Benzodiazepine, Z-Drug Use: No Dementia Risk?

Michael Vlessides

May 08, 2020

There is no association between the use of benzodiazepines or related anxiolytics, commonly referred to as Z-drugs, and subsequent dementia in patients with affective disorders, new research suggests.

A large cohort study of nearly a quarter million Danish citizens showed there was no link between the use of benzodiazepines and increased dementia risk even after multiple adjustments in both a cohort analysis and nested case-control design.

Interestingly, these findings held even with cumulative exposure or exposure to long- or short-acting agents.

"We didn't find any association, either between benzodiazepines or with Z-drugs and the risk of dementia. These findings are aligned with some studies in the literature, but not others," Merete Osler, MD, DMSc, of the Center for Clinical Research and Prevention at Bispebjerg and Frederiksberg Hospitals in Frederiksberg, Denmark, told Medscape Medical News

The study was published online April 7 in the American Journal of Psychiatry.

Commonly Prescribed Drugs

Benzodiazepines and Z-drugs are among the most commonly prescribed medications worldwide, largely because of their efficacy in patients with anxiety disorders.

Nevertheless, studies have documented potential hazards associated with their use, including cognitive side effects, leading researchers to investigate whether they may influence long-term dementia risk.

A recent meta-analysis of five cohort studies and 10 case-control studies found higher odds ratios (pooled odds ratio = 1.38; 95% confidence interval [CI], 1.07 – 1.77) of dementia associated with any benzodiazepine use.

However, Osler noted, more studies with adequate sample sizes are needed to tease out possible differences in the effects of long-acting and short-acting agents as well as various doses and treatment durations on subsequent dementia risk.

"A number of studies have examined the association between benzodiazepines and the risk of dementia; fewer have looked at Z-drugs and dementia," said Osler. "However, most have been based on rather small populations and have been insufficiently powered to study the effect of dose," she said.

The investigators note the "largest limitation" of previous observational studies is a failure to adjust for indication, which can confound results. They also point out that many affective disorders are themselves associated with increased dementia risk.

"Many previous studies have not sufficiently accounted for the problem of confounding by indication. One of the major indication for benzodiazepines is depression, which is also associated with an increased risk of dementia," said Osler.

"If you do not account for this comorbid disorder in your analysis, then you can get some flawed associations. But in our study, we only examined patients with depression, so that we accounted for this confounding by indication," she added.

For the study, Osler and coinvestigator Martin Balslev Jørgensen, MD, DMSc, analyzed prescription registry data for a cohort of 235,465 adult patients (aged 20 years or older) who were identified in the Danish National Patient Registry as having had a first-time hospital contact for an affective disorder between 1996 and 2015.

National Registry Data

The researchers attempted to limit the potential for confounding by indication by limiting the analysis to patients with depression subtypes; these included manic or bipolar disorder, several different levels of single or recurrent depression, and persistent or unspecified affective disorder.

Patients were followed for incident dementia, which was defined either by hospital discharge diagnosis or by the use of acetylcholinesterase inhibitors.

Prescription data regarding use of benzodiazepines, Z-drugs, and other anxiolytics came from the Danish National Prescription Registry. Prescriptions were classified as short-acting, medium-acting, or long-acting.

The investigators assessed confounding by indication by including drugs also used for anxiety as a negative control exposure.

Results showed that more than three quarters of the patients (75.9%; n = 171,287) used any benzodiazepines or Z-drugs. Most (55.7%) used both benzodiazepines and a Z-drug. The most frequently prescribed Z-drugs were zopiclone, oxazepam, and diazepam.

Benzodiazepine and Z-drug use was more common among middle-aged patients with severe single-episode or recurrent depression, as well as those who were undergoing treatment with antipsychotics or antidepressants at study entry.

During a median follow-up period of 6.1 years, 9776 patients (4.2%) were diagnosed with dementia. Those who developed the disorder were more likely to be at least 70 years old, less educated, widowed, and to have diabetes or cardiovascular disease.

After multiple adjustments for both sociodemographic and clinical variables in the cohort analysis and nested case-control design, results showed that there was no association between any use of benzodiazepines or Z-drugs and an increase in risk for incident dementia.

Similarly, there was no association between cumulative benzodiazepine/Z-drug consumption and dose and increased dementia incidence.

Protective Effect?

In the nested case-control portion of the investigation, in which prescriptions were counted from 1995 until 2 years before the index date, there was a slightly higher odds ratio of dementia in patients with the lowest use of benzodiazepines or Z-drugs (odds ratio, 1.08; 95% CI, 1.01 – 1.15) compared to those who had no lifetime use.

Similarly, patients with the highest use had the lowest odds of developing dementia (odds ratio, 0.83; 95% CI, 0.77 – 0.88).

This pattern proved consistent across all drug types, including long-acting, medium-acting, and short-acting drugs. Estimates for drug intensity were similar to those for cumulative dose.

In fact, long-term benzodiazepine use may actually have a protective effect on dementia risk among patients with an affective disorder. Osler suggested this may be due to benzodiazepines' beneficial effect on comorbid anxiety and insomnia, which are also associated with increased dementia risk.

Given these findings, the investigators conclude that concerns regarding the use of benzodiazepines and Z-drugs on cognition and dementia may be unfounded, notwithstanding any other possible adverse short-term or long-term effects the drugs may cause.

"I think doctors could use them, at least if they have patients who have very severe anxiety, because these patients seem to have a better life when they get benzodiazepines or, if they have problem with sleeping, to get a Z-drug.

"Of course, patients may be nervous about the potential for dementia, but I believe physicians could confidently say that they don't think taking this drug will be associated with an increased risk of dementia," Osler said.

Nevertheless, she said, physicians should temper their patients' use of these agents, given the potential for other adverse effects.

"For one thing, they are addictive," she noted. "And patients might develop tolerance so that you need more and more drugs to achieve the desire effect."

"Convincing" Results

Commenting on the findings for Medscape Medical News, Christer Allgulander, MD, of Uppsala University in Sweden, who was not involved in the study, described the findings as "convincing."

"Patients, relatives, and physicians have guilty feelings over the use of benzodiazepines. Physicians refrain from prescribing them for fear of inducing dependence, hip fractures, dementia, and more...and to be reported for violating guidelines, guidelines that clearly have a Calvinistic bias when it comes to treating anxiety and insomnia," he said.

Allgulander noted that physicians do a service to their patients with depression when they distinguish between proper use of benzodiazepines/Z-drugs and potential misuse.

"By failing to make the distinction between legitimate treatment of anxiety and insomnia and nonmedical use, physicians withhold the safe and effective amelioration of such ill health effects as risk of cardiovascular disease, dementia, and self-medication with alcohol," he said.

"The ethical thing to do is to assess the impairment caused by anxiety and insomnia and then provide safe and effective pharmacological relief, which even reduces suicide risk in the depressed patient with severe anxiety and insomnia," Allgulander added.

Osler agreed. "For some patients with depression, benzodiazepines and Z-drugs help them lead a normal life. In some ways, it may be more dangerous for these patients to have untreated depression or anxiety than it is to get these drugs."

The research was supported by the Danish Council for Independent Research. Osler and Allgulander report no relevant financial conflicts.

Am J Psychiatry. Published online April 7, 2020. Abstract

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