What is the differential diagnosis for a patient presenting with an acute psychotic episode, considering potential underlying medical conditions, psychiatric history, and substance use?

Differential Diagnosis of Acute Psychotic Episode

The differential diagnosis of acute psychosis must first distinguish between primary psychiatric disorders and secondary causes (medical conditions, substances, medications), with the critical initial step being assessment of consciousness level to rule out delirium, which carries double the mortality risk if missed. 1, 2

Primary Psychiatric Disorders

Schizophrenia Spectrum Disorders

• Schizophrenia presents with delusions, hallucinations (typically auditory), disorganized speech, disorganized or abnormal motor behavior, and negative symptoms (diminished emotional expression, anergia, social withdrawal) with intact consciousness. 1, 3
• The acute phase lasts 1-6 months with predominance of positive symptoms and significant functional deterioration. 1

Mood Disorders with Psychotic Features

• Bipolar disorder with mania is a critical diagnostic consideration, as approximately 50% or more of bipolar patients experience psychotic features during manic episodes, and 50% of adolescents with bipolar disorder are initially misdiagnosed as having schizophrenia. 1, 4
• In bipolar disorder, psychotic symptoms typically occur during mood episodes and resolve when mood stabilizes, whereas in schizophrenia they persist independent of mood state. 4
• Major depressive disorder with psychotic features must be distinguished from other etiologies, particularly in elderly patients. 2, 5

Secondary Causes (Medical and Substance-Related)

Delirium - The Most Critical Distinction

• Delirium is the most common cause of psychotic symptoms in elderly patients presenting to emergency departments, characterized by inattention, fluctuating consciousness, disorientation, and acute onset over hours to days. 2
• This is the single most important differential to identify immediately, as missing delirium doubles mortality. 2
• Unlike primary psychosis, delirium involves altered consciousness and disorientation, whereas psychosis maintains intact awareness and level of consciousness. 1, 4, 2

Substance-Induced Psychosis

• Illicit drug use is the most common medical cause of acute psychosis, including cannabis, methamphetamine, cocaine, and hallucinogens. 5, 3
• Psychosis associated with substance use typically resolves within 30 days of abstinence from the substance. 5
• Withdrawal states (particularly alcohol and benzodiazepines) require immediate recognition and benzodiazepine treatment to prevent seizures. 2
• Drug-related psychosis occurs through intoxication, withdrawal states, and side effects or toxicity from prescribed medications. 2

Medication-Induced Psychosis

• Legal medications can cause hallucinations and delusions, including antimicrobials, corticosteroids, anticholinergics, and dopaminergic agents. 5, 6

Neurological Causes

• Central nervous system infections (encephalitis, meningitis) typically present with fever and altered mental status. 7, 3
• Traumatic brain injury should be considered with recent head trauma history. 5, 3
• Stroke or cerebrovascular disease may present with psychotic symptoms, particularly in elderly patients. 7, 3
• Brain tumors (oligodendroglioma, glioblastoma, meningioma), intracerebral cysts, and hydrocephalus can present with primarily psychiatric symptoms, though this is rare. 7
• Seizure disorders including nonconvulsive status epilepticus and postictal states. 7, 3
• Dementia with psychotic features, now recognized as a distinct clinical entity. 2
• Inflammatory disorders including autoimmune encephalitis. 7

Metabolic and Endocrine Causes

• Thyroid disorders (thyrotoxicosis or hypothyroidism). 3
• Parathyroid disorders and calcium abnormalities. 3
• Vitamin deficiencies including B12, folate, and niacin (pellagra). 3
• Porphyria may present with fever and psychotic symptoms. 3

Infectious Causes

• HIV infection and associated opportunistic infections. 3
• Neurosyphilis. 3
• Systemic infections with sepsis can precipitate delirium with psychotic features. 7

Age-Specific Considerations

Elderly Patients (≥65 years)

• In patients 65 years or older, secondary medical causes of psychosis are more prevalent than primary psychiatric disorders. 1
• Medical conditions and drug-related causes are more common in this population. 1
• Delirium from infection is the most common cause. 2

Children and Adolescents

• Peer or romantic conflicts may be precipitants. 7
• Bipolar disorder with psychotic features is frequently misdiagnosed as schizophrenia in this age group. 4

Diagnostic Algorithm

Step 1: Assess Level of Consciousness (MOST CRITICAL)

• Altered, fluctuating consciousness = delirium (medical emergency requiring different urgent evaluation). 1, 4, 2
• Intact consciousness = primary psychosis or secondary cause with preserved alertness. 1, 4

Step 2: Obtain Focused History

• Recent substance use (illicit drugs, alcohol, prescription medications). 5, 3
• Recent head injury or trauma. 3
• Seizure history. 3
• New or worsening headaches (suggests intracranial pathology). 3
• Subacute onset (raises suspicion for oncologic cause). 3
• Medication review including recent antimicrobial use. 2, 6
• Collateral history from family is essential, as patients frequently minimize symptoms. 7, 8

Step 3: Physical and Neurological Examination

• Vital signs abnormalities: Tachycardia or severe hypertension suggests drug toxicity or thyrotoxicosis; fever suggests encephalitis or porphyria. 3
• Focal neurological deficits require immediate neuroimaging to exclude intracranial pathology. 1
• Mental status examination including assessment of appearance, behavior, thought process, thought content (delusions, hallucinations), mood, and insight. 7, 8

Step 4: Laboratory Evaluation (When Indicated)

• The American College of Emergency Physicians states that routine laboratory testing need not be performed when patients are clinically stable (alert, cooperative, normal vital signs, noncontributory history and physical examination). 7
• For patients with concerning findings on history/physical examination or new-onset/acute changes in psychiatric symptoms, obtain: 7
  • Complete blood count
  • Metabolic profile
  • Thyroid function tests
  • Urine toxicology
  • Parathyroid hormone and calcium
  • Vitamin B12, folate, and niacin levels
  • HIV and syphilis testing (consider based on risk factors) 3

Step 5: Neuroimaging Decision

• Neuroimaging with CT or MRI is usually appropriate if clinical suspicion for acute neurological cause is high, where the cause is not found on initial assessment, and for patients whose symptoms do not respond appropriately to management. 7
• Neuroimaging is indicated for: 7, 1
  • Focal neurological deficits
  • Head trauma history
  • Atypical features
  • New-onset psychosis in elderly patients
  • First episode psychosis with neurological signs
• Routine brain CT in the absence of focal neurological findings has low yield (only 1.2% clinically significant findings in new-onset acute psychosis). 7

Common Diagnostic Pitfalls to Avoid

• Don't miss delirium - fluctuating consciousness distinguishes it from psychosis and requires different urgent evaluation; missing this doubles mortality. 4, 2
• Don't assume all psychotic symptoms indicate schizophrenia - mania frequently presents with florid psychosis in adolescents and young adults. 1, 4
• Don't overlook secondary causes, particularly in elderly patients where medical conditions are more common. 1, 2
• Don't delay neuroimaging when focal neurological signs, head trauma history, or atypical features are present. 4, 2
• Don't overlook withdrawal states, which require immediate benzodiazepine treatment to prevent seizures. 2
• Don't mistake negative symptoms in schizophrenia for depression, especially when dysphoria accompanies the illness. 4