Is there any pharmacokinetic or clinical interaction between lisdexamfetamine (Vyvanse) and brexpiprazole (Rexulti) when taken together?

Drug Interaction Between Vyvanse and Rexulti

There is no clinically significant pharmacokinetic or pharmacodynamic interaction between lisdexamfetamine (Vyvanse) and brexpiprazole (Rexulti) when taken together, and these medications can be safely co-administered without dose adjustments.

Pharmacologic Basis for Lack of Interaction

Different Metabolic Pathways

• Lisdexamfetamine is a prodrug that is converted to dextroamphetamine primarily through enzymatic hydrolysis in red blood cells and other tissues, not through hepatic cytochrome P450 enzymes 1
• Brexpiprazole is metabolized primarily through CYP3A4 and CYP2D6 hepatic pathways, which are completely separate from amphetamine metabolism 2, 3
• Because these drugs are metabolized through entirely different pathways, no pharmacokinetic interaction is expected 4

Distinct Mechanisms of Action

• Vyvanse works by increasing dopamine and norepinephrine release and inhibiting their reuptake in the prefrontal cortex, enhancing executive function and attention 1
• Rexulti functions as a partial agonist at dopamine D2 and serotonin 5-HT1A receptors and an antagonist at serotonin 5-HT2A receptors, with lower intrinsic activity at D2 receptors than other antipsychotics 3, 5
• While both affect dopamine systems, their mechanisms are complementary rather than antagonistic—Vyvanse increases dopamine availability while Rexulti modulates dopamine receptor activity 2

Clinical Evidence Supporting Co-Administration

Direct Evidence from Treatment-Resistant ADHD

• A controlled trial specifically examined brexpiprazole combined with stimulants (including lisdexamfetamine) in 236 adults with treatment-resistant ADHD, demonstrating that adverse effects on brexpiprazole plus stimulant were equivalent to placebo plus stimulant, with no safety signals suggesting problematic interactions 6
• This study found trends toward benefit in emotional dysregulation symptoms when brexpiprazole was added to stimulants in prior stimulant nonresponders, suggesting potential therapeutic synergy rather than antagonism 6

No Overlapping Dose-Limiting Toxicities

• The primary side effects of Vyvanse include decreased appetite, insomnia, irritability, and cardiovascular effects (increased heart rate and blood pressure) 4
• The primary side effects of Rexulti include akathisia (5.5-8.6%), modest weight gain, and minimal effects on prolactin or QT interval 3, 7
• These side effect profiles do not overlap significantly, reducing the risk of additive toxicity 7

Monitoring Recommendations

Cardiovascular Parameters

• Monitor blood pressure and heart rate at baseline and periodically, as both medications can affect cardiovascular parameters—Vyvanse through sympathetic stimulation and Rexulti through alpha-1B receptor effects 8, 3
• Check for orthostatic hypotension, particularly during Rexulti initiation, as this can occur independently of stimulant use 3

Psychiatric Symptoms

• Monitor for akathisia, which occurs in 5.5-8.6% of patients on Rexulti and could potentially be misinterpreted as stimulant-induced restlessness 7, 5
• Assess for changes in mood, anxiety, or psychotic symptoms, as both medications affect dopaminergic and serotonergic systems 6

Metabolic Effects

• Track weight changes, as Vyvanse typically causes weight loss while Rexulti causes modest weight gain (mean increase of 2-3 kg in short-term trials), potentially offsetting each other 4, 7
• Monitor glucose and lipid parameters if using Rexulti long-term, though effects are generally small 7

Common Clinical Scenarios

ADHD with Comorbid Depression or Psychosis

• This combination is specifically indicated when treating ADHD patients who also have major depressive disorder inadequately responsive to antidepressants alone, or those with psychotic features 6, 5
• Start Vyvanse at 20-30 mg daily and titrate by 10 mg weekly to maximum 70 mg daily 4, 8
• Start Rexulti at 0.5-1 mg daily and titrate to target dose of 2-4 mg daily over 1-2 weeks 3, 7

Treatment-Resistant ADHD

• Consider adding Rexulti 2-3 mg daily to ongoing stimulant therapy in patients who have failed 2 or more stimulants, particularly if emotional dysregulation is prominent 6
• This approach showed trends toward benefit in controlled trials, though the primary outcome measure did not reach statistical significance 6

Important Caveats

Contraindications Apply to Each Drug Independently

• Avoid Vyvanse in patients with uncontrolled hypertension, coronary artery disease, tachyarrhythmias, or active substance use disorders 8
• Use Rexulti cautiously in elderly patients with dementia-related psychosis due to increased mortality risk (black box warning) 3

No Dose Adjustments Required

• Neither medication requires dose adjustment when used together, as no pharmacokinetic interaction exists 4, 6
• Titrate each medication independently to therapeutic effect based on its own dosing guidelines 8, 3

Theoretical Concerns Are Not Clinically Relevant

• While some clinicians worry that Rexulti's dopamine partial agonism might antagonize Vyvanse's dopamine-enhancing effects, clinical trial data show this does not occur at therapeutic doses 6
• The lower intrinsic activity of brexpiprazole at D2 receptors compared to other antipsychotics makes it less likely to interfere with stimulant efficacy 3