What is the appropriate dose and form of Wellbutrin (bupropion) for a patient with Attention Deficit Hyperactivity Disorder (ADHD)?

Bupropion for ADHD: Dosing and Formulation

Bupropion extended-release (XL or SR) at 300-450 mg daily is the appropriate dose and formulation for adults with ADHD, though it should be considered only as a second-line option after stimulants have failed or are contraindicated. 1, 2

Position in Treatment Algorithm

Bupropion is explicitly positioned as a second-line agent for ADHD treatment. 3, 1 Stimulants (methylphenidate or amphetamines) remain the gold standard first-line treatment with 70-80% response rates and the largest effect sizes from over 161 randomized controlled trials. 1, 4 The American Academy of Child and Adolescent Psychiatry recommends trying all three stimulant classes (methylphenidate, dextroamphetamine, and mixed amphetamine salts) before turning to antidepressants like bupropion. 3

Consider bupropion when:

• Two or more stimulants have failed or caused intolerable side effects 3, 1
• Active substance abuse disorder is present (stimulants are contraindicated) 1, 5
• Comorbid depression requires treatment alongside ADHD 1, 2
• Patient has concerns about stimulant misuse or diversion 1
• Smoking cessation is a concurrent treatment goal 6

Specific Dosing Recommendations

Extended-Release Formulations (Preferred)

Bupropion XL (once-daily):

• Starting dose: 150 mg once daily in the morning 1, 2
• Target dose: 300 mg once daily 1, 2
• Maximum dose: 450 mg once daily 1, 2
• Titration: Increase by 150 mg weekly as tolerated 2

Bupropion SR (twice-daily):

• Starting dose: 100-150 mg once daily 1, 5
• Target dose: 150-200 mg twice daily (300-400 mg total daily) 1, 5
• Maximum dose: 200 mg twice daily (400 mg total daily) 5
• Titration: Increase weekly to target dose 5

Time to Effect

Bupropion works more rapidly than atomoxetine (which requires 6-12 weeks), though not as quickly as stimulants which work within days. 1, 4 Clinical response may be observed as early as 2 weeks, with full assessment at 6-8 weeks. 2

Evidence for Efficacy

A Cochrane systematic review found low-quality evidence that bupropion decreased ADHD symptom severity (standardized mean difference -0.50) and increased the proportion achieving clinical improvement (risk ratio 1.50) compared to placebo. 6 The largest randomized controlled trial showed 53% of bupropion XL responders versus 31% placebo responders at 8 weeks, with a treatment effect size of 0.6. 2

In a 6-week Iranian trial, bupropion 150 mg daily showed significant superiority over placebo in reducing ADHD symptoms on the Conners' Adult ADHD Rating Scale. 7

Special Populations

ADHD with Comorbid Substance Use Disorders:

• Bupropion SR (target 200 mg twice daily) showed clinically significant reductions in ADHD symptoms (-43%) but negligible effects on substance use in an open trial of 32 adults with active substance use disorders. 5
• This makes bupropion useful for treating ADHD when stimulants are contraindicated due to active substance abuse. 5

ADHD with Comorbid Bipolar Disorder:

• Bupropion SR (up to 200 mg twice daily) showed significant reductions in ADHD symptoms (-55%) without significant activation of mania in adults with bipolar disorder receiving adjunct mood stabilizers. 8
• This suggests bupropion may be safe in stabilized bipolar patients, though controlled trials are needed. 8

ADHD with Comorbid Depression:

• Bupropion is particularly useful when both ADHD and depression require treatment, as it has proven efficacy for depression and may address both conditions. 1, 2
• However, no single antidepressant is proven to effectively treat both ADHD and depression simultaneously—if ADHD improves but depression persists, adding an SSRI to the regimen is recommended. 1

Critical Safety Considerations

Seizure Risk:

• Bupropion lowers the seizure threshold, particularly at higher doses. 1
• The combination of bupropion and stimulants may increase seizure risk, requiring careful monitoring. 1
• Maximum daily dose should not exceed 450 mg to minimize seizure risk. 2

Common Adverse Effects:

• Headache, insomnia, and anxiety are the most common side effects. 1
• Bupropion is inherently activating and can exacerbate anxiety or agitation, making it potentially problematic for patients with prominent hyperactivity or anxiety. 1
• Monitor closely for worsening hyperactivity, insomnia, anxiety, and agitation during the first 2-4 weeks. 1

Drug Interactions:

• MAO inhibitors should never be used concurrently with bupropion due to risk of hypertensive crisis—at least 14 days should elapse between discontinuation of an MAOI and initiation of bupropion. 1
• There are no significant pharmacokinetic interactions between bupropion and stimulants or SSRIs. 1

Monitoring Requirements

• Screen for suicidality, particularly when bupropion is used in patients with comorbid depression. 1
• Evaluate blood pressure and pulse, though cardiovascular effects are less pronounced than with stimulants. 1
• Assess for worsening anxiety, agitation, or insomnia during initial titration. 1
• If no symptomatic improvement occurs within 6-8 weeks at therapeutic doses, consider alternative treatments. 2

Common Pitfalls to Avoid

• Do not assume bupropion alone will adequately treat both ADHD and depression—evidence shows no single antidepressant is proven for this dual purpose. 1
• Do not use bupropion as first-line treatment—stimulants have superior efficacy and should be tried first unless contraindicated. 3, 1
• Do not prescribe bupropion first-line when prominent hyperactivity or anxiety is present—its activating properties can worsen these symptoms. 1
• Do not exceed 450 mg daily—higher doses significantly increase seizure risk without proven additional benefit. 2
• Do not combine with MAO inhibitors—this combination can cause severe hypertensive crisis. 1