Of the 285 participants who completed the full diagnostic assessment, 129 received a diagnosis of dementia, 93 received a diagnosis of MCI, and 63 were normal.

The researchers merged the IDSD screening and diagnostic data with the Regenstrief Medical Record System, an electronic system that captures more than 85% of the drug-dispensing data of all participants receiving care within the WHS system.

A team of experts categorized medications as mild (an Anticholinergic Cognitive Burden [ACB] score of 1) or severe (an ACB score of 2 or 3). Exposure was based on the AC burden as well as on the duration of AC exposure and the number of ACs taken at the same time. Burden was categorized as no burden (receiving no drug with an ACB score), mild burden (receiving at least 1 drug with an ACB score of 1), and severe burden (receiving at least 1 drug with an ACB score of 2 or 3).

Drugs with mild AC effects were those with serum AC activity or in vitro affinity to muscarinic receptors, but no known clinically relevant negative cognitive effects. Those with established and clinically relevant cognitive AC effects were considered severe.

Exposure Patterns

Various exposure patterns showed that duration and burden increased cognitive impairment. Holding the AC burden at an ACB of 1 and the number of medications at fewer than 3, the study found that compared with patients with an exposure time of less than 90 days, those with an exposure time of 90 days or longer had a higher rate of cognitive impairment (19.69% vs 15.07%), although the difference was not statisticallysignificant (P = .16).

When the AC burden was held at an ACB of 1 but with the number of medications at 3 or more, the rates of impairment were 23.08% with exposure time of 90 days or more and 14.97% for exposure time of lessthan 90 days (P = .02).

There was a marginally significant difference for the patients with exposure time of 60 days or more vs those with less than 60 days: With an ACB of 2 or 3 and the number of medications at 1 or more, the rates of cognitive impairment were 22.5% vs 15.07% (P = .05).

Receiving at least 3 mild ACs for 90 days increased the odds of having a diagnosis of MCI by more than 170%, but this exposure didn't increase the probability of dementia diagnosis. "Most of the previous studies lumped MCI and dementia together, but in our study we were able to dissect them separately," said Dr. Boustani. "We found that these medications are a risk factor for the development of MCI, but they are not risk factor for developing dementia."

We found that these medications are a risk factor for the development of MCI, but they are not risk factor for developing dementia. Dr. Malaz Boustani

MCI is potentially a reversible condition, said Dr. Boustani. He noted that other research has concluded that the probability of converting from MCI back to normal cognition within 1 year is twice that of converting from MCI to AD.

"We have the opportunity to possibly reverse MCI if we stop exposure to these definite ACs, and perhaps stop progression to a more debilitating cognitive disorder such as AD."

Physicians "absolutely" overprescribe ACs, said Dr. Boustani. Patients might push for these drugs in the belief that if they simply take a pill, their symptoms will go away. Also, physicians typically don't have the time to discuss medication alternatives with individual patients. "They take the easy way out, which is to just simply spend 10 seconds writing a prescription," said Dr. Boustani.

Alternative Approaches

When possible, physicians should substitute AC medications with those that have fewer cognitive adverse effects or with nonpharmacologic alternatives, said Dr. Boustani. For example, he said, instead of taking oxybutynin (Ditropan, Janssen Pharmaceuticals) to treat urinary incontinence, patients could try pelvic exercise, biofeedback, and scheduled toileting.

For sleep problems, instead of "jumping" straight to diphenhydramine (Benadryl PM, McNeil-PPC), they might use sleep hygiene tactics, such as having a quiet, dim sleeping area and avoiding alcohol and other stimulants before bed, or they might use alternati
ve non-AC sleep aids. And patients with peripheral neuropathy might take gabapentin (Neurontin, Pfizer) instead of nortriptyline.

All too often, said Dr. Boustani, patients continue to take AC medications even when they're not working.

A limitation of the study was the presence of undetected cases of dementia or MCI in the cognitively normal group. The study also did not systematically measure medication adherence or include AC burden from over-the-counter medications and did not account for possible confounding factors, such as socioeconomic status, education level, depressive symptoms, APOE genotype, and alcohol and tobacco use. There is also the "remote" possibility that patients with unrecognized cognitive symptoms might be treated more with ACs, said the authors.

Asked for his views of the study, Chris Fox, MD, Dementia Research Innovation Group, Norwich School of Medicine, United Kingdom, who has researched ACs in dementia, noted that it's the first to look at the threshold of time exposure to medicines with AC effects.

However, he said, while the study found that 3 months of exposure increases the risk for MCI, "we do not know from this data whether this leads to increased risk of more persistent cognitive impairment."

To address that question, said Dr. Fox, 3 things are needed: a larger sample size, longer duration of follow-up, and better methods of assessing whether people prescribed these medicines are actually taking them.

Dr. Boustani was supported by the Paul A. Beeson Career Development Award in Aging from the National Institute on Aging, the Hartford Foundation, the Atlantic Philanthropy, and the American Federation of Aging Research. Dr. Fox has disclosed no relevant financial relationships.

Alzheimer's & Dementia. Published online November 26, 2012. Abstract

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