What is the preferred intramuscular (IM) medication for acute psychosis, comparing haloperidol, midazolam, and diazepam, in a patient with no specified past medical history or substance abuse?

Acute Psychosis: IM Medication Selection

Primary Recommendation

For acute psychosis with agitation, intramuscular haloperidol 5 mg combined with promethazine is the preferred evidence-based approach, offering superior efficacy and safety compared to haloperidol alone, midazolam monotherapy, or diazepam. 1, 2, 3

Treatment Algorithm

First-Line: Haloperidol + Promethazine Combination

• Haloperidol 5 mg IM plus promethazine provides the most robust evidence for rapid tranquilization in acute psychosis, combining haloperidol's antipsychotic action with promethazine's sedative properties while reducing extrapyramidal side effects through anticholinergic activity. 1, 2, 3
• More patients achieve tranquilization or sleep by 20 minutes with this combination compared to haloperidol alone (RR 1.60,95% CI 1.18-2.16). 1, 2
• The promethazine component dramatically reduces acute dystonia risk (RR 19.48 for dystonia with haloperidol alone versus combination). 1, 2
• Dosing: Haloperidol 2-5 mg IM, may repeat every 1-4 hours as needed for prompt control of moderately severe to very severe symptoms. 4

Alternative Option: IM Atypical Antipsychotics

• IM olanzapine 10 mg or IM ziprasidone 20 mg are superior alternatives if available, demonstrating equivalent efficacy to haloperidol with significantly fewer extrapyramidal symptoms and rapid onset within 15-30 minutes. 1, 5
• Olanzapine has the safest cardiac profile with only 2 ms mean QTc prolongation versus 7 ms for haloperidol. 1
• Ziprasidone should be avoided if QTc >500 ms or significant cardiac disease due to variable QTc prolongation (5-22 ms). 1

Why NOT Benzodiazepines Alone for Psychosis

Midazolam Limitations

• Midazolam does not treat the underlying psychosis—it only provides sedation without antipsychotic effect. 6, 7
• While midazolam 5 mg IM achieves sedation faster than haloperidol (18.3 minutes vs 28.3 minutes), it has no efficacy against hallucinations, delusions, or thought disorder. 6, 8
• Midazolam's shorter duration of action (mean 82 minutes to arousal) requires more frequent redosing compared to antipsychotics. 6
• Consider midazolam only when seizure prophylaxis is needed concurrently or when psychosis etiology is uncertain and substance withdrawal is suspected. 6

Diazepam Limitations

• Diazepam IM has erratic and incomplete absorption, making it unreliable for acute management. 9
• The longer half-life creates unpredictable duration of sedation without addressing psychotic symptoms. 9
• Diazepam is inferior to both haloperidol and midazolam for acute psychosis control. 9

Haloperidol + Benzodiazepine Combination: Weak Evidence

• Adding lorazepam to haloperidol does not significantly improve outcomes and does not offset haloperidol's extrapyramidal side effects (dystonia RR 8.25,95% CI 0.46-147.45). 2
• The combination of haloperidol 5 mg + lorazepam 2 mg IM produces faster sedation than lorazepam alone but carries risk of additional harm without clear benefit over haloperidol + promethazine. 6, 2

Critical Safety Considerations

Extrapyramidal Symptoms

• Acute dystonia occurs in up to 19 times more frequently with haloperidol monotherapy compared to haloperidol + promethazine. 1, 2
• Monitor for movement disorders at every clinical contact, as these predict poor long-term medication adherence. 10, 1
• If promethazine is unavailable and only haloperidol can be used, have anticholinergic agents (benztropine, diphenhydramine) immediately available. 2, 3

Cardiac Monitoring

• Obtain baseline ECG if cardiac risk factors are present, as haloperidol prolongs QTc by 7 ms. 1
• Avoid haloperidol in patients with known QTc prolongation or significant cardiac disease—use olanzapine instead. 1

Respiratory Depression

• Benzodiazepines cause dose-dependent CNS depression with unpredictable duration, particularly problematic in elderly patients. 1
• Never combine olanzapine with benzodiazepines due to FDA warning regarding oversedation and respiratory depression risk. 10

Special Populations

Elderly or Frail Patients

• Reduce haloperidol dose to 2 mg IM initially, as patients over 50 years experience more profound sedation with all agents. 1, 4
• Consider starting with olanzapine 2.5 mg if oral route is feasible to minimize orthostatic hypotension risk. 10, 1

Cooperative Patients

• For cooperative patients with acute psychosis, oral risperidone 2 mg plus lorazepam 2 mg is as effective as IM haloperidol plus lorazepam with significantly less excessive sedation. 1

Transition to Oral Maintenance

• Switch to oral antipsychotic within 12-24 hours following last parenteral dose. 4
• Use the total parenteral dose administered in preceding 24 hours as initial approximation for oral daily dose. 4
• Monitor clinical efficacy, sedation, and adverse effects closely during first several days of switchover. 4

Common Pitfalls to Avoid

• Do not use haloperidol alone without promethazine or another anticholinergic agent when both are available—this approach is potentially unethical given the high dystonia risk. 2, 3
• Do not rely on benzodiazepines as monotherapy for confirmed psychosis—they sedate but do not treat hallucinations or delusions. 6, 8
• Do not use diazepam IM due to erratic absorption—choose lorazepam or midazolam if benzodiazepine is indicated. 9
• Do not exceed haloperidol 5 mg per injection or administer more frequently than every hour without reassessing response. 4