Is it safe to prescribe Rexulti (brexpiprazole) with 225 mg of venlafaxine (Effexor)?

Can You Prescribe Rexulti with 225 mg of Venlafaxine?

Yes, you can prescribe Rexulti (brexpiprazole) with enlafaxine 225 mg/day, as there are no documented contraindications or significant drug-drug interactions between these medications, though careful monitoring for additive side effects is essential.

Key Safety Considerations

Drug Interaction Profile

• Venlafaxine has minimal effect on the CYP450 system compared to SSRIs, making it less likely to cause clinically significant drug-drug interactions 1.
• Brexpiprazole is metabolized primarily by CYP2D6 and CYP3A4, and venlafaxine does not significantly inhibit these pathways 2.
• No contraindication exists for combining SNRIs like venlafaxine with atypical antipsychotics like brexpiprazole 1.

Critical Monitoring Parameters

Cardiovascular monitoring is paramount when using venlafaxine 225 mg/day, as this is the maximum recommended dose:

• Blood pressure and heart rate should be measured weekly for the first 2-4 weeks 3.
• Venlafaxine at doses ≥225 mg/day is associated with cardiac conduction abnormalities and blood pressure increases in a small number of patients 1.
• In older adults (≥60 years), 9.8% developed elevated blood pressure at doses ≥225 mg/day, and 22.4% developed orthostatic hypotension, increasing fall risk 4.

Serotonin Syndrome Risk

• Monitor for serotonin syndrome when combining serotonergic medications, though the risk is primarily with MAOIs, not atypical antipsychotics 1.
• Watch for mental status changes (confusion, agitation), neuromuscular hyperactivity (tremors, clonus), and autonomic hyperactivity (hypertension, tachycardia, diaphoresis) within 24-48 hours of starting the combination 1.

Clinical Context for This Combination

Indication Alignment

• Brexpiprazole is FDA-approved as adjunctive therapy to antidepressants for major depressive disorder with inadequate response 2.
• Venlafaxine 150-225 mg/day is an established therapeutic dose range for depression and anxiety disorders 1.
• This combination is appropriate when a patient has had inadequate response to venlafaxine monotherapy 2.

Additive Side Effects to Monitor

• Both medications can cause increased blood pressure and heart rate, requiring vigilant cardiovascular monitoring 1, 3.
• Both can cause dizziness, headache, insomnia, and nausea 1.
• Brexpiprazole may cause akathisia and somnolence, which could be additive with venlafaxine's sedative effects 2.

Practical Management Algorithm

Before Initiating the Combination

• Obtain baseline sitting and standing blood pressure, heart rate, weight 3, 4.
• Screen for cardiac disease history, as venlafaxine should be prescribed with caution in patients with cardiac disease 1.
• If patient is >40 years old with cardiac risk factors, consider baseline ECG given venlafaxine's association with cardiac conduction abnormalities 1.

During Treatment

• Monitor blood pressure and heart rate weekly for 2-4 weeks, then monthly 3.
• Assess for orthostatic hypotension, especially in older adults, and counsel about fall risk 4.
• Monitor for behavioral activation, suicidal ideation (especially in patients ≤24 years), and serotonin syndrome symptoms 1, 3.
• Evaluate efficacy after 4-6 weeks at therapeutic doses 3.

Common Pitfalls to Avoid

• Do not abruptly discontinue venlafaxine, as it is associated with a withdrawal syndrome characterized by dizziness, nausea, headache, irritability, and anxiety; always taper slowly 1.
• Do not exceed venlafaxine 225 mg/day without compelling clinical justification, as higher doses increase cardiovascular risks without clear additional benefit 1, 4.
• Do not ignore new-onset orthostatic hypotension, as it significantly increases fall risk 4.