Systematic workup of new-onset or acute exacerbation of psychotic symptoms to identify medical, substance, and primary psychiatric causes.
Also known as: acute psychosis, first-episode psychosis, new-onset psychosis
Overview
Acute onset or exacerbation of psychotic symptoms — delusions, hallucinations, disorganized thought, grossly disorganized/catatonic behavior, or negative symptoms — requiring urgent evaluation to distinguish primary psychiatric, substance-induced, and medical/neurologic etiologies, and to initiate safe and effective management.
Epidemiology
First-episode psychosis incidence ~15-30 per 100,000/year. Peak onset late teens through 30s; men present 3-5 years earlier than women. Acute exacerbations common in established schizophrenia, schizoaffective disorder, bipolar I, and severe MDD.
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Sleep deprivation, postpartum (postpartum psychosis is a psychiatric emergency)
Pathophysiology
Final common pathway involves dysregulated mesolimbic dopaminergic signaling, with contributions from glutamatergic, GABAergic, serotonergic, and cholinergic systems depending on etiology. Inflammatory and structural mechanisms in delirium and autoimmune encephalitis.
Clinical presentation
Symptoms
Hallucinations (auditory most common in primary psychiatric; visual, tactile, olfactory raise concern for medical/substance etiology)
Mental status — orientation, attention (asterixis, serial 7s) — inattention/clouded sensorium points to delirium
Differential diagnosis
Delirium — Acute onset, fluctuating course, inattention, altered consciousness — search for underlying medical cause
Substance-induced psychosis — Temporal relationship to use or withdrawal (stimulants, cannabis, hallucinogens, alcohol withdrawal); resolves with abstinence
Primary psychotic disorder — Schizophrenia, schizophreniform, schizoaffective, brief psychotic, delusional — by duration and pattern
Mood disorder with psychotic features — Mood congruent or incongruent psychosis confined to MDE or manic episode
Postpartum psychosis — Onset within days-weeks postpartum; rapid mood/cognition shifts; PSYCHIATRIC EMERGENCY due to suicide and infanticide risk
Diagnostic workup
Diagnostic criteria
Workup-driven differential. Delirium per DSM-5-TR requires disturbance in attention and awareness developing over hours to days with fluctuation and evidence of an underlying medical cause. Primary psychotic disorders categorized by duration and mood context (see Schizophrenia entry).
Labs
CBC, CMP (Ca, glucose), Mg, phosphate, LFTs
TSH, B12, folate; thiamine if malnourished
Urinalysis, urine drug screen (including fentanyl, synthetic cannabinoids if available)
Blood alcohol
Pregnancy test in women of reproductive age
Syphilis serology, HIV; consider hepatitis panel
ESR/CRP; ANA if autoimmune concern
Acetaminophen and salicylate levels if overdose possible
ECG (QTc baseline before antipsychotic, and especially for haloperidol, ziprasidone, IV antipsychotics)
Ammonia, ABG, lactate if metabolic encephalopathy suspected
LP if febrile, meningismus, immunocompromised, or autoimmune encephalitis suspected
Imaging
Non-contrast head CT in first-episode psychosis, focal neurologic findings, trauma, altered consciousness
MRI brain when feasible — higher sensitivity for demyelination, autoimmune encephalitis, structural lesions
EEG if seizure suspected or to evaluate encephalopathy / non-convulsive status epilepticus
Diagnostic algorithm
flowchart TD
A[Acute psychotic presentation] --> B[Stabilize and ensure safety<br/>vital signs, focused exam]
B --> C{Vital sign or<br/>neurologic abnormality?}
C -->|Yes| D[Workup for medical cause<br/>labs, head imaging, +/- LP/EEG]
C -->|No| E[Targeted psychiatric +<br/>substance workup]
D --> F{Delirium / medical /<br/>autoimmune / infectious?}
F -->|Yes| G[Treat underlying cause<br/>+ supportive care]
F -->|No| H[Likely primary psychiatric]
E --> I{Substance present?}
I -->|Yes| J[Substance-induced<br/>reassess after abstinence]
I -->|No| H
H --> K[Antipsychotic +<br/>coordinated specialty care]
Acute psychosis triage from presentation to disposition.
Treatment
First-line
Stabilize ABC; protect patient and staff; ensure safe environment
Verbal de-escalation; offer oral medication before IM
Acute agitation: PO/IM olanzapine, risperidone, haloperidol (often + lorazepam) — avoid combining IM olanzapine + IM benzodiazepine due to respiratory depression risk
Treat underlying cause — correct hypoglycemia, electrolytes, infection; benzodiazepines for alcohol withdrawal; physostigmine for severe anticholinergic toxicity in select cases; immunotherapy for autoimmune encephalitis
Antipsychotic for primary psychotic disorder once medical causes addressed — risperidone, olanzapine, aripiprazole, quetiapine
Admit involuntarily if necessary to protect from self-harm or harm to others
Reduce stimulation; address sleep; involve family for collateral and supports
Iatrogenic worsening of delirium with benzodiazepines or anticholinergics
PANCE pearls
First-episode psychosis warrants thorough medical workup, including neuroimaging — do not assume primary psychiatric etiology.
Visual or tactile hallucinations, fluctuating attention, abnormal vitals, focal neuro findings, or age >50 with new psychosis should escalate medical workup.
Anti-NMDA receptor encephalitis classically affects young women (often with ovarian teratoma) — subacute behavioral change, seizures, dyskinesias, autonomic instability; LP shows CSF antibodies.
Postpartum psychosis is a psychiatric emergency — distinguish from postpartum depression and 'baby blues'; rapid cycling, suicidality, infanticidal thoughts require admission.
Do not use lorazepam IM with IM olanzapine (respiratory and cardiopulmonary depression risk); separate by >=1 hour.
In delirium, antipsychotics are for safety only — they do not shorten delirium duration.
References
APA 2020 — American Psychiatric Association Practice Guideline for the Treatment of Patients with Schizophrenia, 3rd ed. (2020)
EPA Guidance — European Psychiatric Association early intervention in psychosis guidance
Graus 2016 — Graus F et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 2016
ACEP — American College of Emergency Physicians Clinical Policy: Adult Psychiatric Patients in the ED
DSM-5-TR — American Psychiatric Association. DSM-5-TR (2022)
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