What non-stimulant medication options are available for a patient with Attention Deficit Hyperactivity Disorder (ADHD), considering their age and medical history, including potential comorbidities such as anxiety or depression?

Non-Stimulant Medication Options for ADHD

The three FDA-approved non-stimulant medications for ADHD are atomoxetine, extended-release guanfacine, and extended-release clonidine, with atomoxetine recommended as the primary second-line option after stimulant failure or when stimulants are contraindicated. 1, 2, 3

Primary Non-Stimulant: Atomoxetine

Atomoxetine is the only FDA-approved non-stimulant specifically indicated for ADHD in both children and adults, making it the preferred non-stimulant choice. 3, 4

Key Advantages

• Provides 24-hour "around-the-clock" symptom coverage without peaks and valleys of stimulants 1, 5
• Non-controlled substance with no abuse potential, eliminating diversion concerns 3, 6
• Can be administered once daily (morning or evening) or split into two doses to minimize side effects 1, 3
• Particularly beneficial for patients with comorbid anxiety, substance use disorders, tic disorders, or Tourette's syndrome 1, 2
• Does not worsen anxiety in patients with comorbid anxiety disorders 3
• Shows fewer effects on appetite and growth compared to stimulants 1

Dosing Protocol

• Children/adolescents ≤70 kg: Start 0.5 mg/kg/day, increase after minimum 3 days to target 1.2 mg/kg/day (maximum 1.4 mg/kg/day or 100 mg, whichever is less) 3
• Children/adolescents >70 kg and adults: Start 40 mg/day, increase after minimum 3 days to target 80 mg/day, may increase to maximum 100 mg/day after 2-4 additional weeks if needed 3, 5
• Critical timing: Requires 6-12 weeks to achieve full therapeutic effect, with median response time of 3.7 weeks 1, 5

Efficacy Considerations

• Effect size approximately 0.7 compared to stimulants at 1.0 1
• Approximately 50% of methylphenidate non-responders will respond to atomoxetine 7
• Approximately 75% of methylphenidate responders will also respond to atomoxetine 7

Monitoring and Safety

• Black Box Warning: Monitor for suicidal ideation, especially in children and adolescents during first few months or dose changes 5, 3
• Monitor blood pressure and heart rate regularly 5
• Common adverse effects: decreased appetite, nausea, vomiting, headache, somnolence, abdominal pain 5, 3
• Dose adjustment required for hepatic impairment: 50% reduction for moderate (Child-Pugh B), 25% for severe (Child-Pugh C) 3
• Dose adjustment needed when co-administered with strong CYP2D6 inhibitors (paroxetine, fluoxetine, quinidine) 3

Alpha-2 Adrenergic Agonists: Guanfacine and Clonidine

Extended-release guanfacine and clonidine are FDA-approved non-stimulants with effect sizes around 0.7, particularly useful for patients with comorbid sleep disturbances or as adjunctive therapy with stimulants. 1, 2

Clinical Applications

• Approved in the US as adjunctive therapy to stimulants to enhance treatment effects or reduce stimulant side effects (sleep disturbances, cardiovascular effects) 1
• Can be used as monotherapy when atomoxetine is ineffective or not tolerated 2, 5
• Particularly beneficial for patients with comorbid tics, Tourette's syndrome, or oppositional behaviors 1
• Evening administration preferred due to somnolence/fatigue as common adverse effect 1

Onset and Monitoring

• Onset of treatment effects: 2-4 weeks (faster than atomoxetine's 6-12 weeks) 1
• Critical warning: Must be tapered rather than abruptly discontinued to avoid rebound hypertension 2
• Regular blood pressure and heart rate monitoring required 2

Comparative Adverse Effects

• More frequent and pronounced adverse effects compared to atomoxetine within the non-stimulant class 1
• Somnolence and fatigue are relatively common 1

Emerging Non-Stimulant: Viloxazine

Viloxazine, a serotonin norepinephrine modulating agent, has demonstrated favorable efficacy and tolerability in pivotal clinical trials and represents a newer non-stimulant option. 1

• Repurposed antidepressant with moderate norepinephrine transporter inhibition and serotonin modulating activity 1
• Several completed clinical trials in children showing favorable results 1
• Limited data currently available for adult ADHD treatment 2

Treatment Algorithm for Non-Stimulant Selection

First-Line Non-Stimulant Scenarios

Start with atomoxetine when: 1, 2, 3

• Stimulants failed or caused intolerable side effects
• Active substance use disorder present (stimulants contraindicated)
• Comorbid anxiety disorder
• Comorbid tic disorder or Tourette's syndrome
• Patient/family preference for non-controlled substance
• Comorbid autism spectrum disorder

Second-Line Non-Stimulant Options

Switch to extended-release guanfacine or clonidine when: 1, 2

• Atomoxetine ineffective after adequate 6-12 week trial
• Atomoxetine not tolerated
• Comorbid sleep disturbances are prominent
• Need for adjunctive therapy with stimulants

Critical Pitfalls to Avoid

• Do not evaluate atomoxetine efficacy before 6-8 weeks minimum—premature discontinuation is the most common error 5, 7
• Do not abruptly discontinue alpha-2 agonists—always taper to prevent rebound hypertension 2
• Do not assume non-response to one stimulant predicts non-response to atomoxetine—50% of stimulant non-responders will respond 7
• Do not overlook CYP2D6 interactions—dose adjustment required with strong inhibitors or in poor metabolizers 3
• Do not prescribe atomoxetine without discussing delayed onset—patient expectations must be managed regarding the 6-12 week timeline 1, 5