Non-Stimulant Medications for ADHD: Comprehensive Treatment Guide
First-Line Non-Stimulant: Atomoxetine
Atomoxetine is the only FDA-approved non-stimulant for ADHD in both children and adults, and should be your primary non-stimulant choice when stimulants are contraindicated, not tolerated, or have failed after adequate trials of two or more stimulant classes. 1, 2
Dosing Strategy
Children and adolescents ≤70 kg:
- Start at 0.5 mg/kg/day for 3 days 2
- Increase to target dose of 1.2 mg/kg/day after minimum 3 days 2, 3
- Maximum: 1.4 mg/kg/day or 100 mg/day, whichever is less 2
- Can be given once daily in morning or split into morning and late afternoon/evening doses 2
Children >70 kg, adolescents, and adults:
- Start at 40 mg/day 2
- Increase after minimum 3 days to target of 80 mg/day 2
- After 2–4 additional weeks, may increase to maximum 100 mg/day if response inadequate 2
- Administer as single morning dose or divided morning/late afternoon 2
Critical Timeline Expectations
Atomoxetine requires 6–12 weeks to achieve full therapeutic effect, with median response time of 3.7 weeks—this is fundamentally different from stimulants that work within days. 1 Counsel patients that 2–4 weeks minimum are needed before observing clinical benefits, and probability of improvement may continue increasing up to 52 weeks. 4
Efficacy Profile
Atomoxetine demonstrates medium-range effect sizes of approximately 0.7 compared to stimulants (effect size ≈1.0), meaning it is moderately effective but less robust than stimulants. 1, 4 Approximately 50% of methylphenidate non-responders will respond to atomoxetine, and 75% of methylphenidate responders will also respond to atomoxetine. 5
Specific Clinical Advantages
Position atomoxetine as first-line non-stimulant when:
- Active substance use disorder or high abuse/diversion risk exists (uncontrolled substance status) 1, 6
- Comorbid anxiety disorder is present (atomoxetine has evidence for anxiety reduction) 1
- Comorbid autism spectrum disorder exists 1
- Around-the-clock symptom coverage is needed without rebound effects 1, 3
- Tic disorders or Tourette syndrome are present 3
Safety Profile and Monitoring
Black box warning: Atomoxetine carries FDA warning for increased suicidal ideation in children and adolescents—screen for suicidality at baseline and monitor closely during first few months and at dose changes. 1, 2
Baseline assessment:
- Blood pressure and pulse (seated and standing) 1
- Personal and family cardiac history 1
- Screen for bipolar disorder, mania, or hypomania before initiating 2
- Hepatic function if liver disease suspected 2
Ongoing monitoring:
- Blood pressure and pulse at each dose adjustment 1
- Height and weight at every visit 1
- Suicidality screening at every visit 1
- Sleep quality and appetite changes 1
Common adverse effects (generally mild, transient, dose-related):
- Children/adolescents: dyspepsia, nausea, vomiting, decreased appetite, weight loss 7
- Adults: dry mouth, insomnia, nausea, decreased appetite, constipation, urinary retention, erectile dysfunction, dysmenorrhea, dizziness, decreased libido 7
- Sexual dysfunction occurs in ~2% of patients 7
Drug Interactions and Dose Adjustments
When co-administered with strong CYP2D6 inhibitors (paroxetine, fluoxetine, quinidine) or in CYP2D6 poor metabolizers:
- Children ≤70 kg: start 0.5 mg/kg/day, increase to 1.2 mg/kg/day only after 4 weeks if symptoms persist and initial dose tolerated 2
- Children >70 kg and adults: start 40 mg/day, increase to 80 mg/day only after 4 weeks if needed 2
SSRIs can elevate atomoxetine levels through CYP2D6 inhibition, requiring dose adjustment in patients with comorbid depression. 1
Contraindications
- Concurrent MAOI use or within 2 weeks of MAOI discontinuation 2
- Narrow-angle glaucoma 2
- Pheochromocytoma or history thereof 2
- Severe cardiovascular disorders 2
- Known hypersensitivity to atomoxetine 2
Discontinuation
Atomoxetine can be discontinued abruptly without tapering—there is no rebound effect or discontinuation syndrome. 2, 5
Second-Line Non-Stimulants: Alpha-2 Adrenergic Agonists
Extended-Release Guanfacine (Intuniv)
Guanfacine extended-release is FDA-approved for ADHD as monotherapy or adjunctive therapy to stimulants, with particular utility when comorbid sleep disturbances, tics, oppositional symptoms, or substance use risk are present. 1, 8
Mechanism and Advantages
Guanfacine is an alpha-2A adrenergic receptor agonist that enhances noradrenergic neurotransmission in the prefrontal cortex, strengthening top-down regulation of attention and working memory. 8 It has higher alpha-2A receptor specificity than clonidine, resulting in less sedation while maintaining efficacy. 1, 8
Key advantage: Guanfacine provides around-the-clock symptom control with once-daily dosing and actually decreases blood pressure and heart rate (opposite of stimulants), making it uniquely beneficial for patients with cardiovascular concerns. 4, 8
Dosing Protocol
- Starting dose: 1 mg once daily, preferably in evening 8
- Titration: Increase by 1 mg weekly based on response and tolerability 8
- Target range: 0.05–0.12 mg/kg/day or 1–7 mg/day maximum 1, 8
- Weight-based rule of thumb: 0.1 mg/kg once daily 4
Evening administration is strongly preferred to minimize daytime somnolence and fatigue, which are the most common adverse effects. 1, 8
Timeline and Efficacy
Guanfacine requires 2–4 weeks before clinical benefits are observed—set expectations appropriately to prevent premature discontinuation. 1, 8 Effect size is approximately 0.7 compared to placebo, with sustained improvements in ADHD symptoms, functional impairment, and quality of life over 24 months. 1, 8
Specific Indications for Guanfacine
Prioritize guanfacine when:
- Comorbid tic disorders or Tourette syndrome 1, 8
- Sleep disturbances (evening dosing leverages sedative effects) 1, 8
- Disruptive behavior disorders or oppositional symptoms 1, 8
- Substance use risk (non-controlled medication) 1, 8
- Comorbid anxiety or agitation 1, 8
- Stimulant-related insomnia or appetite suppression needs mitigation 1
FDA-Approved Adjunctive Therapy
Guanfacine extended-release and clonidine extended-release are the only two medications with FDA approval and sufficient evidence for adjunctive use with stimulants. 1, 8 Combination therapy allows lower stimulant doses while maintaining efficacy and potentially reducing stimulant-related adverse effects. 1, 8
Safety and Monitoring
Baseline assessment:
- Blood pressure and pulse (seated and standing) 8
- Personal and family cardiac history, specifically Wolf-Parkinson-White syndrome, sudden death, hypertrophic cardiomyopathy, long QT syndrome 8
Ongoing monitoring:
- Blood pressure and heart rate at each dose adjustment 8
- Expect modest decreases: 1–4 mmHg BP, 1–2 bpm heart rate 4, 8
- Height and weight at every visit 1
- ADHD symptom ratings using parent/teacher reports 8
Common adverse effects:
- Somnolence/sedation (most frequent, typically mild-moderate, lessens with time) 8
- Fatigue (15.2% of patients) 8
- Headache (20.5% of patients) 8
- Dry mouth 8
- Constipation (5–16%, dose-dependent) 8
- Dizziness, irritability, abdominal pain 8
Critical safety warning: Never abruptly discontinue guanfacine—taper by 1 mg every 3–7 days to avoid rebound hypertension. 1, 8
Contraindications and Cautions
- Baseline bradycardia (heart rate <60 bpm) or hypotension (systolic BP <90 mmHg) 8
- Cardiac conduction abnormalities 8
- Use with caution in elderly patients and those with autonomic dysfunction 8
- Pregnancy: limited safety data, one study showed 20% low birth weight 8
Extended-Release Clonidine (Kapvay)
Clonidine extended-release is FDA-approved for ADHD as monotherapy or adjunctive therapy, with similar effect size (~0.7) to guanfacine but greater sedation due to lower alpha-2A receptor specificity. 1, 4
Dosing
- Starting dose: 0.1 mg once daily at bedtime 8
- Titration: Increase by 0.1 mg every 3–7 days 8
- Target range: 0.1–0.4 mg/day, typically divided twice daily for ADHD 8
- Maximum: 0.4 mg/day 8
When to Choose Clonidine Over Guanfacine
Clonidine may be preferred when more pronounced sedation is desired for severe sleep disturbances, though guanfacine is generally favored due to once-daily dosing and less sedation. 1, 8
Critical Safety Warning
Clonidine carries higher risk of rebound hypertension and hypertensive crisis upon abrupt discontinuation compared to guanfacine—always taper by 0.1 mg every 3–7 days. 8 Never initiate at full 1 mg dose; start at 0.1 mg to avoid excessive hypotension and sedation. 8
Emerging Non-Stimulant: Viloxazine Extended-Release (Qelbree)
Viloxazine is a repurposed antidepressant classified as a serotonin-norepinephrine modulating agent, FDA-approved for ADHD in both children and adults, representing the first novel non-stimulant mechanism in years. 1, 4
Pivotal clinical trials in children and adults demonstrated favorable efficacy and tolerability. 1, 4 Viloxazine has zero abuse potential and should be considered for patients with substance misuse history. 1 However, long-term data and comparative effectiveness studies are still limited compared to atomoxetine.
Treatment Algorithm for Non-Stimulant Selection
Step 1: Determine why non-stimulant is needed
- Stimulant failure after adequate trials of ≥2 classes (methylphenidate and amphetamine) 1
- Stimulant intolerance (intolerable side effects) 1
- Active substance use disorder or high diversion risk 1
- Patient/family preference against controlled substances 1
- Specific comorbidities favoring non-stimulant 1
Step 2: Select appropriate non-stimulant based on clinical profile
Choose atomoxetine when:
- Need around-the-clock coverage without rebound 1
- Comorbid anxiety or autism spectrum disorder 1
- Substance use history (uncontrolled status) 1
- No specific comorbidities favoring alpha-2 agonists 1
Choose guanfacine when:
- Comorbid tics, Tourette syndrome, or disruptive behavior 1, 8
- Sleep disturbances prominent 1, 8
- Stimulant-related insomnia or appetite suppression needs mitigation 1
- Cardiovascular concerns (guanfacine lowers BP/HR) 4, 8
- Substance use risk (non-controlled) 1, 8
Choose clonidine when:
- Similar indications to guanfacine but more sedation desired 1
- Guanfacine unavailable or not tolerated 1
Consider viloxazine when:
- Atomoxetine and alpha-2 agonists failed or not tolerated 1
- Substance misuse history (zero abuse potential) 1
Step 3: Initiate with appropriate dosing and timeline expectations
- Atomoxetine: 6–12 weeks for full effect 1
- Guanfacine/clonidine: 2–4 weeks for effect 1, 8
- Counsel patients on delayed onset to prevent premature discontinuation 1, 8
Step 4: Monitor systematically
- Cardiovascular parameters at baseline and each adjustment 1, 8
- ADHD symptom ratings weekly during titration 8
- Growth parameters at every visit 1
- Suicidality screening (especially atomoxetine) 1
- Functional improvement across settings 1
Step 5: Optimize dose before declaring failure
- Atomoxetine: titrate to 1.2–1.4 mg/kg/day or 100 mg/day maximum 2
- Guanfacine: titrate to 0.05–0.12 mg/kg/day or 7 mg/day maximum 8
- Allow adequate trial duration (6–8 weeks minimum for atomoxetine, 4–6 weeks for guanfacine) 1, 8
Step 6: Consider adjunctive therapy if monotherapy insufficient
- Add guanfacine or clonidine to atomoxetine (FDA-approved combination) 1, 8
- Combine behavioral therapy with all pharmacotherapy 1
Common Pitfalls to Avoid
Do not assume atomoxetine will work immediately—it requires 6–12 weeks for full effect, unlike stimulants. 1 Premature discontinuation due to unrealistic timeline expectations is a frequent error.
Do not underdose atomoxetine—target 1.2 mg/kg/day in children or 80–100 mg/day in adults. 2 Doses below 40 mg in adolescents or 60 mg in adults are subtherapeutic. 1
Do not abruptly discontinue guanfacine or clonidine—always taper to avoid rebound hypertension. 1, 8 Guanfacine requires 1 mg reduction every 3–7 days; clonidine requires 0.1 mg reduction every 3–7 days. 8
Do not combine two alpha-2 agonists (guanfacine + clonidine)—this increases sedation and cardiovascular effects without clear efficacy benefit. 8
Do not use atomoxetine with MAOIs or within 2 weeks of MAOI discontinuation—serious reactions including hyperthermia and autonomic instability can occur. 2
Do not forget to screen for bipolar disorder before initiating atomoxetine—it can precipitate manic episodes. 2
Do not rely solely on non-stimulant monotherapy when stimulants have not been adequately trialed—stimulants remain first-line with superior effect sizes (1.0 vs 0.7). 1, 4 Non-stimulants are second-line after stimulant failure or when specific contraindications exist.
Do not overlook the need for multimodal treatment—pharmacotherapy must be combined with behavioral interventions, psychoeducation, and psychosocial support. 1, 3
Special Populations
Preschool children (4–5 years):
- Behavioral therapy is first-line 8
- Dextroamphetamine is the only FDA-approved medication for age <6 years 8
- Guanfacine and atomoxetine are not approved for this age group 8
Patients with hepatic impairment:
- Moderate hepatic impairment (Child-Pugh B): reduce atomoxetine to 50% of normal dose 2
- Severe hepatic impairment (Child-Pugh C): reduce atomoxetine to 25% of normal dose 2
Patients on CYP2D6 inhibitors or poor metabolizers:
- Start atomoxetine at 0.5 mg/kg/day (children ≤70 kg) or 40 mg/day (>70 kg, adults) 2
- Increase to usual target only after 4 weeks if symptoms persist and initial dose tolerated 2
Pregnancy:
- Atomoxetine: limited data, use only if benefit outweighs risk 7
- Guanfacine: limited data, one study showed 20% low birth weight 8
Substance use disorders:
- Atomoxetine, guanfacine, and clonidine are all non-controlled and preferred 1, 8
- Viloxazine has zero abuse potential 1
Maintenance and Long-Term Management
Atomoxetine has demonstrated efficacy in preventing relapse of ADHD symptoms over extended periods without increased adverse effects. 7 Improvements sustained over 18 months in clinical trials. 3
Guanfacine improvements in ADHD symptoms and functional impairment were sustained over 24 months in open-label extension trials. 8
Periodically reevaluate the long-term necessity of medication for each individual patient. 2 However, do not discontinue effective treatment solely due to concerns about "taking medication forever"—untreated ADHD is associated with increased risk of accidents, substance abuse, and functional impairment. 4
Pharmacological treatment should always be part of an individualized, multimodal approach including psychoeducation, behavioral therapy, and psychosocial interventions. 1, 3