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The Long-Term Effects of Conventional and Atypical Antipsychotics in Patients With Probable Alzheimer’s Disease
Oscar L. Lopez, M.D.; James T. Becker, Ph.D.; Yue-Fang Chang, Ph.D.; Robert A. Sweet, M.D.; Howard Aizenstein, M.D.; Beth Snitz, Ph.D.; Judith Saxton, Ph.D.; Eric McDade, D.O.; M. Ilyas Kamboh, Ph.D.; Steven T. DeKosky, M.D.; Charles F. Reynolds, III, M.D.; William E. Klunk, M.D., Ph.D.
Am J Psychiatry 2013;170:1051-1058. doi:10.1176/appi.ajp.2013.12081046
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Supported in part by the National Institute on Aging (grants AG15928, AG027224, AG05133, AG025204, AG025516, AG028526, AG014449, AG005133, AG012138, and AG20098) and by NIMH (P30 MH90333). Dr. Sweet is an employee of the VA, and the content of this manuscript does not necessarily represent the official views of the VA.

Dr. Lopez has served as a consultant for Baxter, Eli Lilly, Lundbeck, and Mertz. Dr. Sweet has served as a consultant for Eli Lilly. Dr. DeKosky has served as a consultant for Elan/Wyeth, Eli Lilly, Genzyme, Helicon Therapeutics, Janssen, Merck, and Novartis. Dr. Reynolds has received pharmaceutical supplies for his NIH-sponsored work from Bristol-Myers Squibb, Eli Lilly, Forest Laboratories, and Pfizer. Dr. Klunk has received royalty payments from GE Healthcare for licensed technology; served as a consultant for AstraZeneca, Elan/Janssen AI, Eli Lilly, GE Healthcare, Neuroptix, Roche, and Wyeth/Pfizer; owned stocks in Neuroptix; and obtained research support from GE Healthcare and Neuroptix. Drs. Becker, Chang, Aizenstein, Snitz, Saxton, McDade, and Kamboh report no financial relationships with commercial interests.

From the Departments of Neurology, Psychiatry, Psychology, Neurosurgery, Epidemiology, and Human Genetics, University of Pittsburgh School of Medicine, Pittsburgh; the Alzheimer’s Disease Research Center, Pittsburgh; and the University of Virginia School of Medicine, Charlottesville.

Address correspondence to Dr. Lopez (lopezol@upmc.edu).

Copyright © 2013 by the American Psychiatric Association

Received August 08, 2012; Revised January 09, 2013; Revised February 24, 2013; Accepted February 27, 2013.

Abstract

Objective  The authors sought to determine the effects of conventional and atypical antipsychotic use on time to nursing home admission and time to death in a group of outpatients with mild to moderate probable Alzheimer’s disease.

Method  The authors examined time to nursing home admission and time to death in 957 patients with the diagnosis of probable Alzheimer’s disease who had at least one follow-up evaluation (mean follow-up time, 4.3 years [SD=2.7]; range, 0.78–18.0 years) using Cox proportional hazard models adjusted for age, gender, education level, dementia severity, hypertension, diabetes mellitus, heart disease, extrapyramidal signs, depression, psychosis, aggression, agitation, and dementia medication use.

Results  A total of 241 patients (25%) were exposed to antipsychotics at some time during follow-up (conventional, N=138; atypical, N=95; both, N=8). Nursing home admission (63% compared with 23%) and death (69% compared with 34%) were more frequent in individuals taking conventional than atypical antipsychotics. In a model that included demographic and cognitive variables, hypertension, diabetes mellitus, heart disease, incident strokes, and extrapyramidal signs, only conventional antipsychotic use was associated with time to nursing home admission. However, the association was no longer significant after adjustment for psychiatric symptoms. Psychosis was strongly associated with nursing home admission and time to death, but neither conventional nor atypical antipsychotics were associated with time to death.

Conclusions  The use of antipsychotic medications, both conventional and atypical, was not associated with either time to nursing home admission or time to death after adjustment for relevant covariates. Rather, it was the presence of psychiatric symptoms, including psychosis and agitation, that was linked to increased risk of institutionalization and death after adjustment for exposure to antipsychotics.

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FIGURE 1. Kaplan-Meier Survival Analysis of Time to Death in Patients With Probable Alzheimer's Disease and Antipsychotic Use
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TABLE 1.Demographic and Clinical Characteristics of Patients With Probable Alzheimer's Disease Taking Conventional or Atypical Antipsychotics
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a Eight patients were taking conventional and atypical antipsychotics during follow-up and were excluded from the analysis.

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b From the onset of the symptoms to initial visit.

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c Told by doctor.

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d Told by doctor and taking hypoglycemic agents.

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e History of congestive heart failure, angina, or coronary bypass grafting/coronary angioplasty.

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TABLE 2.Clinical Characteristics of Patients With Probable Alzheimer's Disease Taking Conventional or Atypical Antipsychotics
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a Eight patients were taking conventional and atypical antipsychotics during follow-up and were excluded from the analysis.

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b Presence of bradykinesia, tremors, increased motor tone, abnormal gait, or dyskinesias.

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TABLE 3.Results of the Cox Regression Model Examining Risks Associated With Nursing Home Admission in Patients With Probable Alzheimer's Disease Taking Conventional or Atypical Antipsychoticsa
Table Footer Note

a Model 1 controlled for age, education level, gender, and baseline Mini-Mental State Examination (MMSE) score. Model 2 included items from model 1 plus extrapyramidal signs, incident stroke, heart disease, diabetes mellitus, and hypertension. Model 3 included items from models 1 and 2 plus psychosis, depression, aggression, agitation, and dementia medication.

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TABLE 4.Results of the Cox Regression Model Examining Risks Associated With Death in Patients With Probable Alzheimer's Disease Taking Conventional or Atypical Antipsychoticsa
Table Footer Note

a Model 1 controlled for age, education level, gender, and baseline Mini-Mental State Examination (MMSE) score. Model 2 included items from model 1 plus extrapyramidal signs, incident stroke, heart disease, diabetes mellitus, and hypertension. Model 3 included items from models 1 and 2 plus psychosis, depression, aggression, agitation, and dementia medication.

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1.
This study did not show an association between antipsychotic use and mortality. However, the presence of psychiatric symptoms was associated with death. Which of the following was a predictor of death even after adjustment for antipsychotic use?
2.
Which of the following characterizes patients receiving any type of antipsychotic medication compared to unexposed patients?
3.
Which symptoms or characteristics were associated with nursing home placement?
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