For an adult with co‑occurring major depressive disorder and attention‑deficit/hyperactivity disorder, is Wellbutrin (bupropion) an appropriate first‑line treatment and what dosing, contraindications, and monitoring are recommended?

Wellbutrin (Bupropion) for Co‑Occurring Depression and ADHD in Adults

Bupropion is a reasonable second‑line option for adults with both major depressive disorder and ADHD, but stimulants remain the gold standard first‑line treatment for ADHD, and SSRIs remain first‑line for depression; the optimal approach is to treat ADHD with a stimulant first, then add an SSRI if depressive symptoms persist after 6–8 weeks of optimized stimulant therapy. 1

Treatment Algorithm Based on Symptom Severity

When ADHD Is the Primary Functional Impairment

• Initiate a stimulant medication trial (methylphenidate 5–20 mg three times daily or dextroamphetamine 5 mg three times daily to 20 mg twice daily) as first‑line therapy, because stimulants achieve 70–80% response rates with the largest effect sizes (≈1.0) and work within days, allowing rapid assessment of ADHD symptom control. 1, 2
• If ADHD symptoms improve but depressive symptoms persist after 6–8 weeks of optimized stimulant dosing, add an SSRI (such as sertraline or fluoxetine) to the stimulant regimen; this combination is well‑established, safe, and has no significant pharmacokinetic interactions. 1
• No single antidepressant—including bupropion—is proven to effectively treat both ADHD and depression simultaneously; bupropion is explicitly positioned as a second‑line agent for ADHD compared to stimulants. 1, 2

When Depression Is Severe or Primary

• If major depressive disorder presents with severe symptoms (psychosis, suicidality, or marked neurovegetative signs), address the mood disorder first before initiating ADHD‑specific medication. 1
• Once mood symptoms are stabilized, initiate stimulant therapy for ADHD; treating mood symptoms alone leaves ADHD‑related functional deficits unaddressed and fails to restore optimal quality of life. 1

When to Consider Bupropion as First‑Line

Bupropion should be selected as first‑line treatment only in specific clinical scenarios where stimulants are contraindicated or inappropriate:

• Active substance use disorder – Bupropion is an uncontrolled substance with no abuse potential, making it preferable when diversion or misuse risk is high. 2
• Comorbid smoking cessation needs – Bupropion is FDA‑approved for smoking cessation and addresses both depression and nicotine dependence simultaneously. 2, 3
• Uncontrolled hypertension – Bupropion produces less pronounced cardiovascular effects than stimulants. 2
• Two or more failed stimulant trials – After adequate trials of both methylphenidate and amphetamine classes have failed or caused intolerable side effects, bupropion becomes a reasonable alternative. 1, 2

Dosing and Titration of Bupropion

• Start bupropion SR at 100–150 mg once daily in the morning, or bupropion XL at 150 mg once daily. 1, 2
• Titrate to maintenance doses of 100–150 mg twice daily (SR) or 150–300 mg once daily (XL) based on response and tolerability. 1
• Maximum dose is 450 mg per day; doses above this threshold significantly increase seizure risk. 1, 2
• Bupropion requires 2–4 weeks to achieve therapeutic effect for ADHD symptoms, which is slower than stimulants (days) but faster than atomoxetine (6–12 weeks). 2

Evidence for Efficacy

• Low‑quality evidence from a Cochrane systematic review indicates that bupropion decreases ADHD symptom severity (standardized mean difference −0.50) and increases the proportion of patients achieving clinical improvement (risk ratio 1.50) compared to placebo. 4
• Bupropion has medium‑range effect sizes (≈0.7) for ADHD, which are smaller than stimulants (≈1.0), confirming its second‑line status. 2
• For depression, bupropion is as efficacious as SSRIs (such as escitalopram) and has the advantage of less sexual dysfunction and less somnolence. 5
• In the STAR*D trial, augmenting citalopram with bupropion resulted in lower discontinuation rates due to adverse events (12.5%) compared to buspirone augmentation (20.6%), but switching from one SSRI to another (e.g., citalopram to sertraline) showed no difference in response or remission rates. 6

Absolute Contraindications

Do not prescribe bupropion in the following situations:

• Current or prior seizure disorder (bupropion lowers the seizure threshold). 2
• Active eating disorders (anorexia nervosa or bulimia nervosa) due to increased seizure risk. 2
• Abrupt discontinuation of alcohol, benzodiazepines, or antiepileptic drugs (precipitates withdrawal seizures). 2
• Concurrent MAO inhibitor use or within 14 days of MAO inhibitor discontinuation (risk of hypertensive crisis). 1, 2

Monitoring Requirements

Baseline Assessment

• Measure blood pressure and pulse (bupropion has less pronounced cardiovascular effects than stimulants but still requires monitoring). 2
• Screen for seizure risk factors, eating disorders, substance use history, and suicidality (bupropion carries a black‑box warning for increased suicidal ideation in young adults during the first few months of treatment). 2

Ongoing Monitoring

• Schedule weekly contact during titration and monthly visits during maintenance. 2
• Monitor blood pressure, pulse, mood changes, and ADHD symptom response using standardized rating scales. 2
• Assess for common side effects: headache, insomnia, anxiety, dry mouth, nausea, and constipation. 2, 3

Combination Therapy: Bupropion Plus Stimulants

• If bupropion alone provides inadequate ADHD symptom control after 4–6 weeks at therapeutic doses, adding a stimulant (methylphenidate or amphetamine) to bupropion may enhance the effect on ADHD symptoms. 1
• There are no significant pharmacokinetic interactions between bupropion and stimulants, but careful monitoring for side effects (particularly insomnia, anxiety, and cardiovascular effects) is necessary. 1
• The combination of bupropion and stimulants may increase the risk of seizures, particularly at higher doses of bupropion (>450 mg/day). 1

Common Pitfalls to Avoid

• Do not assume bupropion will effectively treat both ADHD and depression as monotherapy; evidence explicitly states no single antidepressant is proven for this dual purpose, and bupropion is a second‑line agent for ADHD treatment compared to stimulants. 1
• Do not use bupropion as first‑line when stimulants are appropriate; over 161 randomized controlled trials support stimulants as the gold standard for ADHD, with 70–80% response rates and the largest effect sizes. 2
• Do not overlook bupropion's activating properties; it is inherently activating and can exacerbate anxiety, agitation, or hyperactivity, making it potentially problematic for patients with prominent anxiety or hyperactive symptoms. 1
• Do not combine bupropion with MAO inhibitors; at least 14 days must elapse between discontinuation of an MAOI and initiation of bupropion due to the risk of hypertensive crisis. 1, 2

Special Populations

Bipolar Disorder

• For patients with confirmed bipolar disorder, mood stabilizers must be established and optimized before initiating any stimulant or bupropion. 1
• An open trial in adults with ADHD and bipolar disorder (90% bipolar II) showed that bupropion SR (up to 200 mg twice daily) resulted in significant reductions in ADHD symptoms (−55%) without significant activation of mania, but this was an uncontrolled study requiring further validation. 7

Pregnancy

• Bupropion may be considered as an alternative to stimulants during pregnancy, but it has been associated with a small increased risk of certain cardiovascular malformations in first‑trimester exposure. 1
• Continuing stimulant therapy during pregnancy is advised when ADHD symptoms cause significant functional impairment, because abrupt discontinuation may worsen maternal mental health and adversely affect fetal development. 1