Skip to main content

The Benzodiazepine–Dementia Disorders Link: Current State of Knowledge

Abstract

The short-term effects of benzodiazepines on memory are well established and are suspected in the long term. Eleven studies have been published so far concerning benzodiazepine use and the risk of dementia disorders; nine of these studies concluded these drugs have a deleterious effect, one found a protective effect, and one (the most recently published) observed no effect. The positive association found in some studies could be due to a reverse causation bias since the main indications for benzodiazepines (e.g. sleep disorders, anxiety) can also be prodromes of dementia disorders. This bias is less likely for treatments started more than 10 years before the diagnosis. Among others, three mechanisms could underlie the potential influence of benzodiazepines on the development of dementia disorders. First, benzodiazepines can decrease beta-site amyloid precursor protein-cleaving enzyme 1 (BACE-1) and γ-secretase activity and slow down the accumulation of Aβ oligomers in the brain. This potential positive effect has never been confirmed; the same is true for the prevention of excitotoxicity through benzodiazepine anti-glutamatergic action. Second, since astrocytes located in the area of amyloid plaques could have gamma-aminobutyric acid (GABA)-secreting activity, patients with pre-dementia lesions could be at increased risk of presenting with more pronounced deleterious cognitive effects of benzodiazepines. Finally, owing to the neural compensation and cognitive reserve concepts, some subjects could cope with initial lesions by using/developing alternative networks. By lowering the brain activation level, benzodiazepines could limit this capacity. In conclusion, it is essential that animal studies explore the mechanistic hypotheses of this association found by most of the pharmacoepidemiological studies conducted on this topic.

This is a preview of subscription content, access via your institution.

References

  1. 1.

    Donoghue J, Lader M. Usage of benzodiazepines: a review. Int J Psychiatry Clin Pract. 2010;14:78–87.

    PubMed  CAS  Article  Google Scholar 

  2. 2.

    Ghoneim MM, Mewaldt SP. Benzodiazepines and human memory: a review. Anesthesiology. 1990;72(5):926–38.

    PubMed  CAS  Article  Google Scholar 

  3. 3.

    Curran HV. Tranquillising memories: a review of the effects of benzodiazepines on human memory. Biol Psychol. 1986;23(2):179–213.

    PubMed  CAS  Article  Google Scholar 

  4. 4.

    Puustinen J, Nurminen J, Vahlberg T, Lyles A, Isoaho R, Raiha I, et al. CNS medications as predictors of precipitous cognitive decline in the cognitively disabled aged: a longitudinal population-based study. Dement Geriatr Cogn Dis Extra. 2012;2(1):57–68.

    PubMed  PubMed Central  Article  Google Scholar 

  5. 5.

    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(3):285–93.

    PubMed  CAS  Article  Google Scholar 

  6. 6.

    Bierman EJ, Comijs HC, Gundy CM, Sonnenberg C, Jonker C, Beekman AT. The effect of chronic benzodiazepine use on cognitive functioning in older persons: good, bad or indifferent? Int J Geriatr Psychiatry. 2007;22(12):1194–200.

    PubMed  CAS  Article  Google Scholar 

  7. 7.

    Barker MJ, Greenwood KM, Jackson M, Crowe SF. Cognitive effects of long-term benzodiazepine use: a meta-analysis. CNS Drugs. 2004;18(1):37–48.

    PubMed  CAS  Article  Google Scholar 

  8. 8.

    Neutel CI. The epidemiology of long-term benzodiazepine use. Int Rev Psychiatry. 2005;17(3):189–97.

    PubMed  Article  Google Scholar 

  9. 9.

    Egan M, Moride Y, Wolfson C, Monette J. Long-term continuous use of benzodiazepines by older adults in Quebec: prevalence, incidence and risk factors. J Am Geriatr Soc. 2000;48(7):811–6.

    PubMed  CAS  Article  Google Scholar 

  10. 10.

    Taragano FE, Allegri RF, Krupitzki H, Sarasola DR, Serrano CM, Lon L, et al. Mild behavioral impairment and risk of dementia: a prospective cohort study of 358 patients. J Clin Psychiatry. 2009;70(4):584–92.

    PubMed  PubMed Central  Article  Google Scholar 

  11. 11.

    Rosenberg PB, Mielke MM, Appleby B, Oh E, Leoutsakos JM, Lyketsos CG. Neuropsychiatric symptoms in MCI subtypes: the importance of executive dysfunction. Int J Geriatr Psychiatry. 2011;26(4):364–72.

    PubMed  PubMed Central  Article  Google Scholar 

  12. 12.

    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(12):1475–83.

    PubMed  Article  Google Scholar 

  13. 13.

    Wu CS, Wang SC, Chang IS, Lin KM. 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(7):614–20.

    PubMed  Article  Google Scholar 

  14. 14.

    Wu CS, Ting TT, Wang SC, Chang IS, Lin KM. Effect of benzodiazepine discontinuation on dementia risk. Am J Geriatr Psychiatry. 2011;19(2):151–9.

    PubMed  Article  Google Scholar 

  15. 15.

    Lagnaoui R, Tournier M, Moride Y, Wolfson C, Ducruet T, Begaud B, et al. The risk of cognitive impairment in older community-dwelling women after benzodiazepine use. Age Ageing. 2009;38(2):226–8.

    PubMed  Article  Google Scholar 

  16. 16.

    Lagnaoui R, Begaud B, Moore N, Chaslerie A, Fourrier A, Letenneur L, et al. Benzodiazepine use and risk of dementia: a nested case-control study. J Clin Epidemiol. 2002;55(3):314–8.

    PubMed  Article  Google Scholar 

  17. 17.

    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. 2011;66(10):869–73.

    PubMed  Article  Google Scholar 

  18. 18.

    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(11):e49113.

    PubMed  CAS  PubMed Central  Article  Google Scholar 

  19. 19.

    Billioti de Gage S, Moride Y, Ducruet T, Kurth T, Verdoux H, Tournier M, et al. Benzodiazepine use and risk of Alzheimer’s disease: case–control study. BMJ. 2014;349:g5205.

    PubMed  PubMed Central  Article  Google Scholar 

  20. 20.

    Billioti de Gage S, Begaud B, Bazin F, Verdoux H, Dartigues JF, Peres K, et al. Benzodiazepine use and risk of dementia: prospective population based study. BMJ. 2012;345:e6231.

    PubMed  PubMed Central  Article  Google Scholar 

  21. 21.

    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(10):909–19.

    PubMed  CAS  Article  Google Scholar 

  22. 22.

    Fastbom J, Forsell Y, Winblad B. Benzodiazepines may have protective effects against Alzheimer disease. Alzheimer Dis Assoc Disord. 1998;12(1):14–7.

    PubMed  CAS  Article  Google Scholar 

  23. 23.

    Fish M, Bayer AJ, Gallacher JE, Bell T, Pickering J, Pedro S, et al. Prevalence and pattern of cognitive impairment in a community cohort of men in South Wales: methodology and findings from the Caerphilly Prospective Study. Neuroepidemiology. 2008;30(1):25–33.

    PubMed  CAS  Article  Google Scholar 

  24. 24.

    Kang JE, Lim MM, Bateman RJ, Lee JJ, Smyth LP, Cirrito JR, et al. Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle. Science. 2009;326(5955):1005–7.

    PubMed  CAS  PubMed Central  Article  Google Scholar 

  25. 25.

    Mintzer MZ, Kuwabara H, Alexander M, Brasic JR, Ye W, Ernst M, et al. Dose effects of triazolam on brain activity during episodic memory encoding: a PET study. Psychopharmacology. 2006;188(4):445–61.

    PubMed  CAS  Article  Google Scholar 

  26. 26.

    Mintzer MZ, Griffiths RR, Contoreggi C, Kimes AS, London ED, Ernst M. Effects of triazolam on brain activity during episodic memory encoding: a PET study. Neuropsychopharmacology. 2001;25(5):744–56.

    PubMed  CAS  Article  Google Scholar 

  27. 27.

    Sperling R, Greve D, Dale A, Killiany R, Holmes J, Rosas HD, et al. Functional MRI detection of pharmacologically induced memory impairment. Proc Natl Acad Sci USA. 2002;99(1):455–60.

    PubMed  CAS  PubMed Central  Article  Google Scholar 

  28. 28.

    Churcher I, Ashton K, Butcher JW, Clarke EE, Harrison T, Lewis HD, et al. A new series of potent benzodiazepine gamma-secretase inhibitors. Bioorg Med Chem Lett. 2003;13(2):179–83.

    PubMed  CAS  Article  Google Scholar 

  29. 29.

    Imbimbo BP, Giardina GA. Gamma-secretase inhibitors and modulators for the treatment of Alzheimer’s disease: disappointments and hopes. Curr Top Med Chem. 2011;11(12):1555–70.

    PubMed  CAS  Article  Google Scholar 

  30. 30.

    Doody RS, Raman R, Farlow M, Iwatsubo T, Vellas B, Joffe S, et al. A phase 3 trial of semagacestat for treatment of Alzheimer’s disease. N Engl J Med. 2013;369(4):341–50.

    PubMed  CAS  Article  Google Scholar 

  31. 31.

    May PC, Robison PM. GYKI 52466 protects against non-NMDA receptor-mediated excitotoxicity in primary rat hippocampal cultures. Neurosci Lett. 1993;152(1–2):169–72.

    PubMed  CAS  Article  Google Scholar 

  32. 32.

    O’Brien JL, O’Keefe KM, LaViolette PS, DeLuca AN, Blacker D, Dickerson BC, et al. Longitudinal fMRI in elderly reveals loss of hippocampal activation with clinical decline. Neurology. 2010;74(24):1969–76.

    PubMed  PubMed Central  Article  Google Scholar 

  33. 33.

    Hamalainen A, Pihlajamaki M, Tanila H, Hanninen T, Niskanen E, Tervo S, et al. Increased fMRI responses during encoding in mild cognitive impairment. Neurobiol Aging. 2007;28(12):1889–903.

    PubMed  Article  Google Scholar 

  34. 34.

    Jo S, Yarishkin O, Hwang YJ, Chun YE, Park M, Woo DH, et al. GABA from reactive astrocytes impairs memory in mouse models of Alzheimer’s disease. Nat Med. 2014;20(8):886–96.

    PubMed  CAS  Article  Google Scholar 

  35. 35.

    Martinez-Cue C, Martinez P, Rueda N, Vidal R, Garcia S, Vidal V, et al. Reducing GABAA alpha5 receptor-mediated inhibition rescues functional and neuromorphological deficits in a mouse model of down syndrome. J Neurosci. 2013;33(9):3953–66.

    PubMed  CAS  Article  Google Scholar 

  36. 36.

    Hatayama Y, Hashimoto T, Kohayakawa H, Kiyoshi T, Nakamichi K, Kinoshita T, et al. In vivo pharmacological characterization of AC-3933, a benzodiazepine receptor partial inverse agonist for the treatment of Alzheimer’s disease. Neuroscience. 2014;265:217–25.

    PubMed  CAS  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Antoine Pariente.

Ethics declarations

Funding

The authors have received no public or private funding for this manuscript.

Conflict of interest

Antoine Pariente, Sophie Billioti de Gage, Nicholas Moore and Bernard Bégaud declare no conflicts of interest implying collaboration with private companies relevant to the subject discussed.

All authors have contributed in the past years to publically funded pharmacoepidemiological studies that found an association between use of benzodiazepines and an increased risk of developing dementia disorders in the elderly.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Pariente, A., de Gage, S.B., Moore, N. et al. The Benzodiazepine–Dementia Disorders Link: Current State of Knowledge. CNS Drugs 30, 1–7 (2016). https://doi.org/10.1007/s40263-015-0305-4

Download citation

Keywords

  • Dementia
  • Sleep Disorder
  • Reverse Causation
  • Cognitive Reserve
  • Clinical Practice Research Datalink