No Association Found Between Benzodiazepines, ‘Z-Drugs,’ Dementia

Benzodiazepines and the non-benzodiazepine sedatives known as “Z-drugs”—zolpidem, zopiclone, and zaleplon—do not appear to be associated with later dementia, according to a report in AJP in Advance.

The population-based cohort study, drawn from data on more than 230,000 people in a Danish national registry, found no association with later dementia even when exposure to the drugs was cumulated or when short- and long-acting formulations were compared.

Moreover, the drugs may even have a protective effect against dementia, according to authors Merete Osler, M.D., D.M.Sc., of the Center for Clinical Research and Prevention at Bispebjerg and Frederiksberg Hospital, and Martin Balslev Jørgensen, M.D., D.M.Sc., a clinical professor in the Department of Clinical Medicine at the University of Copenhagen.

Previous research has indicated an effect of benzodiazepines on various aspects of cognition, fueling concern about risks for dementia among patients and clinicians, Osler and Jørgensen wrote. They acknowledged, moreover, that they may have other adverse effects, particularly when used for long periods.

But the Danish study appears to settle the controversy about the link between the drugs and dementia. “This study demonstrated that notwithstanding other possible adverse short-term or long-term effects, there is not sufficient evidence that benzodiazepines or Z-drugs increase the risk of dementia,” wrote the authors.

The authors analyzed data on 235,465 Danish citizens over age 20 identified in the Danish National Patient Registry as having had a first-time hospital contact for an affective disorder (defined by ICD diagnosis code) between 1996 and 2015. They obtained information on prescriptions for benzodiazepines, Z-drugs, and other anxiolytics written for the patients in the cohort. Patients were followed through 2016 for first evidence of dementia, defined by hospital discharge diagnosis or use of medication for dementia.

Among the cohort with affective disorders, 171,287 (75.9%) had any use of benzodiazepines or Z-drugs. Most patients (55.7%) had used both benzodiazepines and a Z-drug, and the most frequently prescribed medications were zopiclone, oxazepam, and diazepam.

The researchers also determined that among the cohort, a total of 9,776 patients developed dementia.

Adjusting for multiple socioeconomic, demographic, and clinical variables, the authors found no association between any use of benzodiazepines and Z-drugs (alone or in combination) and dementia. Moreover, the number of prescriptions and cumulated dose of benzodiazepines or Z-drugs were not associated with dementia.

Osler and Jørgensen also conducted an analysis looking at the 9,776 individuals with dementia and matched patients without dementia. In that analysis, those using the lowest dose of benzodiazepines had a slightly higher risk of dementia than patients with no lifetime use of the medications.

However, those using higher doses had a lower risk, suggesting a protective effect. “This may be … attributed to an inhibitory effect of benzodiazepines on excitotoxic or other pathological lesions or symptoms [associated with dementia],” the authors wrote. “Anxiety and insomnia are frequent in these patients and are also associated with risk of dementia. Thus, benzodiazepines may also exert a beneficial effect through treatment of these comorbidities.”

Addiction psychiatrist Petros Levounis, M.D., M.A., chair of psychiatry at Rutgers New Jersey Medical School, told Psychiatric News that the study is remarkably strong—it draws on a large population database in a country with universal health coverage, which ensures that all members of the cohort had equal access to medical care. “On the issue specifically of dementia, this is a methodologically sound study that seems to be conclusive,” he said. “These drugs do not appear to be related to dementia.”

But Levounis said benzodiazepines and Z-drugs carry other risks that still require clinicians and patients to be judicious in their use. “In psychiatry there are two camps—one that says ‘I recognize the possible adverse effects and addictive potential, but there are patients who really benefit from these drugs,’ and another camp that says ‘I recognize the beneficial effects in some patients, but these drugs are addictive and have other adverse effects.’ ”

As an addiction psychiatrist, Levounis said that he falls in the latter camp. “These drugs have sedating effects, and an especially significant risk for psychiatrists to pay attention to is falls in elderly patients,” he said.

Levounis advised psychiatrists to be judicious when prescribing benzodiazepines and sedating drugs. Osler and Jørgensen also suggested that these medications should ideally be confined to short-term use. “[M]any older people and patients with severe anxiety and sleeping problems benefit from using benzodiazepines and Z-drugs as recommended for short-term treatment,” they wrote.

The study was supported by a grant from the Danish Council for Independent Research. ■

“Associations of Benzodiazepines, Z-Drugs, and Other Anxiolytics With Subsequent Dementia: A Nationwide Cohort and Nested Case Control Study” is posted here.