What are alternative treatment options for a patient with Attention Deficit Hyperactivity Disorder (ADHD) who meets the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria but does not want to use stimulant medications?

Non-Stimulant Treatment Options for ADHD

Start with atomoxetine as the first-line non-stimulant medication, titrating to 80-100 mg/day in adults (or 1.2-1.8 mg/kg/day in children), and expect 6-12 weeks for full therapeutic effect. 1, 2, 3

First-Line Non-Stimulant: Atomoxetine

Atomoxetine is the only FDA-approved non-stimulant medication across the entire lifespan (children, adolescents, and adults) and should be your default choice when avoiding stimulants. 1, 2

Dosing protocol:

• Adults: Start at 40 mg/day, then titrate to target dose of 80-100 mg/day (maximum 100 mg/day or 1.4 mg/kg/day, whichever is lower) 1
• Children/adolescents: Start at 0.5 mg/kg/day, titrate to 1.2-1.8 mg/kg/day based on response 3
• Can be dosed once daily in the morning or divided into morning and late afternoon doses 3

Expected efficacy:

• Achieves 28-30% reduction in ADHD symptom scores versus 18-20% with placebo 1
• Effect size approximately 0.7 compared to placebo 2
• Provides continuous 24-hour symptom coverage without peaks and valleys 1
• Critical caveat: Full therapeutic effects require 6-12 weeks, unlike stimulants which work immediately 4, 1, 2

Key advantages over stimulants:

• Non-controlled substance status eliminates abuse potential and allows easier prescription refills 1, 2
• Particularly indicated for patients with comorbid substance use disorders where stimulants pose diversion risk 4, 1, 2
• Lower risk of exacerbating anxiety symptoms compared to stimulants 1, 2
• Fewer effects on appetite and growth with long-term use 1

Critical safety monitoring:

• FDA Black Box Warning: Monitor closely for suicidal ideation, especially during the first few weeks of treatment and during dose adjustments 1, 2
• Assess blood pressure and heart rate at baseline and with dose increases 1
• Common adverse effects include somnolence, fatigue, irritability, insomnia, nightmares, initial gastrointestinal symptoms, and decreased appetite 2
• Contraindications: severe cardiovascular disease, narrow-angle glaucoma, pheochromocytoma, concurrent MAOI use 2

Second-Line Non-Stimulant: Guanfacine Extended-Release

Switch to guanfacine if atomoxetine is ineffective after 12 weeks at therapeutic dose, or if intolerable side effects occur, or if comorbid tics, anxiety, or sleep disturbances are present. 1, 5, 2

Dosing protocol:

• Weight-based dosing: approximately 0.1 mg/kg once daily 1, 5, 2
• Typical range: 1-7 mg/day 5
• Start at 1 mg once daily, titrate by 1 mg per week based on response and tolerability 5
• Administer in the evening to minimize daytime somnolence and fatigue 5

Expected efficacy:

• Effect size approximately 0.7 compared to placebo 5
• Requires 2-4 weeks before clinical benefits are observed 4, 5
• Provides "around-the-clock" symptom control with once-daily dosing 5

Specific indications for guanfacine over atomoxetine:

• Comorbid tic disorders or Tourette's syndrome 4, 2
• Comorbid anxiety disorders 1, 2
• Comorbid sleep disturbances 1
• Comorbid disruptive behavior disorders or oppositional symptoms 5

Critical safety warnings:

• Never abruptly stop guanfacine—must be tapered by 1 mg every 3-7 days to avoid rebound hypertension 5, 2
• Monitor blood pressure and heart rate at baseline and during dose adjustments 5, 2
• Common adverse effects: somnolence, fatigue, headache, dry mouth, dizziness, irritability, bradycardia, hypotension, abdominal pain 5, 2
• Warnings regarding hypotension/bradycardia, cardiac conduction abnormalities 5

Third-Line Option: Bupropion

Consider bupropion if both atomoxetine and guanfacine have failed, or if comorbid depression requires treatment. 1, 6

• Not FDA-approved for ADHD but has demonstrable efficacy in clinical studies 1, 6
• Particularly useful when comorbid depression is present 1
• Shares noradrenergic and dopaminergic components relevant to ADHD pathophysiology 6

Fourth-Line Option: Viloxazine (Qelbree)

Viloxazine is FDA-approved for adults with ADHD and offers another non-stimulant option. 1

Dosing:

• Starting dose: 200 mg once daily 1
• Maximum dose: 600 mg once daily 1

Adjunctive Therapy Considerations

Both guanfacine extended-release and clonidine extended-release are FDA-approved for adjunctive therapy with stimulants, which can increase treatment effects and/or decrease adverse effects of stimulants. 5, 2 However, since your patient does not want stimulants, this is not immediately relevant unless they reconsider in the future.

Monitoring Algorithm

Baseline assessment:

• Blood pressure and heart rate 1, 2
• Weight 1
• Suicidality assessment 1, 2

Follow-up at 2-4 weeks:

• Vital signs 1
• Side effects 1
• Early response 1

Therapeutic assessment:

• 6-12 weeks for atomoxetine 1, 2
• 2-4 weeks for guanfacine 1, 2
• Evaluate ADHD symptom scales, functional impairment, and quality of life 1

Ongoing monitoring:

• Quarterly vital signs 1
• Annual growth parameters if applicable 1
• Continuous suicidality monitoring 1

Psychosocial Interventions

Pharmacological treatment should be provided in parallel with other interventions, such as behavioral therapy, as deemed appropriate according to remaining symptoms and deficits in psychosocial functioning. 4 Behavioral modification techniques should be considered for children with ADHD and oppositional behaviors, while Cognitive Behavioral Therapy (CBT) may be a helpful adjunct for adolescents and adults with ADHD. 7

Common Pitfalls to Avoid

• Premature discontinuation of atomoxetine before 6-12 weeks: Families must understand the delayed onset of action to prevent stopping treatment too early 4, 1, 2
• Abrupt discontinuation of guanfacine: Always taper to avoid rebound hypertension 5, 2
• Inadequate suicidality monitoring with atomoxetine: This is an FDA Black Box Warning and requires vigilant monitoring 1, 2
• Daytime administration of guanfacine: Evening dosing is strongly preferred to minimize daytime sedation that could worsen functional impairment 5
• Expecting immediate results: Non-stimulants have delayed onset compared to stimulants, requiring patience and consistent dosing 4, 1, 2