ICD-116E61	SECONDARY PSYCHOTIC SYNDROME Secondary psychotic syndrome
ICD-10F06.2	Organic delusional [schizophrenia-like] disorder
DSM-5-TRF06.2	Psychotic Disorder Due to Another Medical Condition, With Delusions

1. Definition and nosology

Secondary Psychotic Syndrome (ICD-11: 6E61 Secondary Psychotic Syndrome; DSM-5-TR: F06.2/F06.0 Psychotic Disorder Due to Another Medical Condition) — psychotic episode developing in the context of another medical condition (autoimmune, infectious, endocrine, metabolic, neurological) or a substance. First-line intervention — treatment directed at the primary etiology.

2. History

• The term “Symptomatic psychosis” was formulated in the 20th century.
• Dalmau J. (2007) — discovery of anti-NMDA-R encephalitis; autoimmune psychosis revolution.
• Graus F. et al. (2016) — autoimmune encephalitis clinical guideline.

3. Epidemiology

• 3–8% of all first-episode psychosis cases have secondary etiologies.
• Anti-NMDA-R encephalitis — rare but reversible psychosis in young women; paraneoplastic with teratoma.
• Hashimoto encephalopathy, lupus encephalopathy.

4. Aetiology and pathogenesis

• Autoimmune: Anti-NMDA-R, anti-LGI1, anti-CASPR2 encephalitis; Hashimoto (TPO antibodies); lupus (NPSLE).
• Infectious: HIV, syphilis, herpes encephalitis, COVID-19.
• Endocrine: hyper/hypothyroidism, cortisol disorders (Cushing, Addison), parathyroid disorders (hypercalcemia).
• Metabolic: uremia, hepatic encephalopathy, hyponatremia, hypo/hyperglycemia, B12 deficiency, Wilson's disease.
• Neurological: brain tumor, stroke, epilepsy (postictal-), dementia.
• Substance-induced: Amfetamine, cocaine, cannabis, hallucinogen, alcohol withdrawal, steroids.
• Paraneoplastic: Ovarian teratoma (anti-NMDA-R), small cell lung carcinoma.

5. Clinical features

• Psychotic symptoms (delusion, hallucination, disorganized behavior).
• Atypical features (characteristic of autoimmune encephalitis):
  • Rapid onset
  • Motor symptoms (catatonic, dystonias, orofacial dyskinesia);
  • Autonomic disturbance (hypertension, tachycardia, hyperthermia);
  • Seizures;
  • Impairment of consciousness.
• Compared to classic psychosis (schizophrenia) — atypical presentation raises suspicion.

6. Diagnosis

6.1 Unified diagnostic criteria

A. Psychotic symptoms.

B. Evidence of medical condition (autoimmune, infectious, endocrine, metabolic, neurological) or substance effect.

C. Psychosis does not occur in the context of delirium (but may overlap with delirium).

D. Not better explained by another primary psychotic disorder.

6.2 Source-specific clarifications

• Graus F. et al. Lancet Neurol 2016 — autoimmune encephalitis clinical approach.
• ICD-11 — substance-induced psychosis does NOT belong here: it lives in the substance chapter (6C40.6 alcohol, 6C41.6 cannabis and so on). 6E61 covers only health conditions outside the mental-disorders chapter and is assigned alongside the diagnosis of the underlying disease.

6.3 Diagnostic algorithm

1. Clinical suspicion — new-onset psychosis, especially with atypical features or in young women.
2. Medical assessment:
   • Complete blood count, liver/renal, electrolytes (Na, Ca), glucose, ammonia;
   • TSH, TPO antibodies (Hashimoto);
   • Cortisol level (Cushing/Addison);
   • HIV, syphilis;
   • ANA, lupus panel;
   • B12, folate, ceruloplasmin (Wilson);
   • Toxicology screening.
3. Brain MRI.
4. EEG — non-convulsive status, encephalitis.
5. Lumbar puncture — pleocytosis, antibody panel (anti-NMDA-R, anti-LGI1, anti-CASPR2, paraneoplastic).
6. Tumor screening (when paraneoplastic antibody positive — ovarian USG, pelvic MRI, chest CT).

6.4 Differential diagnosis

7. Examination and assessment

• The above laboratory panel.
• MRI, EEG.
• CSF antibody panel.
• Tumor screening.

8. Treatment

1. Etiological treatment is first-line:
   • Autoimmune encephalitis — IV methylprednisolone 1 g × 5 days → IVIG and/or plasmapheresis; second-line rituximab, cyclophosphamide;
   • Paraneoplastic — tumor treatment (ovarian teratoma surgery);
   • Endocrine — thyroid, cortisol, calcium correction;
   • Infectious — antibiotic, antiviral;
   • Metabolic — correction of the disorder;
   • Medication-induced — discontinuation of the suspected agent.
2. Symptomatic psychiatric intervention — until etiological treatment yields results:
   • Atypical antipsychotic (quetiapine, olanzapine) — with caution;
   • In case of autoimmune encephalitis — typical antipsychotic (haloperidol) contraindicated — Risk of NMS and disease exacerbation;
   • Benzodiazepine (lorazepam) — acute agitation.
3. ECT — alternative for refractory catatonic or autoimmune encephalitis.

Source-specific specifications

• Graus F. et al. Lancet Neurol 2016 — autoimmune encephalitis protocols.
• APA Textbook of Consultation-Liaison Psychiatry (Levenson).

Treatment methods

1. Immunotherapy (Autoimmune Encephalitis) — IV steroids → IVIG → plasmapheresis → rituximab/cyclophosphamide.
2. Treatment of Tumor (Paraneoplastic) — Surgical or oncological treatment.
3. Atypical Antipsychotic, Symptomatic — Until etiological treatment produces results; quetiapine, olanzapine superior.
4. ECT — in refractory cases — Effective in catatonic or immunotherapy-resistant autoimmune encephalitis.

9. Prognosis

• Most cases respond to etiological treatment; reversible condition.
• Anti-NMDA-R encephalitis — 75% good recovery with early immunotherapy.

10. Myths and misconceptions

Myth 1: “First-episode psychosis is always schizophrenia”

Evidence: 3–8% secondary etiologies; atypical features require attention; medical evaluation is mandatory in first-episode psychosis.

Myth 2: “Typical antipsychotic (haloperidol) is safe for every psychotic episode”

Evidence: If suspicion of autoimmune encephalitis, haloperidol and similar first-generation antipsychotics. Prohibited — Risk of NMS, disease exacerbation.

Myth 3: “Anti-NMDA-R encephalitis is rare, not worth looking for”

Evidence: In a young woman atypical psychosis + movement symptoms + seizures is the classic presentation of Anti-NMDA-R; antibody test saves lives; reversible condition.

Myth 4: “If no medical cause is found, a psychiatric diagnosis is made — no further search is needed”

Evidence: Atypical clinical presentation requires expanded investigation (CSF, MRI, paraneoplastic panel).

Myth 5: “Immunotherapy is not suitable for psychiatric conditions”

Evidence: If evidence of autoimmune encephalitis, immunotherapy first-line; standard antipsychotic ineffective.

11. Sources

1. WHO. ICD-11. 6E61 Secondary psychotic syndrome. 2024.
2. APA. DSM-5-TR. 2022.
3. Graus F. et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 2016;15(4):391–404.
4. Dalmau J. et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol 2008;7(12):1091–1098.
5. Levenson J.L. (ed.). APA Publishing Textbook of Psychosomatic Medicine and Consultation-Liaison Psychiatry. 3rd ed. 2018.