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

Non-Stimulant Medication Options for ADHD

The primary non-stimulant medications for ADHD are atomoxetine, extended-release guanfacine, and extended-release clonidine, which should be considered as second-line treatments after stimulants due to their medium effect sizes and delayed onset of action. 1

First-Line Non-Stimulant: Atomoxetine

Atomoxetine (Strattera) is the most established non-stimulant option:

• Mechanism: Selective norepinephrine reuptake inhibitor 2

• Dosing:

  • Children/adolescents: Start at 0.5 mg/kg/day, target dose 1.2 mg/kg/day 3
  • Adults: Similar weight-based approach

• Administration: Can be given once daily or split into two doses 1

• Onset of action: 6-12 weeks (significantly slower than stimulants) 1

• Key advantages:

  • FDA-approved for both children and adults 4
  • 24-hour symptom coverage 1
  • No abuse potential (not a controlled substance) 2
  • Less impact on appetite/growth than stimulants 1
  • Fewer sleep disturbances than stimulants 5

• Key adverse effects:

  • Gastrointestinal symptoms (nausea, dyspepsia, decreased appetite)
  • Somnolence, fatigue
  • Possible increase in suicidal ideation (black box warning) 5
  • Rare liver injury 5

Alpha-2 Agonists

Extended-Release Guanfacine (Intuniv)

• Dosing: Starting dose 1 mg daily, adjusted by weight (0.1 mg/kg as rule of thumb) 1, 3
• Available doses: 1,2,3, and 4 mg tablets 1
• Maximum dose: 4-6 mg daily 1, 3
• Onset of action: 2-4 weeks 1
• Administration: Once daily, preferably in the evening 1

Extended-Release Clonidine (Kapvay)

• Dosing: Starting dose 0.1 mg at bedtime, can increase to twice-daily 1
• Available doses: 0.1 and 0.2 mg tablets; also available as transdermal patch 1
• Maximum dose: 0.4 mg daily 1
• Onset of action: 2-4 weeks 1
• Administration: Typically at bedtime, can be increased to twice daily 1

Common adverse effects of alpha-2 agonists:

• Somnolence, fatigue, sedation
• Hypotension, bradycardia
• Irritability, insomnia, nightmares
• Dry mouth (clonidine)
• Cardiac conduction abnormalities (monitor) 1

Comparative Efficacy and Selection Algorithm

1. Efficacy ranking (from most to least effective):

   • Stimulants (first-line)
   • Non-stimulants (atomoxetine, guanfacine, clonidine) 1

2. When to choose non-stimulants:

   • When stimulants are ineffective or not tolerated
   • In patients with specific comorbidities:
     • Substance use disorders (due to non-abuse potential) 1
     • Tics/Tourette's syndrome 1
     • Anxiety disorders (atomoxetine may be beneficial) 1
     • Sleep disturbances (consider clonidine/guanfacine) 1

3. Choosing between non-stimulants:

   • Atomoxetine: First choice non-stimulant; better for patients needing 24-hour coverage with fewer sedative effects 1, 5
   • Guanfacine/Clonidine: Consider for patients with comorbid tics, sleep disturbances, or disruptive behavior disorders 1

Important Clinical Considerations

• Delayed onset: Unlike stimulants, non-stimulants take weeks to show full effect (atomoxetine: 6-12 weeks; alpha-2 agonists: 2-4 weeks) 1

• Monitoring requirements:

  • Blood pressure and heart rate (especially with alpha-2 agonists)
  • Growth parameters in children
  • Liver function with atomoxetine
  • Suicidal ideation with atomoxetine (especially in children/adolescents) 4

• Combination therapy: In the US, guanfacine and clonidine are approved as adjunctive therapy to stimulants, which can help manage stimulant side effects or provide additional symptom control 1

• Regional differences: Availability and approval status vary by country. In Japan, non-stimulants are often first-line, while in most countries they remain second-line options 1

• Quality of life impact: Atomoxetine and guanfacine have demonstrated improvements in functional impairment and quality of life beyond symptom control 1

Remember that non-stimulants generally have smaller effect sizes than stimulants but offer important advantages for specific patient populations and clinical scenarios where stimulants may not be appropriate or effective.