Can vortioxetine (Trintellix) be co‑prescribed with bupropion in an otherwise healthy adult?

Can Vortioxetine (Trintellix) and Bupropion Be Given Together?

Yes, vortioxetine and bupropion can be co-prescribed, but the vortioxetine dose must be reduced by half when combined with bupropion due to a significant pharmacokinetic interaction. 1

Mandatory Dose Adjustment Required

• The FDA label for vortioxetine explicitly states that the dose must be reduced by one-half when patients are receiving bupropion concomitantly, as bupropion is a strong CYP2D6 inhibitor. 1
• The maximum recommended dose of vortioxetine is 10 mg/day when combined with bupropion (or in known CYP2D6 poor metabolizers). 1
• The vortioxetine dose should be increased back to the original level when bupropion is discontinued. 1

Mechanism of the Drug Interaction

• Bupropion is a strong CYP2D6 inhibitor, and vortioxetine is primarily metabolized by CYP2D6 enzymes. 1, 2
• Co-administration of bupropion significantly increases vortioxetine plasma concentrations by inhibiting its primary metabolic pathway. 2
• This interaction is clinically significant enough to warrant mandatory dose reduction, unlike most other drug combinations with vortioxetine. 2

Clinical Evidence Supporting the Combination

• Combining serotonergic agents (like vortioxetine) with bupropion is a well-established augmentation strategy for treatment-resistant depression. 3, 4
• A clinical case series of 27 patients combining serotonin reuptake inhibitors with bupropion showed that 70% experienced greater symptomatic improvement than with either agent alone, with a mean treatment duration of 11 months. 4
• The combination addresses depression through complementary mechanisms: vortioxetine enhances serotonergic transmission through multiple receptor targets, while bupropion works via noradrenergic and dopaminergic pathways. 3, 5
• Adverse effect risks with the combination were similar to monotherapy, with no seizures reported in the clinical series. 4

Critical Safety Screening Before Combining

Absolute Contraindications to Bupropion

• Seizure disorder or history of epilepsy – bupropion significantly lowers seizure threshold with a documented 0.1% seizure risk. 3, 6, 7
• Current or prior bulimia or anorexia nervosa – higher seizure incidence observed in these populations. 3, 7
• Uncontrolled hypertension – bupropion can elevate blood pressure and heart rate. 3, 7
• Current MAOI use or within 14 days of stopping an MAOI – risk of hypertensive crisis. 3, 6
• Abrupt discontinuation of alcohol, benzodiazepines, or antiepileptic drugs – increased seizure risk. 3

Absolute Contraindications to Vortioxetine

• MAOI use within 14 days – risk of serotonin syndrome. 1
• Hypersensitivity to vortioxetine – anaphylaxis, angioedema, and urticaria have been reported. 1

Practical Dosing Algorithm

Starting the Combination

If patient is already on vortioxetine:

• Reduce vortioxetine dose by 50% before adding bupropion. 1
• Example: If on vortioxetine 20 mg daily, reduce to 10 mg daily when starting bupropion.
• Start bupropion at 150 mg once daily for 3 days, then increase to 150 mg twice daily (300 mg total). 3, 7

If patient is already on bupropion:

• Start vortioxetine at 5 mg daily (half the usual starting dose of 10 mg). 1
• Maximum vortioxetine dose is 10 mg daily while on bupropion. 1

If starting both simultaneously:

• Start vortioxetine at 5 mg daily and bupropion at 150 mg once daily for 3 days. 3, 1
• Increase bupropion to 150 mg twice daily after 3 days if tolerated. 3
• Maximum vortioxetine dose remains 10 mg daily. 1

Monitoring Requirements

Initial Monitoring (First 1-2 Weeks)

• Assess for worsening depression, suicidal ideation, and behavioral changes – particularly critical in patients under 24 years old. 3, 1
• Monitor for increased agitation or activation, as bupropion is an activating medication. 3, 6
• Check blood pressure and heart rate, as bupropion can cause elevations. 3, 7

Ongoing Monitoring

• Blood pressure and heart rate should be monitored periodically, especially in the first 12 weeks. 3, 7
• Screen for seizure risk factors including head trauma, brain metastases, or conditions lowering seizure threshold. 6, 7
• Monitor for serotonin syndrome symptoms if any additional serotonergic agents are added. 6, 1, 8

Efficacy Assessment

• Allow 6-8 weeks at adequate doses before determining treatment response. 3, 7
• Vortioxetine typically shows improvement in depressive symptoms within 2 weeks, with full therapeutic effect at 4-6 weeks. 5
• Bupropion may produce more rapid improvement in energy levels within the first few weeks. 3

Clinical Advantages of This Combination

• Bupropion has significantly lower rates of sexual dysfunction compared to SSRIs, which may counteract any sexual side effects from vortioxetine. 3, 7
• Bupropion is associated with minimal weight gain or even weight loss, unlike many other antidepressants. 3
• The combination is particularly beneficial for patients with depression characterized by low energy, apathy, or hypersomnia due to bupropion's activating properties. 3, 7
• Vortioxetine has demonstrated procognitive effects that may improve cognitive dysfunction associated with depression. 9

Common Pitfalls to Avoid

• Failing to reduce vortioxetine dose by half when adding bupropion – this is a mandatory adjustment per FDA labeling, not optional. 1
• Exceeding bupropion maximum dose of 450 mg/day (XL) or 400 mg/day (SR) – increases seizure risk above 0.1%. 3, 7
• Administering bupropion's second dose after 3 PM – increases insomnia risk. 3
• Discontinuing treatment prematurely before 6-8 weeks unless significant adverse effects occur. 3, 7
• Adding additional serotonergic agents without careful monitoring for serotonin syndrome. 6, 1, 8

Special Population Considerations

Hepatic Impairment

• For moderate to severe hepatic impairment, bupropion maximum dose is 150 mg daily. 3
• Vortioxetine requires no dose adjustment for hepatic impairment per available data. 2

Renal Impairment

• For moderate to severe renal impairment, bupropion dose should be reduced by 50%. 3
• Vortioxetine requires no dose adjustment for renal impairment. 2

Older Adults

• Start bupropion at 37.5 mg every morning, increasing by 37.5 mg every 3 days as tolerated, with maximum of 150 mg twice daily. 3
• No specific vortioxetine dose adjustment required for age alone. 2