Antipsychotic Drug Use and Mortality in Older Adults with Dementia
Publication: Annals of Internal Medicine
Volume 146, Number 11
Abstract
Background:
Antipsychotic drugs are widely used to manage behavioral and psychological symptoms in dementia despite concerns about their safety.
Objective:
To examine the association between treatment with antipsychotics (both conventional and atypical) and all-cause mortality.
Design:
Population-based, retrospective cohort study.
Setting:
Ontario, Canada.
Patients:
Older adults with dementia who were followed between 1 April 1997 and 31 March 2003.
Measurements:
The risk for death was determined at 30, 60, 120, and 180 days after the initial dispensing of antipsychotic medication. Two pairwise comparisons were made: atypical versus no antipsychotic use and conventional versus atypical antipsychotic use. Groups were stratified by place of residence (community or long-term care). Propensity score matching was used to adjust for differences in baseline health status.
Results:
A total of 27 259 matched pairs were identified. New use of atypical antipsychotics was associated with a statistically significant increase in the risk for death at 30 days compared with nonuse in both the community-dwelling cohort (adjusted hazard ratio, 1.31 [95% CI, 1.02 to 1.70]; absolute risk difference, 0.2 percentage point) and the long-term care cohort (adjusted hazard ratio, 1.55 [CI, 1.15 to 2.07]; absolute risk difference, 1.2 percentage points). Excess risk seemed to persist to 180 days, but unequal rates of censoring over time may have affected these results. Relative to atypical antipsychotic use, conventional antipsychotic use was associated with a higher risk for death at all time points. Sensitivity analysis revealed that unmeasured confounders that increase the risk for death could diminish or eliminate the observed associations.
Limitations:
Information on causes of death was not available. Many patients did not continue their initial treatments after 1 month of therapy. Unmeasured confounders could affect associations.
Conclusions:
Atypical antipsychotic use is associated with an increased risk for death compared with nonuse among older adults with dementia. The risk for death may be greater with conventional antipsychotics than with atypical antipsychotics.
Get full access to this article
View all available purchase options and get full access to this article.
References
1.
McKeith I, Cummings J. Behavioural changes and psychological symptoms in dementia disorders. Lancet Neurol. 2005;4:735-42. [PMID: 16239180]
2.
Sink KM, Holden KF, Yaffe K. Pharmacological treatment of neuropsychiatric symptoms of dementia: a review of the evidence. JAMA. 2005;293:596-608. [PMID: 15687315]
3.
Covinsky KE, Johnston CB. Envisioning better approaches for dementia care [Editorial]. Ann Intern Med. 2006;145:780-1. [PMID: 17116923]
4.
Bronskill SE, Anderson GM, Sykora K, Wodchis WP, Gill S, Shulman KI, et al. Neuroleptic drug therapy in older adults newly admitted to nursing homes: incidence, dose, and specialist contact. J Am Geriatr Soc. 2004;52:749-55. [PMID: 15086656]
5.
Liperoti R, Mor V, Lapane KL, Pedone C, Gambassi G, Bernabei R. The use of atypical antipsychotics in nursing homes. J Clin Psychiatry. 2003;64:1106-12. [PMID: 14628988]
6.
Schneider LS, Pollock VE, Lyness SA. A metaanalysis of controlled trials of neuroleptic treatment in dementia. J Am Geriatr Soc. 1990;38:553-63. [PMID: 1970586]
7.
Lanctôt KL, Best TS, Mittmann N, Liu BA, Oh PI, Einarson TR, et al. Efficacy and safety of neuroleptics in behavioral disorders associated with dementia. J Clin Psychiatry. 1998;59:550-61; quiz 562-3. [ 9818639]
8.
Rapoport M, Mamdani M, Shulman KI, Herrmann N, Rochon PA. Antipsychotic use in the elderly: shifting trends and increasing costs. Int J Geriatr Psychiatry. 2005;20:749-53. [PMID: 16035128]
9.
Lee PE, Gill SS, Freedman M, Bronskill SE, Hillmer MP, Rochon PA. Atypical antipsychotic drugs in the treatment of behavioural and psychological symptoms of dementia: systematic review. BMJ. 2004;329:75. [PMID: 15194601]
10.
Schneider LS, Tariot PN, Dagerman KS, Davis SM, Hsiao JK, Ismail MS, et al. Effectiveness of atypical antipsychotic drugs in patients with Alzheimer's disease. N Engl J Med. 2006;355:1525-38. [PMID: 17035647]
11.
Ballard CG, Margallo-Lana ML. The relationship between antipsychotic treatment and quality of life for patients with dementia living in residential and nursing home care facilities. J Clin Psychiatry. 2004;65 Suppl 11 23-8. [PMID: 15264968]
12.
U.S. Food and Drug Administration. FDA issues public health advisory for antipsychotic drugs used for treatment of behavioral disorders in elderly patients. FDA Talk Paper T05-13. Rockville, MD: U.S. Food and Drug Administration; 11 April 2005. Accessed at www.fda.gov/bbs/topics/ANSWERS/2005/ANS01350.html on 9 March 2007.
13.
Health Canada. Health Canada advises consumers about important safety information on atypical antipsychotic drugs and dementia. Advisory 2005-63. Ottawa: Health Canada; 15 June 2005. Accessed at www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/2005/2005_63_e.html on 9 March 2007.
14.
Schneider LS, Dagerman KS, Insel P. Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo-controlled trials. JAMA. 2005;294:1934-43. [PMID: 16234500]
15.
Wang PS, Schneeweiss S, Avorn J, Fischer MA, Mogun H, Solomon DH, et al. Risk of death in elderly users of conventional vs. atypical antipsychotic medications. N Engl J Med. 2005;353:2335-41. [PMID: 16319382]
16.
Kryzhanovskaya LA, Jeste DV, Young CA, Polzer JP, Roddy TE, Jansen JF, et al. A review of treatment-emergent adverse events during olanzapine clinical trials in elderly patients with dementia. J Clin Psychiatry. 2006;67:933-45. [PMID: 16848653]
17.
Rabins PV, Lyketsos CG. Antipsychotic drugs in dementia: what should be made of the risks? [Editorial]. JAMA. 2005;294:1963-5. [PMID: 16234504]
18.
Nasrallah HA, White T, Nasrallah AT. Lower mortality in geriatric patients receiving risperidone and olanzapine versus haloperidol: preliminary analysis of retrospective data. Am J Geriatr Psychiatry. 2004;12:437-9. [PMID: 15249282]
19.
Barnett MJ, Perry PJ, Alexander B, Kaboli PJ. Risk of mortality associated with antipsychotic and other neuropsychiatric drugs in pneumonia patients. J Clin Psychopharmacol. 2006;26:182-7. [PMID: 16633149]
20.
Levy AR, O'Brien BJ, Sellors C, Grootendorst P, Willison D. Coding accuracy of administrative drug claims in the Ontario Drug Benefit database. Can J Clin Pharmacol. 2003;10:67-71. [PMID: 12879144]
21.
Ray WA. Evaluating medication effects outside of clinical trials: new-user designs. Am J Epidemiol. 2003;158:915-20. [PMID: 14585769]
22.
Gurwitz JH, Field TS, Judge J, Rochon P, Harrold LR, Cadoret C, et al. The incidence of adverse drug events in two large academic long-term care facilities. Am J Med. 2005;118:251-8. [PMID: 15745723]
23.
Fahey T, Montgomery AA, Barnes J, Protheroe J. Quality of care for elderly residents in nursing homes and elderly people living at home: controlled observational study. BMJ. 2003;326:580. [PMID: 12637404]
24.
D'Agostino RB Jr. Propensity score methods for bias reduction in the comparison of a treatment to a non-randomized control group. Stat Med. 1998;17:2265-81. [PMID: 9802183]
25.
Brookhart MA, Schneeweiss S, Rothman KJ, Glynn RJ, Avorn J, Stürmer T. Variable selection for propensity score models. Am J Epidemiol. 2006;163:1149-56. [PMID: 16624967]
26.
Austin PC, Grootendorst P, Anderson GM. A comparison of the ability of different propensity score models to balance measured variables between treated and untreated subjects: a Monte Carlo study. Stat Med. 2007;26:734-53. [PMID: 16708349]
27.
Rosenbaum PR, Rubin DB. Constructing a control group using multivariate matched sampling methods that incorporate the propensity score. Am Stat. 1985;39:33-8.
28.
D'Agostino RB Jr. Propensity score methods for bias reduction in the comparison of a treatment to a nonrandomized control group. In: D'Agostino RB Jr, eds. Tutorials in Biostatistics. Volume 1: Statistical Methods in Clinical Studies. New York: J Wiley; 2004.
29.
Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40:373-83. [PMID: 3558716]
30.
Kern LM, Powe NR, Levine MA, Fitzpatrick AL, Harris TB, Robbins J, et al. Association between screening for osteoporosis and the incidence of hip fracture. Ann Intern Med. 2005;142:173-81. [PMID: 15684205]
31.
Schneeweiss S. Sensitivity analysis and external adjustment for unmeasured confounders in epidemiologic database studies of therapeutics. Pharmacoepidemiol Drug Saf. 2006;15:291-303. [PMID: 16447304]
32.
Suh GH, Shah A. Effect of antipsychotics on mortality in elderly patients with dementia: a 1-year prospective study in a nursing home. Int Psychogeriatr. 2005;17:429-41. [PMID: 16252375]
33.
Scarmeas N, Brandt J, Albert M, Hadjigeorgiou G, Papadimitriou A, Dubois B, et al. Delusions and hallucinations are associated with worse outcome in Alzheimer disease. Arch Neurol. 2005;62:1601-8. [PMID: 16216946]
34.
Trifirò G, Verhamme KM, Ziere G, Caputi AP, Ch Stricker BH, Sturkenboom MC. All-cause mortality associated with atypical and typical antipsychotics in demented outpatients. Pharmacoepidemiol Drug Saf. 2006;:. [PMID: 17036366]
35.
Livingston G, Walker AE, Katona CL, Cooper C. Antipsychotics and cognitive decline in Alzheimer's disease: the LASER-Alzheimer's disease longitudinal study. J Neurol Neurosurg Psychiatry. 2007;78:25-9. [PMID: 16801350]
36.
Joukamaa M, Heliövaara M, Knekt P, Aromaa A, Raitasalo R, Lehtinen V. Schizophrenia, neuroleptic medication and mortality. Br J Psychiatry. 2006;188:122-7. [PMID: 16449697]
37.
Tiihonen J, Walhbeck K, Lönnqvist J, Klaukka T, Ioannidis JP, Volavka J, et al. Effectiveness of antipsychotic treatments in a nationwide cohort of patients in community care after first hospitalisation due to schizophrenia and schizoaffective disorder: observational follow-up study. BMJ. 2006;333:224. [PMID: 16825203]
38.
Keene J, Hope T, Fairburn CG, Jacoby R. Death and dementia. Int J Geriatr Psychiatry. 2001;16:969-74. [PMID: 11607941]
39.
Ray WA. Observational studies of drugs and mortality. N Engl J Med. 2005;353:2319-21. [PMID: 16319379]
40.
Ray WA, Meredith S, Thapa PB, Meador KG, Hall K, Murray KT. Antipsychotics and the risk of sudden cardiac death. Arch Gen Psychiatry. 2001;58:1161-7. [PMID: 11735845]
41.
Hennessy S, Bilker WB, Knauss JS, Margolis DJ, Kimmel SE, Reynolds RF, et al. Cardiac arrest and ventricular arrhythmia in patients taking antipsychotic drugs: cohort study using administrative data. BMJ. 2002;325:1070. [PMID: 12424166]
42.
Straus SM, Bleumink GS, Dieleman JP, van der Lei J, 't Jong GW, Kingma JH, et al. Antipsychotics and the risk of sudden cardiac death. Arch Intern Med. 2004;164:1293-7. [PMID: 15226162]
43.
Liperoti R, Gambassi G, Lapane KL, Chiang C, Pedone C, Mor V, et al. Conventional and atypical antipsychotics and the risk of hospitalization for ventricular arrhythmias or cardiac arrest. Arch Intern Med. 2005;165:696-701. [PMID: 15795349]
44.
Straus SM, Sturkenboom MC, Bleumink GS, Dieleman JP, van der Lei J, de Graeff PA, et al. Non-cardiac QTc-prolonging drugs and the risk of sudden cardiac death. Eur Heart J. 2005;26:2007-12. [PMID: 15888497]
45.
Ray WA, Meador KG. Antipsychotics and sudden death: is thioridazine the only bad actor? [Editorial]. Br J Psychiatry. 2002;180:483-4. [PMID: 12042224]
46.
Hennessy S, Bilker WB, Knauss JS, Kimmel SE, Margolis DJ, Morrison MF, et al. Comparative cardiac safety of low-dose thioridazine and low-dose haloperidol. Br J Clin Pharmacol. 2004;58:81-7. [PMID: 15206997]
47.
Warner J. Risk of choking in mental illness. Lancet. 2004;363:674. [PMID: 15001323]
48.
Berzlanovich AM, Muhm M, Sim E, Bauer G. Foreign body asphyxiation—an autopsy study. Am J Med. 1999;107:351-5. [PMID: 10527037]
49.
Ruschena D, Mullen PE, Palmer S, Burgess P, Cordner SM, Drummer OH, et al. Choking deaths: the role of antipsychotic medication. Br J Psychiatry. 2003;183:446-50. [PMID: 14594921]
50.
Zornberg GL, Jick H. Antipsychotic drug use and risk of first-time idiopathic venous thromboembolism: a case–control study. Lancet. 2000;356:1219-23. [PMID: 11072939]
51.
Liperoti R, Pedone C, Lapane KL, Mor V, Bernabei R, Gambassi G. Venous thromboembolism among elderly patients treated with atypical and conventional antipsychotic agents. Arch Intern Med. 2005;165:2677-82. [PMID: 16344428]
52.
Gill SS, Rochon PA, Herrmann N, Lee PE, Sykora K, Gunraj N, et al. Atypical antipsychotic drugs and risk of ischaemic stroke: population based retrospective cohort study. BMJ. 2005;330:445. [PMID: 15668211]
53.
Liperoti R, Gambassi G, Lapane KL, Chiang C, Pedone C, Mor V, et al. Cerebrovascular events among elderly nursing home patients treated with conventional or atypical antipsychotics. J Clin Psychiatry. 2005;66:1090-6. [PMID: 16187764]
54.
Normand SL, Sykora K, Li P, Mamdani M, Rochon PA, Anderson GM. Readers guide to critical appraisal of cohort studies: 3. Analytical strategies to reduce confounding. BMJ. 2005;330:1021-3. [PMID: 15860831]
55.
Tschanz JT, Corcoran C, Skoog I, Khachaturian AS, Herrick J, Hayden KM, et al. Dementia: the leading predictor of death in a defined elderly population: the Cache County Study. Neurology. 2004;62:1156-62. [PMID: 15079016]
56.
Ballard C, Cream J. Drugs used to relieve behavioral symptoms in people with dementia or an unacceptable chemical cosh? Argument. Int Psychogeriatr. 2005;17:4-12; discussion 22-9. [ 15945588]
57.
Shah A, Suh GH. A case for judicious use of risperidone and olanzapine in behavioral and psychological symptoms of dementia (BPSD). Favour. Int Psychogeriatr. 2005;17:12-22. [PMID: 15945589]
58.
Ray WA, Taylor JA, Meador KG, Lichtenstein MJ, Griffin MR, Fought R, et al. Reducing antipsychotic drug use in nursing homes. A controlled trial of provider education. Arch Intern Med. 1993;153:713-21. [PMID: 8447709]
59.
Thapa PB, Meador KG, Gideon P, Fought RL, Ray WA. Effects of antipsychotic withdrawal in elderly nursing home residents. J Am Geriatr Soc. 1994;42:280-6. [PMID: 7907098]
60.
Meador KG, Taylor JA, Thapa PB, Fought RL, Ray WA. Predictors of antipsychotic withdrawal or dose reduction in a randomized, controlled trial of provider education. J Am Geriatr Soc. 1997;45:207-10. [PMID: 9033521]
61.
van Reekum R, Clarke D, Conn D, Herrmann N, Eryavec G, Cohen T, et al. A randomized, placebo-controlled trial of the discontinuation of long-term antipsychotics in dementia. Int Psychogeriatr. 2002;14:197-210. [PMID: 12243210]
62.
Livingston G, Johnston K, Katona C, Paton J, Lyketsos CG; Old Age Task Force of the World Federation of Biological Psychiatry. Systematic review of psychological approaches to the management of neuropsychiatric symptoms of dementia. Am J Psychiatry. 2005;162:1996-2021. [PMID: 16263837]
63.
Callahan CM, Boustani MA, Unverzagt FW, Austrom MG, Damush TM, Perkins AJ, et al. Effectiveness of collaborative care for older adults with Alzheimer disease in primary care: a randomized, controlled trial. JAMA. 2006;295:2148-57. [PMID: 16684985]
64.
Vickrey BG, Mittman BS, Connor KI, Pearson ML, Della Penna RD, Ganiats TG, et al. The effect of a disease management intervention on quality and outcomes of dementia care: a randomized, controlled trial. Ann Intern Med. 2006;145:713-26. [PMID: 17116916]
65.
Belle SH, Burgio L, Burns R, Coon D, Czaja SJ, Gallagher-Thompson D, et al. Enhancing the quality of life of dementia caregivers from different ethnic or racial groups: a randomized, controlled trial. Ann Intern Med. 2006;145:727-38. [PMID: 17116917]
66.
Fossey J, Ballard C, Juszczak E, James I, Alder N, Jacoby R, et al. Effect of enhanced psychosocial care on antipsychotic use in nursing home residents with severe dementia: cluster randomised trial. BMJ. 2006;332:756-61. [PMID: 16543297]
67.
Gill SS, Seitz D, Rochon PA. Atypical antipsychotic drugs, dementia, and risk of death [Letter]. JAMA. 2006;295:495-6. [PMID: 16449609]
Information & Authors
Information
Published In
Annals of Internal Medicine
Volume 146 • Number 11 • 5 June 2007
Pages: 775 - 786
History
Published online: 5 June 2007
Published in issue: 5 June 2007
Keywords
- Adults
- Age groups
- Antipsychotics
- Computer and information sciences
- Data management
- Dementia
- Drugs
- Health care
- Health economics
- Health insurance
- Medical services
- Mortality
- Pharmacology
- Population statistics
- Prevention, policy, and public health
- Psychiatry and mental health
- Public policy
- Research and reporting methods
- Statistical methods
- Survival analysis
- Vital statistics
Copyright
© 2007 American College of Physicians.
Authors
Metrics & Citations
Metrics
Citations
If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. For an editable text file, please select Medlars format which will download as a .txt file. Simply select your manager software from the list below and click Download.
For more information or tips please see 'Downloading to a citation manager' in the Help menu.
Download article citation data for:
Antipsychotic Drug Use and Mortality in Older Adults with Dementia. Ann Intern Med.2007;146:775-786. [Epub 5 June 2007]. doi:10.7326/0003-4819-146-11-200706050-00006
Antipsychotic Drug Use and Mortality in Older Adults with Dementia. Ann Intern Med.2007;146:775-786. [Epub 5 June 2007]. doi:10.7326/0003-4819-146-11-200706050-00006
View More
Get Access
Login Options:
Purchase
You will be redirected to acponline.org to sign-in to Annals to complete your purchase.
Create your Free Account
You will be redirected to acponline.org to create an account that will provide access to Annals.
Submit a Comment
Contributors must reveal any conflict of interest. Comments are moderated. Please see our information for authorsregarding comments on an Annals publication.