What are the guidelines for using bupropion (Wellbutrin) and atomoxetine (Strattera) together in patients with major depressive disorder and Attention Deficit Hyperactivity Disorder (ADHD)?

Bupropion and Atomoxetine Combination Therapy for MDD and ADHD

Bupropion and atomoxetine can be used together for patients with comorbid major depressive disorder (MDD) and ADHD, with careful monitoring for cardiovascular effects and neuropsychiatric symptoms. This combination leverages bupropion's antidepressant properties and atomoxetine's ADHD-specific benefits.

Pharmacological Rationale

• Bupropion: Acts as a norepinephrine and dopamine reuptake inhibitor with stimulating properties 1
• Atomoxetine: Selective norepinephrine reuptake inhibitor specifically indicated for ADHD 2
• Complementary mechanisms: The combination targets both conditions through different but complementary pathways

Treatment Algorithm

First-line Approach

1. Start with bupropion monotherapy for patients with MDD and ADHD

   • Begin with 150 mg daily for 1 week, then increase to target dose (usually 300 mg daily)
   • Bupropion has demonstrated efficacy for both MDD and ADHD (though evidence for ADHD is mixed) 1, 3

2. If ADHD symptoms persist after 4-6 weeks of adequate bupropion dosing:

   • Add atomoxetine starting at 40 mg daily
   • Titrate atomoxetine to target dose (typically 80-100 mg daily) over 2-4 weeks

Alternative Approach

1. For patients with more severe ADHD symptoms:
   • Start both medications simultaneously with careful dose titration
   • Begin with lower doses of both medications (bupropion 150 mg daily, atomoxetine 25-40 mg daily)
   • Increase doses gradually while monitoring for side effects

Monitoring Requirements

Initial Phase (First 12 Weeks)

• Weekly monitoring of blood pressure and heart rate for first 4 weeks 4
• Biweekly monitoring for weeks 5-12
• Assess for neuropsychiatric symptoms at each visit:
  • Anxiety, agitation, insomnia
  • Suicidal ideation (especially in patients under 24 years) 4

Maintenance Phase

• Monthly monitoring of vital signs
• Regular assessment of treatment efficacy using standardized scales for both MDD and ADHD
• Evaluate for adverse effects at each visit

Safety Considerations

Contraindications

• Absolute contraindications:
  • Seizure disorders
  • Current use of MAOIs
  • Uncontrolled hypertension
  • Closed-angle glaucoma 4

Potential Adverse Effects

1. Cardiovascular effects:

   • Increased blood pressure and heart rate (both medications can cause this)
   • More pronounced in combination therapy 4

2. Neuropsychiatric effects:

   • Insomnia, anxiety, agitation
   • Risk of suicidal ideation (black box warning for both medications) 4, 2

3. Common side effects:

   • Decreased appetite, nausea, dry mouth, headache
   • Constipation or diarrhea 4

Special Populations

Hepatic Impairment

• Moderate to severe impairment: Reduce bupropion dose by 50% 4
• Atomoxetine: Consider lower doses and slower titration

Renal Impairment

• Moderate to severe impairment: Reduce bupropion dose by 50% 4
• End-stage renal disease: Avoid bupropion

Elderly Patients

• Start with lower doses of both medications
• More cautious titration schedule
• Enhanced monitoring for adverse effects 4

Evidence for Efficacy

While no studies have specifically examined the bupropion-atomoxetine combination for comorbid MDD and ADHD, evidence supports:

1. Bupropion for MDD: Strong evidence for efficacy comparable to SSRIs 5
2. Bupropion for ADHD: Mixed evidence with moderate efficacy 3
3. Atomoxetine for ADHD: Well-established efficacy 2
4. Atomoxetine with antidepressants: One study showed atomoxetine combined with fluoxetine was well-tolerated in patients with ADHD and comorbid depression 6

Alternative Options

If the bupropion-atomoxetine combination is not tolerated or ineffective:

1. For predominant MDD with ADHD: Consider cognitive behavioral therapy with a second-generation antidepressant 5
2. For predominant ADHD with MDD: Consider stimulant medication with an SSRI
3. For balanced presentation: Consider venlafaxine (affects both norepinephrine and serotonin) 4

Discontinuation

• Gradual tapering recommended for both medications
• Reduce bupropion to 150 mg daily for 1-2 weeks before discontinuation
• Taper atomoxetine over 1-2 weeks to minimize withdrawal effects 4

This approach provides a structured treatment plan for patients with comorbid MDD and ADHD, leveraging the complementary mechanisms of bupropion and atomoxetine while minimizing potential adverse effects through careful monitoring and dose adjustment.