What are non-stimulant alternatives to Wellbutrin (bupropion) for treating Attention Deficit Hyperactivity Disorder (ADHD)?

Non-Stimulant Alternatives to Wellbutrin for ADHD

The most effective non-stimulant alternatives to Wellbutrin (bupropion) for ADHD are atomoxetine, extended-release guanfacine, and extended-release clonidine, with atomoxetine having the most favorable side effect profile among these options. 1

First-Line Non-Stimulant Options

Atomoxetine (Strattera)

• Mechanism: Selective norepinephrine reuptake inhibitor 2
• Efficacy: Effect size of approximately 0.7 (compared to 1.0 for stimulants) 1
• Dosing:
  • Children/adolescents ≤70 kg: Start at 0.5 mg/kg/day, target dose 1.2 mg/kg/day 2
  • Adults and children >70 kg: Target dose 80 mg/day 2
• Benefits:
  • FDA-approved for adults and children 2
  • "Around-the-clock" symptom control 1
  • Fewer appetite/growth effects than stimulants 1
  • Less frequent and less pronounced adverse effects compared to alpha-2 agonists 1
• Drawbacks:
  • Delayed onset of action (6-12 weeks) 1
  • Common side effects: dyspepsia, nausea, decreased appetite 3
  • Black box warning for suicidal ideation in children/adolescents 2

Extended-Release Guanfacine (Intuniv)

• Mechanism: Alpha-2A adrenergic receptor agonist 1
• Efficacy: Effect size of approximately 0.7 1
• Dosing:
  • Start at 1 mg daily 4
  • Weight-based dosing (0.1 mg/kg as rule of thumb) 1
  • Available in 1,2,3, and 4 mg tablets 1
• Benefits:
  • Can be used as monotherapy or adjunct to stimulants 1
  • May help with sleep disturbances 1
  • May benefit patients with comorbid tics or Tourette's syndrome 1
• Drawbacks:
  • Delayed onset (2-4 weeks) 1
  • Common side effects: somnolence, fatigue, headaches, hypotension 1, 4
  • Evening administration generally preferred due to sedation 1

Extended-Release Clonidine (Kapvay)

• Mechanism: Alpha-2 adrenergic receptor agonist 1
• Efficacy: Effect size of approximately 0.7 1
• Dosing:
  • Start at 0.1 mg daily at bedtime 1
  • Maximum recommended dose: 0.4 mg/day 1
  • Available in 0.1 and 0.2 mg tablets 1
• Benefits:
  • Can be used as monotherapy or adjunct to stimulants 1
  • May help with sleep disturbances 1
  • Available as transdermal patch (0.1,0.2,0.3 mg) 1
• Drawbacks:
  • Delayed onset (2-4 weeks) 1
  • Common side effects: somnolence, fatigue, dry mouth, bradycardia, syncope 1
  • More pronounced side effects than atomoxetine 1

Selection Algorithm

1. First choice: Atomoxetine

   • Best overall side effect profile among non-stimulants 1
   • Documented long-term maintenance of effects 1
   • Particularly suitable for patients with comorbid anxiety or substance use disorders 1

2. Second choice: Extended-release guanfacine

   • Consider if atomoxetine is ineffective or not tolerated
   • Particularly useful for patients with:
     • Sleep disturbances 1
     • Comorbid tics or Tourette's syndrome 1
     • Need for adjunctive therapy with stimulants 1

3. Third choice: Extended-release clonidine

   • Consider if other options fail
   • Particularly useful for patients with:
     • Significant sleep disturbances 1
     • Need for adjunctive therapy with stimulants 1

Special Considerations

Comorbidities

• Hypertension: Alpha-2 agonists (guanfacine, clonidine) may be beneficial as they can lower blood pressure 4
• Substance use disorders: Non-stimulants (particularly atomoxetine) preferred over stimulants 1
• Tics/Tourette's: Atomoxetine doesn't worsen tics; guanfacine may potentially reduce tics 1
• Anxiety: Some evidence supports atomoxetine for ADHD with comorbid anxiety 1

Monitoring

• Atomoxetine: Monitor for suicidal ideation, liver function, cardiovascular effects 2
• Guanfacine/Clonidine: Monitor blood pressure, heart rate; watch for hypotension/bradycardia 1, 4
• All medications: Regular assessment of symptom control and side effects

Common Pitfalls to Avoid

• Expecting immediate results (non-stimulants have delayed onset of action) 1
• Discontinuing medication abruptly (particularly alpha-2 agonists) 1
• Overlooking the need for "around-the-clock" coverage versus peak/trough effects 1
• Failing to consider comorbidities when selecting treatment 1
• Inadequate dose titration (underdosing is common) 1

While bupropion has been used off-label for ADHD, evidence for its efficacy is limited compared to FDA-approved non-stimulant options 5. The evidence-based alternatives outlined above provide more reliable and well-studied options for patients who cannot take or do not respond to Wellbutrin or stimulant medications.