What are the recommended non-stimulant (Non-Stimulant) medication options for adults with Attention Deficit Hyperactivity Disorder (ADHD)?

Non-Stimulant ADHD Medications for Adults

Atomoxetine is the primary non-stimulant medication recommended for adults with ADHD, with proven efficacy in multiple controlled trials and FDA approval specifically for adult use. 1, 2, 3

First-Line Non-Stimulant: Atomoxetine

Atomoxetine should be initiated at 40 mg/day for adults, then titrated to a target dose of 80-100 mg/day, with a maximum of 100 mg/day (or 1.4 mg/kg/day, whichever is lower). 1, 4

Efficacy Profile

• Atomoxetine demonstrates 28-30% reduction in ADHD symptom scores versus 18-20% with placebo in controlled adult trials 5, 3
• Full therapeutic effects require 6-12 weeks, unlike stimulants which work within hours 6, 4
• Provides continuous 24-hour symptom coverage without peaks and valleys 6, 4
• Can be administered once daily (morning or evening) or split into two divided doses to minimize side effects 1, 3

Key Advantages Over Stimulants

• Non-controlled substance status eliminates abuse potential and allows easier prescription refills 5, 3
• Particularly indicated for patients with comorbid substance use disorders where stimulants pose diversion risk 6, 7
• Lower risk of exacerbating anxiety symptoms compared to stimulants 6
• Fewer effects on appetite and growth with long-term use 6

Critical Safety Monitoring

• FDA Black Box Warning: Monitor closely for suicidal ideation, especially during first few weeks of treatment 4, 1
• Assess blood pressure and heart rate at baseline and with dose increases 1
• Common adverse effects include dry mouth, insomnia, nausea, decreased appetite, constipation, and sexual dysfunction (2% incidence) 8, 5, 3
• Discontinuation rates due to adverse events: 7-9% versus 2-4% with placebo 5, 3

Dosing Adjustments

• Severe renal impairment (eGFR <30): Start at lower doses and titrate more slowly 1
• CYP2D6 poor metabolizers may require dose reduction 4

Second-Line Non-Stimulant: Extended-Release Guanfacine

Guanfacine extended-release should be considered when atomoxetine is ineffective or poorly tolerated, particularly in patients with comorbid anxiety, tics, or sleep disturbances. 6, 7

Dosing and Administration

• Weight-based dosing: approximately 0.1 mg/kg once daily 6
• Available in 1,2,3, and 4 mg tablets 6
• Evening administration preferred due to sedation risk 6
• Therapeutic effects emerge within 2-4 weeks 6

Specific Indications

• Comorbid tic disorders or Tourette's syndrome 6
• Comorbid anxiety or PTSD symptoms 7
• Sleep disturbances (can be used adjunctively with stimulants) 6, 4
• Patients requiring non-dopaminergic treatment 6

Safety Profile

• Common adverse effects: somnolence, fatigue, irritability, insomnia, nightmares 6
• Monitor for hypotension, bradycardia, and syncope 6
• Critical: Do not abruptly discontinue—taper to avoid rebound hypertension 6

Third-Line Option: Bupropion

Bupropion may be considered as a third-line agent, particularly when comorbid depression is present, though it is not FDA-approved for ADHD. 6, 7

Clinical Context

• Anecdotal evidence supports efficacy in adult ADHD 6
• Dual benefit for ADHD and depressive symptoms 7
• Second-line agent at best for ADHD monotherapy 6

Alternative Non-Stimulant: Viloxazine

Viloxazine (Qelbree) is FDA-approved for adults with ADHD, offering another non-stimulant option. 9

Dosing for Adults

• Starting dose: 200 mg once daily 9
• Titrate in 200 mg weekly increments 9
• Maximum dose: 600 mg once daily 9
• Can be taken with or without food; capsules may be opened and sprinkled on food 9

Safety Considerations

• FDA Black Box Warning: Higher rates of suicidal thoughts and behaviors versus placebo 9
• Monitor heart rate and blood pressure before initiation, after dose increases, and periodically 9
• Screen for personal/family history of suicide, bipolar disorder, and depression before starting 9

Algorithm for Non-Stimulant Selection

1. Start with atomoxetine unless specific contraindications exist (severe cardiovascular disease, narrow-angle glaucoma) 1, 2

2. Switch to guanfacine if:

   • Atomoxetine ineffective after 12 weeks at therapeutic dose 6, 4
   • Intolerable side effects from atomoxetine 6
   • Comorbid tics, anxiety, or sleep disturbances present 6, 7

3. Consider bupropion if:

   • Both atomoxetine and guanfacine have failed 6, 7
   • Comorbid depression requires treatment 7

4. Reserve viloxazine for:

   • Patients who have failed or cannot tolerate atomoxetine and guanfacine 9

Critical Clinical Pitfalls to Avoid

• Do not expect rapid response with non-stimulants—counsel patients about 6-12 week timeline for atomoxetine and 2-4 weeks for alpha-2 agonists 6, 4
• Do not use stimulants as first-line in active substance use disorders—atomoxetine or guanfacine are safer choices 6, 7
• Do not abruptly discontinue guanfacine or clonidine—risk of rebound hypertension requires tapering 6
• Do not overlook suicidality screening—both atomoxetine and viloxazine carry FDA black box warnings 4, 9
• Do not combine multiple non-stimulants without clear rationale—alpha-2 agonists can be added to atomoxetine for specific symptoms like sleep disturbances 6, 4

Monitoring Parameters

• Baseline: Blood pressure, heart rate, weight, suicidality assessment 4, 1, 9
• Follow-up (2-4 weeks): Vital signs, side effects, early response 4
• Therapeutic assessment (6-12 weeks for atomoxetine, 2-4 weeks for guanfacine): ADHD symptom scales, functional impairment, quality of life 6, 4
• Ongoing: Quarterly vital signs, annual growth parameters if applicable, continuous suicidality monitoring 4, 1