What is the first-line antipsychotic for acute agitation?

First-Line Antipsychotic for Acute Agitation

For acute agitation in adults, IM olanzapine 10 mg is the first-line antipsychotic, offering rapid onset within 15–30 minutes, equivalent efficacy to haloperidol, and significantly fewer extrapyramidal side effects. 1

Medication Selection Algorithm

For Non-Cooperative/Severely Agitated Patients

IM olanzapine 10 mg is the preferred first choice because it has:

• Rapid onset of action (15–30 minutes) 1
• The safest cardiac profile with only 2 ms mean QTc prolongation (versus 7 ms for haloperidol) 1, 2
• Minimal risk of extrapyramidal symptoms 1, 3
• Superior efficacy to haloperidol in reducing BPRS total scores, BPRS agitation items, and CGIS scale scores 1

Alternative: IM ziprasidone 20 mg if olanzapine is unavailable:

• Produces reduction in agitation within 15 minutes 1, 2
• Notably absent movement disorders including extrapyramidal symptoms and dystonia 1
• Should be avoided if QTc >500 ms or cardiac disease present (variable QTc prolongation 5–22 ms) 1, 2

For Cooperative/Agitated Patients

Oral risperidone 2 mg plus lorazepam 2 mg is recommended:

• Equivalent efficacy to IM haloperidol plus lorazepam at 30,60, and 120 minutes 1, 4
• Significantly less excessive sedation compared to haloperidol combinations 1
• Level B guideline recommendation from the American College of Emergency Physicians 1

Why NOT Haloperidol First-Line

While haloperidol has the largest evidence base with 20 double-blind studies since 1973 5, atypical antipsychotics are preferred because:

• Haloperidol carries higher risk of extrapyramidal symptoms even at low doses, which severely impacts future medication adherence 1
• Greater QTc prolongation (7 ms versus 2 ms for olanzapine) 1, 2
• The World Health Organization recommends haloperidol only when atypical antipsychotics cannot be assured or are cost-prohibitive 1

Critical Prerequisites Before ANY Antipsychotic

You must systematically evaluate and treat reversible causes first:

• Pain assessment (major contributor to agitation in non-verbal patients) 5
• Infections: UTI, pneumonia, other occult sources 5
• Metabolic disturbances: hypoxia, dehydration, electrolyte abnormalities, hyperglycemia 5
• Constipation and urinary retention 5
• Medication review for anticholinergic agents that worsen agitation 5

Non-Pharmacological Interventions (Attempt First)

The combination of benzodiazepine and antipsychotic is frequently suggested by experts, but only after attempting 5:

• Calm demeanor, simple one-step commands, gentle touch 5
• Two arms' length distance, unobstructed exit path 5
• Adequate lighting, reduced noise 5
• Clear orientation: explain location, staff roles, what to expect 5

Special Population Considerations

Elderly Patients (>75 years)

• Start olanzapine at 2.5 mg daily (more profound sedation in this age group) 1
• Patients over 75 respond less well to antipsychotics, particularly olanzapine 6
• All antipsychotics increase mortality 1.6–1.7 times in elderly dementia patients 6

Cardiac Disease

• Olanzapine is the safest option with minimal QTc prolongation 1
• Avoid thioridazine (25–30 ms QTc prolongation) 1
• Use ziprasidone with caution (variable 5–22 ms QTc prolongation) 1

Common Pitfalls to Avoid

1. Do NOT use benzodiazepines alone for acute psychosis – they provide sedation but don't treat psychotic symptoms 5
2. Avoid benzodiazepines as first-line for undifferentiated agitation – 10% paradoxical agitation rate, especially in younger children and elderly 5, 1
3. Do NOT exceed olanzapine 10 mg IM initially – higher doses provide no additional benefit 3
4. Avoid combining high-dose olanzapine with benzodiazepines – risk of fatal respiratory depression 1

Speed of Onset Comparison

• IM midazolam: 18.3 minutes (fastest, but doesn't treat psychosis) 1
• IM ziprasidone: 15 minutes 1, 2
• IM olanzapine: 15–30 minutes 1, 3
• IM haloperidol: 28.3 minutes 1
• Oral lorazepam: 32.2 minutes 1

The evidence strongly supports IM olanzapine as first-line for acute agitation due to its optimal balance of rapid efficacy, safety profile, and tolerability. 1, 3, 7