What antipsychotic should I start for a patient with acute psychosis?

Initial Antipsychotic Selection for Acute Psychosis

The initial antipsychotic should be selected collaboratively with the patient based on side-effect and efficacy profiles, with atypical antipsychotics (risperidone, olanzapine, or ziprasidone) preferred over haloperidol due to superior tolerability and comparable efficacy. 1

First-Line Oral Options

Preferred Agents

• Risperidone 2 mg/day is an appropriate initial target dose for most patients with acute psychosis, offering rapid onset of action (mean 6.15 days to first response, significantly faster than other antipsychotics) with fewer extrapyramidal symptoms than haloperidol 2, 3
• Olanzapine 7.5-10 mg/day provides comparable efficacy to risperidone with the least QTc prolongation among all antipsychotics (only 2 ms mean prolongation), making it the safest cardiac option 2, 4
• Olanzapine 15-20 mg/day loading can be used for rapid tranquilization in severely agitated patients, administered within 4 hours, with subsequent dose reduction over 2-3 weeks 5

Key Distinction

• The classification of first-generation versus second-generation antipsychotics should not guide treatment choice, as this distinction lacks pharmacological or clinical validity 1

Parenteral Options for Severe Agitation

When Oral Administration Fails

• Ziprasidone 20 mg IM rapidly reduces acute agitation with notably absent movement disorders (no extrapyramidal symptoms or dystonia), superior to haloperidol IM when dosed every 4-6 hours 1, 2, 6
• Olanzapine IM is effective for agitation associated with schizophrenia and bipolar mania, with FDA approval for 24-hour acute treatment 4
• Lorazepam 2-4 mg IM/IV is equally effective as haloperidol for undifferentiated agitation and should be first-line if substance use or withdrawal is suspected 1, 6, 7

Combination Therapy

• Risperidone 2 mg + lorazepam 2 mg orally produces similar improvement to haloperidol plus lorazepam in cooperative agitated patients 2
• Haloperidol 5 mg + lorazepam 2-4 mg IM produces faster sedation than lorazepam monotherapy, but carries higher extrapyramidal symptom risk 1

Critical Safety Considerations

Cardiac Monitoring

• Obtain baseline ECG if cardiac risk factors are present, as all antipsychotics can prolong QTc interval 2
• Avoid thioridazine (25-30 ms QTc prolongation) and use ziprasidone with caution (5-22 ms variable prolongation) in patients with cardiac disease 2
• Olanzapine remains the safest cardiac option compared to haloperidol (7 ms QTc prolongation) 2

Contraindications

• Avoid haloperidol in Parkinson's disease or dementia with Lewy bodies due to severe extrapyramidal symptom risk 2
• Avoid antipsychotics as monotherapy if anticholinergic or sympathomimetic drug intoxication is suspected, as they can exacerbate agitation 1, 6

Treatment Timeline and Monitoring

Initial Assessment Period

• Administer the first antipsychotic at therapeutic dose for at least 4 weeks before declaring treatment failure 1
• Assess treatment effectiveness early and use a proactive approach when inadequate efficacy or poor tolerability occurs 1

When to Switch

• If significant positive symptoms persist after 4 weeks at therapeutic dose with good adherence, switch to an alternative antipsychotic with a different pharmacodynamic profile 1
• For patients started on a D2 partial agonist, second-line options include amisulpride, risperidone, paliperidone, or olanzapine with concurrent metformin 1

Clozapine Consideration

• If positive symptoms remain significant after two adequate trials (each 4 weeks at therapeutic dose with good adherence), reassess diagnosis and consider clozapine with concurrent metformin 1

Special Populations

First-Episode Psychosis

• Olanzapine demonstrates superior efficacy and safety compared to haloperidol in first-episode patients, with 67.2% achieving clinical response versus 29.2% with haloperidol 8
• First-episode patients experience significantly more extrapyramidal symptoms with haloperidol than multiple-episode patients, making atypical antipsychotics particularly important in this population 8

Adolescents (Ages 13-17)

• Olanzapine 2.5-20 mg/day (mean modal dose 10.7 mg/day) is effective for manic or mixed episodes in adolescents, with efficacy extrapolated to schizophrenia 4

Common Pitfalls to Avoid

• Do not delay treatment if symptoms cause severe distress or safety concerns to self or others, even if diagnosis is uncertain 1
• Do delay treatment if symptoms are clearly related to substance use or medical condition without safety concerns 1
• Do not use rapid neuroleptization with first-generation antipsychotics, as this increases side effects without improving efficacy 5
• Do not continue ineffective treatment beyond 4 weeks—early switching improves outcomes 1