Is it safe to take Prozac (fluoxetine) and Wellbutrin (bupropion) together?

Combining Prozac (Fluoxetine) and Wellbutrin (Bupropion)

Yes, combining Prozac (fluoxetine) and Wellbutrin (bupropion) is safe and clinically effective for treating depression, particularly when monotherapy has failed to achieve remission or when SSRI-associated sexual side effects need to be addressed. 1, 2

Evidence for Combination Therapy

The combination of an SSRI like fluoxetine with bupropion is well-established in clinical practice:

• Combination therapy from treatment initiation doubles remission rates compared to fluoxetine monotherapy, with remission rates of 25% for fluoxetine alone versus 46% for mirtazapine plus bupropion combinations in a randomized controlled trial. 3

• The combination is generally well-tolerated and as safe as fluoxetine monotherapy, with controlled and open-label studies supporting its effectiveness for both enhancing antidepressant response and reversing SSRI-associated sexual dysfunction. 2

• Clinical improvement occurs in approximately 70% of patients who were partial responders to monotherapy, with conservative dosing and close monitoring showing the combination to be safe and more effective than single-agent treatment. 4

Common Side Effects to Monitor

When combining these medications, expect the following adverse effects:

• Gastrointestinal symptoms are most common, particularly nausea (the most frequent reason for discontinuation), vomiting, diarrhea, and constipation. 1

• Neurological symptoms occur regularly, including headache, dizziness, tremor, and insomnia. 1

• Other frequent effects include dry mouth, fatigue, sweating, and agitation. 1

• Sexual dysfunction may still occur in approximately 41% of patients on combination therapy, though bupropion can reverse SSRI-associated sexual side effects in many cases. 1, 4

Critical Safety Concerns

Serotonin Syndrome Risk

• Monitor for serotonin syndrome when combining bupropion with SSRIs, watching for mental status changes, neuromuscular hyperactivity (tremor, rigidity, myoclonus), autonomic hyperactivity (diaphoresis, tachycardia, hyperthermia), and advanced symptoms like fever, seizures, and unconsciousness. 1

Seizure Risk

• Bupropion carries a dose-dependent seizure risk of approximately 0.1%, particularly at higher doses. 5

• Avoid this combination in patients with seizure disorders, eating disorders, abrupt alcohol/benzodiazepine withdrawal, or conditions that lower seizure threshold. 1

• Use conservative dosing: typical bupropion doses in combination therapy range from 150-330 mg/day, well below the maximum to minimize seizure risk. 4

QT Prolongation with Fluoxetine

• Fluoxetine (Prozac) can prolong QT interval, though this is less of a concern than with citalopram or escitalopram. 1

• Consider baseline and follow-up ECGs in patients with cardiac risk factors, electrolyte abnormalities, or concurrent QT-prolonging medications.

Practical Dosing Approach

• Start with established monotherapy first (either fluoxetine 20 mg/day or bupropion 150-300 mg/day), then add the second agent if response is inadequate after 4-6 weeks. 2, 4

• When adding bupropion to fluoxetine: Begin with bupropion SR 150 mg daily, increasing to 150 mg twice daily or 300 mg once daily (XL formulation) as tolerated. 4

• When adding fluoxetine to bupropion: Start with fluoxetine 20 mg daily; doses typically range from 20-40 mg in combination therapy. 4

• Maximum doses in combination should be conservative: bupropion up to 450 mg/day and fluoxetine up to 40 mg/day, though lower doses (bupropion 243 mg, fluoxetine 31 mg fluoxetine-equivalents) have proven effective. 4

Drug Interaction Considerations

• Fluoxetine is a potent CYP2D6 inhibitor, which has minimal interaction with bupropion metabolism but may affect other concurrent medications. 1

• Bupropion is metabolized by CYP2B6 and has minimal interaction with fluoxetine's metabolic pathways, making this a relatively safe combination from a pharmacokinetic standpoint. 2

Discontinuation Planning

• Taper gradually when discontinuing either agent to avoid discontinuation syndrome, particularly with fluoxetine which can cause dizziness, fatigue, myalgias, nausea, anxiety, irritability, and sensory disturbances. 1

• In patients who achieve remission on combination therapy, discontinuing one agent produces relapse in approximately 40% of cases, suggesting both medications contribute to the therapeutic effect. 3

Clinical Advantages

• Bupropion can reverse SSRI-associated sexual dysfunction, providing dual benefit of enhanced antidepressant effect and improved tolerability. 1, 2

• The combination targets multiple neurotransmitter systems (serotonin via fluoxetine, dopamine and norepinephrine via bupropion), which may explain superior efficacy in treatment-resistant cases. 2