For a patient with severe attention‑deficit hyperactivity disorder and no contraindications to stimulant therapy (no serious cardiac disease, uncontrolled hypertension, psychosis, or recent substance‑use disorder), should the first‑line treatment be lisdexamfetamine (Vyvanse) or mixed‑amphetamine salts (Adderall XR)?

Lisdexamfetamine (Vyvanse) vs. Mixed Amphetamine Salts (Adderall XR) for Severe ADHD

For a patient with severe ADHD and no contraindications to stimulant therapy, both lisdexamfetamine (Vyvanse) and mixed amphetamine salts (Adderall XR) are equally appropriate first-line options, with the choice based primarily on pharmacokinetic profile, abuse-potential concerns, and individual dosing flexibility rather than superiority of efficacy. Both agents achieve 70–80% response rates when properly titrated and demonstrate comparable large effect sizes for ADHD symptom reduction. 1, 2

Evidence for Comparable Efficacy

• Amphetamine-based stimulants (including both Vyvanse and Adderall XR) are recommended as preferred first-line therapy for adults with ADHD, achieving 70–80% response rates with large effect sizes. 1

• Lisdexamfetamine demonstrates the largest effect size among stimulants in meta-analysis (SMD -0.89), compared with mixed amphetamine salts (SMD -0.64) and methylphenidate (SMD -0.50), though all three agents show robust efficacy superior to placebo. 2

• Both medications work rapidly—within days—allowing quick assessment of ADHD symptom response, unlike non-stimulant alternatives that require 2–12 weeks for full therapeutic effect. 1

• Approximately 40% of patients respond to both methylphenidate and amphetamine classes, while another 40% respond preferentially to only one stimulant class, underscoring that if one amphetamine formulation fails, switching within the same class (e.g., Vyvanse to Adderall XR or vice versa) is less likely to yield benefit than switching to methylphenidate. 1

Key Differentiating Factors

Abuse Potential and Diversion Risk

• Lisdexamfetamine is a prodrug of dextroamphetamine with lower feasibility for abuse because it requires enzymatic conversion in the gastrointestinal tract and red blood cells, attenuating the rapid plasma peaks that drive euphoria and misuse. 3

• Prodrug stimulants such as lisdexamfetamine are intentionally engineered to reduce abuse potential and should not be assumed to carry the same abuse risk as conventional immediate-release or even extended-release amphetamine salts. 1

• When abuse risk or diversion is a primary concern, lisdexamfetamine should be preferentially selected over Adderall XR due to its prodrug mechanism. 1

Dosing Flexibility and Titration

• Adderall XR offers finer dose adjustments, with a starting dose of 10 mg that can be titrated by 5 mg weekly, and availability of 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, and 30 mg capsules up to a maximum of 50 mg daily. 1

• Lisdexamfetamine requires a minimum starting dose of 20–30 mg once daily, titrated by 10–20 mg weekly up to a maximum of 70 mg daily, which may limit flexibility in patients requiring very low initial doses or small incremental adjustments. 1

• When a lower initial dose is desired or more granular titration is needed, Adderall XR is preferable because Vyvanse cannot be started below 20 mg. 1

Pharmacokinetic Profile and Duration of Action

• Lisdexamfetamine provides once-daily dosing with a prodrug formulation that delivers smoother, more sustained plasma levels throughout the day, reducing the likelihood of afternoon rebound symptoms. 1, 3

• Both agents provide extended symptom coverage (10–12 hours), but lisdexamfetamine's prodrug conversion may offer more consistent "around-the-clock" effects compared with the biphasic release of Adderall XR. 1

Adverse Effect Profile

• Common adverse effects are comparable between the two agents, including decreased appetite, insomnia, headache, and modest increases in blood pressure and pulse (each occurring in >10% of treated adults). 1

• Amphetamines (including both Vyvanse and Adderall XR) typically cause greater appetite suppression and sleep disturbance than methylphenidate due to longer elimination half-lives. 1

• Both medications require baseline and regular cardiovascular monitoring (blood pressure and pulse at each visit), along with tracking of height, weight, sleep quality, and appetite changes. 1

Contraindications and Safety Monitoring

• Both stimulants are contraindicated in patients with symptomatic cardiovascular disease, uncontrolled hypertension, active psychosis, or concurrent MAO-inhibitor use (within 14 days). 1

• Prior to initiating either agent, obtain a detailed personal and family cardiac history, specifically screening for sudden cardiac death in relatives younger than 50 years, Wolff-Parkinson-White syndrome, hypertrophic cardiomyopathy, Long QT syndrome, unexplained syncope, and any cardiovascular symptoms such as chest pain or palpitations. 1

• If any cardiac risk factors are present, obtain an ECG and consider cardiology referral before starting treatment. 4

• Baseline blood pressure and pulse should be measured before starting either medication, with ongoing monitoring at each medication adjustment and during stable long-term treatment. 1, 4

Clinical Decision Algorithm

Choose Lisdexamfetamine (Vyvanse) when:

• Abuse potential or diversion risk is a primary concern (e.g., adolescents, college students, patients with personal or family history of substance use). 1, 3

• Once-daily adherence is critical and the patient has difficulty with multiple daily doses or mid-day administration. 1

• Smoother, sustained symptom control is desired to minimize afternoon rebound or "crash" effects. 1

Choose Mixed Amphetamine Salts (Adderall XR) when:

• Finer dose titration is needed, particularly in patients who may require starting below 20 mg or adjusting by increments smaller than 10 mg. 1

• Cost is a significant barrier, as generic mixed amphetamine salts extended-release formulations are typically less expensive than branded lisdexamfetamine. (General clinical knowledge)

• The patient has previously responded well to immediate-release mixed amphetamine salts and is transitioning to an extended-release formulation. 1

Switch to the alternative amphetamine formulation if:

• Intolerable adverse effects emerge (e.g., excessive appetite suppression, insomnia, or cardiovascular effects) that may be formulation-specific. 1

• Inadequate symptom control persists after 4–6 weeks of optimized dosing with the initial agent, though switching to methylphenidate (a different stimulant class) is more likely to yield benefit than switching between amphetamine formulations. 1

Monitoring During Titration and Maintenance

• During titration (first 4–6 weeks): Measure blood pressure and pulse at each dose adjustment, obtain weekly ADHD symptom ratings from the patient or a designated informant, and assess sleep quality and appetite changes. 1

• Maintenance phase: Schedule monthly visits initially, then quarterly once stable; at each visit, record blood pressure and pulse, track height and weight (particularly in younger patients), and monitor for functional improvement across home, work, and social settings. 1

• Systematic titration to optimal effect is more important than strict mg/kg calculations, with approximately 70% of patients achieving optimal response when proper titration protocols are followed. 1

Common Pitfalls to Avoid

• Do not assume lisdexamfetamine is inherently "safer" or "better" than Adderall XR based solely on its prodrug mechanism; both agents have comparable efficacy and safety profiles when dosed appropriately. 2, 3

• Do not switch between amphetamine formulations (Vyvanse ↔ Adderall XR) before ensuring adequate dose optimization of the initial agent; most apparent "failures" reflect insufficient titration rather than true non-response. 1

• Do not overlook the need for multimodal treatment—pharmacotherapy with either agent should be combined with evidence-based psychosocial interventions (e.g., CBT, psychoeducation) to achieve optimal functional outcomes. 1

• Do not prescribe either agent to patients with active substance-use disorders involving stimulants unless treatment is provided in a highly controlled setting with intensive monitoring. 1