What are the non-stimulant (non-stimulant medications) treatment options for Attention Deficit Hyperactivity Disorder (ADHD)?

Non-Stimulant Medications for ADHD

Atomoxetine is the first-line non-stimulant medication for ADHD, with proven efficacy and FDA approval across all age groups, offering particular advantages for patients with comorbid substance use disorders, tics, anxiety, or sleep disturbances. 1, 2

Primary Non-Stimulant Options

Atomoxetine (First-Line Non-Stimulant)

Atomoxetine should be your initial non-stimulant choice due to its FDA approval, established efficacy with 28-30% reduction in ADHD symptom scores versus 18-20% with placebo, and non-controlled substance status. 1, 2

Dosing Strategy

• Start at 40 mg/day in adults, then titrate to target dose of 80-100 mg/day (maximum 100 mg/day or 1.4 mg/kg/day, whichever is lower). 1
• In children and adolescents up to 70 kg, initiate at approximately 0.5 mg/kg/day, then increase to target of 1.2 mg/kg/day. 2
• Critical timing consideration: Full therapeutic effects require 6-12 weeks, unlike stimulants which work immediately—counsel patients accordingly to prevent premature discontinuation. 1
• Administer once daily in the morning, or split into two equal doses (morning and evening) to reduce adverse effects, or give evening-only dosing if needed. 3

Key Advantages Over Stimulants

• Non-controlled substance status eliminates abuse potential and diversion risk—particularly indicated for patients with comorbid substance use disorders where stimulants are contraindicated. 3, 1
• Provides continuous 24-hour symptom coverage without peaks and valleys. 1
• Lower risk of appetite suppression and growth problems compared to stimulants. 3
• Does not exacerbate tics (tics did not worsen in clinical trials). 3
• May benefit patients with comorbid anxiety or autism spectrum disorder. 3

Critical Safety Monitoring

• FDA Black Box Warning: Monitor closely for suicidal ideation, especially during the first few weeks of treatment. 2
• Assess blood pressure and heart rate at baseline and with dose increases. 1
• Common adverse effects include dyspepsia, nausea, vomiting, decreased appetite, weight loss, dry mouth, insomnia, constipation, and urinary retention. 4
• Use with caution in patients with hypertension or significant cardiovascular disorders. 4

Guanfacine Extended-Release (Second-Line Non-Stimulant)

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

Mechanism and Efficacy

• Alpha-2A adrenergic receptor agonist that enhances noradrenergic neurotransmission in the prefrontal cortex, with higher specificity for alpha-2A receptors compared to clonidine (resulting in less sedation). 5
• Demonstrates medium effect sizes (approximately 0.7) compared to placebo for reducing core ADHD symptoms. 5

Dosing Strategy

• Start at 1 mg once daily, titrate by 1 mg per week based on response and tolerability. 5
• Target dose: 0.05-0.12 mg/kg/day or 1-7 mg/day (weight-based dosing at approximately 0.1 mg/kg once daily). 1, 5
• Administer in the evening due to frequent somnolence and fatigue—this minimizes daytime sedation that could interfere with school or work performance. 3, 5
• Onset of therapeutic effects requires 2-4 weeks, unlike stimulants which work immediately. 5

Critical Safety Warnings

• Never abruptly discontinue guanfacine—taper by 1 mg every 3-7 days to avoid rebound hypertension. 5
• Monitor blood pressure and heart rate at baseline and during dose adjustments. 5
• Common adverse effects include somnolence (most frequent), fatigue, headache (20.5%), dry mouth, dizziness, irritability, and abdominal pain. 5
• Warnings exist regarding hypotension/bradycardia, cardiac conduction abnormalities, and allergic reactions. 5

Specific Indications for Guanfacine

• Comorbid tics or Tourette's syndrome (guanfacine may reduce tics, though evidence remains inconclusive). 3, 5
• Sleep disturbances (evening dosing can help with sleep onset). 3
• Comorbid anxiety (lower risk of exacerbating anxiety compared to stimulants). 1
• FDA-approved as adjunctive therapy to stimulants to enhance treatment effects or reduce stimulant-related adverse effects (elevated blood pressure, heart rate, sleep disturbances). 3, 5

Clonidine Extended-Release (Alternative Alpha-2 Agonist)

• Similar mechanism to guanfacine but with less alpha-2A receptor specificity, resulting in more sedative effects. 5
• FDA-approved as adjunctive therapy to stimulants. 3
• Evening administration is generally preferable due to somnolence/fatigue. 3
• Do not combine clonidine with guanfacine—adding a second alpha-2 agonist increases sedation risk and cardiovascular effects without clear evidence of superior efficacy. 5

Bupropion (Third-Line Option)

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

• Not FDA-approved for ADHD but may be used off-label. 1
• Particularly useful when comorbid depression is present. 1
• Avoid in patients with seizure disorders or eating disorders due to increased seizure risk. 1

Viloxazine (Qelbree) (Newer FDA-Approved Option)

• FDA-approved for adults with ADHD, offering another non-stimulant alternative. 1
• Starting dose: 200 mg once daily; maximum dose: 600 mg once daily. 1

Clinical Algorithm for Non-Stimulant Selection

Step 1: Initial Assessment

• Evaluate for comorbid conditions: substance use disorders, tics, Tourette's syndrome, anxiety, sleep disturbances, autism spectrum disorder. 3, 1
• Assess cardiovascular status (blood pressure, heart rate, cardiac history). 1, 5
• Screen for suicidality at baseline. 1, 2

Step 2: First-Line Non-Stimulant Choice

• Start with atomoxetine unless specific contraindications exist (severe cardiovascular disease, narrow-angle glaucoma, pheochromocytoma). 1, 2
• Initiate at appropriate weight-based dose and titrate to target over 1-2 weeks. 1, 2
• Allow 6-12 weeks for full therapeutic assessment before declaring treatment failure. 1

Step 3: If Atomoxetine Fails or Is Not Tolerated

• Switch to guanfacine extended-release if:
  • Atomoxetine is ineffective after 12 weeks at therapeutic dose 1
  • Intolerable side effects from atomoxetine occur 1
  • Comorbid tics, anxiety, or sleep disturbances are present 3, 1, 5
• Initiate guanfacine with slow titration (1 mg weekly increases) and evening dosing. 5
• Allow 2-4 weeks for therapeutic assessment. 5

Step 4: If Both Atomoxetine and Guanfacine Fail

• Consider bupropion, particularly if comorbid depression is present. 1
• Alternatively, consider viloxazine (Qelbree) as another FDA-approved non-stimulant option. 1

Step 5: Adjunctive Therapy

• Guanfacine or clonidine can be added to stimulants (FDA-approved for adjunctive use) to enhance efficacy or reduce stimulant-related adverse effects. 3, 5
• This combination is safe and may improve overall symptom control. 5

Specific Clinical Scenarios

Comorbid Substance Use Disorder

• Atomoxetine is the clear first choice due to non-controlled status and no abuse potential—stimulants are contraindicated due to dopaminergic activity in reward pathways. 3, 1

Comorbid Tics or Tourette's Syndrome

• Consider atomoxetine or guanfacine as first-line options—both do not worsen tics, and guanfacine may reduce tic severity. 3, 5

Comorbid Anxiety

• Atomoxetine or guanfacine are preferred over stimulants, which may exacerbate anxiety symptoms. 3, 1

Sleep Disturbances

• Guanfacine or clonidine with evening dosing can help with sleep onset while providing 24-hour ADHD symptom control. 3

Comorbid Autism Spectrum Disorder

• Atomoxetine has some evidence supporting its use in this population. 3

Monitoring Parameters

Baseline Assessment

• Blood pressure and heart rate 1, 5
• Weight and height (if applicable) 1
• Suicidality screening 1, 2
• Cardiovascular history 1, 5

Follow-Up Monitoring (2-4 Weeks)

• Vital signs (blood pressure, heart rate) 1, 5
• Side effects assessment 1
• Early response evaluation 1

Therapeutic Assessment

• 6-12 weeks for atomoxetine using ADHD symptom scales, functional impairment measures, and quality of life assessments 1
• 2-4 weeks for guanfacine using similar outcome measures 1, 5

Ongoing Monitoring

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

Common Pitfalls and How to Avoid Them

• Premature discontinuation of atomoxetine: Counsel patients that full effects require 6-12 weeks, unlike stimulants which work immediately. 1
• Abrupt discontinuation of guanfacine: Always taper by 1 mg every 3-7 days to avoid rebound hypertension. 5
• Combining clonidine and guanfacine: Avoid this combination due to increased sedation and cardiovascular effects without proven benefit. 5
• Ignoring suicidality screening: FDA Black Box Warning for atomoxetine requires close monitoring, especially in the first few weeks. 2
• Inadequate cardiovascular monitoring: Both atomoxetine and guanfacine require baseline and ongoing blood pressure and heart rate assessment. 1, 5
• Expecting atomoxetine to treat comorbid depression: Despite its development as an antidepressant, evidence does not support efficacy for depression. 3

Integration with Multimodal Treatment

• Non-stimulant pharmacotherapy should always be part of a comprehensive treatment approach that includes psychoeducation, behavioral interventions, and psychosocial support. 3, 2
• Pharmacological treatment represents a sizeable component due to relatively large effect sizes, though stimulants show larger effects than non-stimulants. 3
• The decision to initiate pharmacological treatment depends on ADHD symptom severity: moderate cases "can" while severe cases "should" be offered medication. 3