In a patient with major depressive disorder well controlled on mirtazapine 30 mg daily who has suspected attention‑deficit/hyperactivity disorder and is currently on bupropion 150 mg with minimal response, what are the recommended next steps according to CANMAT guidelines?

Recommended Next Steps for ADHD Management in a Patient on Mirtazapine with Inadequate Bupropion Response

Increase bupropion to 300 mg daily (150 mg twice daily) and reassess after 6–8 weeks; if ADHD symptoms remain inadequately controlled, add a stimulant medication (methylphenidate or lisdexamfetamine) to the regimen. 1

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Primary Recommendation: Optimize Bupropion Dosing First

• Your patient is currently on a subtherapeutic dose of bupropion (150 mg) for ADHD. The standard therapeutic range for bupropion in ADHD is 300 mg daily, administered as 150 mg twice daily for the sustained-release formulation. 2

• Titrate bupropion to 300 mg daily by adding a second 150 mg dose in the early afternoon (before 3 PM to minimize insomnia risk). 2 This dose escalation is necessary because bupropion demonstrates a dose-response relationship for ADHD symptoms, and 150 mg is at the lower end of the therapeutic spectrum. 1

• Maintain this dose for a full 6–8 weeks before concluding that bupropion has failed, as this is the standard timeframe required to assess adequate antidepressant and ADHD response. 2

• Monitor weekly during titration for blood pressure, pulse, sleep quality, appetite changes, and any emergence of agitation or anxiety. 1 Bupropion can elevate blood pressure and heart rate, particularly in the first 12 weeks. 2

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If Bupropion Optimization Fails: Add a Stimulant

• Stimulants remain the gold standard for ADHD treatment, with 70–80% response rates and the largest effect sizes from over 161 randomized controlled trials. 1 Bupropion is explicitly positioned as a second-line agent for ADHD. 1

• Add a long-acting stimulant to the existing regimen rather than discontinuing bupropion, because:

  • The patient's depression is well controlled on mirtazapine, and bupropion may be contributing to mood stability through its noradrenergic/dopaminergic effects. 3
  • Combination therapy (stimulant plus antidepressant) is safe, well-established, and addresses ADHD through complementary mechanisms. 1
  • There are no significant pharmacokinetic interactions between bupropion and stimulants. 1

• Preferred stimulant options include:

  • Methylphenidate extended-release (e.g., Concerta): Start at 18 mg once daily in the morning, titrate by 18 mg weekly up to 54–72 mg daily maximum. 1 Methylphenidate has the most robust clinical trial data and highest response rates among all ADHD medications. 1
  • Lisdexamfetamine (Vyvanse): Start at 20–30 mg once daily in the morning, titrate by 10 mg weekly up to 70 mg daily maximum. 1 This is a prodrug formulation with lower abuse potential and once-daily dosing that improves adherence. 1

• Monitor blood pressure and pulse at baseline and at each titration visit, as both bupropion and stimulants can elevate cardiovascular parameters. 1

• Assess ADHD symptom response within days to weeks after starting the stimulant, as stimulants work rapidly (unlike bupropion, which requires 6–8 weeks). 1

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Why Not Switch Bupropion to a Stimulant Immediately?

• Bupropion is already on board and may be contributing to mood stability in a patient with well-controlled depression. Discontinuing it abruptly could destabilize mood, particularly since around 10% of adults with recurrent depression also have ADHD, and treatment of depression alone is often inadequate when ADHD remains unaddressed. 1

• The current bupropion dose (150 mg) is subtherapeutic for ADHD, so you have not yet given bupropion a fair trial at the recommended 300 mg daily dose. 2

• Augmentation with a stimulant is a well-established strategy when bupropion alone is insufficient for ADHD, and the combination is safe with no significant drug-drug interactions. 1

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Critical Safety Considerations

• Do not exceed bupropion 450 mg/day (or 400 mg/day for sustained-release formulations) to maintain seizure risk at approximately 0.1%. 2 At 300 mg daily, seizure risk remains very low. 2

• Avoid bupropion if the patient has:

  • A history of seizures, epilepsy, or any condition predisposing to seizures (e.g., head trauma, brain tumor, stroke). 2
  • Current or recent use of MAO inhibitors (within 14 days). 2
  • Eating disorders (bulimia or anorexia nervosa), as these increase seizure risk. 2
  • Uncontrolled hypertension. 2

• Stimulants are contraindicated in:

  • Active psychosis or mania. 1
  • Symptomatic cardiovascular disease or uncontrolled hypertension. 1
  • Concurrent or recent MAOI use (within 14 days). 1

• Monitor for suicidal ideation, particularly in patients under 24 years of age, as all antidepressants (including bupropion) carry an FDA black-box warning for increased risk of suicidal thoughts in this age group. 2

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Alternative Approach: Non-Stimulant Options

• If stimulants are contraindicated or not tolerated, consider atomoxetine (60–100 mg daily) as a non-controlled alternative. 1 However, atomoxetine requires 6–12 weeks to achieve full therapeutic effect (much slower than stimulants) and has medium-range effect sizes (approximately 0.7 compared to stimulants). 1

• Atomoxetine is particularly useful if:

  • The patient has a history of substance abuse (it is an uncontrolled substance with no abuse potential). 1
  • Comorbid anxiety is present (atomoxetine has evidence supporting its use in ADHD with comorbid anxiety). 1

• Alpha-2 agonists (guanfacine or clonidine extended-release) are additional non-stimulant options, particularly if sleep disturbances, tics, or disruptive behavior disorders are present. 1 These require 2–4 weeks for full effect. 1

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Common Pitfalls to Avoid

• Do not assume bupropion has failed at 150 mg daily. This is a subtherapeutic dose for ADHD, and you must titrate to 300 mg daily and wait 6–8 weeks before concluding inadequate response. 2

• Do not discontinue mirtazapine. The patient's depression is well controlled on mirtazapine 30 mg, and there is no indication to change this regimen. Mirtazapine is effective for major depression and has a favorable tolerability profile. 4, 5, 6

• Do not combine bupropion with MAOIs or initiate within 14 days of MAOI discontinuation, as this can precipitate hypertensive crisis. 2

• Do not skip cardiovascular monitoring when combining bupropion and stimulants, as both can elevate blood pressure and heart rate. 1, 2

• Do not exceed bupropion 450 mg/day to avoid significantly increasing seizure risk. 2

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Monitoring Timeline

• Weeks 1–2: Monitor for early adverse effects from bupropion dose increase (insomnia, agitation, headache, nausea). 2 Assess blood pressure and pulse. 2

• Weeks 6–8: Formally assess ADHD symptom response to bupropion 300 mg daily using standardized rating scales. 1 If inadequate response, proceed to add a stimulant.

• After stimulant initiation: Assess ADHD symptom response within days to weeks, as stimulants work rapidly. 1 Continue weekly monitoring of blood pressure, pulse, sleep, and appetite during stimulant titration. 1

• Long-term: Once ADHD symptoms are controlled, continue both medications (mirtazapine for depression, bupropion + stimulant for ADHD) with quarterly blood pressure and pulse checks. 1