Can bupropion be added to fluoxetine (Prozac)?

Can Bupropion Be Added to Fluoxetine (Prozac)?

Yes, bupropion can be safely added to fluoxetine (Prozac), and this combination is supported by both FDA labeling and clinical evidence for treating depression, particularly in cases of incomplete response or antidepressant-associated sexual dysfunction.

Pharmacological Compatibility

The combination is pharmacologically feasible with important considerations:

• Bupropion inhibits CYP2D6, which metabolizes fluoxetine, potentially increasing fluoxetine concentrations 1.
• Dose adjustment of fluoxetine may be necessary when combined with bupropion, as bupropion can increase exposures of CYP2D6 substrates like fluoxetine 1.
• The FDA label explicitly lists fluoxetine among drugs whose concentrations can be increased by bupropion's CYP2D6 inhibition 1.

Clinical Evidence for Efficacy

Treatment-Resistant Depression

Combination therapy from treatment initiation doubles remission rates compared to monotherapy:

• A randomized double-blind trial showed 52% remission rate with mirtazapine plus fluoxetine versus 25% with fluoxetine alone at 6 weeks 2.
• The combination of mirtazapine plus bupropion achieved 46% remission, significantly better than fluoxetine monotherapy 2.
• Open-label studies demonstrate that approximately 60% of fluoxetine-resistant patients respond when bupropion is added or switched, with 30-35% achieving full remission 3, 4.

Sexual Dysfunction

• Controlled and open-label studies support bupropion's effectiveness in reversing SSRI-associated sexual dysfunction when added to ongoing SSRI therapy 3.

Safety Considerations

Seizure Risk

Exercise caution as both medications lower seizure threshold:

• Bupropion carries a 0.1% seizure risk at therapeutic doses 5.
• Use low initial doses and titrate gradually when combining with other drugs that lower seizure threshold 1.
• Avoid in patients with seizure disorders, brain metastases, or elevated seizure risk 5.

Neuropsychiatric Effects

• Bupropion has a black box warning for suicidal behavior/ideation in patients younger than 24 years with depression 5.
• However, serious neuropsychiatric adverse events are rarely associated with bupropion, including in patients with mental illness 5.

Cardiovascular Monitoring

• Monitor blood pressure and heart rate, as bupropion can cause elevations 5.
• The combination is generally well-tolerated with side effects including constipation, nausea, headache, dry mouth, and insomnia 5.

Practical Implementation

Start with standard bupropion dosing (150 mg daily) and titrate to 300 mg daily as tolerated:

• The combination is generally well-tolerated and can boost antidepressant response 3.
• Consider dose reduction of fluoxetine if side effects emerge, given bupropion's CYP2D6 inhibition 1.
• Avoid combining with MAOIs (14-day washout required) and use caution with other dopaminergic drugs 1.

Special Populations

Prioritize this combination for patients with:

• Depression refractory to fluoxetine monotherapy 3, 4
• SSRI-associated sexual dysfunction requiring treatment 3
• Comorbid need for smoking cessation 5
• History of depression benefiting from dopaminergic augmentation 5

Contraindications include:

• Uncontrolled hypertension 5
• Active seizure disorder or elevated seizure risk 5, 1
• Concurrent opioid therapy (if using naltrexone-bupropion formulation) 5
• Pregnancy or active attempts to conceive 5