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Risk of Mortality Among Individual Antipsychotics in Patients With Dementia
Helen C. Kales, M.D.; Hyungjin Myra Kim, Sc.D.; Kara Zivin, Ph.D.; Marcia Valenstein, M.D., M.S.; Lisa S. Seyfried, M.D., M.S.; Claire Chiang, Ph.D.; Francesca Cunningham, Pharm.D.; Lon S. Schneider, M.D., M.S.; Frederic C. Blow, Ph.D.
Am J Psychiatry 2012;169:71-79. 10.1176/appi.ajp.2011.11030347
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Received March 2, 2011; revisions received May 18 and June 21, 2011; accepted July 7, 2011.
Dr. Schneider is an editor for the Cochrane Collaborations Dementia and Cognitive Improvement Group; receives a grant from the Alzheimer's Association and a grant or research support from AstraZeneca, Baxter, Elan Pharmaceuticals, Forest Laboratories, Johnson & Johnson, Eli Lilly, Myriad, Novartis, Pfizer, Takeda, and Wyeth; and has served as a consultant for or receives consulting fees from Abbot Laboratories, AC Immune, Allergan, Allon, Alzheimer Drug Discovery Foundation, AstraZeneca, Bristol-Myers Squibb, Elan, Eli Lilly, Exonhit, Forest, GlaxoSmithKline, Ipsen, Johnson & Johnson, Lundbeck, Myriad, Medavante, Merck, Novartis, Roche, Sanofi-Aventis, Servier, Schering-Plough, Schwabe, Teva, Toyama, Transition Therapeutics, Voyager, and Wyeth. All other authors report no financial relationships with commercial interests.
Research supported by NIMH grant R01-MH081070. Resources also contributed by the Serious Mental Illness Treatment, Resource, and Evaluation Center, Ann Arbor. The views expressed in this article are those of the authors and do not necessarily represent the views of the U.S. Department of Veterans Affairs.
From the Ann Arbor VA Center for Clinical Management Research, Serious Mental Illness Treatment, Resource, and Evaluation Center, Ann Arbor, Mich.; the Department of Psychiatry and the Center for Statistical Consultation and Research, University of Michigan, Ann Arbor; the VA Center for Medication Safety, Patient Safety Center of Inquiry, and Pharmacoepidemiologic/Outcomes Research, Hines, Ill.; and University of Southern California Keck School of Medicine, Los Angeles.
Address correspondence to Dr. Kales (kales@umich.edu).
Copyright © American Psychiatric Association
Abstract
Objective: 

The use of antipsychotics to treat the behavioral symptoms of dementia is associated with greater mortality. The authors examined the mortality risk of individual agents to augment the limited information on individual antipsychotic risk.

Method: 

The authors conducted a retrospective cohort study using national data from the U.S. Department of Veterans Affairs (fiscal years 1999–2008) for dementia patients age 65 and older who began outpatient treatment with an antipsychotic (risperidone, olanzapine, quetiapine, or haloperidol) or valproic acid and its derivatives (as a nonantipsychotic comparison). The total sample included 33,604 patients, and individual drug groups were compared for 180-day mortality rates. The authors analyzed the data using multivariate models and propensity adjustments.

Results: 

In covariate-adjusted intent-to-treat analyses, haloperidol was associated with the highest mortality rates (relative risk=1.54, 95% confidence interval [CI]=1.38–1.73) followed by risperidone (reference), olanzapine (relative risk=0.99, 95% CI=0.89–1.10), valproic acid and its derivatives (relative risk=0.91, 95% CI=0.78–1.06), and quetiapine (relative risk=0.73, 95% CI=0.67–0.80). Propensity-stratified and propensity-weighted models as well as analyses controlling for site of care and medication dosage revealed similar patterns. The mortality risk with haloperidol was highest in the first 30 days but decreased significantly and sharply thereafter. Among the other agents, mortality risk differences were most significant in the first 120 days and declined in the subsequent 60 days during follow-up.

Conclusions: 

There may be differences in mortality risks among individual antipsychotic agents used for treating patients with dementia. The use of valproic acid and its derivatives as alternative agents to address the neuropsychiatric symptoms of dementia may carry associated risks as well.

Abstract Teaser
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    FIGURE 1. 

    Covariate-Adjusted Survival Function by Days of Exposure in a Study of Mortality Risk Among Individual Antipsychotics

    Anchor for JumpTABLE 1.   Characteristics of Patients With Dementia Taking One of Five Psychotropic Medications in a Study of Mortality Risk Among Individual Antipsychoticsa
    Table Footer Notea All use and diagnostic data are based on 1 year prior to the initiation of the medication.
    Table Footer Noteb Includes schizophrenia and schizoaffective disorder.
    Table Footer Notec Includes myocardial infarction, congestive heart failure, peripheral vascular disease, cerebrovascular disease, chronic obstructive pulmonary disease, rheumatologic disease, peptic ulcer disease, cirrhosis, hepatic failure, diabetes mellitus, diabetes mellitus with complications, hemiplegia, chronic renal disease, malignant neoplasm, leukemia, lymphomas, metastatic solid tumor, and AIDS.
    Anchor for JumpTABLE 2.   Crude Death Rates for Patients With Dementia Starting a New Medication After a 12-Month Clean Period in a Study of Mortality Risk Among Individual Antipsychotics
    Anchor for JumpTABLE 3.   Relative Risks of 180-Day Mortality for Patients With Dementia Starting a New Medication After a 12-Month Clean Period in a Study of Mortality Risk Among Individual Antipsychoticsa
    Table Footer Notea All relative risks were based on a Cox regression adjusted for gender, age, race, marital status, delirium, depression, schizophrenia, bipolar I disorder, bipolar II disorder, other psychoses, Parkinson's disease, substance abuse, posttraumatic stress disorder, other anxiety disorders, personality disorder, use of benzodiazepines, antidepressants, opioids, days of hospitalization, days in nursing home, fiscal year of index drug use, rurality of facility, facility size, academic affiliation of facility, Charlson comorbidity index, myocardial infarction, congestive heart failure, peripheral vascular disease, cerebrovascular disease, chronic obstructive pulmonary disease, rheumatologic disease, peptic ulcer disease, cirrhosis, hepatic failure, diabetes mellitus, diabetes mellitus with complications, hemiplegia, chronic renal disease, malignant neoplasm, leukemia, lymphomas, metastatic solid tumor, and AIDS.
    Anchor for JumpTABLE 4.   Initially Prescribed Average Daily Dose and Haloperidol Equivalent Daily Dose of Antipsychotic Medications in a Study of Mortality Risk Among Individual Antipsychotics
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