Transitioning from Rexulti 2mg to Vraylar: Recommended Approach
There is no established guideline for cross-tapering atypical antipsychotics like brexpiprazole (Rexulti) to cariprazine (Vraylar), but based on principles from antipsychotic discontinuation research and the pharmacology of these agents, you should initiate Vraylar at a low dose while maintaining Rexulti 2mg, then taper Rexulti hyperbolically over 3-6 months to minimize withdrawal-related symptom exacerbation.
Critical Pharmacological Considerations
Why Gradual Tapering Matters for Antipsychotics
Slower tapering of antipsychotics (over months rather than weeks) is associated with lower relapse rates because it allows time for neuroadaptations—including dopaminergic hypersensitivity—to resolve, reducing disruption to homeostatic equilibrium 1, 2.
Faster antipsychotic reductions cause greater disruption and can precipitate or exacerbate psychotic symptoms, either as direct withdrawal effects or consequences of nonpsychotic withdrawal symptoms like insomnia 1.
PET imaging demonstrates a hyperbolic relationship between antipsychotic doses and D2 receptor blockade, meaning equal dose reductions at lower doses cause disproportionately larger changes in receptor occupancy 2.
Rexulti and Vraylar Pharmacology
Both brexpiprazole and cariprazine are partial dopamine D2 agonists with very long half-lives (Rexulti ~91 hours; Vraylar and its active metabolites 1-3 weeks), which influences withdrawal timing and cross-titration strategy.
The extended half-life of Vraylar means it takes 2-4 weeks to reach steady state, requiring patience during the transition period.
Recommended Cross-Titration Protocol
Week 1-2: Initiate Vraylar While Maintaining Rexulti
Start Vraylar 1.5mg daily while continuing Rexulti 2mg daily to establish therapeutic coverage before beginning the Rexulti taper.
Monitor for excessive sedation, akathisia, or other side effects from the combined dopaminergic effects.
Week 3-4: Begin Hyperbolic Rexulti Taper
Reduce Rexulti by 25% of the current dose (from 2mg to 1.5mg daily) while maintaining Vraylar 1.5mg 2.
This first reduction represents approximately a 5-10 percentage point decrease in D2 receptor blockade, following the principle of reducing receptor occupancy evenly 2.
Month 2: Continue Hyperbolic Reduction
Reduce Rexulti by 25% of the most recent dose (from 1.5mg to approximately 1mg daily) 2.
Assess for emergence of psychiatric symptoms, insomnia, or other withdrawal manifestations at each reduction.
Month 3: Further Reduction
Reduce Rexulti by 25% of the most recent dose (from 1mg to 0.75mg daily) 2.
If withdrawal symptoms emerge (anxiety, insomnia, psychotic symptom exacerbation), pause the taper and maintain the current dose for 4-6 weeks before proceeding 3.
Month 4: Approach Final Doses
Reduce Rexulti by 25% of the most recent dose (from 0.75mg to approximately 0.5mg daily) 2.
These smaller absolute reductions at lower doses prevent large decreases in D2 blockade when approaching complete cessation 2.
Month 5: Near-Complete Discontinuation
Reduce Rexulti to 0.25mg daily (25% of 0.5mg) 2.
Final doses before complete cessation may need to be as small as 1/40th of a therapeutic dose to prevent a large decrease in D2 blockade 2.
Month 6: Complete Discontinuation
Discontinue Rexulti completely after maintaining 0.25mg for 2-4 weeks.
Continue monitoring for 3-6 months post-discontinuation, as neuroadaptations can persist for months or years after stopping antipsychotics 2.
Vraylar Dose Optimization
Titrate Vraylar to the target therapeutic dose (typically 1.5-6mg daily for schizophrenia or bipolar disorder) based on clinical response, independent of the Rexulti taper schedule.
Most patients require 3-4.5mg daily for optimal efficacy; adjust based on symptom control and tolerability.
Monitoring Requirements During Transition
Symptom Monitoring
Assess for psychotic symptom exacerbation, mood destabilization, anxiety, insomnia, and akathisia at each dose reduction 1, 2.
Distinguish between withdrawal-related symptom emergence and true relapse of underlying illness—withdrawal symptoms typically emerge within days to weeks of dose reduction and may resolve with slower tapering 1.
Follow-Up Schedule
Schedule visits every 2-4 weeks during the active taper phase to assess tolerance and adjust the taper rate as needed 2.
More frequent contact (weekly) may be necessary if withdrawal symptoms emerge or psychiatric symptoms worsen 1.
Managing Withdrawal Symptoms During Taper
If Symptoms Emerge
Pause the taper immediately and maintain the current dose for 4-6 weeks to assess whether symptoms represent withdrawal or relapse 3.
If symptoms worsen significantly, consider returning to the previous higher dose temporarily, then resume tapering at a slower rate (10% reductions monthly rather than 25% reductions) 3, 2.
Symptomatic Management
Address insomnia with sleep hygiene education and consider short-term trazodone 25-50mg at bedtime rather than adding another sedating medication 4.
Manage anxiety with non-pharmacologic interventions (CBT, mindfulness) rather than benzodiazepines, which carry their own dependence risks 5, 6.
Critical Pitfalls to Avoid
Never use straight-line dose reductions (e.g., reducing by 0.5mg every month), as this creates disproportionately large decreases in receptor occupancy at lower doses 2.
Do not rush the taper even if the patient appears stable—adaptations to antipsychotic exposure can persist for months, and faster tapering increases relapse risk 1, 2.
Do not abandon the patient if tapering proves difficult; maintain the therapeutic relationship and consider maintenance at a lower Rexulti dose while optimizing Vraylar, rather than forcing complete discontinuation 3.
Do not mistake withdrawal symptoms for relapse—exacerbation of psychotic symptoms during antipsychotic reduction may indicate the need for more gradual reduction, not necessarily a higher long-term dose 1.
When to Refer to Psychiatry
Patients with unstable psychiatric comorbidities, history of rapid cycling, or multiple prior relapses warrant psychiatry consultation before initiating the taper 3.
If office-based cross-titration is unsuccessful after two attempts with different taper rates, refer to a psychiatrist for specialized management 5.
Consider specialist involvement for patients with treatment-resistant illness or those requiring doses outside typical ranges.
Alternative Approach: Direct Switch
For patients who cannot tolerate a prolonged cross-taper, a direct switch (stopping Rexulti and starting Vraylar simultaneously) is possible but carries higher risk of symptom destabilization.
If using a direct switch, start Vraylar at the equivalent therapeutic dose (1.5-3mg) on the same day Rexulti is discontinued, and monitor very closely for the first 4-6 weeks.
This approach is not recommended for patients with marginal symptom control, history of rapid relapse, or significant anxiety about medication changes.