Can Rexulti (brexpiprazole) be added to Effexor (venlafaxine)?

Adding Brexpiprazole (Rexulti) to Venlafaxine (Effexor)

Yes, brexpiprazole (Rexulti) can be safely added to venlafaxine (Effexor) as an adjunctive therapy for major depressive disorder with inadequate response to antidepressant monotherapy. This combination is specifically supported by FDA approval for brexpiprazole as an adjunctive treatment for major depressive disorder 1.

Pharmacological Rationale

Brexpiprazole works as a serotonin-dopamine activity modulator with:

• Partial agonist activity at serotonin 5-HT1A receptors and dopamine D2 receptors
• Antagonist activity at 5-HT2A receptors 2

This complementary mechanism can enhance the antidepressant effect of venlafaxine, which is a serotonin and norepinephrine reuptake inhibitor (SNRI).

Dosing Recommendations

When adding brexpiprazole to venlafaxine:

• Start with brexpiprazole 0.5-1 mg once daily
• Titrate gradually to the target dose of 2-3 mg once daily based on clinical response
• No specific dosage adjustment of brexpiprazole is required when used with venlafaxine 1

Important Drug Interaction Considerations

1. No CYP2D6 dosage adjustment needed in MDD: According to the FDA label, "In the clinical studies examining the adjunctive use of brexpiprazole in the treatment of MDD, dosage was not adjusted for strong CYP2D6 inhibitors. Thus, CYP considerations are already factored into general dosing recommendations and brexpiprazole may be administered without dosage adjustment in patients with MDD" 1.

2. No significant pharmacokinetic interaction: Venlafaxine is not a strong inhibitor of CYP3A4 or CYP2D6 enzymes that would significantly affect brexpiprazole metabolism 1.

Monitoring Recommendations

When using this combination, monitor for:

1. Cardiovascular effects:

   • Blood pressure and heart rate, as venlafaxine can increase both 3
   • ECG if patient has pre-existing cardiac conditions

2. Psychiatric symptoms:

   • Emergence of suicidal thoughts (especially during initial treatment or dose changes)
   • Signs of behavioral activation/agitation
   • Symptoms of hypomania or mania 3

3. Common side effects:

   • Akathisia (less common with brexpiprazole than aripiprazole) 2, 4
   • Weight gain
   • Sedation
   • Nausea, which can be reduced by starting at lower doses 3

Contraindications and Precautions

Absolute contraindications to this combination include:

• Concomitant use of MAOIs due to risk of serotonin syndrome 3, 5
• Severe hepatic impairment 3
• Uncontrolled narrow-angle glaucoma 5

Follow-up Schedule

• Schedule follow-up within 1-2 weeks of initiating brexpiprazole
• Assess for adverse effects, clinical response, and any changes in mood, anxiety, or suicidal ideation 5
• Continue regular monitoring throughout treatment

Clinical Efficacy

Brexpiprazole has demonstrated efficacy as an adjunctive therapy in patients with MDD who have had an inadequate response to antidepressant monotherapy 4, 6. Its efficacy is comparable to other second-generation antipsychotics used for this purpose, but with potentially better tolerability profile, particularly:

• Lower risk for akathisia than aripiprazole
• Lower risk for somnolence than quetiapine-XR 6

This combination provides a valid option for patients with persistent depressive symptoms despite standard antidepressant therapy with venlafaxine.