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Antipsychotics, Other Psychotropics, and the Risk of Death in Patients With Dementia: Number Needed to Harm

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Maust, Donovan T., Kim, Hyungjin Myra, Seyfried, Lisa S., Chiang, Claire, Kavanagh, Janet, Schneider, Lon S., Kales, Helen C.·2015·JAMA Psychiatry
DOI 10.1001/jamapsychiatry.2014.3018PMC PMC4439579
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Abstract

IMPORTANCE: Antipsychotic medications are associated with increased mortality in older adults with dementia, yet their absolute effect on risk relative to no treatment or an alternative psychotropic is unclear. OBJECTIVE: To determine the absolute mortality risk increase and number needed to harm (NNH) (ie, number of patients who receive treatment that would be associated with 1 death) of antipsychotic, valproic acid and its derivatives, and antidepressant use in patients with dementia relative to either no treatment or antidepressant treatment. DESIGN, SETTING, AND PARTICIPANTS: A retrospective case-control study was conducted in the Veterans Health Administration from October 1, 1998, through September 30, 2009. Participants included 90,786 patients 65 years or older with a diagnosis of dementia. Final analyses were conducted in August 2014. EXPOSURES: A new prescription for an antipsychotic (haloperidol, olanzapine, quetiapine, and risperidone), valproic acid and its derivatives, or an antidepressant (46,008 medication users). MAIN OUTCOMES AND MEASURES: Absolute change in mortality risk and NNH over 180 days of follow-up in medication users compared with nonmedication users matched on several risk factors. Among patients in whom a treatment with medication was initiated, mortality risk associated with each agent was also compared using the antidepressant group as the reference, adjusting for age, sex, years with dementia, presence of delirium, and other clinical and demographic characteristics. Secondary analyses compared dose-adjusted absolute change in mortality risk for olanzapine, quetiapine, and risperidone. RESULTS: Compared with respective matched nonusers, individuals receiving haloperidol had an increased mortality risk of 3.8% (95% CI, 1.0%-6.6%; P < .01) with an NNH of 26 (95% CI, 15-99); followed by risperidone, 3.7% (95% CI, 2.2%-5.3%; P < .01) with an NNH of 27 (95% CI, 19-46); olanzapine, 2.5% (95% CI, 0.3%-4.7%; P = .02) with an NNH of 40 (95% CI, 21-312); and quetiapine, 2.0% (95% CI, 0.7%-3.3%; P < .01) with an NNH of 50 (95% CI, 30-150). Compared with antidepressant users, mortality risk ranged from 12.3% (95% CI, 8.6%-16.0%; P < .01) with an NNH of 8 (95% CI, 6-12) for haloperidol users to 3.2% (95% CI, 1.6%-4.9%; P < .01) with an NNH of 31 (95% CI, 21-62) for quetiapine users. As a group, the atypical antipsychotics (olanzapine, quetiapine, and risperidone) showed a dose-response increase in mortality risk, with 3.5% greater mortality (95% CI, 0.5%-6.5%; P = .02) in the high-dose subgroup relative to the low-dose group. When compared directly with quetiapine, dose-adjusted mortality risk was increased with both risperidone (1.7%; 95% CI, 0.6%-2.8%; P = .003) and olanzapine (1.5%; 95% CI, 0.02%-3.0%; P = .047). CONCLUSIONS AND RELEVANCE: The absolute effect of antipsychotics on mortality in elderly patients with dementia may be higher than previously reported and increases with dose.

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  • Antipsychotics are associated with an increased risk of stroke and death in people with dementia.

    “Research has shown that antipsychotics are associated with an increased risk of stroke and death in individuals with dementia.56,57”

    From 2023 Alzheimer's disease facts and figures (2023) · cites this paper as [57]

    The paper’s Importance and Conclusions passages report increased mortality associated with antipsychotic use in older adults with dementia. Its background also reports increased cerebrovascular adverse events in pooled trials, but the passages do not specifically identify stroke as an outcome, so the stroke portion is not fully verified. (LLM, conf=0.84)

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  • There is an association between mortality and antipsychotics in patients with dementia.

    “There is an association between mortality and antipsychotics in patients with dementia650 but it is unclear how this should be managed for patients with BD.”

    From Canadian Network for Mood and Anxiety Treatments ( <scp>CANMAT</scp> ) and International Society for Bipolar Disorders ( <scp>ISBD</scp> ) 2018 guidelines for the management of patients with bipolar disorder (2018) · cites this paper as [650]

  • A review and analysis of nonpharmacologic treatments for agitation and aggression in people with dementia concluded that non-drug interventions seemed to be more effective than pharmacologic interventions for reducing aggression and agitation.

    “For example, a review and analysis of nonpharmacologic treatments for agitation and aggression in people with dementia concluded that non‐drug interventions seemed to be more effective than pharmacologic interventions for reducing aggression and agitation.”

    From 2024 Alzheimer's disease facts and figures (2024) · cites this paper as [69]

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Authors
Maust, D. T., Kim, H. M., Seyfried, L. S., Chiang, C., Kavanagh, J., Schneider, L. S., & Kales, H. C.
Affiliations
  • University of Michigan (US)
  • University of Southern California (US)
ORCID
Venue
JAMA Psychiatry
Publisher
American Medical Association (AMA)
Published
2015-05-01
Volume
72
Issue
5
Pages
438
ISSN
2168-622X (ISSN-L)
DOI
10.1001/jamapsychiatry.2014.3018
PMC
PMC4439579
OpenAlex
W2090527899
Cited by
617
References
30
Citations by year
2026: 38 · 2025: 33 · 2024: 45 · 2023: 49 · 2022: 58 · 2021: 55 · 2020: 57 · 2019: 58 · 2018: 96 · 2017: 48 · 2016: 61 · 2015: 19
FWCI
37.15
Type
journal article
Language
en
Open access
Locations
  • JAMA Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • National Institute on Aging (K08AG048321, P50AG005142, P30AG024824)
  • National Institute of Mental Health (R01MH08107-01)
Topics
  • Health Sciences › Medicine › Geriatrics and Gerontology › Pharmaceutical Practices and Patient Outcomes
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
Keywords
antipsychotic drugs, dementia, mortality risk, number needed to harm, valproic acid, antidepressants, haloperidol, olanzapine, quetiapine, risperidone, psychotropic drugs, older adults, veterans, adverse drug reactions, delirium, dose adjustment, Veterans Health Administration
MeSH terms
Quetiapine Fumarate, Olanzapine, Aged, Antidepressive Agents, Benzodiazepines, Dementia, Dibenzothiazepines, Dose-Response Relationship, Drug, Female, Haloperidol, Humans, Male, Middle Aged, Psychotropic Drugs, Registries, Retrospective Studies, Risk, Antipsychotic Agents, United States, Veterans, Case-Control Studies, Risperidone

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