How to Switch from Antidepressants to Rexulti (Brexpiprazole)
Rexulti (brexpiprazole) is not used as monotherapy for depression—it is FDA-approved only as adjunctive treatment to antidepressants for major depressive disorder, not as a replacement. You should not "switch" from an antidepressant to Rexulti; instead, you add Rexulti to the existing antidepressant regimen 1.
Understanding Rexulti's Role
Rexulti is indicated for patients with major depressive disorder who have inadequate response to antidepressant treatment (ADT). The pivotal trials enrolled patients who failed 1-3 prior antidepressants and then demonstrated continued inadequate response during an 8-week prospective ADT trial 2, 3. The antidepressant must be continued while adding Rexulti.
When to Consider Adding Rexulti
Based on established depression treatment guidelines, you should modify treatment if patients don't have adequate response after 6-8 weeks of antidepressant therapy 4. For Rexulti specifically:
- Patient must be currently taking an established antidepressant at minimum licensed dose for at least 4 weeks 5
- Inadequate response is defined as <50% symptom reduction on current antidepressant 3
- Rexulti showed efficacy in both minimal responders (>0% to <25% improvement) and partial responders (≥25% to <50% improvement) 3
Dosing Protocol for Adding Rexulti
For Major Depressive Disorder (adjunctive therapy):
The FDA-approved dosing from the drug label 1:
- Target dose: 2 mg once daily
- Initiation: Start at 0.5 mg or 1 mg once daily
- Titration: Increase to 2 mg once daily on Days 8-14
- Maximum dose: 3 mg once daily (if needed based on clinical response)
- Dose adjustments: Titrate at weekly intervals based on tolerability
The 2 mg dose demonstrated the most consistent efficacy with a favorable risk-benefit profile 2, 3. The 3 mg dose showed statistical separation from placebo in one trial but with increased akathisia risk 2.
Timeline Expectations
Critical caveat: Brexpiprazole takes considerable time to show benefit:
- Separation from placebo occurred at 6 weeks in the pivotal MDD trials 1, 2
- Continue treatment for at least 6 weeks before determining efficacy
- Early discontinuation before 6 weeks should not be considered treatment failure 5
This is substantially longer than the 1-2 week monitoring interval recommended for antidepressants alone 4.
Managing the Existing Antidepressant
Do not discontinue or taper the antidepressant when adding Rexulti. The evidence base for Rexulti's efficacy is entirely as adjunctive therapy 1, 6, 2.
If you need to switch between antidepressants while on Rexulti:
- Use gradual cross-titration based on half-life and receptor profiles 7
- Discontinue antidepressants over 10-14 days to limit withdrawal symptoms 8
- Consider pharmacokinetic interactions (Rexulti is metabolized by CYP2D6 and CYP3A4) 1
Monitoring Requirements
Before starting Rexulti 1:
- Baseline weight and BMI
- Blood pressure
- Metabolic panel (glucose, lipids)
- Assess for movement disorder risk
During treatment:
- Monitor weekly for first 1-2 weeks for suicidality (FDA requirement for all antidepressants) 4
- Assess for akathisia (most common adverse event: 8.6% in MDD trials) 1, 6
- Monitor weight (modest weight gain observed, mean increase 1.1-1.5 kg) 9
- Reassess efficacy at 6 weeks minimum 2
Common Pitfalls to Avoid
- Do not use Rexulti as monotherapy for depression—this is off-label and lacks evidence
- Do not expect rapid response—allow full 6 weeks before declaring failure
- Do not stop the antidepressant—Rexulti is adjunctive only
- Do not overlook akathisia—occurs in 8.6% of MDD patients and may be mistaken for worsening anxiety 1, 6
- Do not use doses >3 mg—no additional benefit and increased adverse events 2
Safety Profile
Most common adverse events in MDD trials 1, 6:
- Akathisia (8.6%)
- Weight gain (5-7%)
- Somnolence
- Headache
Discontinuation due to adverse events was low (3%) in MDD trials, with NNH of 53 for discontinuation 6. Metabolic effects are modest compared to other atypical antipsychotics 9.
Alternative Strategies
If considering switching antidepressants instead of augmentation, guidelines recommend 4:
- Switch to antidepressant with different mechanism of action
- Use minimum effective dose for at least 4 weeks 5
- Consider switching if no response after 6-8 weeks 4
For treatment-resistant depression after 2 adequate antidepressant trials, other augmentation strategies include antipsychotics (aripiprazole, risperidone) or psychotherapy 10, though Rexulti represents a newer option with demonstrated efficacy 2, 3.