CNS Drugs

, Volume 32, Issue 6, pp 485–497 | Cite as

A Systematic Review and Meta-Analysis of the Risk of Dementia Associated with Benzodiazepine Use, After Controlling for Protopathic Bias

  • Ross Penninkilampi
  • Guy D. EslickEmail author
Systematic Review



Benzodiazepine use is highly prevalent in elderly and late middle-aged populations and may be associated with an increased risk of dementia. Observational studies have suggested that benzodiazepine use may increase the risk of dementia, however there have been significant concerns regarding protopathic bias in these studies, precluding conclusive findings.


The aim of our study was to investigate the risk of dementia associated with the use of benzodiazepines in elderly patients, after controlling for protopathic bias.


We identified observational studies with more than 50 cases, adequate assessment of benzodiazepine exposure, and reliable dementia diagnosis ascertainment, from the MEDLINE, PubMed, EMBASE, CINAHL, LILACS and CENTRAL electronic databases through to 5 June 2018, with no language limits. The association of any current or former use of short- or long-acting benzodiazepines with incident dementia was analysed. A subgroup analysis was performed by the introduction of lag time to assess the effect of protopathic bias. We also performed analyses considering the effect of higher benzodiazepine cumulative doses and adjustment for psychiatric covariates. Study quality was investigated using the Newcastle–Ottawa Scale.


We identified 15 studies reported in 14 articles, involving 159,090 cases. Ever use of benzodiazepines was associated with a significantly increased risk of dementia [odds ratio (OR) 1.39, 95% confidence interval (CI) 1.21–1.59]. Those studies that implemented the longest lag times of ≥ 5 years, and hence most likely to overcome protopathic bias, found a risk estimate that was marginally attenuated, but still significant (OR 1.30, 95% CI 1.14–1.48). Long-acting benzodiazepines were associated with a marginally higher magnitude risk (OR 1.21, 95% CI 0.99–1.49) than short-acting benzodiazepines (OR 1.13, 95% CI 1.02–1.26), although the former failed to reach statistical significance (p = 0.059).


Our findings indicate that the association between benzodiazepine use and dementia incidence is not purely an artefact due to protopathic bias. Reduction of inappropriate benzodiazepine prescription is likely to attenuate dementia risk.


Author Contributions

Study concept and design: GDE, RP. Acquisition of data: RP. Analysis and interpretation of data: GDE, RP. Drafting of the manuscript: RP. Critical revision of the manuscript for important intellectual content: GDE. Statistical analysis: GDE. Study supervision: GDE.

Compliance with ethical standards


A Summer Research Scholarship provided by the University of Sydney funded the costs of retrieving the medical records for this study.

Conflicts of Interest

Ross Penninkilampi and Guy D. Eslick have no potential conflicts of interest to declare.

Supplementary material

40263_2018_535_MOESM1_ESM.docx (12 kb)
Supplementary material 1 (DOCX 11 kb)


  1. 1.
    Seshadri S, Beiser A, Kelly-Hayes M, et al. The lifetime risk of stroke: estimates from the Framingham Study. Stroke. 2006;37:345–50.CrossRefPubMedGoogle Scholar
  2. 2.
    Alzheimer’s Association. Alzheimer’s disease facts and figures. Alzheimers Dement. 2017;2017(13):325–73.Google Scholar
  3. 3.
    Wimo A, Guerchet M, Ali GC, et al. The worldwide costs of dementia 2015 and comparisons with 2010. Alzheimers Dement. 2017;13:1–7.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Solomon A, Mangialasche F, Richard E, et al. Advances in the prevention of Alzheimer’s disease and dementia. J Intern Med. 2014;275:229–50.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Billioti de Gage S, Pariente A, Begaud B. Is there really a link between benzodiazepine use and the risk of dementia? Expert Opin Drug Saf. 2015;14:733–47.CrossRefPubMedGoogle Scholar
  6. 6.
    Verdoux H, Lagnaoui R, Begaud B. Is benzodiazepine use a risk factor for cognitive decline and dementia? A literature review of epidemiological studies. Psychol Med. 2005;35:307–15.CrossRefPubMedGoogle Scholar
  7. 7.
    Zhong G, Wang Y, Zhang Y, Zhao Y. Association between benzodiazepine use and dementia: a meta-analysis. PLoS One. 2015;10:e0127836.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Olfson M, King M, Schoenbaum M. Benzodiazepine use in the United States. JAMA Psychiatry. 2015;72:136–42.CrossRefPubMedGoogle Scholar
  9. 9.
    Fastbom J, Forsell Y, Winblad B. Benzodiazepines may have protective effects against Alzheimer disease. Alzheimer Dis Assoc Disord. 1998;12:14–7.CrossRefPubMedGoogle Scholar
  10. 10.
    Lagnaoui R, Bégaud B, Moore N, et al. Benzodiazepine use and risk of dementia: a nested case-control study. J Clin Epidemiol. 2002;55:314–8.CrossRefPubMedGoogle Scholar
  11. 11.
    Wu C-S, Wang S-C, Chang I-S, Lin K-M. 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;17:614–20.CrossRefPubMedGoogle Scholar
  12. 12.
    Wu CS, Ting TT, Wang SC, Chang IS, Lin KM. Effect of benzodiazepine discontinuation on dementia risk. Am J Geriatr Psychiatry. 2011;19:151–9.CrossRefPubMedGoogle Scholar
  13. 13.
    Imfeld P, Bodmer M, Jick SS, Meier CR. Benzodiazepine use and risk of developing Alzheimer’s disease or vascular dementia: a case-control analysis. Drug Saf. 2015;38:909–19.CrossRefPubMedGoogle Scholar
  14. 14.
    Arfè A, Corrao G. The lag-time approach improved drug–outcome association estimates in presence of protopathic bias. J Clin Epidemiol. 2016;78:101–7.CrossRefPubMedGoogle Scholar
  15. 15.
    Billioti de Gage S, Moride Y, Ducruet T, et al. Benzodiazepine use and risk of Alzheimer’s disease: case-control study. BMJ. 2014;349:g5205.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Gallacher J, Elwood P, Pickering J, Bayer A, Fish M, Ben-Shlomo Y. Benzodiazepine use and risk of dementia: evidence from the Caerphilly Prospective Study (CaPS). J Epidemiol Community Health. 2012;66:869–73.CrossRefPubMedGoogle Scholar
  17. 17.
    Gomm W, von Holt K, Thome F, et al. Regular benzodiazepine and z-substance use and risk of dementia: an analysis of German claims data. J Alzheimers Dis. 2016;54(2):801–8.CrossRefPubMedGoogle Scholar
  18. 18.
    Gray SL, Dublin S, Yu O, et al. Benzodiazepine use and risk of incident dementia or cognitive decline: prospective population based study. BMJ. 2016;352:i90.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Bietry FA, Pfeil AM, Reich O, Schwenkglenks M, Meier CR. Benzodiazepine use and risk of developing Alzheimer’s disease: a case-control study bassed on Swiss claims data. CNS Drugs. 2017;31:245–51.CrossRefPubMedGoogle Scholar
  20. 20.
    Shash D, Kurth T, Bertrand M, et al. Benzodiazepine, psychotropic medication, and dementia: a population-based cohort study. Alzheimers Dement. 2016;12:604–13.CrossRefPubMedGoogle Scholar
  21. 21.
    Chan TT, Leung WC, Li V, et al. Association between high cumulative dose of benzodiazepine in Chinese patients and risk of dementia: a preliminary retrospective case-control study. Psychogeriatrics. 2017;17(5):310–6.CrossRefPubMedGoogle Scholar
  22. 22.
    Mawanda F, Wallace RB, McCoy K, Abrams TE. PTSD, psychotropic medication use, and the risk of dementia among US veterans: a retrospective cohort study. J Am Geriatr Soc. 2017;65:1043–50.CrossRefPubMedGoogle Scholar
  23. 23.
    Tolppanen AM, Taipale H, Hartikainen S. Head or brain injuries and Alzheimer’s disease: a nested case-control register study. Alzheimers Dement. 2017;13(12):1371–9.CrossRefPubMedGoogle Scholar
  24. 24.
    Islam MM, Iqbal U, Walther B, et al. Benzodiazepine use and risk of dementia in the elderly population: a systematic review and meta-analysis. Neuroepidemiology. 2016;47:181–91.CrossRefPubMedGoogle Scholar
  25. 25.
    Moher D, Liberati A, Tetzlaff J, Group P. Altman DG Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Int J Surg. 2010;8:336–41.CrossRefPubMedGoogle Scholar
  26. 26.
    DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–88.CrossRefPubMedGoogle Scholar
  27. 27.
    Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557–60.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Egger M, Smith GD, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–34.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Orwin RG. A fail-safe N for effect size in meta-analysis. J Edu Stat. 1983;8:157–9.Google Scholar
  30. 30.
    Wells GA, Shea B, O’Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. 2009. Accessed 11 Jan 2017.
  31. 31.
    Chen PL, Lee WJ, Sun WZ, Oyang YJ, Fuh JL. Risk of dementia in patients with insomnia and long-term use of hypnotics: a population-based retrospective cohort study. PLoS One. 2012;7:e49113.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Cheng K-C, Chen Y-L, Lai S-W, Mou C-H, Tsai P-Y, Sung F-C. Patients with chronic kidney disease are at an elevated risk of dementia: a population-based cohort study in Taiwan. BMC Nephrol. 2012;13:129.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Hsiao FY, Peng LN, Lin MH, Chen LK. Dose-responsive effect of psychotropic drug use and subsequent dementia: a nationwide propensity score matched case-control study in Taiwan. J Am Med Dir Assoc. 2014;15:509–13.CrossRefPubMedGoogle Scholar
  34. 34.
    Shih HI, Lin CC, Tu YF, et al. An increased risk of reversible dementia may occur after zolpidem derivative use in the elderly population: a population-based case-control study. Medicine (Baltimore). 2015;94:e809.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Chiu HY, Lin EY, Wei L, et al. Hypnotics use but not insomnia increased the risk of dementia in traumatic brain injury patients. Eur Neuropsychopharmacol. 2015;25:2271–7.CrossRefPubMedGoogle Scholar
  36. 36.
    Lagnaoui R, Tournier M, Moride Y, et al. The risk of cognitive impairment in older community-dwelling women after benzodiazepine use. Age Ageing. 2009;38:226–8.CrossRefPubMedGoogle Scholar
  37. 37.
    Saarelainen L, Taipale H, Koponen M, et al. The incidence of benzodiazepine and related drug use in persons with and without Alzheimer’s disease. J Alzheimers Dis. 2016;49:809–18.CrossRefPubMedGoogle Scholar
  38. 38.
    Takada M, Fujimoto M, Hosomi K. Association between benzodiazepine use and dementia: data mining of different medical databases. Int J Med Sci. 2016;13:825–34.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Brodrick JE, Mathys ML. Antidepressant exposure and risk of dementia in older adults with major depressive disorder. J Am Geriatr Soc. 2016;64:2517–21.CrossRefPubMedGoogle Scholar
  40. 40.
    Billioti de Gage S, Begaud B, Bazin F, et al. Benzodiazepine use and risk of dementia: prospective population based study. BMJ. 2012;345:e6231.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Kirkpatrick B, Ross DE. The trap of protopathic bias in neuropsychiatric research. Biol Psychiatry. 1997;41:257–8.CrossRefPubMedGoogle Scholar
  42. 42.
    Horwitz RI, Feinstein AR. The problem of “protopathic bias” in case-control studies. Am J Med. 1980;68:255–8.CrossRefPubMedGoogle Scholar
  43. 43.
    Amieva H, Le Goff M, Millet X, et al. Prodromal Alzheimer’s disease: successive emergence of the clinical symptoms. Ann Neurol. 2008;64:492–8.CrossRefPubMedGoogle Scholar
  44. 44.
    Bennett S, Thomas AJ. Depression and dementia: cause, consequence or coincidence? Maturitas. 2014;79:184–90.CrossRefPubMedGoogle Scholar
  45. 45.
    Byers AL, Yaffe K. Depression and risk of developing dementia. Nat Rev Neurol. 2011;7:323–31.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Lyketsos CG, Lopez O, Jones B, Fitzpatrick AL, Breitner J, DeKosky S. Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the Cardiovascular Health Study. JAMA. 2002;288:1475–83.CrossRefPubMedGoogle Scholar
  47. 47.
    Gallagher D, Coen R, Kilroy D, et al. Anxiety and behavioural disturbance as markers of prodromal Alzheimer’s disease in patients with mild cognitive impairment. Int J Geriatr Psychiatry. 2011;26:166–72.CrossRefPubMedGoogle Scholar
  48. 48.
    Paterniti S, Dufouil C, Alperovitch A. Long-term benzodiazepine use and cognitive decline in the elderly: the Epidemiology of Vascular Aging Study. J Clin Psychopharmacol. 2002;22:285–93.CrossRefPubMedGoogle Scholar
  49. 49.
    Busto UE, Bremner KE, Knight KPT, terBrugge K, Sellers EM. Long-term benzodiazepine therapy does not result in brain abnormalities. J Clin Psychopharmacol. 2000;20:2–6.CrossRefPubMedGoogle Scholar
  50. 50.
    Stern Y. What is cognitive reserve? Theory and research application of the reserve concept. J Int Neuropsychol Soc. 2002;8:448–60.CrossRefPubMedGoogle Scholar
  51. 51.
    Stern Y. Cognitive reserve in ageing and Alzheimer’s disease. Lancet Neurol. 2012;11:1006–12.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Airagnes G, Pelissolo A, Lavallee M, Flament M, Limosin F. Benzodiazepine misuse in the elderly: risk factors, consequences, and management. Curr Psychiatry Rep. 2016;18:89.CrossRefPubMedGoogle Scholar
  53. 53.
    Dell’osso B, Lader M. Do benzodiazepines still deserve a major role in the treatment of psychiatric disorders? A critical reappraisal. Eur Psychiatry. 2013;28:7–20.Google Scholar
  54. 54.
    Barker MJ, Greenwood KM, Jackson M, Crowe SF. Cognitive effects of long-term benzodiazepine use. CNS Drugs. 2004;18:37–48.CrossRefPubMedGoogle Scholar
  55. 55.
    Longo LP, Johnson B. Addiction: part I. Benzodiazepines-side effects, abuse risk and alternatives. Am Fam Phys. 2000;61:2121–8.Google Scholar
  56. 56.
    Gorgels WJ, Oude Voshaar RC, Mol AJ, et al. Discontinuation of long-term benzodiazepine use by sending a letter to users in family practice: a prospective controlled intervention study. Drug Alcohol Depend. 2005;78:49–56.CrossRefPubMedGoogle Scholar
  57. 57.
    Kaur S, Mitchell G, Vitetta L, Roberts MS. Interventions that can reduce inappropriate prescribing in the elderly. Drugs Aging. 2009;26:1013–28.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.The Whiteley-Martin Research Centre, Discipline of Surgery, Nepean HospitalThe University of SydneyPenrithAustralia

Personalised recommendations