Rexulti Dosing as Adjunct to Zoloft 150 mg
For adjunctive treatment with sertraline (Zoloft) 150 mg, start Rexulti at 0.5 mg once daily for Week 1, increase to 1 mg daily at Week 2, then titrate to the target dose of 2-3 mg once daily from Week 3 onward based on tolerability and response.
FDA-Approved Dosing Protocol
The FDA label for Rexulti (brexpiprazole) provides specific guidance for adjunctive treatment in major depressive disorder 1:
- Week 1: 0.5 mg once daily
- Week 2: 1 mg once daily
- Week 3 onward: Increase to target dose of 2 mg or 3 mg once daily
The effective dose range is 2-3 mg daily, with both doses demonstrating statistically significant efficacy over placebo plus antidepressant therapy 1. In clinical trials, the 2 mg dose showed a placebo-subtracted difference of -3.2 points on MADRS (95% CI -4.9 to -1.5), while the 3 mg dose showed -2.0 points (95% CI -3.4 to -0.5) 1.
Choosing Between 2 mg and 3 mg
Start with 2 mg daily as the initial target dose. The 2 mg dose demonstrated robust efficacy in pivotal trials and may have a slightly better tolerability profile. If response is inadequate after 4-6 weeks at 2 mg and the medication is well-tolerated, consider increasing to 3 mg daily.
The 1 mg dose studied in trials did not separate from placebo and should not be considered a therapeutic endpoint 1.
Key Safety Considerations
Monitor for akathisia, weight gain, and somnolence - the most common adverse effects when combining Rexulti with SSRIs 1. In adjunctive MDD trials:
- Akathisia: 9% with Rexulti vs 4% with placebo
- Weight gain: 7% with Rexulti vs 2% with placebo
- Somnolence: 5% with Rexulti vs 0.5% with placebo
Recent PTSD trials combining brexpiprazole with sertraline 150 mg specifically showed similar findings, with weight increase (5.9% vs 1.5%) and somnolence (5.4% vs 2.6%) being more common than with sertraline alone 2.
Important Drug Interaction
Sertraline has minimal effect on CYP450 metabolism compared to other SSRIs 3, making it a favorable partner for combination therapy. No dose adjustment of Rexulti is needed based on the sertraline combination itself. However, if the patient is taking strong CYP2D6 or CYP3A4 inhibitors, Rexulti dose should be reduced by half 1.
Timeline for Response
Allow 4-6 weeks at the target dose to assess efficacy. In clinical trials, separation from placebo was evident by Week 2-3, with continued improvement through Week 6 1. The full therapeutic effect may take 6-8 weeks to manifest.
Common Pitfall to Avoid
Do not stop at 1 mg daily thinking it's therapeutic. The 1 mg dose failed to demonstrate efficacy in controlled trials 1. This is a common error - clinicians sometimes hesitate to increase beyond 1 mg due to concerns about side effects, but 2-3 mg is the evidence-based therapeutic range.
Discontinuation rates due to adverse events were actually lower with brexpiprazole + sertraline (3.9%) compared to sertraline + placebo (10.2%) in recent trials 2, suggesting the combination is generally well-tolerated when properly titrated.