Is Wellbutrin (bupropion) safe to use with fluoxetine?

Safety of Combining Wellbutrin (Bupropion) with Fluoxetine

Bupropion and fluoxetine can be used together with caution, but require monitoring for potential drug interactions as bupropion inhibits CYP2D6, which metabolizes fluoxetine.

Drug Interaction Mechanism

• Bupropion and its metabolites are CYP2D6 inhibitors that can increase the exposure of drugs metabolized by this enzyme, including fluoxetine 1
• When used concomitantly with CYP2D6 substrates like fluoxetine, dosage adjustments may be necessary, particularly for drugs with a narrow therapeutic index 1

Safety Considerations

• The combination is not explicitly contraindicated in guidelines or drug labeling 2, 1
• Bupropion is contraindicated with MAO inhibitors due to increased risk of hypertensive reactions, but fluoxetine is not an MAO inhibitor 1
• Both medications individually carry black box warnings for suicidality risk, particularly in younger patients 2

Potential Benefits of Combination

• The combination of bupropion with SSRIs like fluoxetine has been used clinically to:
  • Enhance antidepressant response in partial responders to monotherapy 3, 4
  • Counteract sexual dysfunction side effects caused by SSRIs 4
  • Provide complementary mechanisms of action (bupropion affects dopamine/norepinephrine while fluoxetine affects serotonin) 4

Potential Risks and Adverse Effects

• Increased risk of seizures, as bupropion lowers seizure threshold 1
• Possible neuropsychiatric effects including agitation, insomnia, and anxiety 2, 1
• Potential for serotonin syndrome, though this is more common with MAOIs than with bupropion 1
• Combined side effect profiles may include:
  • Sexual dysfunction (though bupropion may actually help counteract SSRI-induced sexual dysfunction) 2, 4
  • Insomnia and activation 2, 3
  • Gastrointestinal effects 2, 1

Clinical Evidence for Combination Use

• In an uncontrolled clinical series, 70% of patients showed greater symptomatic improvement with combined SRI and bupropion therapy compared to either agent alone 3
• Common side effects in combined therapy included sexual dysfunction (41%), insomnia (22%), anergy (15%), and tremor (11%), but no seizures were reported 3
• A double-blind study showed that antidepressant combinations from treatment initiation (including mirtazapine plus bupropion) were as well tolerated as fluoxetine monotherapy and more clinically effective 5

Monitoring Recommendations

• Start with conservative dosing and increase gradually 3
• Monitor for neuropsychiatric symptoms, particularly agitation, irritability, or unusual changes in behavior 2
• Assess therapeutic response and adverse effects regularly, beginning within 1-2 weeks of initiation 2
• Be vigilant for signs of increased suicidality, especially during the first 1-2 months of treatment 2

Practical Approach

• Consider starting with lower doses of both medications when using in combination 3
• Bupropion is typically dosed at 150-300 mg daily when used as an antidepressant 2
• Fluoxetine is typically started at 10-20 mg daily 2
• If one medication is already established, add the second medication at a lower dose and titrate gradually 3, 4

Special Considerations

• Contraindicated in patients with seizure disorders or conditions that lower seizure threshold 2, 1
• Use with caution in patients with a history of bipolar disorder, as both medications can potentially trigger manic episodes 1
• The combination may be particularly useful for patients with depression who experience sexual side effects from fluoxetine alone 4