Can a patient with treatment‑resistant depression who is currently taking mirtazapine (Remeron), aripiprazole (Abilify) and trazodone be given brexpiprazole (Rexulti) or another antipsychotic?

Do Not Add Rexulti (Brexpiprazole) to This Regimen

This patient is already taking aripiprazole (Abilify), and adding brexpiprazole (Rexulti) would constitute antipsychotic polypharmacy with two partial D2 agonists—a combination that lacks evidence and violates treatment guidelines. The current regimen already includes an antipsychotic augmentation strategy for treatment-resistant depression, making additional antipsychotic augmentation inappropriate.

Why This Combination Is Problematic

Antipsychotic polypharmacy should only be considered after adequate trials of monotherapy have failed, and specifically after clozapine has been tried (or deemed contraindicated) 1. The patient is already receiving aripiprazole as augmentation to mirtazapine for depression—this IS the evidence-based augmentation strategy. Adding brexpiprazole would mean:

• Two partial D2 agonists simultaneously (aripiprazole + brexpiprazole)—both work through similar mechanisms
• Increased side effect burden without clear additional benefit 1
• Violation of treatment algorithms that recommend trying different pharmacodynamic profiles when switching, not adding similar agents 2

What Should Be Done Instead

First: Optimize the Current Regimen

Before considering any additions:

1. Verify adequate dosing and duration: Has aripiprazole been at therapeutic dose (10-15 mg for depression augmentation) for at least 4-6 weeks? 3
2. Assess actual adherence: Consider blood level monitoring if available
3. Evaluate mirtazapine dosing: Is it at 30-45 mg daily? 4
4. Rule out contributing factors: Substance use, medical conditions, medication interactions 2

Second: If Current Regimen Has Failed

The evidence-based sequence for treatment-resistant depression is:

1. Switch antidepressants (not add another antipsychotic): Consider switching from mirtazapine to a different class—SSRI, SNRI, or bupropion 5, 3

2. Switch the antipsychotic augmentation agent (if keeping augmentation strategy): Replace aripiprazole with a different pharmacodynamic profile:

   • Quetiapine XR (150-300 mg)—D2 antagonist with different receptor profile 6
   • Cariprazine (1.5 mg)—partial D2 agonist but with different D3 preferring profile 7
   • Note: Brexpiprazole could be considered as a replacement for aripiprazole (not addition), though evidence suggests similar efficacy 8, 9

3. Consider non-antipsychotic augmentation:

   • Lithium augmentation (if not contraindicated)
   • Thyroid hormone augmentation
   • Lamotrigine (especially if bipolar features)

4. Evaluate for psychotherapy augmentation: CBT or other evidence-based psychotherapy 5, 3

Third: Address the Polypharmacy Already Present

This patient is on THREE sedating agents (mirtazapine, trazodone, aripiprazole):

• Trazodone's role should be clarified: Is it for insomnia or depression? If solely for sleep, consider whether it's still needed given mirtazapine's sedating properties 4
• Simplification may improve outcomes: Reducing medication burden can improve adherence and reduce side effects 10

Critical Safety Considerations

If antipsychotic polypharmacy were ever considered (which it should NOT be in this case):

• It should only occur after clozapine trial or documented clozapine contraindication 1
• Combining two partial D2 agonists (aripiprazole + brexpiprazole) has no supporting evidence 1
• The combination would increase risks of:
  • Akathisia and restlessness (both drugs cause this) 11, 8
  • Metabolic effects (cumulative risk) 1
  • Cognitive impairment (dose-related with antipsychotics) 1

Drug Interaction Note

Mirtazapine does not significantly interact with brexpiprazole or aripiprazole from a pharmacokinetic standpoint 11. However, this does NOT justify the combination—the issue is pharmacodynamic redundancy and lack of evidence, not drug interactions.

The Bottom Line Algorithm

Current regimen failing?
├─ YES → Optimize current doses first
│         ├─ Still failing after 4-6 weeks?
│         │   ├─ Switch antidepressant (different class)
│         │   ├─ OR switch antipsychotic (different profile)
│         │   └─ Consider non-antipsychotic augmentation
│         └─ Do NOT add second antipsychotic
└─ NO → Continue current regimen

Never add brexpiprazole to aripiprazole—this represents irrational polypharmacy with two mechanistically similar agents 1, 2.