Benzodiazepine Use and the Risk of Dementia

CLINICAL

Available evidence indicates that benzodiazepines are commonly used to treat various disorders including anxiety, insomnia, agitation, alcohol withdrawal, and seizures.¹ The prevalence of benzodiazepine use among older adults in the United States is approximately 8.7%²; but it has been noted that approximately 44% of the prescriptions for benzodiazepine among older adults are potentially inappropriate.³ (The 2019 American Geriatrics Society Beers Criteria identifies benzodiazepines as potentially inappropriate medications for use among older adults.⁴) Factors associated with long-term use of benzodiazepines include the following: female sex, a diagnosis of Alzheimer disease (AD), schizophrenia, bipolar disorder, depression, coronary artery disease, and asthma/chronic obstructive pulmonary disease.⁵

Consequences of Benzodiazepine Use

The use of benzodiazepines is known to be associated with poor outcomes.^3,6-8 One study found that benzodiazepine use was associated with greater risk for hospitalizations, emergency department visits, outpatient visits, and higher health care costs.³ Another study found the overdose death rate increased due to benzodiazepine use from 0.58 to 3.07 per 100,000 adults between 1996 and 2013.⁶ Benzodiazepines use is also associated with an increased risk of falls among older adults.⁷ Additionally, the use of benzodiazepines is associated with a 60% to 80% increase in the risk of traffic accidents.⁸ The co-ingestion of benzodiazepines and alcohol is associated with a 7.7-fold increased risk for traffic accidents.

Now, there is also emerging evidence that the use of benzodiazepines may increase the risk for developing dementia among older adults.^9-11 This review evaluates the evidence from the literature on the association between benzodiazepine use and the risk for developing dementia.

Exploring the Literature and Evidence

A review of the literature indicates that there is a total of 15 studies that have evaluated the association between benzodiazepine use and the development of dementia.^12-26 Four of the 15 studies were published prior to 2010^12-15 and 11 of the studies were published since 2010.^16-26

Although there are no randomized controlled trials (RCTs) looking at the association between benzodiazepine use and the risk for dementia, 6 prospective cohort studies,^{12,14,17,22,23,25} 6 case control studies,^{13,15,16,20,21,24} and 1 retrospective cohort study18 explore the relationship. Two studies had both a prospective cohort and a case control component.^19,26 Three of the studies were conducted in France,^13,19,22 3 in Taiwan,^15,16,18 3 in Canada,^14,20,25 2 in the United Kingdom,^{17, 21} and 1 each in Sweden,14 the United States,²³ Switzerland,²⁴ and Denmark^.26

Of the 15 studies, 8 showed a positive association between benzodiazepine use and the development of dementia.^{13,15,16-20,22} Of these 8 studies, 2 were prospective cohort studies,^17,22 4 were case control studies,^13,15,16,20 and 1 was a retrospective cohort study.¹⁸ One positive study had a prospective cohort and a case control arm to the study.¹⁹

Four studies found benzodiazepines were not associated with the development of dementia.^21,24,25,26 The negative studies included 2 case control studies,^21,24 1 prospective cohort study,²⁵ and 1 study that had a prospective cohort and a case control arm.²⁶

Two studies showed mixed results.^14,23 One study found that previously using benzodiazepines was associated with the development of dementia, but current use was not.¹⁴ The other study found that short-term use of benzodiazepines was associated with the development of dementia, but long-term use was not.²³ Finally, 1 prospective cohort study found that the use of benzodiazepines had a protective effect against the development of dementia.¹²

More than half of the studies (8 out of 15, 53%) identified in the literature search showed a positive association between benzodiazepine use and the development of dementia. It is unclear whether there is any significant difference between men and women. This is true with higher doses; when the duration of use is shorter; for current users; for shorter-acting drugs; and study design (eg, cohort studies). (see Table)

Discussion

Despite the evident association between benzodiazepine use and the development of dementia, a causality cannot be established, as none of the identified studies were RCTs.

Three important reviews have evaluated the association between benzodiazepine use and the development of dementia.^27-29 In the first review, the investigators evaluated 3 studies that found an increased risk of cognitive decline among those using benzodiazepine, and 2 studies that found a lower risk of cognitive decline in former or ever users of benzodiazepines, and 2 studies that found no association between the use of benzodiazepines and the development of dementia.²⁷ In another review that evaluated 10 studies, the investigators found that 9 studies showed an increased risk of dementia among those who used of benzodiazepines.²⁸ The investigators opined that the risk of dementia increases with cumulative doses of medication, longer treatment duration, and when long-acting agents are used. In the third review that evaluated data from 11 studies, the investigators found positive association between benzodiazepine use and the development of dementia from 9 studies.²⁹ One study found a protective effect for benzodiazepine use, and 1 study found no effect for benzodiazepine use and the development of dementia.

Three recent meta-analyses evaluated the risk of developing dementia among individuals who use benzodiazepines.^30,31,32 In the first meta-analysis, which included data from 6 studies, the investigators found the pooled adjusted risk ratios (aRRs) for the development of dementia was 1.49 for those who have used benzodiazepines, 1.55 for those who recently benzodiazepines, and 1.55 for those who have previously used benzodiazepines, when compared with never users of benzodiazepines.³⁰ The researchers stated the risk for dementia increased by 22% for every additional 20 defined daily doses of the drug per year (aRR=1.22).

The second meta-analysis that included data from 10 studies found the odds for developing dementia was higher by 78% among users those who were using benzodiazepines when compared to those who were not (OR=1.78)^.31 The investigators found a higher association when the studies were from Asia (OR=2.40), and a moderate association when the studies were from North America and Europe (OR=1.49).

The third meta-analysis that included data from 12 prospective and retrospective cohort studies and case-control studies found that benzodiazepines can be a risk factor for the development of dementia (OR=1.38).³² The investigators concluded that the current evidence lacks the power to differentiate between the risks for the development of AD versus vascular dementias (VD), the risks when using long-acting versus short-acting benzodiazepines, and the risks based on the duration and the doses of the drugs that are used.

In his recent editorial in the American Journal of Psychiatry, Carl Salzman, MD, provided a counterpoint to the question on whether benzodiazepines cause AD.³³ Salzman stated that “there is little doubt that benzodiazepines like other sedative hypnotics may be associated with impaired cognition which is usually mild and dose-dependent.” He reported that the usual recommendations include only short half-life benzodiazepines at low doses and, if clinically possible, for brief periods of time. Salzman opined that future studies are needed regarding benzodiazepines’ and other medications’ possible associations with the development of late-life cognitive disorders. Until then, he advised that we must assume that the appropriate use of benzodiazepines will not lead to the development of AD. One caution with this editorial is that it cites a limited number of studies evaluating the association benzodiazepines and AD, and it is difficult to develop any definitive conclusions based on these studies.

The available evidence for the association between benzodiazepine use and the development of dementia should be evaluated based on the heterogeneity between the studies and limitations of each of these studies. These studies were conducted in different countries and had differing methodologies. In addition, many studies did not control for confounding variables including educational attainment, the presence of depression, anxiety, insomnia, and alcohol use. Also, 4 studies used the older DSM III-R criteria for the diagnosis of the dementia, causing concerns regarding the validity of the diagnosis. It is unclear whether the observed association between the use of benzodiazepines and the development of dementia is really a causal effect, or the result of unmeasured confounding variables, as none of these studies were RCTs.

Protopathic bias occurs when a pharmaceutical agent has been inadvertently prescribed for an early manifestation of a disease that has not yet been diagnostically detected. A prolonged lag phase between the first appearance of brain pathology associated with dementias, the development of clinical symptoms that may be risk factors for dementias including anxiety and depression, and the actual clinical diagnosis of dementia has led to investigators citing protopathic bias or “reverse causality” as the main area of controversy regarding the association between benzodiazepine use and the development of dementia.²⁹ To prove a definitive association between benzodiazepine use and the development of dementia, the studies would have to be approximately 3 decades long given the prolonged life course of neurodegenerative disorders like dementias.

There are 3 possible mechanisms that have been postulated for the association between benzodiazepine use and the development of dementia.^28,29 For one, benzodiazepines possibly decrease activity of β-amyloid precursor protein-cleaving enzyme 1 (BACE-1) and c-secretase activity, thus promoting β-amyloid accumulation in the brain. Secondly, astrocytes near the β-amyloid accumulation in the brain secreting γ-aminobutyric acid (GABA), thereby promoting the negative cognitive effects of benzodiazepines. Finally, benzodiazepines may reduce the cognitive reserves by lowering brain activation levels.

Concluding Thoughts

Available evidence indicates a positive association between the use of benzodiazepines and the development of dementia, although causality cannot be inferred from this data. Despite the lack of evidence proving causality, the association between benzodiazepine use and the development of dementia is a major cause for concern given the prevalence benzodiazepine use among older adults. The prescription of benzodiazepines to older adults must be carefully reviewed given the lack of data regarding their long-term efficacy and their significant adverse effects including the risk for developing dementia.

Dr Tampi is the chairman of the department of psychiatry and behavioral sciences, Cleveland Clinic Akron General, Akron, OH. Dr Bennett is a psychologist in the Department of Psychiatry and Behavioral Sciences, Cleveland Clinic Akron General, Akron, OH. The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.

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