What are non-stimulant medication options for Attention Deficit Hyperactivity Disorder (ADHD)?

Non-Stimulant Medication Options for ADHD

Atomoxetine, guanfacine, and clonidine are the primary FDA-approved non-stimulant medications for ADHD, with atomoxetine being the first-line non-stimulant option due to its more favorable side effect profile compared to alpha-2 adrenergic agonists. 1

First-Line Non-Stimulant Options

Atomoxetine (Strattera)

• Mechanism: Selective norepinephrine reuptake inhibitor 1
• Efficacy: Medium effect size (0.7) compared to stimulants (1.0) 1
• Dosing:
  • Children/adolescents ≤70kg: Start at 0.5 mg/kg/day, target dose 1.2 mg/kg/day
  • Children/adolescents >70kg and adults: Target dose 80 mg/day
  • Can be administered once daily or split into two doses 1
  • Evening-only dosing possible to reduce adverse effects 1
• Benefits:
  • "Around-the-clock" effects (not time-limited like stimulants)
  • Not a controlled substance
  • Lower impact on appetite/growth compared to stimulants 1
  • Particularly useful for patients with:
    • Substance use disorders
    • Tic disorders/Tourette's syndrome
    • Anxiety disorders
    • Autism spectrum disorder 1
• Side effects:
  • Decreased appetite, headache, stomach pain
  • Somnolence, nausea
  • WARNING: Increased risk of suicidal ideation in children/adolescents 2
  • Requires monitoring for suicidality, clinical worsening, and unusual behavior changes 2
• Onset of action: 6-12 weeks (much slower than stimulants) 1

Alpha-2 Adrenergic Agonists

Guanfacine (Extended-Release)

• Mechanism: Alpha-2 adrenergic receptor agonist 1
• Efficacy: Medium effect size (0.7) 1
• Dosing: Once daily, weight-based (approximately 0.1 mg/kg) 1
• Benefits:
  • "Around-the-clock" effects
  • Not a controlled substance
  • May help with comorbid:
    • Sleep disturbances
    • Tics (though evidence is inconclusive)
    • Disruptive behavior disorders 1
  • Can be used as adjunctive therapy with stimulants 1
• Side effects:
  • Somnolence/sedation (evening administration preferable)
  • Fatigue, irritability
  • Hypotension
  • Dry mouth 1
• Onset of action: 2-4 weeks 1

Clonidine (Extended-Release)

• Mechanism: Alpha-2 adrenergic receptor agonist 1
• Efficacy: Similar to guanfacine (medium effect size) 1
• Dosing: Starting dose 0.1 mg at bedtime, may increase to twice-daily dosing 1
• Benefits:
  • Similar to guanfacine
  • Available as transdermal patch 1
  • Can be used as adjunctive therapy with stimulants 1
• Side effects:
  • Similar to guanfacine but potentially more pronounced
  • Somnolence, fatigue, irritability
  • Hypotension, bradycardia
  • Dry mouth, sedation 1
• Onset of action: 2-4 weeks 1
• Disadvantage: Twice daily dosing often necessary 1

Second-Line Non-Stimulant Options (Off-Label)

Bupropion

• Mechanism: Norepinephrine and dopamine reuptake inhibitor 3
• Cautions:
  • Lowers seizure threshold 4
  • Multiple drug interactions (CYP2D6 inhibitor) 4
  • Not FDA-approved for ADHD

Tricyclic Antidepressants

• Less commonly used due to side effect profile
• Have been used historically for ADHD 3

Clinical Decision-Making Algorithm

1. Consider non-stimulants as first-line when:

   • Patient has history of substance abuse
   • Comorbid tic disorders/Tourette's syndrome
   • Comorbid anxiety disorders
   • Sleep disturbances are prominent
   • Patient/family prefers non-controlled substance 1

2. Choose between non-stimulant options:

   • Atomoxetine: First choice for most patients needing non-stimulant therapy due to better side effect profile 1
   • Guanfacine/Clonidine: Consider when sleep disturbances are prominent or as adjunctive therapy with stimulants 1

3. Monitoring requirements:

   • Atomoxetine: Suicidality, clinical worsening, pulse 1, 2
   • Guanfacine/Clonidine: Blood pressure, pulse, sedation 1

Important Caveats

• Non-stimulants generally have smaller effect sizes than stimulants (0.7 vs 1.0) 1
• Delayed onset of action compared to stimulants (weeks vs days) 1
• Atomoxetine has a black box warning for suicidal ideation in children/adolescents 2
• All ADHD medications should be part of a comprehensive treatment plan that may include behavioral therapy 1
• Medication selection should consider comorbidities, as they may influence treatment response and side effect profile 1

Remember that while stimulants remain first-line therapy for most ADHD patients due to their larger effect sizes, these non-stimulant options provide valuable alternatives for patients who cannot tolerate stimulants or have specific comorbidities that make non-stimulants preferable.