What is the preferred choice between Adderall (amphetamine and dextroamphetamine) XR and Vyvanse (lisdexamfetamine) for a patient with attention deficit hyperactivity disorder (ADHD), considering potential risks and benefits?

Adderall XR vs Vyvanse for ADHD Treatment

Both Adderall XR and Vyvanse are FDA-approved first-line medications with equivalent efficacy for ADHD, but Vyvanse is preferred when there are concerns about diversion, substance use disorder risk, or need for consistent all-day coverage due to its prodrug formulation and lower abuse potential. 1

Efficacy Comparison

• Both medications demonstrate equivalent efficacy for core ADHD symptoms when dosed appropriately, with response rates of approximately 70% for either medication as monotherapy 1
• Nearly 90% of patients respond to either medication if both are tried sequentially, meaning if one fails, the other should be attempted 1
• Both are FDA-approved medications with Grade A evidence supporting their use in elementary school-aged children (6-11 years) and adolescents 2

Key Pharmacological Differences

Vyvanse (lisdexamfetamine):

• A prodrug that is therapeutically inactive until enzymatically hydrolyzed in red blood cells to convert to active d-amphetamine 1, 3
• Requires metabolic conversion in the body, making it impossible to abuse via alternative routes (crushing, snorting, or injection) 4, 5
• Produces a 50% lower peak plasma concentration (Cmax) with significantly delayed time to peak (tmax) compared to immediate-release amphetamines, resulting in lower "drug liking" scores in abuse liability studies 5
• Provides smaller but more sustained increases in striatal dopamine efflux, resulting in less acute stimulant side effects while maintaining therapeutic effect 5

Adderall XR (mixed amphetamine salts):

• A mixture of immediate-release amphetamine salts (75% dextroamphetamine and 25% levoamphetamine) that is active upon ingestion 1
• Does not require metabolic conversion for activity 1
• Higher abuse potential due to immediate pharmacological activity 1

Clinical Decision Algorithm

Choose Vyvanse when:

• Concerns exist about medication diversion or misuse 1
• Patient has history of or risk factors for substance use disorder 1
• Consistent all-day coverage is needed without dose fluctuations 1
• Adolescents and young adults are being treated (American Academy of Pediatrics recommendation) 1

Choose Adderall XR when:

• Flexible dosing throughout the day is needed 1
• Immediate-release formulation is required for initial titration or specific timing needs 1
• Cost is a significant barrier (Adderall XR is typically less expensive) 1

Dosing Protocols

Vyvanse:

• Starting dose: 20-30 mg once daily in the morning 2, 1
• Titration: Increase by 10 mg weekly based on symptom response 2, 1
• Maximum dose: 70 mg daily 2, 1

Adderall XR:

• Starting dose: 10 mg once daily in the morning 2, 1
• Titration: Increase by 5 mg weekly 2, 1
• Maximum dose: 50 mg daily 2, 1

Safety Profile

Both medications carry similar risks:

• Neither is associated with major congenital malformations or cardiac defects 2, 1
• Both have possible small increased risk for gastroschisis (aOR 3.0; 95% CI 1.2-7.4), though absolute risk remains very low given population prevalence of 0.05% 2, 1
• Possible small increased risk for preeclampsia (aRR 1.29; 95% CI 1.11-1.49) and preterm birth (aRR 1.30; 95% CI 1.10-1.55) when continued in second half of pregnancy 2, 1
• Both are Hale Lactation Risk Category L3 2

Common adverse effects (similar for both):

• Decreased appetite, insomnia, upper abdominal pain, headache, irritability, weight loss 4
• Most adverse events are mild to moderate in intensity 4, 6
• Monitor infants for irritability, insomnia, and feeding difficulty if breastfeeding 2

Important Clinical Caveats

• Both medications require an established DSM-IV/DSM-5 diagnosis of ADHD before initiation 7
• Pharmacological treatment should always be part of a multimodal approach including psychoeducation, behavioral interventions, and educational supports 2
• Avoid both medications in patients with uncontrolled hypertension, underlying coronary artery disease, or tachyarrhythmias 2
• Lisdexamfetamine is approved as first-line therapy in the United States but as second-line therapy in many European countries 7
• The prodrug mechanism of Vyvanse provides a larger therapeutic window between efficacy and stimulant side effects compared to immediate-release formulations 5