Medication Adjustment Strategy for Persistent Depression and Anxiety

Your patient requires treatment modification now, as they have not achieved adequate response after what appears to be sufficient time on their current regimen—this warrants either dose optimization of existing medications or addition of a formal antidepressant. 1

Primary Recommendation: Add or Optimize Antidepressant Therapy

The most critical issue here is that this patient is not on a traditional antidepressant (SSRI, SNRI, or other second-generation antidepressant). While Rexulti (brexpiprazole) is FDA-approved as adjunctive treatment for major depressive disorder, it is specifically indicated as an add-on to antidepressant therapy, not as monotherapy 2. The patient's current regimen includes:

Rexulti 2mg: Adjunctive antipsychotic (requires a base antidepressant)
Lamictal 150mg: Mood stabilizer (not a primary antidepressant)
Adderall XR/IR: Stimulant (not FDA-approved for depression treatment)
Propranolol ER 60mg: Beta-blocker (for anxiety/physical symptoms)
Melatonin 10mg: Sleep aid

Step 1: Initiate a Second-Generation Antidepressant

Start an SSRI or SNRI immediately. Guidelines clearly state that when choosing pharmacologic therapy for major depression, clinicians should select second-generation antidepressants based on adverse effect profiles, cost, and patient preferences 1.

Specific recommendations:

Sertraline 50mg daily or Escitalopram 10mg daily are excellent first choices given:
- Lower sexual dysfunction rates than paroxetine
- Well-tolerated in combination with stimulants
- No significant drug interactions with current regimen 3
- Sertraline transfers minimally to breast milk if relevant 3
Avoid fluoxetine or paroxetine initially because:
- Both are strong CYP2D6 inhibitors that would increase Rexulti exposure, though the FDA label notes that in MDD trials, dose adjustments weren't made for strong CYP2D6 inhibitors, so this is already factored into the 2mg dose 2
- Paroxetine has higher sexual dysfunction rates 1

Step 2: Optimize Rexulti Dosing

Once an antidepressant is on board, consider increasing Rexulti from 2mg to 3mg daily (the maximum FDA-approved dose for MDD is 3mg) 2. The patient reports Rexulti is helping but "not enough"—this suggests partial response warranting dose optimization. Research shows adjunctive brexpiprazole improves both depressive symptoms and sleep disturbances in MDD patients 4, 5.

Titration approach:

Wait 2-4 weeks after starting the antidepressant
If still inadequate response, increase Rexulti to 3mg daily
Monitor for akathisia, weight gain, and somnolence 2

Step 3: Reassess Lamictal Dosing

Lamictal 150mg may be subtherapeutic for mood stabilization. Typical therapeutic doses for bipolar depression range from 200-400mg daily. However, before increasing:

Important drug interaction: Lamotrigine at doses >200mg/day can reduce quetiapine levels by 46%, though this interaction appears specific to immediate-release formulations and may not significantly affect brexpiprazole 6
Consider increasing to 200mg daily if bipolar spectrum disorder is part of the diagnosis
If purely unipolar depression, the Lamictal may be less critical than establishing adequate antidepressant therapy

Step 4: Address the Stimulant Regimen

The patient reports Adderall is "the only thing that has helped." This raises two possibilities:

Undiagnosed or undertreated ADHD contributing to functional impairment and mood symptoms
Stimulant-induced temporary mood elevation masking inadequate depression treatment

The total daily Adderall dose (45mg) is reasonable but consider:

Research shows stimulants can be effective adjuncts in treatment-resistant depression, particularly for patients with comorbid anxiety when combined with SSRIs/SNRIs 7
One study found brexpiprazole combined with stimulants showed trends toward improvement in emotional dysregulation symptoms in ADHD patients 8
Do not discontinue the stimulants—they may be providing genuine benefit for attention and energy

Timeline for Assessment

Monitor response within 1-2 weeks of starting the antidepressant for worsening symptoms, suicidal ideation, or agitation 1. The FDA specifically advises close monitoring during the first 1-2 months of antidepressant treatment.

Expect meaningful improvement by 6-8 weeks. If inadequate response at 6-8 weeks, modify treatment by:

Increasing antidepressant dose
Switching to a different antidepressant class
Optimizing Rexulti to 3mg (if not already done)
Considering psychotherapy augmentation 1

Critical Pitfalls to Avoid

Do not continue current regimen unchanged—the patient has persistent symptoms indicating treatment failure
Do not rely on Rexulti as monotherapy—it is FDA-approved only as adjunctive treatment 2
Do not assume stimulants alone will treat depression—while they may help energy and focus, they are not adequate monotherapy for MDD
Do not forget to continue treatment for 4-9 months after achieving remission to prevent relapse 1

Addressing Anxiety and Crying Spells

The propranolol 60mg HS is addressing physical anxiety symptoms but not the underlying mood disorder. Once adequate antidepressant therapy is established:

Anxiety symptoms often improve as depression improves
The beta-blocker can continue for performance anxiety or physical symptoms
Research shows brexpiprazole improves both depressive and anxiety symptoms when used adjunctively 4, 5

Bottom Line Algorithm

Week 0: Start sertraline 50mg or escitalopram 10mg daily
Week 1-2: Monitor closely for adverse effects and worsening symptoms
Week 4: If partial response, consider increasing antidepressant dose
Week 6: If still inadequate response, increase Rexulti to 3mg daily
Week 8: If still inadequate response, switch antidepressant or add psychotherapy
After remission: Continue all medications for 4-9 months minimum

The evidence strongly supports that this patient needs a foundation antidepressant to work synergistically with the Rexulti, rather than relying on the current medication combination that lacks a primary antidepressant agent.

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