How should brexpiprazole (Rexulti) be initiated and titrated as augmentation for major depressive disorder with post‑traumatic stress disorder in a patient currently on duloxetine (Cymbalta) 60 mg daily and amitriptyline (Elavil) 10 mg twice daily, who also has hypertension, relapsing polychondritis, a possible intracranial lesion, and regular cannabis use?

Initiating Brexpiprazole Augmentation in Treatment-Resistant Depression with Complex Medical Comorbidities

Brexpiprazole (Rexulti) should be initiated at 0.5 mg once daily for 4 days, then increased to 1 mg daily for 3 days, followed by titration to the target dose of 2 mg daily, which is the FDA-approved dose for augmenting major depressive disorder. 1

Pre-Initiation Safety Screening

Before starting brexpiprazole, you must verify several critical contraindications and risk factors:

• Confirm blood pressure is controlled – Uncontrolled hypertension is a relative contraindication for both duloxetine and brexpiprazole augmentation; baseline BP measurement is mandatory before initiation. 2
• Assess seizure risk – The combination of duloxetine, amitriptyline, and cannabis may lower seizure threshold; brexpiprazole does not significantly increase seizure risk but requires documentation of any seizure history. 2
• Screen for akathisia risk factors – This patient's anxiety and PTSD symptoms may be exacerbated by akathisia, which occurs in approximately 8.6% of MDD patients receiving brexpiprazole (NNH = 15). 3
• Evaluate cannabis use impact – Regular cannabis use (twice daily) may aggravate dissociative symptoms and affect dysregulation characteristic of PTSD, potentially interfering with brexpiprazole's therapeutic effects. 4
• Document intracranial lesion status – The possible brain tumor/old injury requires neurosurgery consultation before initiating any psychotropic that could complicate neurological assessment. 1

FDA-Approved Titration Schedule

The mandatory titration protocol from the pivotal trials is:

• Days 1–4: Brexpiprazole 0.5 mg once daily
• Days 5–7: Increase to 1 mg once daily
• Day 8 onward: Increase to target dose of 2 mg once daily 1

This gradual titration minimizes akathisia risk and allows assessment of tolerability before reaching the therapeutic dose. 1

Target Dose and Efficacy Timeline

• The recommended target dose for MDD augmentation is 2 mg daily – This dose demonstrated statistically significant superiority over placebo (MADRS improvement: -8.4 vs -5.2, placebo-subtracted difference -3.2,95% CI -4.9 to -1.5, p<0.001). 1
• The 3 mg dose showed marginal additional benefit (placebo-subtracted difference -2.0) but is not the recommended starting target. 1
• Allow 6–8 weeks at the target dose before declaring treatment failure – Approximately 50% of patients who ultimately achieve remission do so between weeks 6 and 14 of treatment. 5

Critical Drug Interactions and Monitoring

Duloxetine Continuation

• Continue duloxetine 60 mg daily unchanged – The pivotal brexpiprazole trials specifically included patients on duloxetine as the background antidepressant, demonstrating safety and efficacy of this combination. 1
• No dose adjustment of duloxetine is required when adding brexpiprazole. 1

Amitriptyline Consideration

• Amitriptyline 10 mg twice daily is a subtherapeutic dose for depression (therapeutic range 50–400 mg daily) and appears to be prescribed for pain or sleep rather than mood. 5
• This low dose does not constitute a contraindication to brexpiprazole augmentation, though the combination increases anticholinergic burden. 2

Cannabis Interaction

• Cannabis use may impede PTSD treatment response – Regular cannabis use can aggravate dissociation, reckless behavior, and substance abuse patterns characteristic of complex PTSD. 4
• Counsel the patient that cannabis may reduce brexpiprazole efficacy for anxiety and PTSD symptoms, though it may provide short-term relief of insomnia and nightmares. 4

Hypertension Management

• Baseline blood pressure must be documented before initiating brexpiprazole. 2
• Monitor BP at weeks 2,4,8, and 12 – Brexpiprazole can cause modest BP elevations, particularly when combined with duloxetine. 2
• Lisinopril 20 mg daily should be optimized if BP exceeds 130/80 mmHg during treatment. 2

Monitoring Protocol for Adverse Effects

Akathisia Assessment

• Evaluate for akathisia at each visit during titration – Akathisia is the most common adverse effect (8.6% vs 3.7% placebo in MDD trials). 3
• Distinguish akathisia from anxiety exacerbation – Akathisia presents as motor restlessness and inner tension, distinct from PTSD-related anxiety. 3
• If akathisia develops, reduce dose to 1 mg daily or add propranolol 10–20 mg twice daily before discontinuing. 3

Metabolic Monitoring

• Baseline weight, fasting glucose, and lipid panel are required before initiation. 3
• Repeat metabolic parameters at 12 weeks – Short-term weight gain is modest (mean 1.2 kg), but 7% of patients gain ≥7% body weight in long-term studies. 3

Suicidality Surveillance

• Assess suicidal ideation at every contact during the first 8 weeks – The risk of suicide attempts is greatest during the first 1–2 months after any antidepressant medication change. 6
• This patient's multiple stressors (housing insecurity, medical complexity, recent trauma) amplify suicide risk and require weekly contact during titration. 6

Expected Clinical Response

• Initial improvement in energy and motivation may occur within 2–4 weeks, but full antidepressant response requires 6–8 weeks at the target dose. 1
• Response rate is approximately 45% with brexpiprazole augmentation (23.2% responders vs 14.5% placebo, NNT = 12). 3
• PTSD symptoms may show delayed improvement – Brexpiprazole's serotonergic 5-HT1A partial agonism may benefit anxiety and hyperarousal, but evidence for PTSD-specific efficacy is limited. 7

Management of Inadequate Response

If after 6–8 weeks at brexpiprazole 2 mg daily there is insufficient improvement:

• Increase to 3 mg daily – This dose showed additional benefit in one pivotal trial (placebo-subtracted difference -2.0 vs -1.3 for 1 mg). 1
• Add cognitive-behavioral therapy for PTSD – Combination of medication and trauma-focused psychotherapy demonstrates superior efficacy to medication alone. 6
• Consider switching to aripiprazole augmentation – One trial showed higher remission rates with aripiprazole (55.4%) vs bupropion (34.0%) augmentation, though discontinuation rates were similar. 6

Critical Pitfalls to Avoid

• Do not skip the mandatory titration schedule – Rapid dose escalation increases akathisia risk and may precipitate treatment discontinuation. 1
• Do not exceed 3 mg daily – Higher doses have not been studied and may increase adverse effects without additional benefit. 1
• Do not discontinue duloxetine when adding brexpiprazole – The pivotal trials specifically tested augmentation, not monotherapy switching. 1
• Do not attribute worsening anxiety to brexpiprazole during the first 2 weeks – Transient activation can occur during titration and typically resolves by week 4. 5
• Do not delay neurosurgery consultation – The possible intracranial lesion requires definitive evaluation before attributing cognitive or mood symptoms solely to depression. 1

Renal and Hepatic Considerations

• No dose adjustment is required for the relapsing polychondritis or methotrexate discontinuation. 1
• Brexpiprazole is primarily hepatically metabolized – Monitor for increased adverse effects if hepatic function declines. 1

Cannabis Counseling

• Advise gradual reduction of cannabis use – Regular cannabis may aggravate PTSD symptoms of dissociation, affect dysregulation, and reckless behavior that brexpiprazole aims to improve. 4
• Cannabis may provide short-term relief of insomnia and nightmares but can impede participation in trauma-focused psychotherapy. 4
• Document cannabis use patterns at each visit to assess impact on treatment response. 4