Guidelines for Using Prozac (Fluoxetine) and Wellbutrin (Bupropion) Together
The combination of fluoxetine (Prozac) and bupropion (Wellbutrin) is generally well tolerated and can be effective for enhancing antidepressant response or reducing SSRI-associated sexual side effects in patients with depression. 1
Indications for Combination Therapy
- Treatment-resistant depression: When patients show partial or inadequate response to either medication alone
- Management of SSRI-induced side effects: Particularly sexual dysfunction
- Complementary mechanisms of action: Fluoxetine primarily affects serotonin, while bupropion affects dopamine and norepinephrine
Dosing Guidelines
Fluoxetine (Prozac)
- Initial dose: 10 mg every other morning 2
- Maximum dose: 20 mg every morning 2
- For OCD or severe depression, higher doses may be required but increase risk of side effects 2
- Long half-life (2-3 days for parent compound, 7-9 days for active metabolite)
Bupropion (Wellbutrin)
- Initial dose: 37.5 mg every morning 2
- Titration: Increase by 37.5 mg every 3 days 2
- Maximum dose: 150 mg twice daily 2
- Timing: Second dose should be taken before 3 PM to minimize insomnia risk 2
Administration Considerations
- Start with lower doses of both medications when using in combination
- Fluoxetine is a potent inhibitor of CYP2D6, which may increase bupropion levels
- Gradual titration is essential to minimize side effects
- Monitor closely during the first few weeks of combination therapy
Pharmacokinetic Considerations
- CYP2D6 interactions: Fluoxetine is a strong CYP2D6 inhibitor and can increase bupropion levels 2
- Phenocopying: Fluoxetine at 20 mg/day can convert approximately 43% of extensive metabolizers to poor metabolizers 2
- Dose adjustments: May be needed based on patient response and side effects
Monitoring Parameters
- Efficacy: Assess depression symptoms every 1-2 weeks initially
- Side effects: Monitor for:
- Nausea, vomiting, headache, dizziness
- Insomnia or somnolence
- Anxiety or agitation
- Sexual dysfunction
- Blood pressure changes
- Suicidal ideation: Especially during first few weeks of treatment
Potential Adverse Effects
Common side effects:
- Nausea (most common)
- Insomnia
- Headache
- Dry mouth
- Anxiety or agitation
- Sexual dysfunction (though less than with fluoxetine alone)
Serious adverse effects:
- Seizure risk (primarily with bupropion at higher doses)
- Serotonin syndrome (rare but serious)
- QT prolongation (particularly in CYP2D6 poor metabolizers) 2
Special Populations and Considerations
- Hepatic impairment: Reduce bupropion dose to 150 mg daily in moderate to severe impairment 2
- Renal impairment: Reduce bupropion dose by half in moderate to severe impairment 2
- Seizure disorders: Bupropion is contraindicated in patients with seizure disorders 2
- Pregnancy: Risks and benefits must be carefully weighed
Efficacy Assessment
- Approximately 70% of patients show greater improvement with the combination than with either agent alone 3
- If no improvement after 4-6 weeks on optimized doses, consider alternative strategies
- Assess response at 8-12 weeks; if <5% weight loss with naltrexone-bupropion, consider discontinuation 2
Common Pitfalls to Avoid
- Starting with full doses: Begin with lower doses to minimize side effects
- Rapid titration: Increase doses gradually to improve tolerability
- Evening dosing of bupropion: Can worsen insomnia; administer before 3 PM 2
- Inadequate monitoring: Close follow-up is essential during the first few weeks
- Overlooking drug interactions: Be aware of other medications that affect CYP2D6
Discontinuation
- Fluoxetine can be discontinued without tapering due to its long half-life
- Bupropion should be tapered gradually to minimize withdrawal symptoms
- If switching to opioid therapy, discontinue bupropion due to potential interactions 2
This combination has shown promise in clinical practice, with studies suggesting improved outcomes in treatment-resistant depression and reduction in SSRI-associated sexual side effects 1, 3.