Abstract
Introduction
Previous observational studies have associated benzodiazepine use with an increased risk of dementia. However, limitations in the study methods leave questions unanswered regarding the interpretation of the findings.
Methods
A case–control analysis was conducted using data from the UK-based Clinical Practice Research Datalink (CPRD). A total of 26,459 patients aged ≥65 years with newly diagnosed Alzheimer’s disease (AD) or vascular dementia (VaD) between 1998 and 2013 were identified and matched 1:1 to dementia-free controls on age, sex, calendar time, general practice, and number of years of recorded history. Adjusted odds ratios (aORs) were calculated with 95 % confidence intervals (CIs) of developing AD or VaD in relation to previous benzodiazepine use, stratified by duration and benzodiazepine type.
Results
The aOR (95 % CI) of developing AD for those who started benzodiazepines <1 year before diagnosis was 2.20 (1.91–2.53), and fell to the null for those who started between 2 and <3 years before [aOR 0.99 (0.84–1.17)]. The aOR (95 % CI) of developing VaD for those who started benzodiazepines <1 year before diagnosis was 3.30 (2.78–3.92), and fell close to the null for those who started between 3 and <4 years before [aOR 1.16 (0.96–1.40)]. After accounting for benzodiazepine use initiated during this prodromal phase, long-term use of benzodiazepines was not associated with an increased risk of developing AD [aOR 0.69 (0.57–0.85)] or VaD [aOR 1.11 (0.85–1.45)].
Conclusion
After taking a prodromal phase into consideration, benzodiazepine use was not associated with an increased risk of developing AD or VaD.
Similar content being viewed by others
References
NHS Business Services Authority, NHS Prescription Services. Central nervous system national charts. 2014. Available at: http://www.nhsbsa.nhs.uk/PrescriptionServices/2584.aspx. Accessed 26 Apr 2015.
Buffett-Jerrott SE, Stewart SH. Cognitive and sedative effects of benzodiazepine use. Curr Pharm Des. 2002;8:45–58.
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.
Chen P-L, Lee W-J, Sun W-Z, Oyang Y-J, Fuh J-L. Risk of dementia in patients with insomnia and long-term use of hypnotics: a population-based retrospective cohort study. PLoS One. 2012;7:e49113.
Wu C-S, Ting T-T, Wang S-C, Chang I-S, Lin K-M. Effect of benzodiazepine discontinuation on dementia risk. Am J Geriatr Psychiatry. 2011;19:151–9.
Lagnaoui R, Bégaud 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;55:314–8.
Billioti de Gage S, Bégaud B, Bazin F, Verdoux H, Dartigues J-F, Pérès K, et al. Benzodiazepine use and risk of dementia: prospective population based study. BMJ. 2012;345:e6231.
Horwitz RI, Feinstein AR. The problem of “protopathic bias” in case–control studies. Am J Med. 1980;68:255–8.
Stella F, Radanovic M, Balthazar ML, Canineu PR, de Souza LC, Forlenza OV. Neuropsychiatric symptoms in the prodromal stages of dementia. Curr Opin Psychiatry. 2014;27:230–5.
Tamim H, Tahami Monfared AA, LeLorier J. Application of lag-time into exposure definitions to control for protopathic bias. Pharmacoepidemiol Drug Saf. 2007;16:250–8.
Fastbom J, Forsell Y, Winblad B. Benzodiazepines may have protective effects against Alzheimer disease. Alzheimer Dis Assoc Disord. 1998;12:14–7.
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.
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.
Jick SS, Kaye JA, Vasilakis-Scaramozza C, Garcia Rodríguez LA, Ruigómez A, Meier CR, et al. Validity of the general practice research database. Pharmacotherapy. 2003;23:686–9.
Wood L, Martinez C. The general practice research database: role in pharmacovigilance. Drug Saf. 2004;27:871–81.
Herrett E, Thomas SL, Schoonen WM, Smeeth L, Hall AJ. Validation and validity of diagnoses in the General Practice Research Database: a systematic review. Br J Clin Pharmacol. 2010;69:4–14.
Khan NF, Harrison SE, Rose PW. Validity of diagnostic coding within the General Practice Research Database: a systematic review. Br J Gen Pract. 2010;60:e128–36.
Seshadri S, Zornberg GL, Derby LE, Myers MW, Jick H, Drachman DA. Postmenopausal estrogen replacement therapy and the risk of Alzheimer disease. Arch Neurol. 2001;58:435–40.
Davies NM, Kehoe PG, Ben-Shlomo Y, Martin RM. Associations of anti-hypertensive treatments with Alzheimer’s disease, vascular dementia, and other dementias. J Alzheimers Dis. 2011;26:699–708.
Jick H, Zornberg G, Jick S, Seshadri S, Drachman D. Statins and the risk of dementia. Lancet. 2000;356:1627–31.
Martinez C, Jones RW, Rietbrock S. Trends in the prevalence of antipsychotic drug use among patients with Alzheimer’s disease and other dementias including those treated with antidementia drugs in the community in the UK: a cohort study. BMJ Open. 2013;3:e002080.
Imfeld P, Bodmer M, Schuerch M, Jick SS, Meier CR. Risk of incident stroke in patients with Alzheimer disease or vascular dementia. Neurology. 2013;81:910–9.
Imfeld P, Brauchli Pernus YB, Jick SS, Meier CR. Epidemiology, co-morbidities, and medication use of patients with Alzheimer’s disease or vascular dementia in the UK. J Alzheimers Dis. 2013;35:565–73.
Greenblatt DJ, Shader RI, Divoll M, Harmatz JS. Benzodiazepines: a summary of pharmacokinetic properties. Br J Clin Pharmacol. 1981;11:11S–6S.
Diniz BS, Butters MA, Albert SM, Dew MA, Reynolds CF. Late-life depression and risk of vascular dementia and Alzheimer’s disease: systematic review and meta-analysis of community-based cohort studies. Br J Psychiatry. 2013;202:329–35.
Lader M. Benzodiazepine harm: how can it be reduced? Br J Clin Pharmacol. 2014;77:295–301.
Ooms S, Overeem S, Besse K, Rikkert MO, Verbeek M, Claassen JA. Effect of 1 night of total sleep deprivation on cerebrospinal fluid β-amyloid 42 in healthy middle-aged men: a randomized clinical trial. JAMA Neurol. 2014;71:971–7.
Madhusoodanan S, Bogunovic OJ. Safety of benzodiazepines in the geriatric population. Expert Opin Drug Saf. 2004;3:485–93.
Acknowledgments
The authors would like to thank Pascal Egger for programming and technical support.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Funding
No funding was received for this study.
Conflicts of interest
Patrick Imfeld, Michael Bodmer, Susan S. Jick, and Christoph R. Meier declare that they have no conflicts of interest.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Imfeld, P., Bodmer, M., Jick, S.S. et al. Benzodiazepine Use and Risk of Developing Alzheimer’s Disease or Vascular Dementia: A Case–Control Analysis. Drug Saf 38, 909–919 (2015). https://doi.org/10.1007/s40264-015-0319-3
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40264-015-0319-3