In a patient with systemic lupus erythematosus who develops psychosis, how can I differentiate steroid‑induced psychosis from lupus psychosis based on recent glucocorticoid dose, onset timing, somatic symptoms, delusional content, and personality factors?

Differentiating Steroid-Induced Psychosis from Lupus Psychosis in SLE

Steroid-induced psychosis predominantly manifests as mood disorder (93% of cases) rather than true psychosis, occurs in only 10% of patients on prednisone ≥1 mg/kg, and typically resolves within days to weeks of dose reduction—whereas lupus psychosis presents with delusions and hallucinations, often accompanies other neuropsychiatric manifestations, and requires immunosuppressive therapy rather than steroid withdrawal. 1

Critical Distinguishing Features

Glucocorticoid Dose and Timing

• Steroid-induced psychosis occurs almost exclusively at prednisone doses ≥0.75–1 mg/kg/day and develops within days to weeks of dose escalation 2, 3
• The temporal relationship is key: symptoms appearing shortly after steroid initiation or dose increase strongly suggest steroid-induced etiology 4, 5
• Lupus psychosis typically occurs early in the disease course—80–90% of cases present either as the initial SLE manifestation or within the first year after diagnosis, often independent of recent steroid changes 6
• In patients on chronic stable steroid doses who develop psychosis during a taper, lupus cerebritis becomes more likely 4

Clinical Presentation Patterns

Steroid-induced psychiatric disease:

• Predominantly mood disorders (mania, depression) in 93% of cases 1
• True psychosis is rare 1
• Isolated psychiatric symptoms without other neurological findings 3
• Resolves completely with steroid dose reduction 2, 3

Lupus psychosis:

• Characterized by delusions (false beliefs refuted by objective evidence) and/or hallucinations (perceptions without external stimuli) 1
• Frequently accompanied by other neuropsychiatric manifestations: seizures, cognitive dysfunction, cranial/peripheral neuropathy, or acute confusional state 7, 8
• Associated with active systemic lupus disease in other organs 2
• Does not resolve with steroid reduction alone; requires immunosuppression 1

Somatic and Neurological Accompaniments

• The presence of concurrent neurological deficits (cranial nerve palsies, peripheral neuropathy, seizures, focal signs) strongly favors lupus psychosis over steroid-induced psychosis 7, 8
• Lupus psychosis during disease follow-up is associated with positive antiphospholipid antibodies (OR 3.2) and less frequently with renal or cutaneous involvement 2
• Steroid-induced psychosis presents as isolated psychiatric symptoms without focal neurological findings 3

Laboratory and Imaging Differentiation

Serological markers:

• Anti-ribosomal P antibodies have limited diagnostic utility (sensitivity 25–27%, specificity 75–80%) but when elevated may support lupus cerebritis 1, 5
• Positive antiphospholipid antibodies (moderate-to-high anticardiolipin, anti-β2-glycoprotein IgG/IgM, or lupus anticoagulant) favor inflammatory CNS lupus 7
• Hypoalbuminemia was present in 10 of 28 patients with steroid-induced psychosis in one cohort, possibly reflecting severe disease activity 2

Neuroimaging:

• Brain MRI has modest sensitivity (50–70%) and specificity (40–67%) for lupus psychosis; a normal scan does not exclude the diagnosis 1, 7
• MRI patterns showing inflammatory changes (T2/FLAIR hyperintensities, enhancement) support lupus cerebritis 4
• Brain SPECT identifies perfusion deficits in 80–100% of severe lupus psychosis cases, and residual hypoperfusion during remission predicts future relapse 1, 7

Essential exclusions:

• CSF analysis is mandatory to exclude CNS infection, which is a leading cause of morbidity and mortality in SLE 7, 6
• EEG should be performed to identify seizure disorders manifesting as psychosis 1, 7

Algorithmic Approach to Diagnosis

Step 1: Establish Temporal Relationship

• Recent steroid initiation or dose escalation (within days to weeks) → suspect steroid-induced psychosis 2, 3
• Psychosis during steroid taper or on stable low-dose steroids → suspect lupus psychosis 4
• Psychosis at SLE onset or within first year of diagnosis → suspect lupus psychosis 6

Step 2: Assess for Concurrent Manifestations

• Isolated psychiatric symptoms without neurological findings → more consistent with steroid-induced psychosis 3
• Psychosis plus seizures, cognitive dysfunction, cranial neuropathy, or focal signs → lupus psychosis 7, 8
• Active systemic lupus disease (renal, cutaneous, hematologic) → lupus psychosis more likely 2

Step 3: Exclude Secondary Causes (Mandatory)

• Perform CSF analysis to exclude CNS infection 7, 6
• Obtain EEG to exclude seizure disorder 1, 7
• Check for metabolic derangements, electrolyte abnormalities 1

Step 4: Obtain Neuroimaging

• Brain MRI with T1/T2, FLAIR, diffusion-weighted, and contrast-enhanced sequences 7
• Consider brain SPECT if MRI is inconclusive and clinical suspicion for lupus psychosis remains high 1, 7

Step 5: Check Relevant Antibodies

• Antiphospholipid antibodies (anticardiolipin, anti-β2-glycoprotein, lupus anticoagulant) 7, 2
• Anti-ribosomal P antibodies (limited utility but may support diagnosis) 1, 5

Treatment Based on Diagnosis

If Steroid-Induced Psychosis Is Confirmed:

• Reduce or discontinue glucocorticoids if clinically feasible 7
• Initiate antipsychotic medication (haloperidol or atypical agents) for symptom control 7, 3
• Do not add immunosuppression, which could worsen the condition 7
• Symptoms should resolve within days to weeks of steroid dose reduction 2, 3

If Lupus Psychosis Is Confirmed:

• Initiate high-dose glucocorticoids combined with immunosuppressive agents (typically cyclophosphamide), achieving 60–80% response rates 1, 7
• Methylprednisolone IV 0.25–0.50 g/day for 1–3 days, followed by oral prednisone ~0.35–1.0 mg/kg/day, tapered over months 6, 8
• Cyclophosphamide IV 500 mg every 2 weeks × 6 doses for severe manifestations 6, 8
• Add antipsychotic medication for symptom control while immunosuppression takes effect 1, 7
• Maintenance therapy with azathioprine or mycophenolate after induction to prevent relapse (which occurs in up to 50% of cases) 1, 6

If Diagnosis Remains Uncertain:

• In the acute setting with diagnostic uncertainty, a cautious trial of steroid dose reduction with close monitoring may help differentiate: improvement suggests steroid-induced psychosis, while worsening suggests lupus psychosis requiring immunosuppression 4, 5
• However, this approach requires careful monitoring as it risks undertreating active lupus cerebritis 4

Common Pitfalls and Caveats

• Do not assume all psychosis in steroid-treated SLE patients is steroid-induced: true steroid-induced psychosis is rare (10% at high doses) and predominantly causes mood disorders, not psychosis 1
• Recurrence of psychosis favors lupus etiology: patients with prior steroid-induced psychosis who develop subsequent psychosis may actually have lupus cerebritis, especially if occurring during steroid taper 4
• Normal MRI does not exclude lupus psychosis: sensitivity is only 50–70% 1, 7
• Most psychiatric episodes resolve within 2–4 weeks of appropriate treatment; lack of improvement warrants reassessment or specialist referral 1, 6
• Only 20% of SLE patients develop chronic mild psychotic disorder; most have complete resolution 1

Personality Factors and Delusional Content

• Neither personality characteristics nor specific delusional content reliably distinguish steroid-induced from lupus psychosis 1, 2
• Both conditions can present with similar psychotic symptoms (delusions, hallucinations, disorganized behavior) 1, 3
• The distinguishing features are temporal relationship to steroids, presence of other neuropsychiatric manifestations, and response to treatment rather than symptom phenomenology 4, 2, 5