What is the differential diagnosis for a first‑episode psychosis in a 59‑year‑old woman?

Differential Diagnosis of First-Episode Psychosis in a 59-Year-Old Woman

In a 59-year-old woman presenting with first-episode psychosis, delirium is the most common cause and must be ruled out first, followed by systematic exclusion of secondary medical etiologies—including infections, metabolic disorders, medications, neurological disease, and autoimmune conditions—before considering primary psychiatric disorders. 1, 2

Step 1: Rule Out Delirium (Highest Priority)

Delirium is the most common cause of psychotic symptoms in elderly patients and missing it doubles mortality. 1, 2

Key Distinguishing Features:

• Fluctuating level of consciousness over hours to days (waxing and waning alertness) 1, 2
• Acute onset (hours to days, not weeks to months) 1, 2
• Inattention and disorientation to time, place, or person 1, 2
• Altered awareness versus the intact consciousness seen in primary psychosis 1, 2
• Hypoactive delirium is especially common in older adults and carries higher mortality than hyperactive forms 1

Common Precipitants in This Age Group:

• Urinary tract infection (most common infectious trigger) 1
• Pneumonia 1
• Recent medication changes, especially anticholinergics or corticosteroids 1

---

Step 2: Systematic Medical Workup (Mandatory Before Psychiatric Diagnosis)

Systematic exclusion of secondary causes is required before diagnosing primary psychosis, especially in patients ≥65 years or without prior psychiatric history. 1

A. Infectious Causes

• CNS infections: Encephalitis or meningitis (look for fever, altered mental status, nuchal rigidity) 2
• Systemic infections: UTI, pneumonia, sepsis 1, 2
• HIV-related opportunistic infections (assess risk factors) 1

B. Metabolic and Endocrine Disorders

• Thyroid dysfunction (hyper- or hypothyroidism) 1, 2
• Electrolyte abnormalities (sodium, calcium, glucose) 1, 2
• Vitamin B12 deficiency (reversible cause) 1
• Thiamine deficiency 3

C. Neurological Causes

• Stroke or cerebrovascular disease (especially with focal deficits) 1, 2
• Seizure disorders: Non-convulsive status epilepticus, post-ictal states 1, 2
• Brain tumors: Oligodendroglioma, glioblastoma, meningioma (rare but can present primarily with psychiatric symptoms) 1, 2
• Neurodegenerative diseases: Alzheimer's, Parkinson's, Lewy body dementia, frontotemporal dementia 1
• Traumatic brain injury (even remote history) 2, 3

D. Autoimmune and Inflammatory Conditions

• Autoimmune encephalitis (anti-NMDA receptor, others) 1, 2
• Systemic autoimmune diseases (lupus, vasculitis) 1
• Paraneoplastic syndromes 1

E. Substance-Related Causes

• Acute intoxication: Amphetamines, cocaine, cannabis, methamphetamine, hallucinogens, alcohol 1, 4
• Withdrawal states: Alcohol or benzodiazepine withdrawal (requires immediate benzodiazepine treatment to prevent seizures) 1, 2
• Medication-induced: Corticosteroids, anticholinergics, stimulants 1, 2
• Heavy metal toxicity: Lead, mercury 1

Critical Rule: If psychotic symptoms persist >1 week after documented detoxification, consider primary psychotic disorder rather than substance-induced psychosis. 1

---

Step 3: Essential Diagnostic Testing

Mandatory Laboratory Tests:

• Complete blood count 1
• Basic metabolic panel (electrolytes, glucose, renal function) 1, 3
• Thyroid function tests (TSH, free T4) 1, 3
• Vitamin B12 level 1, 3
• Urinalysis and urine culture 1
• Urine drug screen 1

Neuroimaging (Brain MRI Preferred):

Brain MRI is recommended to exclude structural lesions and assess for cerebral atrophy patterns. 1, 2

Indications for Urgent Imaging:

• New-onset psychosis in elderly patients (≥65 years) 1, 2
• Focal neurological deficits 2
• History of head trauma 2, 3
• Atypical features (e.g., visual hallucinations, altered consciousness) 1, 2
• Symptoms not responding to initial management 2

Additional Testing When Indicated:

• EEG if seizure activity suspected 1, 2
• HIV testing if risk factors present 1
• Genetic testing (e.g., C9orf72) if family history of neurodegeneration 1

---

Step 4: Primary Psychiatric Differential (After Medical Exclusion)

A. Dementia with Psychosis

• Chronic, progressive cognitive decline over months to years 1
• Memory-first presentation with gradual loss of ADL independence 1
• Symmetric cortical or subcortical atrophy on MRI 1
• Obtain collateral history from reliable informant to establish baseline cognitive status 1
• Perform validated cognitive screening (MMSE or CAMCOG) 1

B. Major Depressive Disorder with Psychotic Features

• Acute, episodic onset of psychotic symptoms during a depressive episode 1
• Must meet established depressive episode criteria first 1
• Mood-first presentation with cognition intact between episodes 1
• Responds to combination of antidepressant plus antipsychotic 1

C. Bipolar Disorder with Psychotic Features

• Cyclical mood episodes (manic or depressive) 1, 3
• Grandiose delusions especially common during manic phases 1, 3
• Increased talkativeness, reduced sleep, yearly cyclical pattern 3
• Frequently misdiagnosed as schizophrenia 2

D. Schizoaffective Disorder

• Concurrent features of mood disorder and schizophrenia 1, 3
• Psychotic symptoms persist beyond mood episodes 1
• Longitudinal reassessment essential for discrimination 1, 3

E. Delusional Disorder

• Prominent, non-bizarre delusions without other schizophrenia criteria 1
• Overall functioning relatively preserved outside delusional system 1

F. Late-Onset Schizophrenia

• Less common in this age group without prior psychiatric history 1
• Requires 6 months of symptoms including active phase 1
• Observable features: disorganized speech, bizarre behavior, negative symptoms (diminished emotional expression, social withdrawal) 1

---

Critical Clinical Pitfalls

• Missing delirium doubles mortality—always assess for fluctuating consciousness first 1, 2
• Visual hallucinations should raise suspicion for delirium or other medical etiologies rather than primary psychiatric disorder 1
• Don't overlook withdrawal states—alcohol or benzodiazepine withdrawal requires immediate benzodiazepine treatment to prevent seizures 1, 2
• Age matters: In patients ≥65 years, secondary medical causes are significantly more prevalent 1, 2
• Relying solely on patient-reported symptoms without documenting observable psychotic phenomena leads to misdiagnosis 1

---

Longitudinal Monitoring Strategy

• Re-evaluate repeatedly over time, as initial presentation may not clearly separate disorders 1, 3
• Track symptom trajectory: Episodic episodes with full inter-episode recovery suggest mood disorder; steady progressive decline indicates dementia or neurodegenerative disease 1
• Improvement following treatment of identified medical condition supports secondary (medical) psychosis etiology 1