Cumulative Use of Strong Anticholinergics and Incident Dementia: A Prospective Cohort Study | Dementia and Cognitive Impairment | JAMA Internal Medicine | JAMA Network
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Jessen  F, Kaduszkiewicz  H, Daerr  M,  et al.  Anticholinergic drug use and risk for dementia: target for dementia prevention.  Eur Arch Psychiatry Clin Neurosci. 2010;260(suppl 2):S111-S115.PubMedGoogle ScholarCrossref
Ancelin  ML, Artero  S, Portet  F, Dupuy  AM, Touchon  J, Ritchie  K.  Non-degenerative mild cognitive impairment in elderly people and use of anticholinergic drugs: longitudinal cohort study.  BMJ. 2006;332(7539):455-459.PubMedGoogle ScholarCrossref
Lechevallier-Michel  N, Molimard  M, Dartigues  JF, Fabrigoule  C, Fourrier-Réglat  A.  Drugs with anticholinergic properties and cognitive performance in the elderly: results from the PAQUID Study.  Br J Clin Pharmacol. 2005;59(2):143-151.PubMedGoogle ScholarCrossref
Boustani  M, Campbell  N, Munger  S, Maidment  I, Fox  C.  Impact of anticholinergics on the aging brain: a review and practical application.  Aging Health.2008;4:311-320.Google ScholarCrossref
Ness  J, Hoth  A, Barnett  MJ, Shorr  RI, Kaboli  PJ.  Anticholinergic medications in community-dwelling older veterans: prevalence of anticholinergic symptoms, symptom burden, and adverse drug events.  Am J Geriatr Pharmacother. 2006;4(1):42-51.PubMedGoogle ScholarCrossref
Fick  DM, Cooper  JW, Wade  WE, Waller  JL, Maclean  JR, Beers  MH.  Updating the Beers criteria for potentially inappropriate medication use in older adults: results of a US consensus panel of experts.  Arch Intern Med. 2003;163(22):2716-2724.PubMedGoogle ScholarCrossref
Campbell  N, Boustani  M, Limbil  T,  et al.  The cognitive impact of anticholinergics: a clinical review.  Clin Interv Aging. 2009;4:225-233.PubMedGoogle Scholar
American Geriatrics Society 2012 Beers Criteria Update Expert Panel.  American Geriatrics Society updated Beers criteria for potentially inappropriate medication use in older adults.  J Am Geriatr Soc. 2012;60(4):616-631.PubMedGoogle ScholarCrossref
Ray  PG, Meador  KJ, Loring  DW, Zamrini  EW, Yang  XH, Buccafusco  JJ.  Central anticholinergic hypersensitivity in aging.  J Geriatr Psychiatry Neurol. 1992;5(2):72-77.PubMedGoogle ScholarCrossref
Molchan  SE, Martinez  RA, Hill  JL,  et al.  Increased cognitive sensitivity to scopolamine with age and a perspective on the scopolamine model.  Brain Res Brain Res Rev. 1992;17(3):215-226.PubMedGoogle ScholarCrossref
Flicker  C, Ferris  SH, Serby  M.  Hypersensitivity to scopolamine in the elderly.  Psychopharmacology (Berl). 1992;107(2-3):437-441.PubMedGoogle ScholarCrossref
Flicker  C, Serby  M, Ferris  SH.  Scopolamine effects on memory, language, visuospatial praxis and psychomotor speed.  Psychopharmacology (Berl). 1990;100(2):243-250.PubMedGoogle ScholarCrossref
Fox  C, Richardson  K, Maidment  ID,  et al.  Anticholinergic medication use and cognitive impairment in the older population: the Medical Research Council Cognitive Function and Ageing Study.  J Am Geriatr Soc. 2011;59(8):1477-1483.PubMedGoogle ScholarCrossref
Carrière  I, Fourrier-Reglat  A, Dartigues  JF,  et al.  Drugs with anticholinergic properties, cognitive decline, and dementia in an elderly general population: the 3-City Study.  Arch Intern Med. 2009;169(14):1317-1324.PubMedGoogle ScholarCrossref
Perry  EK, Kilford  L, Lees  AJ, Burn  DJ, Perry  RH.  Increased Alzheimer pathology in Parkinson’s disease related to antimuscarinic drugs.  Ann Neurol. 2003;54(2):235-238.PubMedGoogle ScholarCrossref
Sperling  RA, Aisen  PS, Beckett  LA,  et al.  Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging–Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease.  Alzheimers Dement. 2011;7(3):280-292.PubMedGoogle ScholarCrossref
Amieva  H, Le Goff  M, Millet  X,  et al.  Prodromal Alzheimer’s disease: successive emergence of the clinical symptoms.  Ann Neurol. 2008;64(5):492-498.PubMedGoogle ScholarCrossref
Richard  E, Reitz  C, Honig  LH,  et al.  Late-life depression, mild cognitive impairment, and dementia.  JAMA Neurol. 2013;70(3):374-382.PubMedGoogle ScholarCrossref
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(3):230-235.PubMedGoogle ScholarCrossref
Kukull  WA, Higdon  R, Bowen  JD,  et al.  Dementia and Alzheimer disease incidence: a prospective cohort study.  Arch Neurol. 2002;59(11):1737-1746.PubMedGoogle ScholarCrossref
Teng  EL, Hasegawa  K, Homma  A,  et al.  The Cognitive Abilities Screening Instrument (CASI): a practical test for cross-cultural epidemiological studies of dementia.  Int Psychogeriatr. 1994;6(1):45-58.PubMedGoogle ScholarCrossref
Gray  SL, Anderson  M, Hubbard  R,  et al.  Frailty and incident dementia.  Gerontol A Biol Sci Med Sci. 2013;68(9):1083-1090. PubMedGoogle ScholarCrossref
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders.4th ed. Washington, DC: American Psychiatric Association; 1994.
McKhann  G, Drachman  D, Folstein  M, Katzman  R, Price  D, Stadlan  EM.  Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease.  Neurology. 1984;34(7):939-944.PubMedGoogle ScholarCrossref
Goodman  LS, Gilman  A, eds.  The Pharmacological Basis of Therapeutics.6th ed. New York, NY: MacMillan; 1982.
American Medical Association.  AMA Drug Evaluations.5th ed. Chicago, IL: American Medical Association; 1983.
Semla  TP, Beizer  JL, Higbee  MD.  Geriatric Dosage Handbook.15th ed. Hudson, OH: Lexicomp; 2010.
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):1012-1018.PubMedGoogle ScholarCrossref
Hanlon  JT, Boudreau  RM, Roumani  YF,  et al.  Number and dosage of central nervous system medications on recurrent falls in community elders: the Health, Aging and Body Composition Study.  J Gerontol A Biol Sci Med Sci. 2009;64(4):492-498.PubMedGoogle ScholarCrossref
Tamim  H, Monfared  AA, LeLorier  J.  Application of lag-time into exposure definitions to control for protopathic bias.  Pharmacoepidemiol Drug Saf. 2007;16(3):250-258.PubMedGoogle ScholarCrossref
National Heart, Lung, and Blood Institute (NHLBI).  Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults 1998. Accessed December 17, 2014.
Larson  EB, Wang  L, Bowen  JD,  et al.  Exercise is associated with reduced risk for incident dementia among persons 65 years of age and older.  Ann Intern Med. 2006;144(2):73-81.PubMedGoogle ScholarCrossref
Emi  M, Wu  LL, Robertson  MA,  et al.  Genotyping and sequence analysis of apolipoprotein E isoforms.  Genomics. 1988;3(4):373-379.PubMedGoogle ScholarCrossref
Hixson  JE, Vernier  DT.  Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI.  J Lipid Res. 1990;31(3):545-548.PubMedGoogle Scholar
Andresen  EM, Malmgren  JA, Carter  WB, Patrick  DL.  Screening for depression in well older adults: evaluation of a short form of the CES-D (Center for Epidemiologic Studies Depression Scale).  Am J Prev Med. 1994;10(2):77-84.PubMedGoogle Scholar
Korn  EL, Graubard  BI, Midthune  D.  Time-to-event analysis of longitudinal follow-up of a survey: choice of the time-scale.  Am J Epidemiol. 1997;145(1):72-80.PubMedGoogle ScholarCrossref
Steenland  K, Karnes  C, Seals  R, Carnevale  C, Hermida  A, Levey  A.  Late-life depression as a risk factor for mild cognitive impairment or Alzheimer’s disease in 30 US Alzheimer’s disease centers.  J Alzheimers Dis. 2012;31(2):265-275.PubMedGoogle Scholar
Ionov  ID, Pushinskaya  II.  Amyloid-β production in aged guinea pigs: atropine-induced enhancement is reversed by naloxone.  Neurosci Lett. 2010;480(1):83-86.PubMedGoogle ScholarCrossref
Beach  TG, Potter  PE, Kuo  YM,  et al.  Cholinergic deafferentation of the rabbit cortex: a new animal model of Aβ deposition.  Neurosci Lett. 2000;283(1):9-12.PubMedGoogle ScholarCrossref
Roher  AE, Kuo  YM, Potter  PE,  et al.  Cortical cholinergic denervation elicits vascular Aβ deposition.  Ann N Y Acad Sci. 2000;903:366-373.PubMedGoogle ScholarCrossref
Durán  CE, Azermai  M, Vander Stichele  RH.  Systematic review of anticholinergic risk scales in older adults.  Eur J Clin Pharmacol. 2013;69(7):1485-1496.PubMedGoogle ScholarCrossref
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    6 Comments for this article
    I suspect cyproheptadine
    Lisa Robinson | none
    Perhaps the mystery of my mother's dementia is answered here.
    Aluminium is an additive and/or contaminant of these drugs
    Chris Exley | Professor of Bioinorganic Chemistry, Keele University, UK
    I would like to point out that aluminium is either an additive or a common contaminant of these drugs. One example is a drug commonly prescribed in Alzheimer's disease;The Al content of Reminyl (Galantamine hydrobromide) is approximately 600 mg/g. When a single tablet is added to 50 mL of a simulated stomach solution (0.25% w/v sodium lauryl sulphate, 0.05% w/v sodium azide, 35mM sodium chloride, 5mL 15.8M HNO3 and ultapure water, pH 1.5 – 1.7) and incubated for 1h at 37C the tablet dissolves giving an orange solution*. The total [Al] of this solution is 1300.0 (76.7) mg/L (n=9). This is but one, if shocking, example of how many common drugs contain high amounts of aluminium.
    Concerns regarding statistical analysis
    T.B. | Unaffiliated
    After reading the original investigation, “Cumulative Use of Strong Anticholinergics and Incident Dementia: A Prospective Study,” I have a few concerns and questions for the authors. My critique, which I will explain below, is that the authors failed to fully examine the range of data available to them regarding total standardized daily doses (TSDDs), and thus fall short of examining whether or not there is an association between cumulative anticholinergic use and increased risk for dementia along the entire range of TSDDs. Given the therapeutic importance of the medications under investigation, it is imperative that their use is not discouraged without fully examining all of the data available. To begin my explanation, the authors did not provide readers with the upper limit of the range of observed TSDDs for the study population. The lower limit was 0 (no use), but what was the highest observed TSDD? It is reasonable to assume that the range of TSDDs went quite high (much higher than 1,095). For example, an individual on a 30mg dose of Nortriptyline for 7 years would have 7,665 TSDDs ((30 x 365 x 7)/10). It is likely that many participants had even higher TSDDs.This leads to my primary concern regarding the authors’ analysis. They stop their statistical analysis at a relatively low number of TSDDs, lumping everything above 1,095 into one category. This fails to tell us whether or not cumulative use at higher levels of use continues to be linearly associated with increased risk for dementia. Why did they stop their analysis at such a relatively low level of use when they are trying to prove that cumulative use is associated with increased risk? This question is especially concerning because the authors have at least 10 years of data to investigate. Why stop short of looking at the entire relationship between cumulative use and risk of dementia?To explain more fully, for the statistical analysis, the authors divide TSDDs into 5 rather odd cut points: 0; 1-90; 91-365; 366-1095; and >1095. This is an unsound way to divide the cumulative use for three reasons. The first, which I have already touched upon, is that it stops the analysis at a relatively low level of use, failing to give us the entire picture of the relationship between cumulative use and increased risk. The second reason that these cut points of TSDDs are unsound is that they are supposed to represent \"timeframes\" (1-90 is three months of use; 91-365 is 3 months to 1 year of use; 366 to 1095 is 1 to 3 years of use; and >1095 is 3 years of use or more). However, the authors’ stated purpose is to demonstrate that cumulative use increases the risk for dementia, NOT duration of use, so it makes little sense to divide the data by these unequal and seemingly arbitrary durations.The third reason that these subdivisions of TSDDs are unsound is that these “timeframes” do not even correspond with actual timeframes of use. They would only correspond with an actual timeframe of use if an individual took only one medication at the lowest possible dose. For example, 1095 TSDDs may actually correspond with 8 months of use, not 3 years. Therefore, dividing the data by these “timeframes” makes no statistical sense, no clinical sense, and appears completely arbitrary, or even like post hoc analysis. What would make sense is if the authors divided the TSDDs into equal increments of 500 or 1,000 (i.e., 0-1,000; 1,000-2,000; 2,000-3,000….. ) all the way to the top of the range of TSDDs, while continuing to exclude medications prescribed for prodromal symptoms for two years prior to diagnosis. This would allow us to see if there really is an association between cumulative use and increased risk for dementia. My request to the authors is to please provide readers with the upper limit of the range of TSDDs observed in the population, and to provide us with the hazard ratios for categories of use that go up by equal increments of 500 or 1,000 TSDDs, all the way to the top of the range of TSDDs, while continuing to exclude medications used for two years prior to a dementia diagnosis. Having this information will help us to determine if and what risk patients face with cumulative use of these medications. Many of these medications are extremely important therapeutically, so having all of the information is crucial to making sound medical decisions.
    Cognitive change after discontinuing Benadryl
    Shelly L. Gray, Rebecca Hubbard | none
    I am a healthy 67 year old female. I had been taking one or two Benadryl tablets each night for 25 years to help me sleep. After seeing your article online I stopped. I thought you might like to know about a change I experienced in the months that followed. I had for several years been doing an odd thing. I would reverse the meanings of words occasionally (maybe several times a week) without realizing it. I would say up instead of down, in instead of out, month instead of year, and so forth. It was very annoying and occasionally embarrassing. My husband noticed first that I stopped doing that after being off Benadryl for several months. I just thought you might like to know.
    Lauryn Miranda Escobar Beales | No affiliation
    Is there enough of a population in the same age range for the study for a control group? Perhaps a population of those who do not report using anticholinergics for >5 years throughout their lifetime and agree not to take anticholinergics throughout the study. That seems hard to prove/anticipate, but I'd like to compare results from this study with the results from the control group.
    A cause or a side effect of poor sleep?
    Heather Bruce, PhD Molecular Biology | University of California Berkeley
    From my reading, it doesn't seem like the authors have controlled for the fact that poor sleep can predate the onset of Alzheimer's by at least a decade. Perhaps the reason people who take anticholinergics then later develop Alzheimer's is due to pre-Alzheimer's trouble sleeping. In this interpretation, these drugs don't cause Alzheimer's, but are merely an early warning sign that the person is experiencing the sleep disturbances that are associated with the late developmentioned of Alzheimer's. Perhaps a way to distinguish between these two hypotheses is to assess how tired patients are. If patients sleep soundly and do not take these medications to help them sleep nevertheless develop Alzheimer's, then this would indicate it is indeed the drug and not the attempt to use drugs to sleep better.
    Original Investigation
    March 2015

    Cumulative Use of Strong Anticholinergics and Incident Dementia: A Prospective Cohort Study

    Author Affiliations
    • 1School of Pharmacy, University of Washington, Seattle
    • 2Group Health Research Institute, Seattle, Washington
    • 3Department of Epidemiology, University of Washington, Seattle
    • 4Division of Geriatric Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
    • 5Department of Biostatistics, University of Washington, Seattle
    • 6currently with the Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia
    • 7Division of General Internal Medicine, University of Washington, Seattle
    JAMA Intern Med. 2015;175(3):401-407. doi:10.1001/jamainternmed.2014.7663

    Importance  Many medications have anticholinergic effects. In general, anticholinergic-induced cognitive impairment is considered reversible on discontinuation of anticholinergic therapy. However, a few studies suggest that anticholinergics may be associated with an increased risk for dementia.

    Objective  To examine whether cumulative anticholinergic use is associated with a higher risk for incident dementia.

    Design, Setting, and Participants  Prospective population-based cohort study using data from the Adult Changes in Thought study in Group Health, an integrated health care delivery system in Seattle, Washington. We included 3434 participants 65 years or older with no dementia at study entry. Initial recruitment occurred from 1994 through 1996 and from 2000 through 2003. Beginning in 2004, continuous replacement for deaths occurred. All participants were followed up every 2 years. Data through September 30, 2012, were included in these analyses.

    Exposures  Computerized pharmacy dispensing data were used to ascertain cumulative anticholinergic exposure, which was defined as the total standardized daily doses (TSDDs) dispensed in the past 10 years. The most recent 12 months of use was excluded to avoid use related to prodromal symptoms. Cumulative exposure was updated as participants were followed up over time.

    Main Outcomes and Measures  Incident dementia and Alzheimer disease using standard diagnostic criteria. Statistical analysis used Cox proportional hazards regression models adjusted for demographic characteristics, health behaviors, and health status, including comorbidities.

    Results  The most common anticholinergic classes used were tricyclic antidepressants, first-generation antihistamines, and bladder antimuscarinics. During a mean follow-up of 7.3 years, 797 participants (23.2%) developed dementia (637 of these [79.9%] developed Alzheimer disease). A 10-year cumulative dose-response relationship was observed for dementia and Alzheimer disease (test for trend, P < .001). For dementia, adjusted hazard ratios for cumulative anticholinergic use compared with nonuse were 0.92 (95% CI, 0.74-1.16) for TSDDs of 1 to 90; 1.19 (95% CI, 0.94-1.51) for TSDDs of 91 to 365; 1.23 (95% CI, 0.94-1.62) for TSDDs of 366 to 1095; and 1.54 (95% CI, 1.21-1.96) for TSDDs greater than 1095. A similar pattern of results was noted for Alzheimer disease. Results were robust in secondary, sensitivity, and post hoc analyses.

    Conclusions and Relevance  Higher cumulative anticholinergic use is associated with an increased risk for dementia. Efforts to increase awareness among health care professionals and older adults about this potential medication-related risk are important to minimize anticholinergic use over time.