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

Non-Stimulant Treatment Options for ADHD

The primary non-stimulant medications for ADHD are atomoxetine, extended-release guanfacine, extended-release clonidine, and bupropion, with atomoxetine being the first-line non-stimulant option due to its established efficacy and favorable safety profile. 1, 2

First-Line Non-Stimulant Option: Atomoxetine

Mechanism and Efficacy

• Selective norepinephrine reuptake inhibitor that acts almost exclusively on the noradrenergic pathway 3
• FDA-approved for both children and adults with ADHD 4
• Effect size of approximately 0.7 compared to 1.0 for stimulants 2
• Provides all-day coverage including evening hours with a single morning dose 2

Dosing Protocol

• Children and adolescents ≤70 kg:

  • Starting dose: 0.5 mg/kg/day
  • Target dose: 1.2 mg/kg/day after minimum 3 days
  • Maximum dose: 1.4 mg/kg/day or 100 mg (whichever is less)
  • Can be administered as single morning dose or divided doses 4

• Children >70 kg and adults:

  • Starting dose: 40 mg/day
  • Target dose: 80 mg/day after minimum 3 days
  • Maximum dose: 100 mg/day
  • Can be administered as single morning dose or divided doses 4

Monitoring

• Blood pressure and heart rate at each visit
• Liver function if concerns arise or hepatic impairment present
• Regular assessment for suicidal ideation (carries FDA black box warning for children/adolescents) 2, 4

Common Side Effects

• Children: Dyspepsia, nausea, vomiting, decreased appetite, weight loss 3
• Adults: Dry mouth, insomnia, nausea, decreased appetite, constipation 5
• Cardiovascular: Mild increases in blood pressure and heart rate 2

Alpha-2 Adrenergic Agonists

Extended-Release Guanfacine and Clonidine

• FDA-approved as both monotherapy and adjunctive therapy with stimulants 2
• Particularly useful for patients with comorbid tics or anxiety 2
• May be beneficial when sleep disturbances are present 1
• Guanfacine may reduce tics, though evidence remains inconclusive 1

Bupropion

Dosing Protocol

• Sustained-release: Start 100-150 mg daily; maintenance 100-150 mg twice daily
• Extended-release: Start 150 mg daily; maintenance 150-300 mg daily
• Maximum dose: 450 mg per day 2

Precautions

• Contraindicated in patients with seizure disorders, eating disorders
• Contraindicated during abrupt discontinuation of alcohol or sedatives
• Caution during pregnancy (possible small increased risk of cardiovascular malformations)
• Caution during breastfeeding (rare reports of seizures in breastfed infants) 2

Clinical Decision Algorithm for Non-Stimulant Selection

1. Consider atomoxetine as first-line non-stimulant when:

   • Stimulants have failed or are contraindicated
   • All-day symptom control is needed, including evenings
   • Substance use concerns exist (no abuse potential)
   • Patient has comorbid anxiety or autism spectrum disorder 1, 2

2. Consider alpha-2 agonists (guanfacine/clonidine) when:

   • Comorbid tics or Tourette's syndrome present
   • Sleep disturbances are prominent
   • Adjunctive therapy with stimulants is desired 1, 2

3. Consider bupropion when:

   • Comorbid depression is present
   • Other non-stimulants have failed 2

Special Populations and Considerations

Comorbid Conditions

• Substance use disorders: Non-stimulants preferred due to lower abuse potential 1, 2
• Tic disorders/Tourette's: Atomoxetine doesn't worsen tics; guanfacine may reduce them 1
• Anxiety: Some evidence supports atomoxetine use 1
• Oppositional defiant disorder: Atomoxetine recommended as first-line 2

Treatment Resistance

• Approximately 50% of non-responders to methylphenidate will respond to atomoxetine 6
• Consider a trial period of at least 6-8 weeks before evaluating atomoxetine efficacy 6

Important Clinical Pearls

• Atomoxetine can be discontinued abruptly without tapering 4
• Atomoxetine should be taken whole, not opened 4
• When switching from stimulants to atomoxetine, a cross-tapering approach with slow titration minimizes adverse events 6
• Combination of behavioral interventions with non-stimulant medication offers the best outcomes 2
• Screen for bipolar disorder before starting atomoxetine 4

Non-stimulant medications provide valuable alternatives for ADHD treatment, particularly when stimulants are ineffective, poorly tolerated, or contraindicated due to comorbidities or substance use concerns.