What non-stimulant medications are available for treating Attention Deficit Hyperactivity Disorder (ADHD) in patients?

Non-Stimulant Medications for ADHD

Atomoxetine is the first-line non-stimulant medication for ADHD across all age groups, starting at 40 mg/day and titrating to 80-100 mg/day, with full therapeutic effects requiring 6-12 weeks. 1, 2, 3

FDA-Approved Non-Stimulant Options

Three medications have FDA approval for ADHD treatment as non-stimulants:

• Atomoxetine - The only non-stimulant approved across the entire lifespan (children ≥6 years, adolescents, and adults), making it the preferred first-line non-stimulant choice 2, 3
• Guanfacine extended-release - Approved for children and adolescents ages 6-17 years 2
• Clonidine extended-release - Approved for children and adolescents ages 6-17 years 2
• Viloxazine extended-release - Recently approved for patients ≥6 years and adults 4, 5

Atomoxetine: First-Line Non-Stimulant

Dosing Protocol

• Start at 40 mg/day in adults, then titrate to target dose of 80-100 mg/day 1, 3
• Maximum dose is the lesser of 1.4 mg/kg/day or 100 mg/day 1, 3
• Can be administered once daily or split into two doses to reduce adverse effects 1
• Full therapeutic effect requires 6-12 weeks of treatment 1, 2

Efficacy

• Achieves 28-30% reduction in ADHD symptom scores versus 18-20% with placebo 1
• Effect size of approximately 0.7 compared to placebo 1, 2
• Provides continuous 24-hour symptom coverage without peaks and valleys 1

Clinical Advantages

• Non-controlled substance status eliminates abuse potential and diversion risk 2
• Lower risk of exacerbating anxiety symptoms compared to stimulants 1, 2
• Particularly beneficial for patients with comorbid substance use disorders 1, 2
• Does not worsen tics in patients with comorbid tic disorders or Tourette's syndrome 1, 2
• Less impact on appetite and growth compared to stimulants 1

Critical Safety Monitoring

• FDA Black Box Warning: Close monitoring for suicidal ideation is mandatory, especially during the first few weeks of treatment and during dose adjustments 1, 2, 3
• Baseline assessment must include blood pressure, heart rate, weight, and comprehensive suicidality assessment 1, 2
• Follow-up at 2-4 weeks to monitor vital signs, side effects, and early response 1, 2
• Therapeutic assessment at 6-12 weeks evaluating ADHD symptom scales, functional impairment, and quality of life 1, 2

Common Adverse Effects

• Somnolence, fatigue, irritability, insomnia, nightmares 2
• Initial gastrointestinal symptoms and decreased appetite 2

Contraindications

• Severe cardiovascular disease 2
• Narrow-angle glaucoma 2
• Pheochromocytoma 2
• Concurrent MAOI use 2

Guanfacine Extended-Release: Second-Line Non-Stimulant

Dosing Protocol

• Approximately 0.1 mg/kg once daily 1, 2
• Typical range of 1-7 mg/day 1
• Requires 2-4 weeks before clinical benefits are observed 1

Efficacy

• Effect size of approximately 0.7 compared to placebo 1, 2

Specific Indications

• Particularly indicated for patients with comorbid tic disorders, anxiety disorders, or sleep disturbances due to sedating properties 1, 2
• FDA-approved specifically as adjunctive therapy to stimulants to increase treatment effects and/or decrease stimulant adverse effects, particularly sleep disturbances and cardiovascular effects 1, 2

Critical Safety Warning

• Must be tapered by 1 mg every 3-7 days upon discontinuation to avoid rebound hypertension 1, 2
• Abrupt discontinuation is contraindicated 1

Common Adverse Effects

• Somnolence/sedation (frequent) - evening administration is preferable 1, 2
• Dry mouth, dizziness, irritability, headache 2
• Bradycardia, hypotension, abdominal pain 2

Viloxazine Extended-Release: Newer Option

Dosing Protocol

• Pediatric patients 6-11 years: Start at 100 mg once daily, titrate in 100 mg increments weekly to maximum 400 mg/day 4
• Pediatric patients 12-17 years: Start at 200 mg once daily, titrate by 200 mg after 1 week to maximum 400 mg/day 4
• Adults: Start at 200 mg once daily, titrate in 200 mg increments weekly to maximum 600 mg/day 4

Safety Monitoring

• FDA Warning: Higher rates of suicidal thoughts and behavior reported in clinical studies 4
• Close monitoring required for clinical worsening and emergence of suicidal thoughts and behaviors 4

Renal Impairment Adjustments

• Severe renal impairment (eGFR <30 mL/min/1.73m²): Start at 100 mg once daily, titrate in 50-100 mg increments to maximum 200 mg/day 4
• No adjustment needed for mild to moderate renal impairment 4

Clinical Algorithm for Non-Stimulant Selection

Step 1: First-Line Choice

• Start with atomoxetine unless specific contraindications exist 2
• Atomoxetine is the only non-stimulant approved across the entire lifespan 2

Step 2: Second-Line Alternatives

• Consider guanfacine extended-release if:

  • Atomoxetine is ineffective after adequate trial (6-12 weeks at target dose) 1, 2
  • Atomoxetine is intolerable 2
  • Comorbid tics, anxiety, or sleep disturbances are present 1, 2

• Consider viloxazine extended-release as an alternative newer option 4, 5

Step 3: Adjunctive Therapy

• Only guanfacine extended-release and clonidine extended-release have FDA approval for adjunctive use with stimulants 2
• This combination can increase treatment effects and/or decrease adverse effects of stimulants 1, 2

Monitoring Parameters

Baseline Assessment

• Blood pressure and heart rate 1, 2, 4
• Weight 1, 2
• Comprehensive suicidality assessment 1, 2, 4
• Personal and family cardiac history 1
• Screen for personal or family history of suicide, bipolar disorder, and depression 4

Follow-Up Schedule

• 2-4 weeks: Assess vital signs, side effects, and early response 1, 2
• 6-12 weeks for atomoxetine: Therapeutic assessment of ADHD symptom scales, functional impairment, and quality of life 1, 2
• 2-4 weeks for guanfacine: Therapeutic assessment 1, 2
• Quarterly: Vital signs monitoring 1
• Annually: Growth parameters if applicable 1
• Continuous: Suicidality monitoring 1, 2

Special Population Considerations

Preschool-Aged Children

• No non-stimulant medication has received sufficient rigorous study in children 4-5 years of age to be recommended 2

Adolescents with Substance Use

• Before beginning medication treatment of adolescents with newly diagnosed ADHD, assess for symptoms of substance use 2
• Refer to a subspecialist for consultative support if active substance use is identified 2
• Non-stimulants are preferred due to non-controlled substance status 2

Patients with Bipolar Disorder

• Bipolar symptoms must be adequately controlled on a mood stabilizer regimen before initiating any ADHD treatment 6
• Atomoxetine is the recommended first-line non-stimulant when mood stabilization is achieved 6
• Continue regular monitoring of bipolar symptoms throughout ADHD treatment 6

Common Pitfalls to Avoid

• Do not expect immediate results with atomoxetine - Full therapeutic effects require 6-12 weeks, unlike stimulants which work within hours 1, 2
• Do not abruptly discontinue guanfacine or clonidine - Must taper to avoid rebound hypertension 1, 2
• Do not overlook suicidality monitoring - FDA Black Box Warning for atomoxetine and viloxazine requires vigilant monitoring, especially in first few weeks 1, 2, 4, 3
• Do not use non-stimulants as first-line in general ADHD treatment - Stimulants remain first-line therapy; non-stimulants are second-line except in specific circumstances (substance use disorder, tics, anxiety, patient preference) 7, 2

Comprehensive Treatment Approach

• Non-stimulant medications should be part of a total treatment program that may include psychological, educational, and social interventions 3
• Adjunctive behavioral therapy, cognitive behavioral therapy, or other interventions should be considered based on remaining symptoms and deficits in psychosocial functioning 1
• Periodically reevaluate the long-term use of medication and adjust dosage as needed 4