What alternative Attention Deficit Hyperactivity Disorder (ADHD) medications can be considered for a 29-year-old female patient with no response to Vyvanse (lisdexamfetamine) 60 mg?

Alternative ADHD Medication for Non-Response to Vyvanse 60 mg

Switch to methylphenidate-based stimulants (starting with long-acting formulations like Concerta 18-36 mg daily) as the next step, since approximately 40% of patients respond to one stimulant class but not the other. 1, 2

Why Methylphenidate Should Be Your Next Choice

The evidence strongly supports trying the alternative stimulant class before abandoning stimulants entirely. Here's the critical reasoning:

• Stimulants remain superior to all alternatives, with 70-80% overall response rates when both classes are tried, and the largest effect sizes from over 161 randomized controlled trials 1, 2
• Class-specific response patterns are common: About 40% of patients respond optimally to both methylphenidate and amphetamines, while another 40% respond to only one class 2
• Vyvanse (lisdexamfetamine) is an amphetamine prodrug, so lack of response suggests trying the methylphenidate class before moving to non-stimulants 3, 4

Specific Methylphenidate Initiation Protocol

Start with long-acting methylphenidate (Concerta/OROS-MPH) 18-36 mg once daily in the morning 1, 2:

• Titrate by 18 mg weekly based on response and tolerability 1
• Maximum dose typically 54-72 mg daily 2
• Long-acting formulations provide 8-12 hours of coverage and improve adherence compared to immediate-release 2
• Allow at least one week between dose adjustments to properly evaluate response 2

Monitor at baseline and during titration: blood pressure, pulse, weight, sleep quality, and appetite 1, 2

If Methylphenidate Also Fails: Non-Stimulant Options

Only after adequate trials of both stimulant classes should you consider non-stimulants 1, 5:

First-Line Non-Stimulant: Atomoxetine

Atomoxetine 40 mg daily, titrating to 60-100 mg daily is the primary non-stimulant alternative 1, 6, 7:

• Start at 40 mg daily, increase after 7-14 days to 60 mg, then 80 mg as needed 1
• Maximum dose: lesser of 1.4 mg/kg/day or 100 mg/day 1, 6
• Critical timing consideration: Requires 6-12 weeks for full therapeutic effect, unlike stimulants that work within days 1, 2
• Can be dosed once daily in morning or split into morning/evening to reduce side effects 1
• No abuse potential, making it ideal if substance use concerns exist 1, 7

FDA Black Box Warning: Monitor for suicidal ideation, especially in first few months or at dose changes 1, 6

Second-Line Non-Stimulants: Alpha-2 Agonists

Consider guanfacine extended-release (1-4 mg daily) or clonidine extended-release as alternatives 1, 7:

• Particularly useful if comorbid sleep disturbances, tics, anxiety, or disruptive behaviors are present 1, 7
• Require 2-4 weeks for full effect 1
• Dose in evening due to sedating properties 1
• Never discontinue abruptly—taper by 1 mg every 3-7 days to avoid rebound hypertension 1

Third-Line Option: Bupropion

Bupropion XL 150-300 mg daily is explicitly a second-line agent for ADHD 1, 2:

• Start 150 mg once daily, titrate to 150-300 mg based on response 2
• Maximum 450 mg daily 1, 2
• Contraindications: Seizure history, eating disorders, abrupt alcohol/benzodiazepine withdrawal 2
• Consider if comorbid depression or smoking cessation is needed 1
• Important limitation: Smaller effect sizes than stimulants and atomoxetine 1

Critical Pitfalls to Avoid

Do not assume Vyvanse 60 mg represents adequate stimulant trial 5:

• The maximum FDA-approved dose of Vyvanse is 70 mg daily 8
• Before switching medications, ensure the current dose has been optimized 8, 5
• Assess adherence, as once-daily formulations like Vyvanse generally improve compliance but non-adherence still occurs 1

Do not skip methylphenidate and go directly to non-stimulants 1, 2:

• Non-stimulants have medium-range effect sizes (approximately 0.7) compared to stimulants 1
• Guidelines consistently position non-stimulants as second-line when stimulants fail or are contraindicated 1, 7

Do not use bupropion as first-line for ADHD alone 1:

• No single antidepressant is proven to effectively treat both ADHD and depression 1
• Bupropion is explicitly a second-line agent at best for ADHD treatment 1

Before Switching: Rule Out These Factors

Evaluate whether apparent "non-response" is actually due to 5:

• Poor adherence: Verify the patient is actually taking the medication consistently
• Wearing-off effects: Vyvanse provides 10-12 hours of coverage; symptoms may return in evening
• Inadequate dose: Consider increasing to 70 mg before declaring treatment failure
• Comorbid conditions: Untreated anxiety, depression, or sleep disorders can mask ADHD treatment response
• Tolerance: Rare in ADHD treatment, but assess if initial response has diminished 1