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

Drug Interactions Between Wellbutrin (Bupropion) and Strattera (Atomoxetine)

The combination of bupropion and atomoxetine can be used together with appropriate monitoring, but requires caution due to potential pharmacokinetic interactions and additive cardiovascular effects.

Pharmacokinetic Interaction Mechanism

Bupropion is a strong inhibitor of the CYP2D6 enzyme, which is the primary metabolic pathway for atomoxetine. This interaction can significantly increase atomoxetine blood levels, potentially leading to enhanced therapeutic effects but also increased risk of adverse events 1.

Key Metabolic Considerations:

• Atomoxetine is extensively metabolized by CYP2D6, and patients who are poor metabolizers or those taking CYP2D6 inhibitors (like bupropion) will have substantially higher plasma concentrations 1
• Bupropion's well-established inhibition of CYP2D6 can increase blood levels of medications metabolized through this pathway, similar to its interactions with SSRIs and tricyclic antidepressants 1
• This interaction necessitates conservative dosing of atomoxetine when combined with bupropion, starting at lower doses and titrating slowly 2

Cardiovascular Monitoring Requirements

Both medications have cardiovascular effects that may be additive when combined:

• Monitor pulse and blood pressure regularly when using either stimulant or non-stimulant ADHD medications, as both classes have cardiovascular effects 3
• Atomoxetine dosing should typically start at 40 mg daily with titration every 7-14 days to 60-80 mg/day, with maximum dosing at the lesser of 1.4 mg/kg/day or 100 mg/day 4
• Bupropion dosing ranges from 100-150 mg daily (SR formulation BID) to 150-300 mg daily (XL formulation), with a maximum of 450 mg per day 4

Seizure Risk Considerations

Bupropion carries a dose-dependent seizure risk that must be considered:

• The incidence of seizures with bupropion is less than 1 per 1,000 at usual outpatient doses and less than 1 per 100 at usual inpatient doses 5
• Keep bupropion doses within recommended limits (maximum 450 mg/day) to minimize seizure risk 4
• Avoid exceeding recommended doses when combining with other medications 5

Serotonin Syndrome Risk

While less common than with SSRIs, there is a documented case report of serotonin syndrome with bupropion combinations:

• One case report exists of serotonin syndrome occurring with the combination of bupropion and sertraline, attributed to bupropion's CYP2D6 inhibition increasing SSRI levels 1
• Although atomoxetine is not primarily serotonergic, monitor for early signs of serotonin syndrome including mental status changes, neuromuscular hyperactivity (tremors, clonus, hyperreflexia), and autonomic hyperactivity (hypertension, tachycardia) 4
• Symptoms can arise within 24-48 hours after combining medications or dose changes 4

Clinical Efficacy Evidence

The combination approach has precedent in psychiatric practice:

• Combinations of pharmacologically dissimilar antidepressants have shown benefit in treatment-refractory cases, with bupropion combinations demonstrating 70% improvement rates in partial responders 2
• Both medications are effective for ADHD in adults, with effect sizes of similar magnitude to those seen in children when robust doses are used 3
• Conservative dosing with close monitoring has been shown to be safe and often more effective than monotherapy in uncontrolled clinical series 2

Practical Management Algorithm

When combining these medications:

1. Start atomoxetine at a lower dose (consider 40 mg daily or less) if bupropion is already on board 4
2. Titrate atomoxetine more slowly than usual (every 14 days rather than 7 days) due to anticipated higher plasma levels 2
3. Monitor cardiovascular parameters (pulse and blood pressure) at baseline and with each dose adjustment 3
4. Keep bupropion doses conservative (avoid exceeding 300 mg/day when possible) to minimize seizure risk 5
5. Watch for early signs of adverse effects including agitation, tremor, insomnia, and autonomic symptoms in the first 24-48 hours after initiation or dose changes 4, 2, 1

Common Adverse Effects to Monitor

With combined therapy, expect similar adverse effect profiles to monotherapy but potentially at higher rates:

• Sexual dysfunction (41% incidence reported with bupropion combinations) 2
• Insomnia (22% incidence) 2
• Anergy (15% incidence) 2
• Tremor (11% incidence) 2
• Agitation/excitement (most common cause for discontinuation at 9.1%) 5

Critical Pitfall to Avoid

Do not misinterpret early manifestations of serotonin syndrome or adverse drug interactions as worsening of the underlying psychiatric condition, which could lead to inappropriate dose escalation and clinical deterioration 1. If new neurological or autonomic symptoms emerge after combining medications, consider drug interaction effects first before attributing symptoms to disease progression.