What are the options for add-on treatment for Attention Deficit Hyperactivity Disorder (ADHD) in a patient already taking Vyvanse (lisdexamfetamine)?

Add-On Treatment for ADHD on Vyvanse

If ADHD symptoms persist despite optimized Vyvanse dosing, add guanfacine extended-release (1-4 mg daily) or clonidine as adjunctive therapy, as these alpha-2 agonists are specifically approved for combination use with stimulants and demonstrate effect sizes around 0.7. 1

Treatment Algorithm for Inadequate Response

First: Optimize Current Vyvanse Therapy

• Ensure adequate dosing and duration of trial before adding medications 2
• Vyvanse (lisdexamfetamine) is a prodrug that requires enzymatic hydrolysis to release active d-amphetamine, providing consistent pharmacokinetics with low intrasubject variability 3
• Assess medication adherence, as once-daily dosing formulations like Vyvanse generally improve compliance 4

Second: Add Alpha-2 Agonists as First-Line Adjunctive Therapy

• Guanfacine extended-release (1-4 mg daily) or extended-release clonidine are the preferred add-on options, as they are FDA-approved for adjunctive use with stimulants 1
• These agents require 2-4 weeks to achieve full therapeutic effect 1
• Administer in the evening due to somnolence/fatigue as common adverse effects 1
• Particularly useful if sleep disturbances or tics are present 1
• Monitor blood pressure and pulse regularly, as these are alpha-2 adrenergic agonists 5

Third: Consider Atomoxetine for Specific Situations

• Atomoxetine (60-100 mg daily) can be added if there is comorbid anxiety or concerns about substance misuse 1
• Requires 2-4 weeks to achieve full effect, unlike stimulants which work within days 1
• Critical warning: Monitor closely for suicidality and clinical worsening, especially during the first few months or at dose changes, as atomoxetine carries an FDA black box warning for increased suicidal ideation 1
• Be aware that SSRIs can elevate serum atomoxetine levels through CYP2D6 inhibition, requiring dose adjustment if the patient is on concurrent antidepressants 1

Managing Comorbid Conditions

If Depression Emerges or Persists

• Add an SSRI to the Vyvanse regimen rather than switching medications, as there are no significant drug-drug interactions between stimulants and SSRIs 1
• SSRIs remain the treatment of choice for depression and are weight-neutral with long-term use 1
• Do not assume a single antidepressant like bupropion will effectively treat both ADHD and depression—no single antidepressant is proven for this dual purpose 1

If Considering Bupropion as Add-On

• Bupropion can be added to enhance ADHD symptom control, particularly when stimulants alone are insufficient 1
• Start with bupropion SR 100-150 mg daily or XL 150 mg daily 1
• Titrate to maintenance doses of 100-150 mg twice daily (SR) or 150-300 mg daily (XL), with a maximum of 450 mg per day 1
• Monitor closely for seizure risk, which increases with the combination of bupropion and stimulants, particularly at higher bupropion doses 1
• Be cautious about bupropion's activating properties—it can exacerbate anxiety, agitation, insomnia, and hyperactivity 1

Critical Safety Considerations

Absolute Contraindications

• Never use MAO inhibitors concurrently with Vyvanse or bupropion due to risk of hypertensive crisis and potential cerebrovascular accidents 1
• Allow at least 14 days between discontinuation of an MAOI and initiation of stimulants or bupropion 1

Special Populations

• For patients with substance abuse history, Vyvanse may actually be preferred due to its prodrug formulation, which provides lower abuse potential compared to immediate-release amphetamines 6
• One case report demonstrated successful treatment with lisdexamfetamine in a patient with methamphetamine use disorder, with decreased cravings and no relapse 6
• Consider long-acting formulations like Vyvanse as they are resistant to diversion and tampering 1

Monitoring Parameters When Adding Medications

• Blood pressure and pulse at baseline and regularly during treatment 5
• Height and weight, particularly in younger patients 1
• Sleep disturbances and appetite changes 1
• Suicidality and clinical worsening if using atomoxetine 1
• Cardiovascular effects, though less pronounced with non-stimulant add-ons 1

Common Pitfalls to Avoid

• Do not switch from Vyvanse to bupropion monotherapy—bupropion is a second-line agent for ADHD with weaker evidence compared to stimulants 1
• Avoid benzodiazepines for comorbid anxiety, as they may reduce self-control and have disinhibiting effects 1
• Do not prescribe tricyclic antidepressants due to greater lethal potential in overdose and second-line status for ADHD 1
• Avoid assuming that inadequate response means treatment failure—multimodal approaches combining medications are common in clinical practice and recommended by guidelines 4