Can I mix Selective Serotonin Reuptake Inhibitors (SSRIs) and Wellbutrin (bupropion)?

Combining SSRIs and Wellbutrin (Bupropion)

Yes, SSRIs and Wellbutrin (bupropion) can be safely combined and this combination is often used clinically for treatment-resistant depression and to counteract SSRI-induced side effects.

Safety and Efficacy of the Combination

• Bupropion works differently than SSRIs - it inhibits norepinephrine and dopamine reuptake rather than primarily affecting serotonin 1
• The FDA drug label for bupropion acknowledges that it can be used with SSRIs, but notes that bupropion inhibits CYP2D6, which may increase blood levels of certain SSRIs 2
• This combination is well-documented in clinical practice and research:
  • Studies show 56-70% of patients respond positively to the combination 3, 4
  • The combination is generally well-tolerated even in geriatric and "medically frail" patients 3

Common Reasons for Combining These Medications

1. Enhanced antidepressant efficacy:

   • For patients with incomplete response to SSRI monotherapy
   • 70% of patients showed greater improvement with combination therapy than with either agent alone 4

2. Reduction of SSRI side effects:

   • Particularly sexual dysfunction (bupropion can counteract SSRI-induced sexual side effects) 1
   • The American College of Physicians notes that "bupropion is associated with a lower rate of sexual adverse events than fluoxetine or sertraline" 5

Important Precautions

• Dosage adjustments may be necessary:

  • Bupropion inhibits CYP2D6, potentially increasing levels of SSRIs like paroxetine, fluoxetine, and sertraline 2
  • Start with lower doses and titrate carefully

• Contraindications:

  • NEVER combine with MAOIs - bupropion with MAOIs is contraindicated due to increased risk of hypertensive reactions 2
  • At least 14 days should elapse between discontinuing an MAOI and starting bupropion 2

• Seizure risk:

  • Use caution in patients with seizure disorders or factors that lower seizure threshold 2
  • Use low initial doses of bupropion and increase gradually

• Rare risk of serotonin syndrome:

  • While uncommon with this specific combination, there have been rare case reports 6
  • Monitor for symptoms like confusion, agitation, muscle twitching, sweating, shivering, and elevated heart rate

Practical Recommendations for Combination Therapy

• Starting the combination:

  • Begin with established dose of one medication (typically the SSRI)
  • Add bupropion at a low dose (typically 150mg daily) and titrate up as needed
  • Maximum bupropion dose is typically 300-450mg daily when used in combination

• Monitoring:

  • Regular follow-up visits (monthly initially) as recommended for antidepressant therapy 5
  • Monitor for side effects, particularly during the first 1-2 weeks after initiation 5

• Common side effects to watch for:

  • Insomnia (22%)
  • Tremor (11%)
  • Anergy/fatigue (15%) 4

Bottom Line

This combination is widely used in clinical practice with good evidence for both safety and efficacy. The complementary mechanisms of action (serotonergic from SSRIs and dopaminergic/noradrenergic from bupropion) often provide better symptom control than either medication alone, while potentially reducing SSRI-associated side effects like sexual dysfunction.