Original Study
Association of Benzodiazepine and Anticholinergic Drug Usage With Incident Dementia: A Prospective Cohort Study of Community-Dwelling Older Adults

https://doi.org/10.1016/j.jamda.2019.05.010Get rights and content

Abstract

Objectives

To examine the association of benzodiazepines and anticholinergic drug usage with the risk of dementia.

Setting

Community-dwelling participants, recruited in family practices in the Netherlands.

Participants

In total, 3526 individuals aged 70 to 78 years without dementia within 116 participating family practices.

Methods

Information about drug use was reported at baseline and at 2-year follow-up and was cross-checked with the participants’ electronic health records. Anticholinergic drug exposure was defined by the anticholinergic cognitive burden score. Participants were evaluated for dementia during follow-up assessments every 2 years, supplemented by information from electronic health records and the National Death Registry.

Results

During a median follow-up of 6.7 years, dementia developed in 233 participants (7%). In participants using benzodiazepines, 6% developed dementia vs 7% in nonusers [hazard ratio (HR) 0.71, 95% confidence interval (CI) 0.58–1.07]. Persistent usage of benzodiazepines at baseline and after 2-year follow-up did not substantially alter the point-estimate (HR 0.60, 95% CI 0.34–1.10). Use of any anticholinergic drugs was not associated with incident dementia (HR 1.01, 95% CI 0.50–1.10). Dementia risk was significantly increased for participants with persistent drug use with a high anticholinergic cognitive burden score (HR 1.95, 95% CI 1.13–3.38) though this effect was absent when excluding participants taking antidepressants or antipsychotics (HR 0.42, 95% CI 0.06–3.01).

Conclusions and Implications

In our study population, benzodiazepine usage was not associated with an increased risk of dementia. Persistent high anticholinergic exposure was associated with an increased risk of dementia over 6 years of follow-up, and this association was driven by antidepressant or antipsychotic drug use, suggesting confounding by indication bias contributing to this. Although this observation could ameliorate prescription hesitance, healthcare providers are still advised to carefully weigh the potential benefits of benzodiazepines and anticholinergic drugs against the associated adverse health outcomes.

Section snippets

Study Design and Participants

We performed a post-hoc analysis on the data of The Prevention of Dementia by Intensive Vascular care (preDIVA) trial. The preDIVA trial was a pragmatic, multisite, cluster-randomized, open-label trial in 116 family practices within 26 healthcare centers in the Netherlands with a follow-up for dementia of 6-8 years.15 We used a population-based approach, inviting all community-dwelling older people (aged 70 to 78 years) registered with a participating family practice (>98% of the Dutch

Results

Table 1 provides baseline characteristics. The mean age of participants at study entry was 74.3 years; 54% were female; and most had intermediate to high education (63% and 14%, respectively).

Overall, 15% of the participants were using at least 1 benzodiazepine at baseline, of which 94% were short-acting. Furthermore, 36% of the participants were taking at least 1 drug with anticholinergic effects. Of the participants taking anticholinergic drugs, 17% had an ACB score classified as high (Table 2

Discussion

In our study population of community-dwelling older people, there was no association with the baseline usage of benzodiazepines and dementia. We did not observe an overall association between any use of anticholinergic drugs and incident dementia. However, there was a significantly increased risk of dementia for participants with persistent anticholinergic drug usage with a high ACB score, which was mainly driven by the use of antidepressants and antipsychotics.

Our results concerning a neutral

Conclusions and Implications

In conclusion, in our study population of community-dwelling older people benzodiazepine usage is not associated with an increased risk of dementia. Persistent high anticholinergic exposure classified as an ACB score of 3 or higher is associated with an increased risk of dementia over 6 years of follow-up, though this association was driven by participants using antidepressants or antipsychotics, suggesting confounding by indication concerning this association. Future research could address

Acknowledgments

We are grateful to all the participants of the preDIVA study. The preDIVA trial was supported by the Dutch Ministry of Health,Welfare and Sport (grant number 50-50110-98-020), the Dutch Innovation Fund of Collaborative Health Insurances (grant number 05-234), and the Netherlands Organisation for Health Research and Development (grant number 62000015). The authors would like to thank all practice nurses and family doctors involved in the preDIVA study.

References (28)

  • T. Mura et al.

    Chronic use of benzodiazepines and latent cognitive decline in the elderly: Results from the Three-city study

    Eur Neuropsychopharmacol

    (2013)
  • C.S. Wu et al.

    The association between dementia and long-term use of benzodiazepine in the elderly: Nested case-control study using claims data

    Am J Geriatr Psychiatry

    (2009)
  • World Health Organization

    Dementia; Fact sheet

    (2017)
  • P.B. Gorelick

    Risk factors for vascular dementia and Alzheimer disease

    Stroke

    (2004)
  • H. Verdoux et al.

    Is benzodiazepine use a risk factor for cognitive decline and dementia? A literature review of epidemiological studies

    Psychol Med

    (2005)
  • C. Fox et al.

    Anticholinergic medication use and cognitive impairment in the older population: The medical research council cognitive function and ageing study

    J Am Geriatr Soc

    (2011)
  • G. Zhong et al.

    Association between benzodiazepine use and dementia: A meta-analysis

    PLoS One

    (2015)
  • I. Carrière et al.

    Drugs with anticholinergic properties, cognitive decline, and dementia in an elderly general population

    Arch Intern Med

    (2009)
  • S.L. Gray et al.

    Cumulative use of strong anticholinergics and incident dementia

    JAMA Intern Med

    (2015)
  • N. Campbell et al.

    The cognitive impact of anticholinergics: A clinical review

    Clin Interv Aging

    (2009)
  • M. Linden et al.

    Prevalence and appropriateness of psychotropic drug use in old age: Results from the Berlin Aging Study (BASE)

    Int Psychogeriatr

    (2004)
  • F. Jessen et al.

    Anticholinergic drug use and risk for dementia: Target for dementia prevention

    Eur Arch Psychiatry Clin Neurosci

    (2010)
  • M.L. Ancelin et al.

    Nondegenerative mild cognitive impairment in elderly people and use of anticholinergic drugs: Longitudinal cohort study

    BMJ

    (2006)
  • S.L. Gray et al.

    Benzodiazepine use and risk of incident dementia or cognitive decline: Prospective population-based study

    BMJ

    (2016)
  • Cited by (26)

    • Anticholinergic drugs and the risk of dementia: A systematic review and meta-analysis

      2021, Neuroscience and Biobehavioral Reviews
      Citation Excerpt :

      Anticholinergic drug exposure was distinctly measured and evaluated among the studies. Six studies (Cai et al., 2013; Campbell et al., 2010; Hafdi et al., 2020; Liu et al., 2020; Naharci et al., 2017; Shah et al., 2013) used the ACB scale, Richardson et al. (Richardson et al., 2018) applied both ACB and anticholinergic drug scales, and Coupland et al. (Coupland et al., 2019) used the Beers criteria and ACB scale in combination. Other scales and measures, such as serum anticholinergic activity (Ancelin et al., 2006; Whalley et al., 2012), Anatomical Therapeutic Chemical Classification (Carriere et al., 2009), Chew list (Jessen et al., 2010), Beers Criteria (Gray et al., 2015), and Anticholinergic Drug Scale (Chatterjee et al., 2016), were also applied in the study.

    • Clarifying the Relationship Between Benzodiazepines and Dementia

      2020, Journal of the American Medical Directors Association
    • Anxiety disorders, benzodiazepine prescription, and incident dementia

      2023, Journal of the American Geriatrics Society
    View all citing articles on Scopus

    The preDIVA trial was supported by the Dutch Ministry of Health,Welfare and Sport (grant number 50-50110-98-020), the Dutch Innovation Fund of Collaborative Health Insurances (grant number 05-234), and the Netherlands Organisation for Health Research and Development (grant number 62000015).

    The authors declare no conflicts of interest.

    View full text