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

Non-Amphetamine Treatment Options for ADHD

For patients seeking non-amphetamine ADHD treatment, methylphenidate-based stimulants remain first-line therapy, while non-stimulant medications (atomoxetine, guanfacine, clonidine) serve as effective second-line alternatives with medium effect sizes but important advantages in specific clinical scenarios. 1

Methylphenidate (Non-Amphetamine Stimulant)

Methylphenidate is the preferred non-amphetamine option and should be initiated first, as it demonstrates large effect sizes for ADHD core symptoms comparable to amphetamines, with 70-80% response rates. 1, 2

Formulation Selection

• Long-acting formulations (OROS methylphenidate/Concerta, extended-release preparations) are strongly preferred over immediate-release due to better adherence, lower rebound risk, and 8-12 hours of symptom control. 2, 3
• Short-acting formulations allow dosing flexibility but require multiple daily doses and carry higher rebound potential. 1
• Novel delivery systems include chewable tablets, liquid formulations, and transdermal patches for patients with swallowing difficulties. 1

Dosing Protocol

• Start with 5-10 mg in the morning after breakfast for adults. 3
• Titrate by 5-10 mg increments weekly based on response and tolerability. 3
• Maximum dose typically 60-72 mg/day depending on formulation. 3
• Afternoon doses may need to be higher than morning doses to prevent symptom attenuation. 3

Monitoring Requirements

• Baseline and ongoing cardiovascular assessment (blood pressure, pulse). 1
• Height and weight monitoring, particularly in children. 1
• Monthly visits until symptoms stabilize. 3

Non-Stimulant Medications (Second-Line)

Non-stimulants should be considered when methylphenidate is ineffective, not tolerated, or contraindicated, particularly in patients with comorbid substance use disorders, severe anxiety, tics/Tourette's, or sleep disturbances. 1, 2

Atomoxetine (Preferred Non-Stimulant)

Atomoxetine is the primary non-stimulant alternative with FDA approval for both children and adults, offering "around-the-clock" effects without controlled substance status. 1, 4

Mechanism and Efficacy

• Selective norepinephrine reuptake inhibitor that increases both norepinephrine and dopamine in prefrontal cortex. 1
• Medium effect size compared to stimulants but superior to placebo. 1
• Critical limitation: 6-12 weeks required to observe full treatment effects. 1

Dosing Protocol

• Weight-based dosing: target 1.2 mg/kg/day for children/adolescents ≤70 kg. 1, 5
• Adults: start 40 mg/day, titrate to maximum 100 mg/day. 3
• Can be administered once daily or split into two doses (morning/evening) to reduce adverse effects. 1
• Evening-only dosing is acceptable if needed. 1

Advantages Over Stimulants

• Non-controlled substance status (easier prescription refills). 1, 6
• 24-hour symptom coverage without rebound effects. 1
• Lower impact on appetite and growth compared to stimulants. 1
• Preferred for comorbid substance use disorders, anxiety, or tics. 1, 6
• No abuse potential. 6, 7

Monitoring Requirements

• Black box warning: monitor for suicidal ideation, particularly in first weeks of treatment. 1, 6
• Assess for clinical worsening. 1
• Monitor pulse and cardiovascular effects (similar to stimulants but generally milder). 1, 6
• Screen for rare but serious liver injury. 6

Common Adverse Effects

• Decreased appetite, headache, stomach pain, nausea. 1, 6
• Generally less frequent and less pronounced than alpha-2 agonists. 1
• Discontinuation rate approximately 3.5% due to adverse events. 8

Alpha-2 Adrenergic Agonists

Guanfacine (extended-release) and clonidine (extended-release) provide alternative non-stimulant options with effect sizes around 0.7, particularly useful as adjunctive therapy or when sedation is beneficial. 1, 2

Guanfacine (Extended-Release)

Guanfacine is preferred over clonidine due to once-daily dosing and potentially better tolerability. 1

Dosing Protocol

• Weight-based dosing: 0.1 mg/kg once daily as rule of thumb. 1
• Available in 1,2,3, and 4 mg tablets. 1
• Administer in evening due to sedation risk. 1

Approval Status

• US: approved as monotherapy or adjunctive to stimulants. 1
• Europe: only approved when stimulants are unsuitable, not tolerated, or ineffective. 1

Clinical Advantages

• First-line consideration for comorbid sleep disturbances, substance use disorders, disruptive behavior disorders, or tics. 1
• May reduce tic severity (though evidence remains inconclusive). 1
• Can augment stimulant treatment to reduce cardiovascular effects and sleep disturbances. 1

Onset and Duration

• 2-4 weeks until treatment effects observed. 1
• Around-the-clock symptom coverage. 1

Clonidine (Extended-Release)

Dosing Protocol

• Start 0.1 mg at bedtime. 1
• Increase to twice-daily administration with careful uptitration. 1
• Maximum 0.4 mg/day recommended. 1
• Transdermal patch available (0.1,0.2,0.3 mg). 1

Approval Status

• US: approved as monotherapy or adjunctive therapy. 1
• Europe: not approved for ADHD treatment. 1

Monitoring Requirements

• Obtain full medical history of patient and first-degree family members before initiating—history of sudden death, repeated fainting, or arrhythmias may contraindicate use. 3
• Monitor for hypotension/bradycardia, cardiac conduction abnormalities. 1
• When combining with stimulants, start 0.05 mg at bedtime, increase slowly, never exceed 0.3 mg/day. 3

Common Adverse Effects (Both Alpha-2 Agonists)

• Somnolence/sedation (most frequent—administer in evening). 1
• Fatigue, irritability, insomnia, nightmares. 1
• Hypotension, bradycardia, syncope. 1
• Dry mouth (clonidine). 1

Additional Non-Stimulant Options

Bupropion XL

Bupropion serves as a second-line non-stimulant alternative when other options are contraindicated or ineffective. 2, 3

Dosing Protocol

• Start 150 mg once daily in morning. 3
• Titrate to maintenance dose 150-300 mg daily. 3
• Maximum 450 mg per day. 3

Critical Contraindications

• Screen for seizure risk factors—bupropion lowers seizure threshold. 3
• Avoid in patients with eating disorders, seizure history, or abrupt alcohol/benzodiazepine withdrawal. 3
• Do not combine with stimulants until further safety data available. 3

Viloxazine

• Additional non-stimulant option for adult ADHD treatment. 2
• Limited evidence provided in current guidelines.

Treatment Algorithm

Step 1: Initial Assessment

• Screen for cardiovascular disease (contraindication to stimulants). 3
• Assess for active substance use disorder (relative contraindication to stimulants). 3
• Evaluate comorbidities (anxiety, tics, sleep disturbances, disruptive behaviors). 1

Step 2: First-Line Treatment Selection

• If no contraindications to stimulants: initiate long-acting methylphenidate. 1, 2
• If stimulants contraindicated or patient refuses controlled substances: initiate atomoxetine. 1
• If comorbid sleep disturbances or tics are prominent: consider guanfacine or clonidine. 1, 2

Step 3: If First Methylphenidate Trial Fails

• Switch to alternative methylphenidate formulation before moving to non-stimulants. 3
• If multiple methylphenidate trials fail: transition to atomoxetine. 1

Step 4: Augmentation Strategy

• If partial response to stimulants with residual symptoms or adverse effects: add guanfacine or clonidine. 1
• Particularly effective for sleep disturbances or cardiovascular effects from stimulants. 1

Critical Pitfalls to Avoid

• Do not expect rapid onset with non-stimulants—atomoxetine requires 6-12 weeks, alpha-2 agonists require 2-4 weeks for full effect. 1
• Do not start atomoxetine at excessively high doses—begin conservatively and titrate slowly. 3
• Do not discontinue stimulants abruptly for "drug holidays" during important events—symptoms return rapidly. 3
• Do not overlook suicidal ideation monitoring with atomoxetine, especially in first weeks. 1, 6
• Do not combine bupropion with stimulants until further safety data available. 3
• Allow minimum one week between dose adjustments to properly evaluate response. 3