Background Benzodiazepine use can potentially cause confusion and delays in mental processes. These well-known side effects appear to be linked to an increased risk of being diagnosed with dementia. Objective To evaluate the possibility of an association between benzodiazepine and dementia. Setting Korean healthcare database from 2002 to 2013. Methods Sequence symmetry analysis was conducted to investigate whether benzodiazepine use increases the risk of dementia or not. We defined exposure as new benzodiazepine users and outcome as new diagnosis of dementia (ICD-10: F00-03, G30, and G318). Benzodiazepines were categorized into two groups (long-acting and short-acting) based on the duration of action. Antidepressants, opioid analgesic, and statin were used as active comparators to rule out any possible non-causal interpretations of our results. The time-trend adjusted sequence ratio (ASR) with 95% confidence intervals (CI) was measured to identify possible associations. Main outcome measure Adjusted sequence ratio. Results Benzodiazepine users were shown to be associated with dementia [benzodiazepine: 4212 pairs, ASR = 2.27 (95% CI 2.11–2.44)]. In addition, long-acting benzodiazepines had a higher ASR than that of short-acting benzodiazepines [long-acting: 3972 pairs, ASR = 2.22 (95% CI 2.06–2.39] and [short-acting: 5213 pairs, ASR = 1.88 (95% CI 1.77–2.00)]. However, our SSA found no duration-response relationship. Conclusion Our signal detection suggests that there is a possible association between benzodiazepines and dementia. Additionally, it proposes that persons receiving long-acting benzodiazepines are at a higher risk of developing dementia than those receiving short-acting benzodiazepines. Further studies are recommended to confirm whether this epidemiological association is a causal effect or not.
Benzodiazepines Data-mining Dementia Sequence symmetry analysis (SSA) South Korean health care database
This is a preview of subscription content, log in to check access.
This research was supported by a Grant from the Korean Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (Grant no.: NHCR-HC17C0020).
Conflicts of interest
The authors declare that they have no conflicts of interest.
Kim YJ, Han JW, So YS, et al. Prevalence and trends of dementia in Korea: a systematic review and meta analysis. J Korean Med Sci. 2014;29(7):903–12.CrossRefGoogle Scholar
Airagnes G, Pelissolo A, Lavallée M, et al. BZD misuse in the elderly: risk factors, consequences, and management. Curr Psychiatry Rep. 2016;18(10):89.CrossRefGoogle Scholar
Pariente A, de Gage SB, Moore N, et al. The BZD–dementia disorders link: current state of knowledge. CNS Drugs. 2016;30(1):1–7.CrossRefGoogle Scholar
Shash D, Kurth T, Bertrand M, et al. BZD, psychotropic medication, and dementia: a population-based cohort study. Alzheimers Dement. 2016;12(5):604–13.CrossRefGoogle Scholar
Sophie BG, Bernard B, Fabienne B, et al. BZD use and risk of dementia: prospective population based study. BMJ. 2012;345:e6231.CrossRefGoogle Scholar
Shelly G, Dublin S, Yu O et al. BZD use and risk of incident dementia or cognitive decline: prospective population based study. BMJ. 2016;352:i90Google Scholar
Proy-vega B, Martines BA, Solis Garcia DPJ, et al. Pharmacovigilance signals detection: BZDs and skin and subcutaneous tissue disorders. IJPSR. 2017;8(6):2433–42.Google Scholar
Wahab IA, Nicole LP, et al. The validity of sequence symmetry analysis (SSA) for adverse drug reaction signal detection. Pharmacoepidemiol Drug Saf. 2013;22:496–502.CrossRefGoogle Scholar
Wahab IA, Nicole LP, et al. Comparing time to adverse drug reaction signals in a spontaneous reporting database and a claims database: a case study of rofecoxib-induced myocardial infarction and rosiglitazone-induced heart failure signals in Australia. Drug Saf. 2014;37(1):53–64.CrossRefGoogle Scholar
Wahab IA, Nicole LP, et al. Sequence symmetry analysis and disproportionality analyses: what percentage of adverse drug reaction do they signal? Drug Saf. 2013;2:4.Google Scholar
Lai E, Pratt N, Hsieh C, et al. Sequence symmetry analysis in pharmacovigilance and pharmacoepidemiologic studies. Eur J Epidemiol. 2017;32:567–82.CrossRefGoogle Scholar
Hallas J. Evidence of depression provoked by cardiovascular medication: a prescription sequence symmetry analysis. Epidemiology. 1996;7:478–84.CrossRefGoogle Scholar
Mitsutaka T, Mai F, Kouichi H. Association between BZD Use and dementia: data mining of different medical databases. Int J Med Sci. 2016;13(11):825–34.CrossRefGoogle Scholar
Maclure M, Fireman B, Nelson JC, et al. When should case-only designs be used for safety monitoring of medical products? Pharmacoepidemiol Drug Saf. 2012;21(Suppl 1):50–61.CrossRefGoogle Scholar
Park SY, Bae S, Shin JY. Real-world patterns of long-acting BZD prescription among elderly Koreans in 2013. Int J Clin Pharmacol Ther. 2017;55(6):472–9.CrossRefGoogle Scholar
de Gage BS, Moride Y, Ducruet T, et al. BZD use and risk of Alzheimer’s disease: case–control study. BMJ. 2014;349:g5205.CrossRefGoogle Scholar
Stern Y. Cognitive reserve in ageing and Alzheimer’s disease. Lancet Neurol. 2012;11(11):1006–12.CrossRefGoogle Scholar
Stranks EK, Crowe SF. The acute cognitive effects of zopiclone, zolpidem, zaleplon, and eszopiclone: a systematic review and meta-analysis. J Clin Exp Neuropsychol. 2014;36(7):691–700.CrossRefGoogle Scholar
Tannenbaum C, Paquette A, Hilmer S, et al. A systematic review of amnestic and non-amnestic mild cognitive impairment induced by anticholinergic, antihistamine, GABAergic and opioid drugs. Drugs Aging. 2012;29(8):639–58.PubMedGoogle Scholar
Hutchinson MA, Smith PF, Darlington CL. The behavioural and neuronal effects of the chronic administration of BZD anxiolytic and hypnotic drugs. Prog Neurobiol. 1996;49(1):73–97.CrossRefGoogle Scholar
Shimohama S, Taniguchi T, Fujiwara M, et al. Changes in BZD receptors in Alzheimer-type dementia. Ann Neurol. 1988;23(4):404–6.CrossRefGoogle Scholar
Limon A, Reyes-Ruiz JM, Miledi R. Loss of functional GABAA receptors in the Alzheimer diseased brain. Proc Natl Acad Sci USA. 2012;109(25):10071–6.CrossRefGoogle Scholar
Jo S, Yarishkin O, Hwang YJ, et al. GABA from reactive astrocytes impairs memory in mouse models of Alzheimer’s disease. Nat Med. 2014;20(8):886–96.CrossRefGoogle Scholar
Pratt Nicole, Chan Esther W, et al. Prescription sequence symmetry analysis: assessing risk, temporality, and consistency for adverse drug reactions across datasets in five countries. Pharmacoepidemiol Drug Saf. 2015;24(8):858–64.CrossRefGoogle Scholar