Is reducing Olanzapine to 5mg and increasing Risperidone to 2mg nocte and 1mg mane more effective than increasing Risperidone to 3mg nocte?

Medication Adjustment Strategy for Olanzapine and Risperidone

The better approach is to reduce olanzapine to 5mg and increase risperidone to 2mg nocte and 1mg mane (total 3mg/day split dosing), rather than giving all 3mg at night, as this provides therapeutic dosing while minimizing peak-related side effects and allows for gradual olanzapine discontinuation over 2 weeks to reduce discontinuation rates. 1, 2, 3

Rationale for Split Dosing of Risperidone

• The therapeutic dose range for risperidone is 2-6 mg/day, with optimal efficacy and tolerability typically achieved at ≤6 mg/day 4
• Split dosing (2mg nocte + 1mg mane) reduces peak plasma concentrations compared to single 3mg nocte dosing, which may decrease side effects like orthostatic hypotension, drowsiness, and insomnia while maintaining 24-hour coverage 5, 2
• Risperidone can cause both insomnia and drowsiness; split dosing allows the larger evening dose to aid sleep while the morning dose maintains daytime symptom control without excessive sedation 5, 6

Olanzapine Tapering Strategy

• When switching from olanzapine to risperidone, gradual dose reduction over 2 weeks (rather than abrupt discontinuation) reduces all-cause treatment discontinuation by 23% (12% vs 25-28%) 3
• The relative risk of early discontinuation is 0.77 (CI 0.61-0.99) with gradual 2-week taper compared to faster strategies 3
• Maintain olanzapine at 5mg (approximately 50% of typical therapeutic dose) for 1 week, then reduce to 2.5mg for the second week before discontinuing 3

Dosing Considerations and Monitoring

• Allow 14-21 days at each risperidone dose level before determining inadequate response and increasing further 1, 2
• The maximum recommended dose is 4 mg/day in first-episode psychosis, as doses above 6 mg/day show no greater efficacy but increased extrapyramidal symptoms (EPS) 2
• Monitor for EPS, which can occur even at 2 mg/day, particularly orthostatic hypotension, insomnia, agitation, and drowsiness 5, 2, 6

Drug Interaction Alert

• Both medications may be affected by CYP2D6 metabolism; if unusual side effects occur at low doses, consider the patient may be a slow metabolizer 1
• This is less likely given the current subtherapeutic dosing, but warrants monitoring during dose escalation 1

Comparative Efficacy Evidence

• Olanzapine and risperidone demonstrate comparable efficacy on overall psychopathology measures, though olanzapine may have advantages for negative and depressive symptoms while risperidone shows benefits for positive symptoms 7, 8
• Both agents are equally effective in real-world outcomes like duration of hospitalization (7.9 vs 8.1 days, no significant difference) 9
• Olanzapine carries higher risk of weight gain and metabolic effects, while risperidone has higher risk of EPS and hyperprolactinemia 7, 8

Common Pitfalls to Avoid

• Do not abruptly discontinue olanzapine—this doubles the risk of treatment discontinuation 3
• Avoid giving all risperidone at night if the patient experiences daytime breakthrough symptoms or morning sedation 5
• Do not exceed 6 mg/day risperidone total dose, as EPS risk increases significantly without additional efficacy benefit 2, 4
• Monitor for anticholinergic burden if the patient is on other medications, as this can worsen cognitive function 1