1. History
- Onset and timeline: Acute vs. subacute vs. insidious onset; a subacute onset should raise suspicion for an oncologic or autoimmune cause [1-2]
- Symptom characterization: Hallucinations (auditory vs. visual — visual hallucinations suggest a medical/organic etiology), delusions (content, complexity), disorganized speech/thought, bizarre behavior [1-2]
- Triggers: Recent substance use (cannabis, stimulants, hallucinogens, PCP), medication changes (steroids, anticholinergics, stimulants), sleep deprivation, psychosocial stressors [3-4]
- Progression: First episode vs. recurrence; prior psychiatric diagnoses; duration of symptoms (<1 month suggests brief psychotic disorder, 1–6 months suggests schizophreniform disorder) [4]
- Associated symptoms: Mood symptoms (mania, depression), cognitive changes, seizures, headache, fever, recent head trauma [1][4]
- Important negatives: Absence of substance use, no recent medication changes, no focal neurologic deficits, no trauma, no fever
2. Alarm Features
- Visual hallucinations — strongly suggest organic/medical etiology over primary psychiatric disorder [1]
- Abnormal vital signs — tachycardia, hypertension (drug toxicity, thyrotoxicosis), fever (encephalitis, NMS, serotonin syndrome, porphyria) [1][5]
- Focal neurologic deficits — stroke, mass lesion, encephalitis [2]
- Altered level of consciousness — delirium, not primary psychosis; awareness is typically intact in primary psychosis [2]
- Acute onset in elderly — high suspicion for delirium, stroke, or medication-induced psychosis
- Catatonia — rigidity, mutism, posturing, waxy flexibility; risk of malignant catatonia with autonomic instability [5]
- Command hallucinations to harm self or others [3]
- Signs of NMS — rigidity, hyperthermia, autonomic instability, elevated CK in a patient on antipsychotics [5]
- Seizure activity — ictal or postictal psychosis [6]
3. Medications
Common contributors to psychosis
Acute agitation management (ACEP recommendations): [7]
- Cooperative patient: PO lorazepam 1–2 mg + PO risperidone 2 mg, or PO olanzapine 5–10 mg
- Uncooperative/parenteral needed:
- IM droperidol 5–10 mg (fastest onset, fewer respiratory events) [8-9]
- IM olanzapine 10 mg (do NOT combine with IM benzodiazepines — risk of respiratory depression)
- IM haloperidol 5 mg + IM lorazepam 2 mg (classic "B52" with diphenhydramine 50 mg)
- IM midazolam 5 mg (rapid onset but higher respiratory depression risk) [10]
- Rescue/extreme agitation: IM ketamine 2–4 mg/kg; higher doses (5 mg/kg) associated with increased intubation risk [10]
- Stimulant intoxication or alcohol withdrawal: Benzodiazepines preferred over antipsychotics [8]
Contraindications/cautions
- Avoid antipsychotics in suspected NMS, serotonin syndrome, or anticholinergic toxicity
- Avoid IM olanzapine + IM benzodiazepines concurrently
- QTc monitoring with haloperidol and droperidol (though clinically significant torsades is uncommon) [10]
- Avoid haloperidol in Parkinson's disease or Lewy body dementia
4. Diet
- Not a primary consideration in the acute setting
- Ensure adequate hydration and nutrition, especially in catatonic or severely disorganized patients who may not be eating/drinking [5]
- Assess for Wernicke encephalopathy (thiamine deficiency) in malnourished or alcohol-dependent patients — give thiamine before glucose [6]
- Long-term: Metabolic monitoring is critical once antipsychotics are initiated (weight gain, dyslipidemia, hyperglycemia)
5. Review of Systems
- Neurologic: Headache, seizures, focal weakness, vision changes, gait abnormalities
- Infectious: Fever, neck stiffness, photophobia, recent illness
- Endocrine: Heat/cold intolerance, weight changes, tremor (thyroid), polyuria/polydipsia
- Substance use: Recent ingestion, withdrawal timeline, IV drug use
- Psychiatric: Mood symptoms (mania, depression), anxiety, sleep disturbance, prior episodes
- Autoimmune: Joint pain, rash, oral ulcers (SLE)
- GI/Hepatic: Jaundice, abdominal pain (Wilson disease, porphyria, hepatic encephalopathy)
6. Collateral History and Family History
- Collateral is essential — patients with acute psychosis are often poor historians; family, friends, EMS, and law enforcement can provide critical timeline and behavioral context [1]
- Establish baseline functioning, prodromal symptoms, prior psychiatric hospitalizations, medication adherence
- Family history: Schizophrenia, bipolar disorder, psychotic disorders (strong genetic component); also ask about autoimmune diseases, Wilson disease, Huntington disease, 22q11.2 deletion syndrome [3][11]
- Social context: Housing stability, substance use patterns, recent incarceration, trauma exposure, access to weapons
7. Risk Factors
- Age: Peak onset of primary psychotic disorders is late adolescence to mid-20s (males) and late 20s (females) [12]
- Substance use: Cannabis (especially high-potency/synthetic), methamphetamine, cocaine, hallucinogens, PCP — illicit drug use is the most common medical cause of acute psychosis [1]
- Family history of schizophrenia or bipolar disorder
- Recent psychosocial stressors (brief psychotic disorder)
- Comorbidities: Epilepsy, autoimmune disease (SLE, anti-NMDA receptor encephalitis), HIV, neurodegenerative disease, TBI [3-4]
- Medication exposure: Corticosteroids, dopamine agonists, anticholinergics [3]
- Sleep deprivation and postpartum state
8. Differential Diagnosis
Primary psychiatric causes
- Schizophrenia / schizophreniform disorder — auditory hallucinations, complex delusions, negative symptoms, duration >1 month [4]
- Bipolar disorder (manic episode with psychotic features) — grandiosity, decreased sleep, pressured speech, mood-congruent delusions [4]
- Major depressive disorder with psychotic features — mood-congruent hallucinations/delusions (guilt, worthlessness)
- Brief psychotic disorder — duration <1 month, often with identifiable stressor [4]
- Schizoaffective disorder
Cannot-miss secondary/organic causes
- Substance intoxication/withdrawal — stimulants, cannabis, alcohol withdrawal, benzodiazepine withdrawal, hallucinogens [3][5]
- Anti-NMDA receptor encephalitis — young women, psychiatric symptoms → seizures → movement disorder → autonomic instability [3][13]
- Delirium (any cause) — fluctuating consciousness, inattention; may co-occur with psychosis [2][5]
- CNS infection — meningitis, encephalitis (HSV), HIV, neurosyphilis [11]
- Stroke / intracranial mass — especially temporal lobe lesions [2]
- Seizure disorder — ictal, postictal, or interictal psychosis [6]
- Endocrine — thyrotoxicosis, myxedema, Cushing syndrome, Addisonian crisis, hyper/hypocalcemia [4]
- NMS / serotonin syndrome [5]
- Hepatic/uremic encephalopathy
- Porphyria — abdominal pain, neuropathy, psychosis, fever [1]
- Wilson disease — young patient, liver disease, Kayser-Fleischer rings [11]
9. Past Medical History
- Prior psychiatric diagnoses and hospitalizations
- Previous psychotic episodes and response to treatment
- Medication history (current and past antipsychotics, adherence)
- Seizure disorder, TBI, stroke
- Autoimmune disease (SLE, MS)
- Endocrine disorders (thyroid, parathyroid, adrenal)
- Liver/kidney disease
- HIV status
- Surgical history (especially neurosurgical)
10. Physical Exam
Vital signs — fever, tachycardia, hypertension, tachypnea (each narrows the differential significantly) [1]
Focused exam
- Mental status: Level of consciousness (intact in primary psychosis, impaired in delirium), orientation, attention (serial 7s, months backward), thought content/process, perceptual disturbances [1]
- Neurologic: Cranial nerves, motor strength, reflexes, gait, cerebellar function, meningeal signs (Kernig, Brudzinski); focal deficits mandate imaging [2]
- Eyes: Pupil size/reactivity (mydriasis in anticholinergic/sympathomimetic toxicity), nystagmus (PCP, Wernicke), Kayser-Fleischer rings (Wilson disease) [11]
- Skin: Track marks, diaphoresis, rash (SLE butterfly rash), jaundice
- Thyroid: Goiter, tremor, exophthalmos
- Catatonia screen: Observe for immobility, mutism, staring, posturing, waxy flexibility, negativism; use the Bush-Francis Catatonia Rating Scale [5]
- Rigidity assessment: Lead-pipe rigidity (NMS) vs. cogwheeling (parkinsonism)
11. Lab Studies
Recommended initial labs: [1][11][14]
- CBC — infection, leukocytosis
- BMP/CMP — glucose, electrolytes, renal/hepatic function, calcium
- TSH — hyper/hypothyroidism
- Urine toxicology screen — most common medical cause of acute psychosis is substance use [1]
- Blood alcohol level
- Urinalysis
Additional labs based on clinical suspicion
- Vitamin B12, folate, niacin [1]
- HIV, RPR/VDRL (syphilis) [1][11]
- ANA, ESR/CRP (autoimmune) [11]
- Ceruloplasmin (Wilson disease, especially age <40) [11]
- PTH, calcium/phosphorus [1]
- LFTs, ammonia (hepatic encephalopathy)
- CK (NMS, catatonia, rhabdomyolysis) [5]
- Autoimmune encephalitis panel — strongly consider in new-onset psychosis, especially with seizures, movement disorder, or autonomic instability [13]
- Iron studies — low iron is a risk factor for catatonia and malignant catatonia [13]
- Pregnancy test in women of childbearing age
Note: The ACEP clinical policy states that routine laboratory testing in alert psychiatric patients with a known psychiatric history and no medical complaints has a low yield and should be guided by clinical assessment rather than performed reflexively. [7]
12. Imaging
First-line: CT head without contrast — rapid, available in ED; primarily to rule out acute hemorrhage, mass, or hydrocephalus [2]
Gold standard: MRI brain — superior for detecting temporal lobe lesions, encephalitis, demyelination, small tumors, and white matter disease [2][15]
ACR Appropriateness Criteria (2024): [2]
- CT or MRI may be appropriate for new-onset psychosis in the ED
- Yield of brain imaging is low in the absence of focal neurologic deficits, seizure, head trauma, or headache [11]
- Imaging is strongly indicated when focal neurologic deficits, seizures, headache, or head trauma are present
Meta-analysis data: A JAMA Psychiatry meta-analysis found that while neuroradiological abnormalities are common in first-episode psychosis, clinically relevant abnormalities leading to a change in diagnosis or management are found in a minority of cases. [15]
13. Special Tests
- Bush-Francis Catatonia Rating Scale — standardized screening for catatonia [5]
- Lorazepam challenge — 1–2 mg IV lorazepam; improvement in catatonic signs supports the diagnosis [5]
- EEG — indicated if seizure is suspected, persistent encephalopathy, or nonconvulsive status epilepticus; not routine [6][11]
- Lumbar puncture — if meningitis/encephalitis suspected (fever, meningeal signs, altered consciousness); include autoimmune encephalitis panel in CSF [6][13]
- Slit-lamp exam — Kayser-Fleischer rings (Wilson disease) in young patients [11]
- Urine porphyrins — if porphyria suspected (abdominal pain, neuropathy, psychosis)
14. ECG
- Obtain baseline ECG before administering antipsychotics, particularly haloperidol and droperidol [10]
- QTc prolongation — risk with haloperidol (especially IV), droperidol, ziprasidone; clinically significant torsades de pointes is uncommon but must be monitored [9-10]
- Rule out cardiac causes of altered mental status (arrhythmia, MI)
- Dangerous patterns: Prolonged QTc >500 ms, Brugada pattern (if considering certain medications), torsades de pointes
15. Assessment
Acute psychosis is a symptom complex — not a diagnosis — that may include hallucinations, delusions, disorganized thought/speech, and disorganized or catatonic behavior. [1-2] The critical clinical task is distinguishing primary psychiatric psychosis (schizophrenia, bipolar, brief psychotic disorder) from secondary/organic psychosis (substance-induced, medical condition, delirium).
Key distinguishing features: [1]
- Primary psychiatric: auditory hallucinations, complex/systematized delusions, intact consciousness, normal vital signs
- Secondary/organic: visual hallucinations, cognitive changes, abnormal vital signs, altered consciousness, acute onset in older adults
Severity stratification ranges from cooperative patients with isolated psychotic symptoms to severely agitated, violent, or catatonic patients requiring immediate intervention. Complications include self-harm, harm to others, rhabdomyolysis (from agitation or NMS), aspiration, and medical deterioration from unrecognized organic causes.
16. Treatment Plan
Initial stabilization
- Ensure scene and staff safety; de-escalation techniques first (verbal, environmental)
- 1:1 observation; remove dangerous objects
- Physical restraints only when necessary and with continuous monitoring
Pharmacologic management of agitation (see Medications section above): [7-8][16]
- Cooperative: PO olanzapine 5–10 mg or PO lorazepam 2 mg + PO risperidone 2 mg
- Uncooperative: IM droperidol 5–10 mg (preferred for speed) or IM olanzapine 10 mg or IM haloperidol 5 mg ± IM lorazepam 2 mg ± diphenhydramine 50 mg
- Rescue: IM ketamine 2–4 mg/kg with airway preparedness [10]
Treat underlying cause if identified
- Substance intoxication: supportive care, benzodiazepines for stimulant toxicity/alcohol withdrawal
- Infection: antibiotics/antivirals (acyclovir for HSV encephalitis)
- Metabolic: correct electrolytes, glucose, thyroid
- Anti-NMDA receptor encephalitis: immunotherapy (IVIG, steroids, plasmapheresis)
- Catatonia: lorazepam challenge → scheduled benzodiazepines → ECT if refractory [5]
- NMS: stop offending agent, dantrolene, bromocriptine, supportive care
Antipsychotic initiation for primary psychosis: [12]
- First-episode patients tend to respond to lower doses
- Start at low-to-moderate doses; avoid rapid dose escalation (antipsychotic effect lags behind sedation)
- Improvement in broader psychotic symptoms typically occurs within the first 2 weeks
17. Disposition
Admission criteria: [3][11]
- Danger to self or others (suicidal/homicidal ideation, command hallucinations)
- Grossly disorganized behavior or catatonia
- Inability to care for self or meet basic needs
- First-episode psychosis requiring workup and stabilization
- Suspected organic cause requiring inpatient evaluation (encephalitis, NMS, etc.)
- Failed outpatient management or medication nonadherence
Observation indications
- Substance-induced psychosis expected to resolve (e.g., stimulant intoxication) — observe until resolution
- Mild symptoms with unclear etiology pending lab/imaging results
Discharge criteria
- Symptoms resolved (e.g., substance-induced psychosis cleared)
- No safety concerns (no SI/HI, no command hallucinations)
- Able to care for self, has safe disposition plan
- Reliable follow-up arranged
- Known psychiatric patient with mild exacerbation, medication adjusted, outpatient follow-up confirmed
Specialist consultation triggers
- Psychiatry: all first-episode psychosis, all patients requiring admission
- Neurology: focal deficits, seizures, suspected encephalitis or autoimmune encephalitis
- Toxicology: complex ingestions or unclear toxidromes
18. Follow Up / Return Precautions
Follow-up timing
- First-episode psychosis: psychiatry follow-up within 1 week of discharge; referral to coordinated specialty care (CSC) program if available [3]
- Known psychiatric patient with exacerbation: psychiatry follow-up within 3–7 days
- PCP follow-up for metabolic monitoring after antipsychotic initiation
Return precautions — instruct patient and family to return immediately for:
- Worsening hallucinations or delusions
- Suicidal or homicidal thoughts
- Inability to eat, drink, or care for self
- Fever, rigidity, or muscle stiffness (NMS)
- Seizures or new neurologic symptoms
- Medication side effects (dystonia, akathisia, severe sedation)
Patient/family counseling
- Psychoeducation about the nature of psychosis and treatment expectations
- Medication adherence is critical; improvement may take 1–2 weeks [12]
- Avoid substances (cannabis, stimulants, alcohol)
- Expected recovery: first-episode patients generally have a higher likelihood of response to treatment than those with multiple episodes [12]
Images
References
1. Recognition and Differential Diagnosis of Psychosis in Primary Care. — Griswold KS, Del Regno PA, Berger RC. American Family Physician. 2015.
2. ACR Appropriateness Criteria® Altered Mental Status, Coma, Delirium, and Psychosis: 2024 Update. — Soares BP, Shih RY, Utukuri PS, et al. Journal of the American College of Radiology : JACR. 2024.
3. Management of First-Episode Psychosis and Schizophrenia (SCZ) (2023). — Marlene Arias-Reynoso DNP PMHNP-BC, Jennifer L. Bell MD, Pamela Blueford LICSW, et al Department of Veterans Affairs. 2023.
4. Diagnostic and Statistical Manual of Mental Disorders. — Dilip V. Jeste, Jeffrey A. Lieberman, David Fassler, et al American Psychiatric Association (2022). 2022.
5. Catatonia. — Heckers S, Walther S. The New England Journal of Medicine. 2023.
6. Management of Stimulant Use Disorder. — Steven Batki MD, Daniel Ciccarone MD MPH, Scott E. Hadland MD MPH, et al American Academy of Addiction Psychiatry (2023). 2023.
7. Clinical Policy: Critical Issues in the Diagnosis And Management of the Adult Psychiatric Patient In the Emergency Department. — Nazarian DJ, Broder JS, Thiessen MEW, et al. Annals of Emergency Medicine. 2017.
8. What Is the Best Approach for Parenteral Sedation to Manage Severe Acute Behavioral Disturbance in the Emergency Department?. — Isoardi KZ, Cole JB, Hoffman RS, Isbister GK. Clinical Toxicology. 2026.
9. Randomized Double-Blind Trial of Intramuscular Droperidol, Ziprasidone, and Lorazepam for Acute Undifferentiated Agitation in the Emergency Department. — Martel ML, Driver BE, Miner JR, Biros MH, Cole JB. Academic Emergency Medicine : Official Journal of the Society for Academic Emergency Medicine. 2021.
10. Safety and Efficacy of Pharmacologic Agents Used for Rapid Tranquilization of Emergency Department Patients With Acute Agitation or Excited Delirium. — Kim HK, Leonard JB, Corwell BN, Connors NJ. Expert Opinion on Drug Safety. 2021.
11. Collaborative Care in the Identification and Management of Psychosis in Adolescents and Young Adults. — Hua LL. Pediatrics. 2021.
12. Schizophrenia. — Marder SR, Cannon TD. The New England Journal of Medicine. 2019.
13. Resource Document on Acute Neuropsychiatric Sequelae of COVID-19 Infection. — Scott Beach, Nadia Cacodcar, Erica Baller, Jon Levenson American Psychiatric Association (2023). 2023.
14. Initial Physical Health Assessment for Psychosis in Australia and New Zealand: 2026 Recommendations. — Warren N, O'Gorman C, Dark F, et al. The Australian and New Zealand Journal of Psychiatry. 2026.
15. Prevalence of Neuroradiological Abnormalities in First-Episode Psychosis: A Systematic Review and Meta-analysis. — Blackman G, Neri G, Al-Doori O, et al. JAMA Psychiatry. 2023.
16. "Pharmacological Management of Acute Agitation in Psychiatric Patients: An Umbrella Review". — Uribe ES, Rodríguez CAB, Juárez MEN, et al. BMC Psychiatry. 2025.