Risk of Mortality Among Individual Antipsychotics in Patients With Dementia
Open accessAbstract
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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The mortality findings among individual antipsychotic agents seem to be consistent with the tolerability profile of individual atypical antipsychotics in the CATIE-AD trial, where olanzapine and risperidone were more efficacious than either quetiapine or placebo, but quetiapine and placebo were better tolerated.
“The mortality findings among individual antipsychotic agents seem to be consistent with the tolerability profile of individual atypical antipsychotics in the CATIE-AD trial, where olanzapine and risperidone were more efficacious than either quetiapine or placebo, but quetiapine and placebo were better tolerated.126”
From Assessment and management of behavioral and psychological symptoms of dementia (2015) · cites this paper as [126]
Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredSide effects of valproic acid and derivatives include sedation, gait disturbances, and tremor. Other risks include alopecia, thrombocytopenia, hyperammonemia, pancreatitis, liver injury, cognitive changes, and mortality.
“Side effects of valproic acid and derivatives include sedation, gait disturbances, and tremor. Other risks include alopecia, thrombocytopenia, hyperammonemia, pancreatitis, liver injury, cognitive changes, and mortality.126 145”
From Assessment and management of behavioral and psychological symptoms of dementia (2015) · cites this paper as [126]
The Discussion reports that valproic acid and its derivatives carried a mortality risk in outpatients with dementia, and it mentions somnolence (consistent with sedation) and thrombocytopenia in connection with anticonvulsant use in older adults. The Results give a 9.8% crude six-month mortality rate for the valproic-acid group. Our copy does not substantiate the other listed effects: gait disturbances, tremor, alopecia, hyperammonemia, pancreatitis, liver injury, or cognitive changes. (LLM, conf=0.88)
Experimental — accuracy not yet measuredQuetiapine (and valproic acid) may have a better safety profile than olanzapine and risperidone, but this needs to be balanced against their reduced efficacy.
“Thus, although quetiapine (and valproic acid) may have a better safety profile than olanzapine and risperidone, this fact needs to be balanced against their reduced efficacy.”
From Assessment and management of behavioral and psychological symptoms of dementia (2015) · cites this paper as [126]
The Discussion (page not provided) reports lower mortality risk for quetiapine, supporting that part of the safety comparison. It says valproic acid’s mortality risk was generally no different from risperidone’s or olanzapine’s, rather than showing a better safety profile. It also notes a lack of evidence for valproic acid’s efficacy, but does not establish that quetiapine is less effective than those drugs. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe guidelines discuss the risks of use of antipsychotic drugs but do not detail the literature for comparative risk between individual antipsychotics and with other psychotropic drugs.
“In terms of pharmacologic strategies, the guidelines discuss the risks of use of antipsychotic drugs but also do not detail the literature for comparative risk between individual antipsychotics and with other psychotropic drugs.122 126”
From Assessment and management of behavioral and psychological symptoms of dementia (2015) · cites this paper as [126]
The Introduction and Discussion (pages not provided) address mortality risks and compare individual antipsychotics with valproic acid, a non-antipsychotic drug. They do not assess what the guidelines discuss or omit, so the claim about the guidelines is unsupported by this source. (LLM, conf=0.82)
Experimental — accuracy not yet measuredA large retrospective cohort study of more than 33 000 older veterans with dementia newly started on haloperidol, risperidone, olanzapine, quetiapine, or valproic acid found mortality was highest in those receiving haloperidol (relative risk 1.54, 1.38 to 1.73), followed by risperidone (reference, relative risk 1) and olanzapine (0.99, 0.89 to 1.10), then valproic acid (0.91, 0.78 to 1.06), and qu
“Most recently, a large retrospective cohort study examined the mortality risk associated with individual antipsychotics using various methods to control for confounding.126 It looked at a national sample of more than 33 000 older veterans with dementia newly started on haloperidol, risperidone, olanzapine, quetiapine, or valproic acid and derivatives (as a non-antipsychotic comparator). Mortality”
From Assessment and management of behavioral and psychological symptoms of dementia (2015) · cites this paper as [126]
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- Authors
- Kales, H. C., Kim, H. M., Zivin, K., Valenstein, M., Seyfried, L. S., Chiang, C., Cunningham, F., Schneider, L. S., & Blow, F. C.
- Affiliations
- University of Southern California (US)
- ORCID
- Venue
- American Journal of Psychiatry
- Published
- 2012-01
- Volume
- 169
- Issue
- 1
- Pages
- 71-79
- ISSN
- 0002-953X (ISSN-L)
- 1535-7228
- PMC
- PMC4269551
- OpenAlex
- W2115432748
- Cited by
- 384
- References
- 28
- Citations by year
- 2026: 8 · 2025: 16 · 2024: 16 · 2023: 18 · 2022: 45 · 2021: 43 · 2020: 21 · 2019: 23 · 2018: 18 · 2017: 34 · 2016: 42 · 2015: 25 · 2014: 26 · 2013: 29 · 2012: 18
- FWCI
- 16.19
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (R01MH081070)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Geriatrics and Gerontology › Pharmaceutical Practices and Patient Outcomes
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Keywords
- antipsychotic drugs, dementia, mortality risk, haloperidol, risperidone, olanzapine, quetiapine, valproic acid, neuropsychiatric symptoms, behavioral symptoms of dementia, older adults, veterans
- MeSH terms
- Quetiapine Fumarate, Olanzapine, Aged, Aged, 80 and over, Benzodiazepines, Dementia, Dibenzothiazepines, Female, Haloperidol, Humans, Male, Retrospective Studies, Risk, Time Factors, Antipsychotic Agents, Valproic Acid, Risperidone, Propensity Score
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