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

Non-Stimulant Medications for ADHD

The primary non-stimulant medications for ADHD are atomoxetine (first-line), guanfacine extended-release (second-line), clonidine extended-release (second-line), and bupropion (third-line/off-label). 1, 2

First-Line Non-Stimulant: Atomoxetine (Strattera)

Atomoxetine is the only FDA-approved non-stimulant specifically indicated for ADHD across the lifespan and should be the initial non-stimulant choice. 2, 3, 4

Dosing Strategy

• Starting dose: 40 mg/day orally for adults; 0.5 mg/kg/day for children/adolescents up to 70 kg 2, 5
• Target dose: 80-100 mg/day for adults; 1.2 mg/kg/day for children (maximum 1.4 mg/kg/day or 100 mg/day, whichever is lower) 1, 2, 5
• Titration schedule: Adjust every 7-14 days 1, 5
• Administration timing: Can be given once daily (morning or evening) or split into two equal doses to minimize side effects 1, 5

Key Clinical Advantages

• Provides continuous 24-hour symptom coverage without the peaks and valleys of stimulants 1, 2, 5
• Non-controlled substance status eliminates abuse potential and simplifies prescribing, particularly critical for patients with substance use disorders 1, 2
• Lower risk of appetite suppression and growth effects compared to stimulants 1
• Does not exacerbate tics and may be preferred in patients with comorbid tic disorders or Tourette's syndrome 1, 6

Critical Safety Monitoring

• FDA Black Box Warning for suicidal ideation: Monitor closely, especially during the first few weeks and with dose changes 2, 5, 3
• Cardiovascular monitoring: Check blood pressure and heart rate at baseline and with dose increases 2, 5
• Hepatotoxicity risk: Watch for jaundice, dark urine, right upper quadrant pain, or unexplained flu-like symptoms 3
• Common adverse effects: Decreased appetite, nausea, somnolence, fatigue, headache, abdominal pain 5, 3

Important Caveat: Delayed Onset

Full therapeutic effects require 6-12 weeks, significantly longer than stimulants which work within hours 1, 2, 5. This delayed response necessitates patient counseling about realistic expectations and adherence during the initial treatment period.

Second-Line Non-Stimulants: Alpha-2 Agonists

Guanfacine Extended-Release (Intuniv)

Switch to guanfacine if atomoxetine fails after 12 weeks at therapeutic dose, causes intolerable side effects, or when comorbid tics, anxiety, or sleep disturbances are present. 2

• Dosing: Approximately 0.1 mg/kg once daily; available in 1,2,3, and 4 mg tablets 2
• Administration: Evening dosing preferred due to sedation risk 1, 2
• Specific indications: Particularly useful for comorbid anxiety, tics, sleep disturbances, or as adjunctive therapy with stimulants 1, 2
• FDA approval: Approved in the USA as adjunctive therapy to stimulants 1

Clonidine Extended-Release (Kapvay)

• Similar profile to guanfacine with evening administration recommended 1
• FDA approval: Also approved as adjunctive therapy to stimulants in the USA 1
• Adverse effects: Somnolence and fatigue are relatively frequent 1

Comparative Note on Alpha-2 Agonists

Adverse effects of atomoxetine are considered less frequent and less pronounced compared to clonidine and guanfacine, making atomoxetine the preferred first-line non-stimulant. 1

Third-Line Option: Bupropion (Wellbutrin)

Consider bupropion if both atomoxetine and guanfacine have failed, or when comorbid depression requires treatment. 2

• Dosing (SR formulation): Start 100-150 mg daily, maintenance 100-150 mg twice daily 1
• Dosing (XL formulation): Start 150 mg daily, maintenance 150-300 mg daily, maximum 450 mg/day 1
• Status: Not FDA-approved for ADHD but used off-label 2
• Advantage: Addresses both ADHD and depressive symptoms simultaneously 6, 2

Newer Option: Viloxazine (Qelbree)

• FDA-approved for adults with ADHD as another non-stimulant alternative 2
• Dosing: Starting dose 200 mg once daily, maximum 600 mg once daily 2

Clinical Decision Algorithm

Step 1: Initial Non-Stimulant Selection

Start with atomoxetine unless specific contraindications exist (severe cardiovascular disease, narrow-angle glaucoma, pheochromocytoma, concurrent MAOI use). 2, 3

Step 2: When to Switch from Atomoxetine

• Ineffective after 12 weeks at therapeutic dose 2
• Intolerable side effects (particularly gastrointestinal symptoms, excessive sedation, or cardiovascular effects) 2
• Comorbid conditions better addressed by alternatives: tics, anxiety, or sleep disturbances favor guanfacine 2

Step 3: Second-Line Selection

Switch to guanfacine extended-release for the scenarios above 2

Step 4: Third-Line Consideration

Trial bupropion if both atomoxetine and guanfacine fail, or if comorbid depression is present 2

Specific Clinical Scenarios Favoring Non-Stimulants

Substance Use Disorders

Non-stimulants are first-line in patients with active or past substance use disorders due to stimulants' dopaminergic activity in reward pathways and abuse potential. 1, 2

Tic Disorders and Tourette's Syndrome

Atomoxetine does not worsen tics and may be preferred; guanfacine may reduce tics though evidence is inconclusive. 1

Anxiety Disorders

Atomoxetine has supportive evidence for comorbid anxiety, and guanfacine may help with anxiety symptoms. 1, 2

Autism Spectrum Disorder

Evidence supports atomoxetine use in ADHD with comorbid autism spectrum disorder. 1

Sleep Disturbances

Guanfacine and clonidine may be considered when sleep problems are prominent, as they can improve sleep and are dosed in the evening. 1

Monitoring Parameters

Baseline Assessment

• Blood pressure and heart rate 2
• Weight 2
• Suicidality screening 2

Early Follow-Up (2-4 weeks)

• Vital signs 2
• Side effects assessment 2
• Early treatment response 2

Therapeutic Assessment

• For atomoxetine: 6-12 weeks using standardized ADHD rating scales 2, 5
• For guanfacine: 2-4 weeks 2
• Functional impairment and quality of life measures 2

Ongoing Monitoring

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

Common Pitfalls to Avoid

Do not discontinue atomoxetine prematurely before 6-12 weeks at therapeutic dose, as the delayed onset often leads to premature treatment failure declarations. 1, 2, 5

Do not combine atomoxetine with MAOIs or within 14 days of MAOI discontinuation due to risk of hypertensive crisis. 3

Do not overlook CYP2D6 interactions with atomoxetine, as poor metabolizers or concurrent CYP2D6 inhibitors require dose adjustments. 5

Do not ignore cardiovascular screening before initiating any non-stimulant, particularly in patients with known heart problems or family history of sudden cardiac death. 3