What is the recommended management for delusional disorder, including first‑line antipsychotic choice, dosing and titration, monitoring, and adjunctive psychotherapy?

Management of Delusional Disorder

First-Line Antipsychotic Selection

Start with risperidone 2 mg/day or olanzapine 7.5–10 mg/day as first-line treatment for delusional disorder, chosen through shared decision-making based on side-effect profiles. 1 Both agents have demonstrated efficacy in case series and retrospective reviews, with approximately 50% of patients showing positive response to antipsychotic treatment. 2

Evidence Supporting Specific Agents

• Risperidone and olanzapine are highly effective for delusional disorder, with historical data also supporting pimozide (particularly for somatic subtype), though newer atypical antipsychotics have largely replaced it. 3

• Aripiprazole shows promise as a treatment option, possibly due to its effects on both dopaminergic and serotonergic receptors, and may be particularly useful in patients who fail risperidone. 4

• Quetiapine may be considered as an alternative, though it is more sedating than risperidone or olanzapine and should be started at 12.5 mg twice daily with cautious titration to a maximum of 200 mg twice daily. 5

• Clozapine may be more effective than other antipsychotics for treatment-resistant cases, though robust evidence is not yet available and it requires intensive monitoring. 3, 6

Dosing and Titration Strategy

Initial Dosing

• For risperidone: Start at 2 mg/day, with a maximum of 4 mg/day in first-episode presentations. 1

• For olanzapine: Start at 7.5–10 mg/day, with a maximum of 20 mg/day, and always offer concurrent metformin 500 mg daily to prevent weight gain. 1

• For quetiapine: Begin at 12.5 mg twice daily, monitoring closely for sedation and orthostatic hypotension. 5

Titration Principles

• Start low and go slow—begin with low doses to minimize extrapyramidal side effects and encourage adherence. 1

• Wait 14–21 days between dose increases to allow adequate time for response assessment and side-effect monitoring. 1, 5

• Allow 4 weeks at therapeutic dose before declaring treatment failure, and confirm good adherence before switching medications. 1

Pre-Treatment Assessment and Baseline Monitoring

Mandatory Baseline Evaluation

• Obtain comprehensive baseline metabolic monitoring before initiating any antipsychotic, including metabolic panel, cardiac monitoring, and laboratory tests. 1

• Baseline measurements must include BMI, waist circumference, blood pressure, fasting glucose, and fasting lipid panel. 1

• Rule out organic causes of psychotic symptoms before attributing symptoms solely to delusional disorder. 1

Ongoing Monitoring Protocol

Short-Term Monitoring (First 6 Weeks)

• Monitor weekly for the first 6 weeks, assessing psychiatric symptoms, side effects, and adherence. 1

• Check BMI, waist circumference, and blood pressure weekly during initial treatment. 1

• Obtain fasting glucose at 4 weeks to detect early metabolic changes. 1

Long-Term Monitoring

• Repeat all baseline metabolic measures at 3 months, then annually, including fasting glucose, lipid panel, BMI, waist circumference, and blood pressure. 1

• Monitor for extrapyramidal symptoms at every visit, including acute dystonia, parkinsonism, and akathisia. 1

When to Switch Antipsychotics

• Switch to an alternative antipsychotic with a different pharmacodynamic profile if significant delusions persist after 4 weeks at therapeutic dose with confirmed adherence. 1

• Consider aripiprazole if risperidone fails, as case reports suggest marked improvement with this switch. 4

• Avoid premature switching—treatment response may vary according to the presence or absence of specific symptoms such as cognitive defect and depression. 3

When to Consider Clozapine

• Consider clozapine after two failed trials, each 4 weeks at therapeutic dose with confirmed adherence, and always offer concurrent metformin to prevent weight gain. 1

• Clozapine requires routine laboratory monitoring (weekly complete blood count to detect agranulocytosis) and should only be used for treatment-resistant cases. 6

Managing Common Side Effects

Extrapyramidal Symptoms

• Treat acute dystonia, parkinsonism, and akathisia with anticholinergic medication, dose reduction, or switching to quetiapine or olanzapine. 1

• Reduce the antipsychotic dose to the minimum effective amount if extrapyramidal symptoms develop, rather than routinely adding anticholinergic agents. 1

Metabolic Side Effects

• Monitor fasting glucose at baseline, 4 weeks, 3 months, then annually, as atypical antipsychotics increase risk of new-onset diabetes. 1

• Consider metformin prophylaxis with olanzapine or clozapine due to their particularly high metabolic risk. 1

• Olanzapine carries the highest risk of weight gain and metabolic effects, so metformin 500 mg daily should be started concurrently. 1

Adjunctive Psychotherapy

Cognitive Behavioral Therapy (CBT)

• CBT may be beneficial as an adjunct to antipsychotic medication, though evidence is limited to one small trial (n=17) comparing CBT to supportive psychotherapy. 7

• Combination treatment (CBT plus medication) showed a positive effect for social self-esteem (MD 30.5, CI 7.51 to 53.49), though this evidence is of very low quality. 7

• CBT may reduce early discontinuation rates compared to supportive psychotherapy alone, though the difference was not statistically significant in the available trial. 7

Psychoeducation and Family Engagement

• Discuss potential risks and benefits of antipsychotic treatment, expected timeline for symptom improvement, side-effect profiles, and importance of adherence with patients and their families before starting treatment. 1

• Address adherence explicitly, as medication adherence is seldom recorded in case reports but is critical for treatment success. 2

Common Pitfalls to Avoid

• Underdosing antipsychotics delays therapeutic response—ensure patients reach therapeutic doses (risperidone 2–4 mg/day, olanzapine 7.5–20 mg/day) before concluding treatment failure. 1

• Premature discontinuation leads to inadequate trials—an adequate therapeutic trial requires 4–6 weeks at target doses before deeming a medication ineffective. 1

• Failure to monitor for metabolic side effects is a common pitfall, particularly with olanzapine and clozapine, which require proactive metabolic monitoring and metformin prophylaxis. 1

• Overlooking comorbid depression, which is more frequent in delusional disorder than previously recognized and may require additional treatment. 2

• Avoiding antipsychotic polypharmacy without clear rationale—there is no evidence supporting the use of multiple antipsychotics simultaneously in delusional disorder. 1

Special Populations

Elderly Patients

• Avoid typical antipsychotics in elderly patients with dementia-related psychosis due to increased risk of extrapyramidal side effects and cerebrovascular events. 1

• Start risperidone at 0.25 mg/day or olanzapine at 2.5 mg/day in elderly patients, using doses in the lower range. 8, 1

• Reduce doses in older patients and patients with hepatic or renal impairment. 8

Treatment-Resistant Cases

• Long-acting injectable antipsychotics and partial D2 agonists may be more effective than oral formulations, but the evidence is not yet robust. 3

• Clozapine remains the option for treatment-resistant delusional disorder after two adequate antipsychotic trials, though it requires weekly hematologic monitoring. 6, 1

Evidence Limitations and Clinical Reality

• Despite international recognition of delusional disorder in ICD-10 and DSM-5, there is a paucity of high-quality randomized trials, and most guidance derives from case reports and small case series. 7

• Treatment guidelines for the optimal management of delusional disorder are not yet available due to the absence of robust evidence. 3

• Until further evidence is found, it is reasonable to offer treatments which have efficacy in other psychotic disorders, including the antipsychotics discussed above. 7