Benzodiazepines, Z-Drugs Not Associated With Subsequent Dementia Risk

Use of benzodiazepines, Z-drugs, or other anxiolytics was not associated with incident dementia in either the cohort or nested case-control design.

Benzodiazepines or Z-drugs, regularly prescribed medications that have known cognitive side effects, are not associated with subsequent dementia risk in a large cohort study of Danish adults with affective disorders published in the American Journal of Psychiatry.

Merete Osler, MD, DMSc, of the Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospitals, Denmark, and Martin Balslev Jørgensen, MD, DMSc, of the Psychiatric Center Copenhagen, Denmark, conducted a cohort and nested case-control study of adult patients who had a hospital contact for an affective disorder between 1996 and 2015. Participants were identified from the Danish National Patient Registry, which comprises administrative and clinical data for all patients discharged from Danish nonpsychiatric hospitals since 1977. The primary outcome was incident dementia, defined per first hospital discharge diagnosis of dementia or first logged acetylcholinesterase inhibitor use.

Exposure to benzodiazepines, Z-drugs, and other anxiolytics was ascertained using the Danish National Prescription Registry. The investigators calculated cumulative exposure and intensity of use with number of prescriptions and prescribed daily doses, as well as hazard ratios (HRs) of incident dementia with Cox proportional hazards models. They used conditional logistic regression for the nested case-control analysis, in which patients with incident dementia were matched 1:4 with controls without dementia.

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The total study cohort comprised 235,465 patients (mean age at baseline, 73.2±11.7 years; 61.2% women) with any affective disorder discharge diagnosis. The median follow-up period was 6.1 years (interquartile range, 2.7-11 years), and 75.9% of patients had any use of benzodiazepines or Z-drugs during the study period.

Dementia was diagnosed in 9776 (4.2%) patients between 1996 and 2015, for an incidence rate of 57.1 per 10,000 person-years (95% CI, 56.0-58.2%). Use of benzodiazepines, Z-drugs, or other anxiolytics was not associated with incident dementia in either the cohort or nested case-control design. In fact, the cohort study appeared to demonstrate a protective effect of benzodiazepines during the first 2 years after study entry (adjusted HR [aHR], 0.74; 95% CI, 0.69-0.78).

In the nested case-control analysis, the odds of developing dementia were slightly elevated among patients with the lowest rate of benzodiazepine use compared with no use (odds ratio [OR], 1.08; 95% CI, 1.01-1.15). However, patients with the highest use had lower odds compared with the no-use strata (OR, 0.83; 95% CI, 0.77-0.88). This pattern was observed for all drug types: benzodiazepines, Z-drugs, as well as long-, medium-, and short-acting drugs.

These data challenge prior publications that suggest a relationship between benzodiazepine use and subsequent dementia risk. However, results must be extrapolated with care: the protective effect of benzodiazepines may be a result of depletion of susceptible cases, whereby mortality and other diseases preclude diagnosis of dementia. The investigators hypothesized that the potential protective effect of benzodiazepines may be a result of their beneficial effect on certain comorbidities, such as anxiety and insomnia.


Osler M, Jørgensen MB. Associations of benzodiazepines, z-drugs, and other anxiolytics with subsequent dementia in patients with affective disorders: a nationwide cohort and nested case-control study [April 7, 2020]. Am J Psychiatry. doi:10.1176/appi.ajp.2019.19030315