Dosing of Rexulti (Brexpiprazole) as Adjunct for Major Depressive Disorder
Start brexpiprazole at 0.5 mg or 1 mg once daily, titrate to a target dose of 2 mg/day, with a maximum of 3 mg/day for adjunctive treatment of MDD in adults. 1
Standard Dosing Protocol
The FDA-approved starting dose is either 0.5 mg/day or 1 mg/day, taken orally once daily with or without food. 1 The recommended target dose is 2 mg/day, which represents the optimal balance between efficacy and tolerability for most patients with MDD. 1
Titration should proceed gradually: Begin at 0.5–1 mg/day for the first week, then increase to 2 mg/day based on clinical response and tolerability. 1 The maximum recommended dose is 3 mg/day for MDD. 1
Clinical response typically emerges within 6 weeks of adjunctive treatment. In pooled Phase 3 trials, patients receiving brexpiprazole 2–3 mg/day as adjunct to antidepressants showed significantly greater improvement in Montgomery-Åsberg Depression Rating Scale (MADRS) scores compared to placebo, with least squares mean differences of approximately -2.5 points in minimal responders and -1.5 points in partial responders to prior antidepressant therapy. 2
Special Population Dosing Adjustments
Patients Aged 65 Years or Older
Elderly patients (≥65 years) should follow the same starting dose of 0.5–1 mg/day, with careful titration to the target of 2 mg/day. 1, 3 In a 26-week open-label study of elderly patients with MDD, flexible-dose brexpiprazole 1–3 mg/day adjunct to antidepressants was generally well tolerated, with 66.7% of patients completing the study. 3
The most common adverse events in elderly patients were fatigue (15.2%) and restlessness (12.9%), with 18.2% withdrawing due to adverse events. 3 Monitor elderly patients closely for orthostatic hypotension, falls risk, and cognitive changes during titration.
No specific dose reduction is mandated by the FDA label for age alone, but clinical judgment should guide slower titration in frail elderly patients. 1
Hepatic Impairment
For patients with moderate to severe hepatic impairment (Child-Pugh score 7–15), the maximum recommended dose is 2 mg once daily for MDD. 1 Start at 0.5 mg/day and titrate slowly to avoid accumulation of brexpiprazole, which is extensively metabolized hepatically.
Patients with mild hepatic impairment (Child-Pugh score 5–6) do not require dose adjustment but should be monitored for increased adverse effects. 1
Renal Impairment
For patients with creatinine clearance (CrCl) <60 mL/minute, the maximum recommended dose is 2 mg once daily for MDD. 1 Begin at 0.5 mg/day and titrate cautiously, as brexpiprazole metabolites may accumulate in moderate to severe renal dysfunction.
Patients with CrCl ≥60 mL/minute do not require dose adjustment. 1
CYP2D6 Poor Metabolizers and Drug Interactions
CYP2D6 poor metabolizers require dose reduction to half the usual dose because brexpiprazole is primarily metabolized by CYP2D6 and CYP3A4. 1 For example, if the target dose is 2 mg/day, reduce to 1 mg/day in poor metabolizers.
When brexpiprazole is co-administered with strong CYP2D6 inhibitors (e.g., paroxetine, fluoxetine, quinidine), reduce the brexpiprazole dose to half the usual dose. 1 When co-administered with strong CYP3A4 inhibitors (e.g., itraconazole, clarithromycin), also reduce the dose to half. 1
When brexpiprazole is co-administered with both a strong CYP2D6 inhibitor and a strong CYP3A4 inhibitor, reduce the brexpiprazole dose to one-quarter of the usual dose. 1
When brexpiprazole is co-administered with strong CYP3A4 inducers (e.g., rifampin, carbamazepine, St. John's wort), double the brexpiprazole dose over 1–2 weeks. 1 When the inducer is discontinued, reduce brexpiprazole to the original dose over 1–2 weeks.
Efficacy by Response Level
Brexpiprazole demonstrates efficacy regardless of whether patients show minimal (>0% to <25%) or partial (≥25% to <50%) response to prior antidepressant treatment. 2 In minimal responders, adjunctive brexpiprazole 2–3 mg/day produced a least squares mean MADRS improvement of -8.8 points versus -6.3 points for placebo (difference -2.47 points, p<0.001, Cohen's d=0.41). 2
In partial responders, adjunctive brexpiprazole produced a MADRS improvement of -6.4 points versus -4.9 points for placebo (difference -1.53 points, p=0.035, Cohen's d=0.28). 2 This suggests brexpiprazole is effective even in patients with some antidepressant response, not just treatment-resistant cases.
Safety and Tolerability Profile
The most common adverse events in MDD trials were weight increase (17.0%), headache (21.3%), and somnolence (17.0%). 4 Akathisia occurred in 6.4% of patients in the young adult MDD study, which is notably lower than rates seen with some other atypical antipsychotics. 4
Clinically relevant weight gain (≥7% increase) occurred in 10.5% of patients receiving brexpiprazole versus 4% on placebo (NNH=17). 5 Monitor weight, glucose, and lipids at baseline, 3 months, and annually thereafter.
Brexpiprazole has minimal effects on prolactin and no clinically relevant QTc prolongation. 5 This makes it a safer option than some alternatives in patients with cardiac risk factors or prolactin-sensitive conditions.
Functional Outcomes in Young Adults
In young adults (18–35 years) with MDD who were working or studying, adjunctive brexpiprazole 1–3 mg/day (target 2 mg/day) produced significant improvements in work and school functioning. 4 Sheehan Disability Scale scores improved by a least squares mean of -11.2 points (p<0.0001), and Work Limitations Questionnaire scores also improved significantly (p<0.0001). 4
These functional improvements suggest brexpiprazole may reduce the socioeconomic burden of MDD by helping patients return to productive work or educational activities. 4
Common Pitfalls to Avoid
Do not start at doses higher than 1 mg/day, as this increases the risk of akathisia and other adverse effects without improving efficacy. 1 The FDA label explicitly recommends starting at 0.5–1 mg/day.
Do not exceed 3 mg/day for MDD, as higher doses have not been shown to provide additional benefit and increase adverse event risk. 1
Do not forget to adjust doses in patients with hepatic impairment (max 2 mg/day), renal impairment (max 2 mg/day), or CYP2D6 poor metabolizer status (half the usual dose). 1 Failure to adjust can lead to drug accumulation and increased adverse effects.
Do not discontinue antidepressant therapy when adding brexpiprazole—it is approved only as adjunctive treatment, not monotherapy for MDD. 1 Continue the same stable dose of antidepressant throughout brexpiprazole treatment.
Do not rush titration in elderly patients, as they are more susceptible to orthostatic hypotension, sedation, and falls. 3 A slower titration schedule (e.g., increasing every 2 weeks instead of weekly) may improve tolerability.