What are non-controlled medication options for a patient with Attention Deficit Hyperactivity Disorder (ADHD)?

Non-Controlled ADHD Medications

The non-controlled medication options for ADHD include atomoxetine, guanfacine extended-release, clonidine extended-release, and viloxazine extended-release, with atomoxetine being the only FDA-approved non-stimulant for both children and adults. 1, 2

First-Line Non-Controlled Option: Atomoxetine

Atomoxetine is the primary non-controlled medication for ADHD, offering the advantage of no abuse potential and "around-the-clock" symptom coverage without the scheduling restrictions of stimulants. 1

Dosing and Administration

• Children and adolescents ≤70 kg: Start at 0.5 mg/kg/day, increase after minimum 3 days to target dose of 1.2 mg/kg/day (maximum 1.4 mg/kg or 100 mg daily, whichever is less) 2
• Children and adolescents >70 kg and adults: Start at 40 mg daily, increase after minimum 3 days to target of 80 mg daily, may increase to maximum 100 mg daily after 2-4 additional weeks 2
• Can be administered as single morning dose or split into morning and evening doses to reduce adverse effects 1
• Evening-only dosing is also an option if needed 1

Timeline for Effect

• Requires 6-12 weeks to achieve full therapeutic effect, significantly longer than stimulants which work within days 1
• Median time to response is 3.7 weeks, with probability of improvement potentially continuing up to 52 weeks 3

Efficacy Considerations

• Medium-range effect sizes of approximately 0.7 compared to stimulants (effect size 1.0) 1, 3
• Fewer cardiovascular effects, decreased appetite issues, and growth/height problems compared to stimulants 1
• Adverse effects less frequent and less pronounced compared to clonidine and guanfacine 1

Critical Safety Warning

FDA black box warning: Increased risk of suicidal ideation in children and adolescents (0.4% vs 0% placebo), requiring close monitoring especially during first few months and at dose changes. 2

Second-Line Non-Controlled Options: Alpha-2 Agonists

Guanfacine Extended-Release

• Dosing: 1-4 mg daily, with 0.1 mg/kg as a rule of thumb 3
• Timeline: Requires 2-4 weeks for full treatment effects 1
• Administration: Evening dosing generally preferable due to somnolence/fatigue as common adverse effect 1
• Effect size: Approximately 0.7 3

Clonidine Extended-Release

• Timeline: Requires 2-4 weeks for treatment effects 1
• Administration: Evening dosing generally preferable due to somnolence/fatigue 1
• Effect size: Approximately 0.7 3

Specific Advantages of Alpha-2 Agonists

Both guanfacine and clonidine are particularly useful as first-line non-controlled options when specific comorbidities are present:

• Disruptive behavior disorders 1
• Tic disorder or Tourette's syndrome 1
• Substance use disorders (where stimulants may be unviable due to dopaminergic activity in nucleus accumbens and striatum) 1
• Sleep disturbances 1
• Comorbid anxiety or agitation 3

In the United States, both are approved "as adjunctive therapy to stimulant medications" to either increase treatment effects or decrease stimulant adverse effects (particularly sleep disturbances and cardiovascular effects). 1

Emerging Non-Controlled Option: Viloxazine Extended-Release

Viloxazine is a repurposed antidepressant classified as a serotonin norepinephrine modulating agent that has completed several pivotal clinical trials in children showing favorable efficacy and tolerability, with demonstrated efficacy in adults with ADHD. 3, 4, 5

This represents a newer alternative beyond the traditional noradrenergic-focused non-stimulants. 5

Clinical Decision Algorithm

When substance use disorder or abuse potential is a concern: Start with atomoxetine as first-line, as it is an uncontrolled substance with no abuse potential. 1, 3

When comorbid tics, Tourette's, or disruptive behavior disorders are present: Consider guanfacine or clonidine as first-line non-controlled options. 1

When comorbid anxiety or autism spectrum disorder is present: Atomoxetine has evidence supporting its use in these populations. 1

When sleep disturbances are prominent: Guanfacine or clonidine may be preferred due to their sedating properties when dosed in the evening. 1

Common Pitfalls to Avoid

Do not expect rapid response with non-stimulants: Unlike stimulants that work within days, atomoxetine requires 6-12 weeks and alpha-2 agonists require 2-4 weeks for full effect. 1, 3

Do not assume atomoxetine will treat comorbid depression: Despite initial development as an antidepressant, evidence does not support efficacy in this symptom domain. 1

Do not overlook the need for multimodal treatment: Pharmacological treatment should always be part of an individualized approach including psychoeducation and psychotherapeutic/psychosocial interventions. 1

Monitor for suicidality with atomoxetine: Particularly important in the first few months of treatment and at dose changes, especially in children and adolescents. 2

Monitor cardiovascular parameters: Blood pressure and pulse should be checked at baseline and regularly during treatment with all ADHD medications, including non-stimulants. 3