Can fluoxetine (Prozac) be taken with bupropion (Wellbutrin)?

Can Fluoxetine Be Taken with Wellbutrin (Bupropion)?

Yes, fluoxetine can be safely combined with bupropion (Wellbutrin), but the fluoxetine dose may need to be reduced because bupropion inhibits the enzyme that metabolizes fluoxetine, potentially increasing fluoxetine levels in the blood. 1

Key Drug Interaction Mechanism

• Bupropion is a CYP2D6 inhibitor, meaning it blocks the enzyme responsible for breaking down fluoxetine and other SSRIs 1
• When these medications are combined, fluoxetine concentrations can increase, requiring dose adjustment of the fluoxetine to avoid excessive drug levels 1
• The FDA drug label specifically lists fluoxetine among antidepressants whose exposure increases when combined with bupropion 1

Dosing Recommendations When Combining

• Consider reducing the fluoxetine dose when initiating bupropion, particularly since fluoxetine has a narrow therapeutic index for some effects 1
• Start bupropion at low initial doses and increase gradually when combining with other antidepressants that lower seizure threshold 1
• Take the second daily dose of bupropion before 3 PM to minimize insomnia risk 2

Clinical Evidence Supporting Combination Use

• Multiple case series demonstrate safety and enhanced efficacy when combining SSRIs (including fluoxetine) with bupropion in treatment-resistant depression 3, 4
• In one series of 27 patients, 70% showed greater improvement with the combination than with either agent alone, using mean doses of 243 mg/day bupropion and 31 mg/day fluoxetine-equivalents 4
• A case series of 4 treatment-refractory patients found the bupropion-sertraline (another SSRI) combination effective without adverse effects 3
• Direct comparison studies show both medications have similar efficacy profiles when used as monotherapy, supporting their complementary mechanisms 5

Safety Profile of the Combination

• Adverse effects with combination therapy are similar to monotherapy with each agent individually 4
• Common side effects include sexual dysfunction (41%), insomnia (22%), low energy (15%), and tremor (11%) 4
• No seizures were reported in the clinical series of combined use, though this remains a theoretical concern 4
• Use extreme caution as both medications can lower seizure threshold when combined with other antidepressants 1

Important Monitoring Considerations

• Monitor blood pressure, especially at treatment initiation, as bupropion can elevate blood pressure 6, 2
• Assess for signs of serotonin syndrome, though this is rare with this combination 6
• Evaluate treatment response after 12 weeks and adjust accordingly 2
• Watch for increased side effects from elevated fluoxetine levels, particularly sexual dysfunction, GI symptoms, and activation 6, 4

Contraindications and Precautions

• Do not use if the patient is taking MAOIs or within 14 days of MAOI discontinuation 1
• Avoid in patients with seizure disorders, eating disorders (anorexia/bulimia), or abrupt alcohol/benzodiazepine discontinuation 2, 1
• Contraindicated in uncontrolled hypertension 2
• Both medications carry warnings about suicidal ideation, particularly in patients under 24 years old 6

Rationale for Combination Therapy

• The combination targets multiple neurotransmitter systems: fluoxetine affects serotonin while bupropion affects dopamine and norepinephrine 3, 4
• This synergistic mechanism may explain superior efficacy in treatment-resistant cases 3
• Bupropion can counteract SSRI-induced sexual dysfunction, a common reason for treatment discontinuation 7
• The combination is particularly useful for patients with prominent apathy, fatigue, or low energy alongside depression 2