What are the potential interactions between Strattera (atomoxetine) and Wellbutrin (bupropion)?

Strattera and Wellbutrin Drug Interaction

Combining atomoxetine (Strattera) with bupropion (Wellbutrin) requires significant caution due to a clinically important pharmacokinetic interaction that can substantially increase atomoxetine levels, potentially leading to increased adverse effects including cardiovascular complications and seizure risk.

Mechanism of Interaction

Bupropion is a strong CYP2D6 inhibitor, and since atomoxetine is primarily metabolized by CYP2D6, concurrent use can convert normal metabolizers into "phenotypic poor metabolizers," resulting in significantly elevated atomoxetine plasma concentrations and prolonged half-life. 1

• Approximately 7% of the population are genetically poor CYP2D6 metabolizers who naturally experience higher atomoxetine levels and increased adverse effects 1
• When bupropion blocks CYP2D6 in normal metabolizers, it mimics this poor metabolizer phenotype pharmacologically 1
• Concomitant use with CYP2D6 inhibitors necessitates dose adjustments to prevent toxicity 1

Clinical Management Strategy

If Combination is Necessary:

Start with reduced atomoxetine doses (approximately 50% of standard dosing) and titrate more slowly than usual when adding bupropion to existing atomoxetine therapy, or vice versa. 1

• Standard atomoxetine starting dose is 40 mg daily, titrating every 7-14 days to 60-80 mg daily 2
• With concurrent bupropion, consider starting at 20-25 mg daily with slower titration intervals
• Maximum atomoxetine dose should remain at 1.4 mg/kg/day or 100 mg/day, whichever is lower 2, 1

Monitoring Requirements:

Close monitoring for cardiovascular effects is essential, including baseline and ongoing assessment of heart rate and blood pressure, as both medications can cause increases in these parameters. 3

• Atomoxetine causes statistically significant increases in heart rate and blood pressure 3
• Preexisting cardiovascular disease or cardiac abnormalities require careful assessment before initiating this combination 1
• Monitor for signs of atomoxetine toxicity: excessive sedation, agitation, cardiovascular symptoms

Psychiatric Monitoring:

All patients on this combination must be monitored closely for suicidal ideation, clinical worsening, and unusual behavioral changes, particularly during the first few months or after dose changes. 1

• Atomoxetine carries a black-box warning for suicidal ideation 3
• Bupropion can cause agitation, which may be amplified by elevated atomoxetine levels 4

Seizure Risk Considerations

The combination carries theoretical increased seizure risk due to bupropion's dose-dependent seizure threshold lowering and potentially elevated atomoxetine levels. 4

• Bupropion's maximum dose is 450 mg/day for immediate-release and 400 mg/day for sustained-release formulations to minimize seizure risk 4
• Gradual titration of bupropion is mandatory 4
• Two case reports exist of seizures in infants exposed to bupropion via breastfeeding, highlighting seizure concerns 2

Limited Evidence Base

There is virtually no research establishing the safety and effectiveness of combining atomoxetine with other medications, making this an off-label combination requiring careful clinical judgment. 5

• One small case series (N=4) described combining atomoxetine with stimulants (not bupropion) for ADHD, noting effectiveness but emphasizing the need for careful monitoring due to lack of research 5
• No published studies specifically examine atomoxetine-bupropion combinations 6

Alternative Approaches

Consider whether monotherapy optimization or sequential trials might be preferable to combination therapy, as both medications can be effective as single agents. 3, 7

• Atomoxetine is effective as monotherapy for ADHD, though less effective than extended-release stimulants 3
• Bupropion is less efficacious than stimulants for ADHD but may be particularly useful for co-occurring depression 6
• If treating both ADHD and depression, consider whether one agent might address both conditions before combining

Common Pitfalls to Avoid

• Do not use standard atomoxetine dosing when bupropion is present - this will result in excessive atomoxetine exposure 1
• Do not assume the combination is safe simply because both are non-stimulants - the pharmacokinetic interaction is clinically significant 1
• Do not neglect cardiovascular monitoring - both agents affect heart rate and blood pressure 3
• Do not combine without informed consent - patients should understand this is an evidence-limited combination requiring close monitoring 5