What is the recommended titration schedule for brexpiprazole (Rexulti) in adults with schizophrenia or schizoaffective disorder and in major depressive disorder, and how should the dose be adjusted for elderly patients, hepatic impairment, or concomitant strong CYP3A4/CYP2D6 inhibitors?

Titration of Rexulti (Brexpiprazole)

Recommended Titration for Schizophrenia in Adults

For schizophrenia, start brexpiprazole at 1 mg once daily on Days 1-4, increase to 2 mg once daily on Days 5-7, then titrate to the target dose of 2-4 mg once daily on Day 8 based on clinical response and tolerability. 1

• The maximum recommended daily dose is 4 mg once daily 1
• The recommended target dosage range is 2-4 mg once daily 1
• Administer once daily with or without food 1
• Clinical effects typically become apparent after 1-2 weeks of treatment 2
• An adequate trial requires 4-6 weeks at therapeutic doses before concluding ineffectiveness 2

Recommended Titration for Major Depressive Disorder (Adjunctive Therapy)

For adjunctive treatment of MDD, start at 0.5 mg or 1 mg once daily, titrate to 1 mg daily, then increase to the target dose of 2 mg once daily with weekly dose adjustments based on clinical response. 1

• The maximum recommended daily dose is 3 mg once daily 1
• Increase dosage at weekly intervals based on patient's clinical response and tolerability 1
• Periodically reassess to determine continued need and appropriate dosage 1

Dose Adjustments for Hepatic Impairment

In patients with moderate to severe hepatic impairment (Child-Pugh score ≥7), reduce the maximum dose to 2 mg once daily for MDD and 3 mg once daily for schizophrenia. 1

• This dose reduction applies to all patients with Child-Pugh score ≥7 1
• No specific titration schedule modification is provided beyond the maximum dose restriction 1

Dose Adjustments for Renal Impairment

In patients with creatinine clearance <60 mL/minute, reduce the maximum dose to 2 mg once daily for MDD and 3 mg once daily for schizophrenia. 1

• This applies to all patients with CrCl below 60 mL/minute regardless of severity 1
• Follow the standard titration schedule but do not exceed these maximum doses 1

Dose Adjustments for Elderly Patients

Reduce starting doses in older patients, though specific elderly dosing recommendations are not explicitly provided in the FDA label. 3

• Elderly patients with dementia-related psychosis have increased mortality risk with antipsychotics, and brexpiprazole is not approved for this indication 1
• Consider lower initial doses and slower titration in elderly patients based on clinical judgment 3

Dose Adjustments for CYP2D6 Poor Metabolizers

For known CYP2D6 poor metabolizers, administer half of the recommended dosage throughout the titration and maintenance phases. 1

• If a CYP2D6 poor metabolizer is also taking strong or moderate CYP3A4 inhibitors, administer one quarter of the recommended dosage 1
• These adjustments apply to both the titration phase and maintenance dosing 1
• PBPK modeling suggests that current labeling may overcompensate for decreased clearance in CYP2D6 PMs, though the FDA-approved dosing should be followed 4

Dose Adjustments for Concomitant Strong CYP3A4 Inhibitors

When co-administered with strong CYP3A4 inhibitors (e.g., itraconazole, clarithromycin), administer half of the recommended brexpiprazole dosage. 1

• This dose reduction applies throughout both titration and maintenance phases 1
• When the CYP3A4 inhibitor is discontinued, adjust brexpiprazole back to the original dosage level 1

Dose Adjustments for Concomitant Strong CYP2D6 Inhibitors

When co-administered with strong CYP2D6 inhibitors (e.g., paroxetine, fluoxetine), administer half of the recommended brexpiprazole dosage. 1

• For MDD patients, dosage adjustment for strong CYP2D6 inhibitors is already factored into general dosing recommendations, so no adjustment is needed 1
• For schizophrenia patients, reduce the dose by half when strong CYP2D6 inhibitors are used 1

Dose Adjustments for Combined CYP2D6 and CYP3A4 Inhibitors

When strong or moderate CYP2D6 inhibitors are combined with strong or moderate CYP3A4 inhibitors, administer one quarter of the recommended brexpiprazole dosage. 1

• This represents the maximum dose reduction scenario 1
• When concomitant inhibitors are discontinued, adjust brexpiprazole back to the original level 1

Dose Adjustments for Concomitant Strong CYP3A4 Inducers

When co-administered with strong CYP3A4 inducers (e.g., rifampin, carbamazepine), double the recommended brexpiprazole dosage over 1-2 weeks. 1

• This dose increase compensates for increased brexpiprazole metabolism 1
• When the CYP3A4 inducer is discontinued, reduce brexpiprazole back to the original level over 1-2 weeks 1
• The gradual reduction prevents potential toxicity from suddenly elevated brexpiprazole levels 1

Clinical Efficacy Expectations

Pooled responder rates in acute schizophrenia trials were 46% for brexpiprazole 2-4 mg/day versus 31% for placebo, yielding a number needed to treat (NNT) of 7. 2

• In 52-week relapse prevention studies, 13.5% of brexpiprazole patients relapsed versus 38.5% on placebo, yielding an NNT of 4 2
• The highest antipsychotic efficacy was observed with the 4 mg/day dose 5
• Brexpiprazole reduces not only positive symptoms but also negative symptoms, depressive symptoms, and anxiety 5

Common Pitfalls to Avoid

Never rapid-load brexpiprazole—the gradual titration schedule minimizes akathisia and other adverse effects while allowing assessment of tolerability. 1, 2

• Akathisia rates were 5.5% for brexpiprazole 1-4 mg/day versus 4.6% for placebo (NNH=112), which is lower than aripiprazole 2, 6
• Weight gain occurs in approximately 10% of patients (≥7% increase from baseline) versus 4% on placebo (NNH=17) 2
• Do not exceed maximum doses in patients with hepatic impairment, renal impairment, or those on CYP inhibitors, as this increases adverse effect risk 1
• Failing to adjust doses for CYP2D6 poor metabolizers or drug interactions can lead to excessive plasma concentrations and increased side effects 1, 4