Can an adult with ADHD and major depressive disorder (or who is attempting smoking cessation) be treated concurrently with bupropion and atomoxetine, and what are the appropriate dosing and monitoring recommendations?

Bupropion and Atomoxetine Combination Therapy for Adult ADHD with Comorbid Depression or Smoking Cessation

Concurrent use of bupropion and atomoxetine is feasible and can be considered when a patient with ADHD has comorbid major depressive disorder or is attempting smoking cessation, though stimulants remain the gold standard first-line treatment for ADHD. 1

Treatment Algorithm: When to Consider This Combination

Primary Recommendation: Optimize Monotherapy First

• Start with a stimulant medication (methylphenidate or amphetamine) as first-line treatment for ADHD, even when depression is present, as stimulants achieve 70-80% response rates and work within days, allowing rapid assessment of both ADHD and mood symptom response 1, 2
• If ADHD symptoms improve on stimulants but depressive symptoms persist, add an SSRI to the stimulant regimen rather than switching to bupropion or atomoxetine, as no single antidepressant is proven to effectively treat both ADHD and depression 1

When Bupropion + Atomoxetine Combination Makes Clinical Sense

Consider this combination specifically when:

• Active substance use disorder is present, as both medications are uncontrolled substances with no abuse potential 1, 3
• The patient requires smoking cessation support, as bupropion is FDA-approved for this indication and can address nicotine cravings while atomoxetine treats ADHD 4, 3
• Two or more stimulant trials have failed or caused intolerable side effects 1, 3
• Uncontrolled hypertension or symptomatic cardiovascular disease exists, as both medications have less pronounced cardiovascular effects than stimulants 1, 3
• Comorbid depression requires treatment and the patient has failed or cannot tolerate SSRIs, making bupropion's antidepressant properties advantageous 4, 3, 5

Dosing Recommendations

Atomoxetine Dosing

• Start atomoxetine at 40 mg orally once daily 1
• Titrate every 7-14 days: 40 mg → 60 mg → 80 mg daily 1
• Target therapeutic dose: 60-100 mg daily 1, 6
• Maximum dose: 1.4 mg/kg/day or 100 mg/day, whichever is lower 1, 6
• Atomoxetine requires 6-12 weeks to achieve full therapeutic effect, significantly longer than stimulants 1, 6

Bupropion Dosing

• Start bupropion SR at 100-150 mg once daily in the morning, or bupropion XL at 150 mg once daily 1, 3
• After 3 days, increase to bupropion SR 150 mg twice daily (or XL 300 mg once daily) if tolerated 4
• Maximum dose: 450 mg per day for immediate-release, 400 mg per day for sustained-release 3, 7
• Initiate dosing 1-2 weeks prior to smoking quit date when used for cessation 4

Sequencing the Combination

• Optimize atomoxetine to 60-100 mg daily before adding bupropion, as atomoxetine should reach therapeutic dosing first 1
• Once atomoxetine is at target dose for 2-4 weeks, add bupropion if ADHD symptoms remain inadequately controlled or depression/smoking cessation needs are unmet 1, 3

Critical Safety Considerations and Contraindications

Absolute Contraindications for Bupropion

• Current or prior seizure disorder 3, 7
• Eating disorders (anorexia nervosa or bulimia nervosa) 3
• Abrupt discontinuation of alcohol, benzodiazepines, or antiepileptic drugs 3
• Concurrent MAO inhibitor use or within 14 days of discontinuation 1, 3
• Brain metastases due to seizure risk 4
• Closed-angle glaucoma 4

Atomoxetine-Specific Warnings

• FDA black box warning for increased risk of suicidal ideation in children and adolescents; monitor closely for suicidality, clinical worsening, and unusual behavioral changes, especially during the first few months or at dose changes 1, 6
• Atomoxetine is contraindicated with MAO inhibitors or within 14 days of discontinuation 1

Drug Interaction: No Significant Pharmacokinetic Concerns

• There are no significant pharmacokinetic interactions between bupropion and atomoxetine, making concurrent use pharmacologically safe 1
• However, if the patient is also taking an SSRI, be aware that SSRIs can elevate serum atomoxetine levels through CYP2D6 inhibition, requiring dose adjustment 1

Monitoring Requirements

Baseline Assessment

• Blood pressure and pulse in both seated and standing positions 1, 3
• Screen for seizure risk factors, eating disorders, substance use history 3
• Assess for suicidality using standardized screening 1, 3
• Height and weight (establish baseline for growth monitoring) 1

During Titration

• Weekly contact to assess ADHD symptom response, side effects, and mood changes 1, 3
• Blood pressure and pulse at each dose adjustment 1, 3
• Systematic inquiry about suicidal ideation, especially with atomoxetine 1

Maintenance Phase

• Monthly follow-up visits 1, 3
• Blood pressure and pulse quarterly 1
• Height and weight at each visit 1
• Monitor for neuropsychiatric adverse effects including depression, suicidal ideation/behavior, hostility 4, 3

Common Adverse Effects

Bupropion

• Headache, insomnia, anxiety, dry mouth, nausea, constipation 3, 7
• Agitation and tremor 7
• Seizure risk increases at doses >450 mg/day 3, 7

Atomoxetine

• Somnolence and fatigue (most common) 1
• Decreased appetite and weight loss 1
• Nausea, dry mouth 6
• Cardiovascular effects (less pronounced than stimulants but still present) 1

Evidence Quality and Efficacy

Bupropion for ADHD

• Low-quality evidence shows bupropion decreased ADHD symptom severity (standardized mean difference -0.50) and increased the proportion achieving clinical improvement (RR 1.50) compared to placebo 8
• Bupropion is explicitly positioned as a second-line agent for ADHD, to be considered after stimulant failure 1, 3
• Effect sizes are smaller than stimulants, which have the largest effect sizes from over 161 randomized controlled trials 1, 3

Atomoxetine for ADHD

• Atomoxetine has medium-range effect sizes of approximately 0.7 compared to stimulants 1, 6
• Atomoxetine has been extensively studied and showed significant efficacy in treating adult ADHD 6, 9
• Atomoxetine is the only FDA-approved non-stimulant for adult ADHD 1, 6

Combination Therapy Rationale

• Adding bupropion to atomoxetine may enhance ADHD symptom control when atomoxetine monotherapy is insufficient 1
• Bupropion addresses comorbid depression and smoking cessation simultaneously, providing synergistic benefits for patients with multiple treatment goals 4, 3, 5

Common Pitfalls to Avoid

• Do not assume bupropion alone will adequately treat both ADHD and depression; no single antidepressant is proven for this dual purpose 1
• Do not prescribe atomoxetine first-line when fatigue is a chief complaint, as somnolence and fatigue are its most common adverse effects 1
• Do not underestimate the time to therapeutic effect for atomoxetine (6-12 weeks) compared to stimulants (days) or bupropion (2-4 weeks) 1, 7, 6
• Never combine either medication with MAO inhibitors due to severe risk of hypertensive crisis 1, 3
• Do not exceed bupropion maximum doses (450 mg/day IR, 400 mg/day SR) due to dose-dependent seizure risk 3, 7

Special Population: Smoking Cessation Context

• Bupropion at 150 mg twice daily (300 mg total daily dose) is FDA-approved for smoking cessation 4
• Limited data show the combination of sustained-release bupropion and naltrexone (not atomoxetine) reduced nicotine use and mitigated associated weight gain 4
• For patients requiring both ADHD treatment and smoking cessation, the bupropion + atomoxetine combination addresses both goals without stimulant-related concerns 4, 3