Benzodiazepines, Z-drugs do not increase dementia risk

Use of benzodiazepines and nonbenzodiazepines, or Z-drugs, did not appear associated with subsequent dementia, according to results of a nationwide cohort and nested case-control study published in American Journal of Psychiatry.

Researchers arrived at this conclusion after cumulating or dividing exposures into long- and short-acting drugs.

“Current evidence on benzodiazepines and dementia risk suggests that larger studies with enough power to infer differences between long-acting and short-acting benzodiazepines, and between various exposure loads (duration and dose), are needed,” wrote Merete Osler, MD, DMSc, of the Center for Clinical Research and Prevention at Bispebjerg and Frederiksberg Hospitals in Denmark, and Martin Balslev Jørgensen, MD, DMSc, of Psychiatric Center Copenhagen. “However, the largest limitation of previous observational studies is inappropriate adjustment for factors associated with selection into treatment (confounding by indication). Affective disorders are closely associated with dementia risk and often prompt initiation of treatment with benzodiazepines, and when affective disorders are not considered, a flawed association between initiation of benzodiazepines and dementia may be present.”

Although prior cohort studies have been based largely on older populations and benzodiazepine use in terminal care, none accounted for competing mortality. In the current study, the investigators aimed to determine the association of benzodiazepines, Z-drugs and other anxiolytics with incident dementia among patients with affective disorders. Using the Danish National Patient Registry, they conducted a cohort and nested case-control study of 235,465 patients aged older than 20 years who had a first-time hospital contact for an affective disorder between 1996 and 2015. From a separate registry, they obtained information on all benzodiazepine, Z-drug and other anxiolytic prescriptions, and they followed patients for incident dementia, defined by hospital discharge diagnosis or acetylcholinesterase inhibitor use. They calculated HRs and ORs with adjustment for sociodemographic and clinical variables using Cox proportional hazards and conditional logistic regression models.

Among the patients, 171,287 (75.9%) had any use of benzodiazepines or Z-drugs. During median follow-up of 6.1 years, 9,776 (4.2%) received a dementia diagnosis. After multiple adjustments in either the nested case-control design or cohort analysis, the investigators found no association between any use of benzodiazepines or Z-drugs and dementia. In the cohort analysis, the cumulated dose and number of prescriptions of benzodiazepines or Z-drugs at baseline were not linked to dementia. In the nested case-control study, which included prescriptions counted from 1995 until 2 years before the index date, the researchers reported a slightly higher OR of dementia among patients with the lowest use of benzodiazepines or Z-drugs (OR = 1.08; 95% CI, 1.01-1.15) compared with no lifetime use; however, those with the highest use had the lowest odds of developing dementia (OR = 0.83; 95% CI, 0.77-0.88).

“The adverse effects of benzodiazepines on cognition and studies reporting elevated risk with any use of benzodiazepines have fueled the fear of dementia among patients and clinicians,” the researchers wrote. “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 [for] dementia.” – by Joe Gramigna

Disclosures: The authors report no relevant financial disclosures.