What non-stimulant medication options are available for treating Attention Deficit Hyperactivity Disorder (ADHD) in adults?

Non-Stimulant Medications for Adult ADHD

Start with atomoxetine as your first-line non-stimulant medication for adults with ADHD, beginning at 40 mg/day and titrating to a target dose of 80-100 mg/day over several weeks. 1, 2

Primary Recommendation: Atomoxetine

Atomoxetine is the only FDA-approved non-stimulant specifically studied and approved for adult ADHD based on controlled trials in adult populations. 2, 3, 4

Evidence of Efficacy

• In two large 10-week placebo-controlled trials in adults, atomoxetine (60-120 mg/day) reduced ADHD symptom scores by 28-30% versus 18-20% with placebo 1, 3, 4
• The medication provides continuous 24-hour symptom coverage without the peaks and valleys seen with stimulants 1, 5
• Full therapeutic effects require 6-12 weeks, unlike stimulants which work immediately 6, 1, 5

Dosing Protocol

• Start at 40 mg once daily in the morning 1, 2
• Titrate to target dose of 80-100 mg/day after 3-7 days 1, 2
• Maximum dose is 100 mg/day (or 1.4 mg/kg/day, whichever is lower) 1, 2
• Can split into two divided doses (morning and late afternoon/evening) if side effects occur 6, 5, 2

Key Advantages

• Non-controlled substance status eliminates abuse potential and allows easier prescription refills - particularly critical for patients with comorbid substance use disorders where stimulants pose diversion risk 1, 5, 3, 4
• Lower risk of exacerbating anxiety symptoms compared to stimulants 1
• Fewer effects on appetite and growth with long-term use 6, 5
• Does not worsen tics and may be preferred for patients with tic disorders or Tourette's syndrome 6, 5

Critical Safety Monitoring

• FDA Black Box Warning: Monitor closely for suicidal ideation, especially during the first few weeks of treatment 1, 2
• Assess blood pressure and heart rate at baseline and with dose increases 1, 3, 4
• Common adverse effects include dry mouth, insomnia, nausea, decreased appetite, constipation, dizziness, sweating, dysuria, sexual problems, and palpitations 3, 4
• Withdrawal rates due to adverse events range from 7.8-9.3% versus 2.4-4.3% with placebo 3, 4

Second-Line Option: 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

Dosing and Administration

• Weight-based dosing at approximately 0.1 mg/kg once daily 1
• Available in 1,2,3, and 4 mg tablets 1
• Administer in the evening due to sedation risk 6, 1

Specific Indications

• Particularly useful for patients with comorbid anxiety, tics, Tourette's syndrome, or sleep disturbances 6, 1
• May reduce tics, though evidence regarding beneficial effects on tics comorbid to ADHD remains inconclusive 6
• In the USA, approved as adjunctive therapy to stimulants to reduce stimulant-related side effects (sleep disturbances, elevated blood pressure and heart rate) 6

Common Adverse Effects

• Somnolence and fatigue are relatively frequent 6, 1
• Irritability, nightmares 1
• Cardiovascular effects require monitoring 1

Third-Line Option: Bupropion

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

Important Caveats

• Bupropion is NOT FDA-approved for ADHD 1, 7
• Evidence from older studies suggests potential benefit, but it is considered a second-line agent at best for ADHD 6
• Primarily useful when comorbid depression is present 6, 1
• Antidepressant activity in adults is well-established, but utility as an ADHD treatment is limited 6

Emerging Option: Viloxazine

• Viloxazine (Qelbree) is FDA-approved for adults with ADHD 1
• Starting dose of 200 mg once daily with maximum dose of 600 mg once daily 1
• Represents another non-stimulant option when atomoxetine or guanfacine are not suitable 1, 7

Treatment Algorithm

Step 1: Initial Selection

• Start with atomoxetine unless specific contraindications exist (severe cardiovascular disease, narrow-angle glaucoma) 1
• Particularly indicated for patients with substance use disorders, anxiety, or tic disorders 6, 1, 5

Step 2: Baseline Monitoring

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

Step 3: Early Follow-Up (2-4 weeks)

• Assess vital signs, side effects, and early response 1
• Critical period for monitoring suicidal ideation 1, 2

Step 4: Therapeutic Assessment (6-12 weeks for atomoxetine)

• Use ADHD symptom scales to assess response 1, 2
• Evaluate functional impairment and quality of life 1, 5
• If inadequate response after 12 weeks at therapeutic dose, switch to guanfacine 1

Step 5: Alternative if Atomoxetine Fails

• Switch to guanfacine extended-release if atomoxetine ineffective or poorly tolerated 1
• Reassess at 2-4 weeks (guanfacine has faster onset than atomoxetine) 1

Step 6: Third-Line Consideration

• Consider bupropion or viloxazine if both atomoxetine and guanfacine have failed 1, 7
• Prioritize bupropion if comorbid depression is present 6, 1

Step 7: Ongoing Monitoring

• Quarterly vital signs 1
• Continuous suicidality monitoring 1, 2
• Annual growth parameters if applicable 1

Common Pitfalls to Avoid

• Do not discontinue atomoxetine prematurely - full effects take 6-12 weeks, unlike stimulants which work immediately 6, 1, 5
• Do not overlook the FDA Black Box Warning - suicidal ideation risk is highest in the first few weeks of treatment and requires close monitoring 1, 2
• Do not use bupropion as first-line - it is not FDA-approved for ADHD and should only be considered after atomoxetine and guanfacine have failed, or when comorbid depression is present 6, 1
• Do not prescribe stimulants to patients with active substance use disorders - atomoxetine's non-controlled status and lack of abuse potential make it the clear first choice in this population 1, 5, 3, 4