What is the fastest‑acting atypical antipsychotic for an adult presenting with acute psychosis or severe agitation?

Fastest-Acting Atypical Antipsychotic

IM ziprasidone 20 mg is the fastest-acting atypical antipsychotic, producing rapid reduction in agitation within 15 minutes with notably absent movement disorders. 1

Speed of Onset Comparison

The two fastest atypical antipsychotics available for acute psychosis are:

• IM ziprasidone 20 mg: Onset within 15 minutes 1, 2
• IM olanzapine 10 mg: Onset within 15-30 minutes 1

Both agents demonstrate rapid efficacy, but ziprasidone has a slight edge in speed of onset, with documented improvement as early as 15 minutes post-administration and sustained effect for ≥4 hours 2.

Clinical Decision Algorithm

For Non-Cooperative or Severely Agitated Patients:

First choice: IM olanzapine 10 mg 1

• Provides rapid tranquilization within 15-30 minutes 1
• Safest cardiac profile with only 2 ms mean QTc prolongation 1
• Minimal extrapyramidal symptom risk 1
• Equivalent efficacy to haloperidol with superior tolerability 1

Alternative: IM ziprasidone 20 mg 1, 2

• Fastest onset at 15 minutes 1, 2
• Notably absent movement disorders including extrapyramidal symptoms and dystonia 1
• Avoid if QTc >500 ms or cardiac disease due to variable QTc prolongation (5-22 ms) 1

For Cooperative Patients:

Oral olanzapine 2.5-5 mg 1

• Can be given as standard tablet or orally disintegrating formulation 1
• Repeat after 2 hours if needed 1
• Maximum 10 mg/day in divided doses 1

Important Caveats

Cardiac Considerations:

• Obtain baseline ECG if cardiac risk factors are present before using ziprasidone 1
• Olanzapine has the least QTc prolongation among all antipsychotics studied, making it safer for patients with cardiomyopathy 1
• Avoid thioridazine entirely due to severe QTc prolongation (25-30 ms) 1

Combination Therapy Warning:

• Fatal outcomes have been reported when high-dose olanzapine is combined with benzodiazepines 1
• Only low-dose benzodiazepines should be added if necessary, with close monitoring for respiratory depression 1

Monitoring Requirements:

• Monitor vital signs and sedation level every 5-15 minutes during the first hour after IM administration 1
• Assess for extrapyramidal symptoms at every visit, as these predict poor long-term adherence 1

Why These Are Preferred Over Haloperidol

Both IM olanzapine and IM ziprasidone demonstrate:

• Equivalent or superior efficacy to haloperidol for acute agitation 1, 2
• Significantly fewer extrapyramidal side effects 1
• Better overall tolerability profile 1
• Haloperidol carries higher risk of movement disorders even at low doses, which severely impacts future medication adherence 1

Transition to Oral Therapy

IM olanzapine allows for ease of transition to the same agent oral therapy once acute agitation has diminished 3, maintaining consistency in treatment and avoiding the need to switch medications during the stabilization phase.