Yet another study has linked benzodiazepine use to an increased risk for Alzheimer’s disease (AD).

“Even though the association between benzodiazepine use and Alzheimer’s disease was small in this study, the threshold for prescribing these drugs should be high enough due to their overall adverse effect profile, including higher risk of falls and hip fractures,” lead author Vesa Tapiainen, MD, PhD, a student in the School of Pharmacy, University of Eastern Finland, Kuopio, told Medscape Medical News.

These drugs are often used to treat sleep problems, but their efficacy for this indication diminishes over time, whereas the risks for adverse events remain, she added.

“Physicians should consider the risks and benefits, as well as appropriate duration of treatment, before prescribing these drugs,” said Tapiainen.

Although other studies have linked benzodiazepines with AD risk, Tapiainen believes this one is the largest to date.

The study was published in the August issue of Acta Psychiatrica Scandinavica.

Widely Used

In addition to insomnia, benzodiazepines and other so-called “Z” drugs, such as zolpidem (multiple brands) and zopiclone (Lunesta, Sunovion), are used to treat other neuropsychiatric symptoms of dementia, such as anxiety.

Although these drugs have different molecular structures, they have a similar mechanism of action and similar anxiolytic, anticonvulsive, hypnotic, and relaxing effects. In addition, they have similar adverse effects, including drowsiness, and their use is associated with mobility problems, falls, and fractures.

Benzodiazepines are used in 9% to 32% of older patients, the authors report.

The researchers used the Medication Use and Alzheimer’s Disease (MEDALZ) cohort, which includes all 70,719 residents of Finland. The patients selected for the study had been diagnosed with AD between 2005 and 2011. The patients’ ages ranged from 34 to 105 years. The study also included 282,862 matched control persons from nation-wide registers.

AD diagnoses were based on criteria from the DSM‐IV, as well as from the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association, now known as the Alzheimer’s Association.

Investigators extracted information on drug use from the Finnish Prescription Register. They looked at short-, medium- and long-acting benzodiazepines and related drugs.

In addition, the researchers examined different durations of drug use (1 day to 1 month; 1 month to 1 year; 1 to 5 years; and more than 5 years), and cumulative consumption in defined daily doses (DDDs), divided by tertiles.

“Worrying” Results

To account for reverse causality, the researchers investigated drug use only from 1995 to 5 years before AD diagnosis.

They controlled for various chronic disorders, including asthma/chronic obstructive pulmonary disease, cardiovascular disease, and diabetes, as well as for substance abuse, socioeconomic status (SES), and use of antidepressants and antipsychotics. All confounders were extracted until 5 years before the AD diagnosis.

Results showed that compared to individuals who had not used any of the relevant drugs, any use was associated with an increased risk of AD (odds ratio [OR], 1.19, 95% confidence interval [CI], 1.17 – 1.21).

After adjusting for comorbidities, SES, and use of other psychotropic medications, the association was somewhat lower (OR, 1.06; 95% CI, 1.04 – 1.08).

Using statistical calculations, the authors determined that the proportion of AD cases that could be attributed to exposure to these drugs was 5.7%.

Although the authors acknowledge that the increased absolute risk is modest, they point out that because these drugs are frequently used in older people, even a small increase in risk may be important.

“This is worrying,” the investigators note, not only because these drugs are commonly used by older patients but also because, despite recommendations, they’re often used long term in this population of patients.

In this study, the AD risk with all drugs was highest in patients who used the drugs for longer than a year. In the fully adjusted model, there were no risks for use during periods of less than a month.

The risks and benefits of these drugs should be reevaluated regularly, stressed Tapiainen.

She added that targeting the causes of sleep problems in patients and using nonpharmacologic treatments “should be prioritized.”

The relationships uncovered by the authors were similar for the various drugs and for short-, medium- and long-acting formulations.

Puzzling Finding

Interestingly, lower average doses (<0.5 DDD/day) of many of the drugs increased the AD risk more than higher doses in the unadjusted model.

“We were puzzled by this observation and investigated it in more detail,” said Tapiainen. “This investigation revealed that those who used the highest average doses actually used these drugs for a shorter period of time, and so their total consumption was less.”

In addition, high and low doses may have been used for different indications.

The authors noted that the dose-response relationship that was uncovered for both cumulative consumption and duration was lessened in the highest drug dose category after adjusting for use of other psychotropics.

“This indicates that the association may be partially due to antidepressants and/or antipsychotics, or concomitant use of these medications,” said Tapiainen.

When asked whether the relationship between drug use and AD risk was more pronounced among the oldest patients in the study, Tapiainen said she and her colleagues did not investigate this in the published study.

“But because we found this question interesting, we did further analysis and found that the association was similar regardless of age,” she said.

A limitation of the study was that it did not include data regarding nonreimbursed drugs or drugs used in hospital.

Plausible Risk

Commenting on the findings for Medscape Medical News, David S. Knopman, MD, professor of neurology, Mayo Clinic, Rochester, Minnesota, and a member of the Alzheimer’s Association Medical and Scientific Advisory Council, noted that many studies have suggested that patients who are exposed to certain psychoactive drugs, such as those with cholinomimetic properties, are at increased risk for dementia.

“I therefore find it plausible that benzodiazepines and related drugs could carry the same risks,” he said.

However, he added that the risk uncovered in this current study was “very modest.”

When the authors refer to “risk of Alzheimer’s” they mean “risk of dementia,” said Knopman. “They have no evidence from either neuropathology or biomarkers that the affected individuals had amyloidosis and tauopathy — so Alzheimer’s disease in the biological sense of the word.”

Tapiainen noted that all AD cases in the study were clinically verified with CT/MRI and that the diagnoses were confirmed by a registered neurologist or geriatrician.

The “bottom line” for Knopman is the same — that use of certain psychoactive drugs seems to increase the risk for dementia.

However, it is unclear whether the drugs are temporarily worsening cognition or symptoms are being treated with these drugs, said Knopman.

“In other words, the direction of causality from drugs to dementia could go in either direction, and this study that used administrative data can’t determine the direction of causality,” he said.

Nevertheless, a take-home message is that benzodiazepines and related sleep medications should be avoided “if at all possible” in older individuals, said Knopman.

Also weighing in on the findings for Medscape Medical News, Ronald Petersen, MD, PhD, director, Alzheimer’s Disease Research Center, Mayo Clinic, agreed that it is “appropriate” to be cautious about benzodiazepine use.

Petersen said he found the study “interesting,” although he “would want to be certain the clinical diagnoses were not confounded by benzodiazepine use prior to testing.”