What is the best approach to cross-taper an adult patient with a stable psychiatric condition from Rexulti (brexpiprazole) 4 mg to lurasidone?

Cross-Tapering from Rexulti 4 mg to Lurasidone

Perform a gradual cross-titration over 2-3 weeks by starting lurasidone 40 mg with food while simultaneously reducing Rexulti in stepwise decrements, monitoring closely for withdrawal symptoms and maintaining symptom control throughout the transition. 1

Rationale for Cross-Tapering Approach

The cross-tapering method is preferred over abrupt switching to minimize withdrawal symptoms and maintain continuous symptom control during the transition. 1 Brexpiprazole (Rexulti) has a long half-life of approximately 91 hours, similar to aripiprazole, which requires careful consideration during tapering to avoid both withdrawal phenomena and prolonged receptor occupancy effects. 1

Gradual tapering is critical because antipsychotic discontinuation can trigger neuroadaptations including dopaminergic hypersensitivity that may persist for months after cessation, potentially increasing relapse risk. 2 The hyperbolic relationship between antipsychotic dose and D2 receptor blockade means that dose reductions should become progressively smaller as you approach discontinuation. 2

Specific Cross-Taper Protocol

Week 1:

• Start lurasidone 40 mg once daily with food (at least 350 calories) - food administration is mandatory as it significantly increases absorption 3, 4
• Reduce Rexulti from 4 mg to 3 mg 1
• Monitor for sedation, akathisia, nausea, and somnolence (common early lurasidone side effects) 3, 4

Week 2:

• Continue lurasidone 40 mg with food
• Reduce Rexulti from 3 mg to 1.5 mg 1
• Monitor for withdrawal symptoms including headache, agitation, anxiety, insomnia, and dizziness, which typically emerge 1-4 days after dose reduction 1

Week 3:

• Continue lurasidone 40 mg with food
• Reduce Rexulti from 1.5 mg to 0.75 mg 2
• Continue monitoring for both withdrawal and emerging side effects

Week 4:

• Continue lurasidone 40 mg with food
• Discontinue Rexulti completely 1

Lurasidone Dosing Considerations

Lurasidone requires no initial titration - the recommended starting dose is 40 mg once daily. 3 The therapeutic range is 40-160 mg/day, but starting at 40 mg allows assessment of tolerability during the cross-taper period. 3, 5 If symptom control is inadequate after completing the cross-taper, lurasidone can be increased to 80 mg or higher based on clinical response. 3

Critical administration requirement: Lurasidone must be taken with food (at least 350 calories) as food significantly affects absorption and blood concentrations. 6, 4

Monitoring Parameters During Cross-Taper

Immediate monitoring (weekly during taper):

• Psychiatric symptoms: Monitor for symptom exacerbation, particularly positive symptoms like hallucinations or delusions 7
• Withdrawal symptoms: Headache, agitation, anxiety, insomnia, dizziness, drowsiness 1
• Akathisia and extrapyramidal symptoms (EPS): These are the most common side effects with lurasidone and may require dose adjustment or adjunctive treatment 3, 5, 4
• Somnolence and nausea: Typically transitory but common early in lurasidone treatment 3, 4

Baseline and ongoing metabolic monitoring:

• Weight, BMI, fasting glucose, and lipid panel at baseline before starting lurasidone 1
• Lurasidone has a highly favorable metabolic profile with minimal weight gain and no clinically meaningful alterations in glucose or lipids 3, 4
• Patients switching from Rexulti to lurasidone may experience weight reduction given lurasidone's lower propensity for metabolic side effects 5

Cardiovascular monitoring:

• Blood pressure monitoring is less critical with lurasidone compared to other antipsychotics as it causes no orthostatic hypotension or QTc prolongation 4

Managing Common Side Effects

Akathisia (occurs in a minority of patients): Manage with dose adjustment, adjunctive therapy (beta-blockers or benzodiazepines), and/or psychosocial interventions. 5 Most lurasidone side effects are transitory and easily managed. 5

Somnolence: Usually resolves within the first few weeks; consider timing of administration if problematic. 3, 4

Nausea and parkinsonism: Typically occur early in treatment and may improve with continued use or dose adjustment. 3, 4

Critical Pitfalls to Avoid

• Never administer lurasidone without food - this is a common error that results in subtherapeutic blood levels and apparent treatment failure 6
• Avoid tapering Rexulti too rapidly - the long half-life means withdrawal symptoms may be delayed, and rapid discontinuation increases relapse risk 2
• Do not increase lurasidone dose during the cross-taper - wait until Rexulti is fully discontinued to assess true lurasidone response at 40 mg 3
• Do not assume treatment failure prematurely - allow at least 4-6 weeks at a stable lurasidone dose after completing the cross-taper before concluding inadequate response 7

Alternative Approach for Slower Taper

For patients with history of relapse on medication changes or significant anxiety about switching, consider a more conservative 4-6 week taper with smaller Rexulti dose reductions (reducing by approximately 25% of the most recent dose every 1-2 weeks). 2 This hyperbolic tapering approach may reduce relapse risk by allowing neuroadaptations more time to resolve. 2