Purpose of Review
Adverse effects of sedative-hypnotic medications on cognition are concerning. Past studies have examined benzodiazepine (BZD) use and cognitive outcomes; however, few studies have examined newer non-BZD hypnotic agents (nBHs; e.g., zolpidem). This systematic review examined observational studies assessing the association between nBH use and cognitive outcomes.
Five studies met eligibility requirements and were included in the review. Most studies did not find an association between nBH use and dementia diagnosis; however, we found no studies assessing other cognitive outcomes such as cognitive performance (e.g., word recall tasks). Characterization of nBH use mostly consisted of incident new use; one study assessed nBH dosing; none examined duration of use. Studies included were of strong quality.
This review found no association between nBH use and dementia diagnosis, although there is a need for more research on more cognitive outcomes and nBH use patterns.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Price excludes VAT (USA)
Tax calculation will be finalised during checkout.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Brandt J, Leong C. Benzodiazepines and Z-drugs: an updated review of major adverse outcomes reported on in epidemiologic research. Drugs R D. 2017;17(4):493–507. https://doi.org/10.1007/s40268-017-0207-7.
Lader M. Benzodiazepines revisited—will we ever learn? Addiction. 2011;106(12):2086–109. https://doi.org/10.1111/j.1360-0443.2011.03563.x.
Mendelson WB. The use of sedative/hypnotic medication and its correlation with falling down in the hospital. Sleep. 1996;19(9):698–701.
Rossat A, Fantino B, Bongue B, Colvez A, Nitenberg C, Annweiler C, et al. Association between benzodiazepines and recurrent falls: a cross-sectional elderly population-based study. J Nutr Health Aging. 2011;15(1):72–7.
Herings RM, Stricker BH, de Boer A, Bakker A, Sturmans F. Benzodiazepines and the risk of falling leading to femur fractures. Dosage more important than elimination half-life. Arch Intern Med. 1995;155(16):1801–7.
Ray WA, Griffin MR, Schaffner W, Baugh DK, Melton LJ 3rd. Psychotropic drug use and the risk of hip fracture. N Engl J Med. 1987;316(7):363–9. https://doi.org/10.1056/NEJM198702123160702.
Gray SL, LaCroix AZ, Blough D, Wagner EH, Koepsell TD, Buchner D. Is the use of benzodiazepines associated with incident disability? J Am Geriatr Soc. 2002;50(6):1012–8. https://doi.org/10.1046/j.1532-5415.2002.50254.x.
Gray SL, LaCroix AZ, Hanlon JT, Penninx BW, Blough DK, Leveille SG, et al. Benzodiazepine use and physical disability in community-dwelling older adults. J Am Geriatr Soc. 2006;54(2):224–30. https://doi.org/10.1111/j.1532-5415.2005.00571.x.
Peron EP, Gray SL, Hanlon JT. Medication use and functional status decline in older adults: a narrative review. Am J Geriatr Pharmacother. 2011;9(6):378–91. https://doi.org/10.1016/j.amjopharm.2011.10.002.
By the American Geriatrics Society Beers Criteria Update Expert P. American Geriatrics Society 2019 updated AGS beers criteria(R) for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2019;67(4):674–94. https://doi.org/10.1111/jgs.15767.
Qaseem A, Kansagara D, Forciea MA, Cooke M, Denberg TD, Clinical Guidelines Committee of the American College of P. Management of chronic insomnia disorder in adults: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2016;165(2):125–33. https://doi.org/10.7326/M15-2175.
O'Mahony D, O'Sullivan D, Byrne S, O'Connor MN, Ryan C, Gallagher P. STOPP/START criteria for potentially inappropriate prescribing in older people: version 2. Age Ageing. 2015;44(2):213–8. https://doi.org/10.1093/ageing/afu145.
Food and Drug Administration. FDA adds Boxed Warning for risk of serious injuries caused by sleepwalking with certain prescription insomnia medicines. 2019. https://www.fda.gov/drugs/drug-safety-and-availability/fda-adds-boxed-warning-risk-serious-injuries-caused-sleepwalking-certain-prescription-insomnia. Accessed November 8 2019.
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. https://doi.org/10.2165/00023210-200418010-00004.
Buffett-Jerrott SE, Stewart SH. Cognitive and sedative effects of benzodiazepine use. Curr Pharm Des. 2002;8(1):45–58. https://doi.org/10.2174/1381612023396654.
Campagne DM. Fact: antidepressants and anxiolytics are not safe during pregnancy. Eur J Obstet Gynecol Reprod Biol. 2007;135(2):145–8. https://doi.org/10.1016/j.ejogrb.2007.06.010.
Rummans TA, Davis LJ Jr, Morse RM, Ivnik RJ. Learning and memory impairment in older, detoxified, benzodiazepine-dependent patients. Mayo Clin Proc. 1993;68(8):731–7. https://doi.org/10.1016/s0025-6196(12)60628-4.
Barbui C, Gastaldon C, Cipriani A. Benzodiazepines and risk of dementia: true association or reverse causation? Epidemiol Psychiatr Sci. 2013;22(4):307–8. https://doi.org/10.1017/S2045796013000358.
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. https://doi.org/10.1136/bmj.e6231.
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. https://doi.org/10.1136/bmj.g5205.
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(5):733–47. https://doi.org/10.1517/14740338.2015.1014796.
Gray SL, Dublin S, Yu O, Walker R, Anderson M, Hubbard RA, et al. Benzodiazepine use and risk of incident dementia or cognitive decline: prospective population based study. BMJ. 2016;352:i90. https://doi.org/10.1136/bmj.i90.
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.
Pariente A, de Gage SB, Moore N, Begaud B. The benzodiazepine-dementia disorders link: current state of knowledge. CNS Drugs. 2016;30(1):1–7. https://doi.org/10.1007/s40263-015-0305-4.
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(3):307–15. https://doi.org/10.1017/s0033291704003897.
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. https://doi.org/10.1097/JGP.0b013e3181a65210.
Golombok S, Moodley P, Lader M. Cognitive impairment in long-term benzodiazepine users. Psychol Med. 1988;18(2):365–74. https://doi.org/10.1017/s0033291700007911.
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. https://doi.org/10.1097/00004714-200206000-00009.
Sakol MS, Power KG. The effects of long-term benzodiazepine treatment and graded withdrawal on psychometric performance. Psychopharmacology. 1988;95(1):135–8. https://doi.org/10.1007/bf00212782.
Tata PR, Rollings J, Collins M, Pickering A, Jacobson RR. Lack of cognitive recovery following withdrawal from long-term benzodiazepine use. Psychol Med. 1994;24(1):203–13. https://doi.org/10.1017/s0033291700026969.
Hindmarch I, Legangneux E, Stanley N, Emegbo S, Dawson J. A double-blind, placebo-controlled investigation of the residual psychomotor and cognitive effects of zolpidem-MR in healthy elderly volunteers. Br J Clin Pharmacol. 2006;62(5):538–45. https://doi.org/10.1111/j.1365-2125.2006.02705.x.
Li Pi Shan RS, Ashworth NL. Comparison of lorazepam and zopiclone for insomnia in patients with stroke and brain injury: a randomized, crossover, double-blinded trial. Am J Phys Med Rehabil. 2004;83(6):421–7. https://doi.org/10.1097/00002060-200406000-00003.
Fairweather DB, Kerr JS, Hindmarch I. The effects of acute and repeated doses of zolpidem on subjective sleep, psychomotor performance and cognitive function in elderly volunteers. Eur J Clin Pharmacol. 1992;43(6):597–601. https://doi.org/10.1007/bf02284957.
Kaufmann CN, Spira AP, Alexander GC, Rutkow L, Mojtabai R. Trends in prescribing of sedative-hypnotic medications in the USA: 1993-2010. Pharmacoepidemiol Drug Saf. 2016a;25(6):637–45. https://doi.org/10.1002/pds.3951.
Kaufmann CN, Spira AP, Depp CA, Mojtabai R. Continuing versus new prescriptions for sedative-hypnotic medications: United States, 2005-2012. Am J Public Health. 2016b;106(11):2019–25. https://doi.org/10.2105/AJPH.2016.303382.
Kaufmann CN, Spira AP, Depp CA, Mojtabai R. Long-term use of benzodiazepines and nonbenzodiazepine hypnotics, 1999-2014. Psychiatr Serv. 2018;69(2):235–8. https://doi.org/10.1176/appi.ps.201700095.
Wells G, Shea B, O’connell D, Peterson J, Welch V, Losos M, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Ottawa: Ottawa Hospital Research Institute; 2014.
Modesti PA, Reboldi G, Cappuccio FP, Agyemang C, Remuzzi G, Rapi S, et al. Panethnic differences in blood pressure in Europe: a systematic review and meta-analysis. PLoS One. 2016;11(1):e0147601. https://doi.org/10.1371/journal.pone.0147601.
Islam MM, Iqbal U, Walther B, Atique S, Dubey NK, Nguyen PA, et al. Benzodiazepine use and risk of dementia in the elderly population: a systematic review and meta-analysis. Neuroepidemiology. 2016;47(3–4):181–91. https://doi.org/10.1159/000454881.
Hosoya R, Sato Y, Ishida E, Shibamoto H, Hino S, Yokote H, et al. Association between delirium and prehospitalization medication in poststroke patients. J Stroke Cerebrovasc Dis. 2018;27(7):1914–20. https://doi.org/10.1016/j.jstrokecerebrovasdis.2018.02.038.
• Burke SL, Hu T, Spadola CE, Li T, Naseh M, Burgess A, et al. Mild cognitive impairment: associations with sleep disturbance, apolipoprotein e4, and sleep medications. Sleep Med. 2018;52:168–76. https://doi.org/10.1016/j.sleep.2018.09.001Study uses a well-established ADRD dataset to examine sleep disturbance and MCI stratified by nBH use. This was the only study found in our systematic review examining MCI.
Burke SL, Hu T, Spadola CE, Burgess A, Li T, Cadet T. Treatment of sleep disturbance may reduce the risk of future probable Alzheimer’s disease. J Aging Health. 2019;31(2):322–42. https://doi.org/10.1177/0898264318795567.
•• Cheng HT, Lin FJ, Erickson SR, Hong JL, Wu CH. The association between the use of zolpidem and the risk of Alzheimer’s disease among older people. J Am Geriatr Soc. 2017;65(11):2488–95. https://doi.org/10.1111/jgs.15018This study used a large administrative dataset to examine specially zolpidem use and ADRD risk. Apears to be the only large obsevational study examining specifically zolpidem as a risk factor.
Richardson K, Mattishent K, Loke YK, Steel N, Fox C, Grossi CM, et al. History of benzodiazepine prescriptions and risk of dementia: possible bias due to prevalent users and covariate measurement timing in a nested case-control study. Am J Epidemiol. 2019;188(7):1228–36. https://doi.org/10.1093/aje/kwz073.
Chang MC, Chun MH. The effect of hypnotics on sleep quality and cognitive function in patients with brain tumors. J Korean Neurosurg Soc. 2019. https://doi.org/10.3340/jkns.2019.0057.
Basta M, Simos P, Vgontzas A, Koutentaki E, Tziraki S, Zaganas I, et al. Associations between sleep duration and cognitive impairment in mild cognitive impairment. J Sleep Res. 2019:e12864. https://doi.org/10.1111/jsr.12864.
Lee J, Jung SJ, Choi JW, Shin A, Lee YJ. Use of sedative-hypnotics and the risk of Alzheimer’s dementia: a retrospective cohort study. PLoS One. 2018;13(9):e0204413. https://doi.org/10.1371/journal.pone.0204413.
Puustinen J, Nurminen J, Kukola M, Vahlberg T, Laine K, Kivela SL. Associations between use of benzodiazepines or related drugs and health, physical abilities and cognitive function: a non-randomised clinical study in the elderly. Drugs Aging. 2007;24(12):1045–59. https://doi.org/10.2165/00002512-200724120-00007.
This study was supported by funding from the NIA (CNK: K01AG061239; MWB: R01AG049810; AAM: P30AG059299, P30AG062429). Dr. Bondi receives royalties from Oxford University Press and serves as a consultant for Eisai and Novartis pharmaceutical companies. Dr. Murphy reports personal fees from Boston Consulting Group. Dr. Malhotra is PI on NHLBI grants and has received consulting income from Merck related to medical education. ResMed provided a philanthropic donation to UC San Diego in support of a sleep center.
Conflict of Interest
Dr. Kaufmann, Dr. Moore, and Dr. Hart each declare no potential conflicts of interest.
Dr. Murphy reports personal fees from Boston Consulting Group, outside the submitted work.
Dr. Malhotra reports his role as a PI on NHLBI grants and has received consulting income from Merck related to medical education. ResMed provided a philanthropic donation to UC San Diego in support of a sleep center.
Dr. Bondi reports royalties from Oxford University Press and serves as a consultant for Eisai and Novartis pharmaceutical companies.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
This article is part of the Topical Collection on Sleep and Aging
Rights and permissions
About this article
Cite this article
Kaufmann, C.N., Moore, A.A., Bondi, M.W. et al. Association Between the Use of Non-benzodiazepine Hypnotics and Cognitive Outcomes: A Systematic Review. Curr Sleep Medicine Rep 6, 11–20 (2020). https://doi.org/10.1007/s40675-020-00163-1
- Alzheimer’s disease
- Sleep medications
- Non-benzodiazepine hypnotics