Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Comparative Study
. 2025 Sep;73(9):2893-2904.
doi: 10.1111/jgs.19485. Epub 2025 Apr 24.

Comparative Safety of Medications for Severe Agitation: A Geriatric Emergency Department Guidelines 2.0 Systematic Review

Martin F Casey  1 , Natalie M Elder  2 , Alexander Fenn  1 , Joshua Niznik  3   4   5 , Danya Khoujah  6   7 , Jon B Cole  8 , Zachary Cardon  1 , Ming Ding  1 , Naira Goukasian  1 , Elizabeth Moreton  9 , Jennifer L Koehl  10 , Phillip D Magidson  11 , Rachel M Skains  12 , Katren Tyler  13 , Shan W Liu  10 ; Geriatric Emergency Department Guidelines Medication Safety Group
Collaborators, Affiliations
Comparative Study

Comparative Safety of Medications for Severe Agitation: A Geriatric Emergency Department Guidelines 2.0 Systematic Review

Martin F Casey et al. J Am Geriatr Soc. 2025 Sep.

Abstract

Background: Managing undifferentiated, severe agitation in older adults may require antipsychotic or sedative medications to prevent harm to self or others. Unfortunately, these medications are associated with serious adverse events in older adults, and little is known about their comparative safety.

Methods: We conducted a systematic review to identify comparative effectiveness studies on the safety of medications used in the treatment of severe agitation among older adults in the prehospital or emergency department (ED) setting. We searched eight databases including PubMed, EMBASE, SCOPUS, Cochrane library, CINAHL, Proquest Central, Ageline, and PsycInfo published in or before February 2024. Studies were included if they examined 1st generation antipsychotics, 2nd generation antipsychotics, benzodiazepines, or ketamine. Data were extracted on adverse respiratory events (apnea, hypoxemia, intubation) and other adverse events (arrhythmia, hypotension, worsening delirium, cardiac arrest, and mortality). We report the aggregate occurrence of any adverse events pooled by drug and report odds ratios (ORs) using haloperidol as the reference group.

Results: Among 8600 studies identified, eight observational studies and one randomized clinical trial met eligibility for further qualitative and quantitative analysis. The observational studies included 838 older adults receiving haloperidol (n = 117), droperidol (n = 129), lorazepam (n = 350), midazolam (n = 68), olanzapine (n = 101), quetiapine (n = 56), and ziprasidone (n = 17). Any adverse events were observed in 16.8% of the patients (141/838). Adverse events were most common among patients receiving midazolam (53%; 36/68). Relative to haloperidol, midazolam significantly increased the risk for any adverse events (OR 5.25 [95% CI: 2.64-10.45]). Quetiapine was the only drug observed to have a lower frequency of adverse events (OR 0.27 [95% CI: 0.08, 0.97]).

Conclusions: Adverse drug events are common among older adults receiving antipsychotic or anxiolytic medications for severe agitation. Benzodiazepines, particularly midazolam, pose an excessive risk to older adults requiring pharmacologic treatment for severe agitation.

Keywords: agitation; antipsychotics; anxiolytics; medication safety; older adults.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
PRISMA flow diagram of the study selection process.
FIGURE 2
FIGURE 2
Risk of bias assessment (ROB) for studies included in the meta‐analysis for (a) the eight observational studies using the ROB‐I tool and (b) randomized controlled trial using the ROB 2 tool.
See this image and copyright information in PMC

References

    1. Miner J. R., Klein L. R., Cole J. B., Driver B. E., Moore J. C., and Ho J. D., “The Characteristics and Prevalence of Agitation in an Urban County Emergency Department,” Annals of Emergency Medicine 72, no. 4 (2018): 361–370, 10.1016/j.annemergmed.2018.06.001. - DOI - PubMed
    1. Green S. M., Roback M. G., Krauss B. S., et al., “Unscheduled Procedural Sedation: A Multidisciplinary Consensus Practice Guideline,” Annals of Emergency Medicine 73, no. 5 (2019): 51–65, 10.1016/j.annemergmed.2019.02.022. - DOI - PubMed
    1. Kennedy M., Koehl J., Shenvi C. L., et al., “The Agitated Older Adult in the Emergency Department: A Narrative Review of Common Causes and Management Strategies,” Journal of the American College of Emergency Physicians Open 1, no. 5 (2020): 812–823, 10.1002/emp2.12110. - DOI - PMC - PubMed
    1. Shenvi C., Kennedy M., Austin C. A., Wilson M. P., Gerardi M., and Schneider S., “Managing Delirium and Agitation in the Older Emergency Department Patient: The ADEPT Tool,” Annals of Emergency Medicine 75, no. 2 (2020): 136–145, 10.1016/j.annemergmed.2019.07.023. - DOI - PMC - PubMed
    1. Livingston G., Kelly L., Lewis‐Holmes E., et al., “Non‐Pharmacological Interventions for Agitation in Dementia: Systematic Review of Randomised Controlled Trials,” British Journal of Psychiatry 205, no. 6 (2014): 436–442, 10.1192/bjp.bp.113.141119. - DOI - PubMed

MeSH terms

LinkOut - more resources