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Association Between the Use of Non-benzodiazepine Hypnotics and Cognitive Outcomes: A Systematic Review

  • Sleep and Aging (A Spira, Section Editor)
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Abstract

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.

Recent Findings

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.

Summary

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.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  2. 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.

    Article  PubMed  Google Scholar 

  3. Mendelson WB. The use of sedative/hypnotic medication and its correlation with falling down in the hospital. Sleep. 1996;19(9):698–701.

    CAS  PubMed  Google Scholar 

  4. 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.

    Article  CAS  PubMed  Google Scholar 

  5. 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.

    Article  CAS  PubMed  Google Scholar 

  6. 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.

    Article  CAS  PubMed  Google Scholar 

  7. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  8. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  9. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. 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.

    Article  Google Scholar 

  11. 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.

    Article  PubMed  Google Scholar 

  12. 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.

    Article  PubMed  Google Scholar 

  13. 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.

  14. 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.

    Article  CAS  PubMed  Google Scholar 

  15. 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.

    Article  CAS  PubMed  Google Scholar 

  16. 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.

    Article  CAS  PubMed  Google Scholar 

  17. 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.

    Article  CAS  PubMed  Google Scholar 

  18. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 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.

    Article  CAS  PubMed  Google Scholar 

  22. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. 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.

    Article  PubMed  Google Scholar 

  24. 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.

    Article  CAS  PubMed  Google Scholar 

  25. 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.

    Article  PubMed  Google Scholar 

  26. 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.

    Article  PubMed  Google Scholar 

  27. 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.

    Article  CAS  PubMed  Google Scholar 

  28. 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.

    Article  CAS  PubMed  Google Scholar 

  29. 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.

    Article  CAS  PubMed  Google Scholar 

  30. 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.

    Article  CAS  PubMed  Google Scholar 

  31. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. 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.

    Article  PubMed  Google Scholar 

  33. 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.

    Article  CAS  PubMed  Google Scholar 

  34. 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.

    Article  CAS  PubMed  Google Scholar 

  35. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  36. 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.

    Article  PubMed  Google Scholar 

  37. 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.

    Google Scholar 

  38. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. 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.

    Article  PubMed  Google Scholar 

  40. 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.

    Article  PubMed  Google Scholar 

  41. • 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.

    Article  PubMed  PubMed Central  Google Scholar 

  42. 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.

    Article  PubMed  Google Scholar 

  43. •• 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.

    Article  PubMed  Google Scholar 

  44. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  45. 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.

  46. 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.

  47. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. 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.

    Article  CAS  PubMed  Google Scholar 

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Funding

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.

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Correspondence to Christopher N. Kaufmann.

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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.

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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

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