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Published Online: 1 January 2012

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., and Frederic C. Blow, Ph.D.Authors Info & Affiliations
Publication: American Journal of Psychiatry
Volume 169, Number 1
https://doi.org/10.1176/appi.ajp.2011.11030347
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Abstract

Haloperidol had 1.5 times the risk of mortality of other psychotropics in patients with dementia studied in an outpatient VA setting. Risperidone, valproic acid and derivatives, and olanzapine had intermediate risk, and quetiapine had the lowest risk. Haloperidol was more frequently prescribed by nonpsychiatrists and more often in older, medically ill African Americans. Quetiapine was prescribed in lower doses, often for less ill patients, but was associated with increased parkinsonian symptoms. The increased risk of haloperidol was primarily in the first 30 days. The efficacy of quetiapine in the behavioral disturbances associated with dementia is questionable, whereas risperidone and olanzapine have significant beneficial effects and therefore would be preferred for treatment.

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.

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Information & Authors

Information

Published In

Go to American Journal of Psychiatry
Go to American Journal of Psychiatry
American Journal of Psychiatry
Volume 169 • Number 1 • January 2012
Pages: 71 - 79
PubMed: 22193526

History

Received: 2 March 2011
Revision received: 18 May 2011
Revision received: 21 June 2011
Accepted: 7 July 2011
Published online: 1 January 2012
Published in print: January 2012

Authors

Details

Helen C. Kales, M.D.
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.
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Hyungjin Myra Kim, Sc.D.
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.
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Kara Zivin, Ph.D.
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.
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Marcia Valenstein, M.D., M.S.
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.
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Lisa S. Seyfried, M.D., M.S.
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.
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Claire Chiang, Ph.D.
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.
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Francesca Cunningham, Pharm.D.
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.
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Lon S. Schneider, M.D., M.S.
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.
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Frederic C. Blow, Ph.D.
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.
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Notes

Address correspondence to Dr. Kales ([email protected]).

Funding Information

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.

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