What is the likely cause of headaches, fatigue, and brain fog in a patient taking 60mg of Strattera (Atomoxetine) for approximately three weeks, who recently added 100mg of Wellbutrin (Bupropion) SR three days ago?

Likely Cause of Symptoms: Bupropion-Related Side Effects

The headaches, fatigue, and brain fog are most likely caused by the recently added Wellbutrin (bupropion), particularly because the patient is taking a subtherapeutic dose of 100 mg SR once daily, which creates unstable drug levels that can contribute to these symptoms. 1

Primary Culprit: Bupropion

Common Side Effects Profile

• Headache is one of the most common adverse effects of bupropion, occurring frequently in clinical trials alongside nausea, insomnia, and dizziness. 2
• The timing is highly suggestive: symptoms appeared within 3 days of starting bupropion, which aligns with the typical onset of medication-related adverse effects. 2
• Fatigue and cognitive symptoms (brain fog) can occur with bupropion, though paradoxically, bupropion is sometimes used to treat brain fog in other contexts. 3

Dosing Problem

• The patient is taking only 100 mg SR once daily, which is below the standard therapeutic dose of 150 mg twice daily. 1
• This subtherapeutic dosing creates unstable drug levels that may contribute to afternoon headaches and other symptoms. 1
• The American Family Physician recommends starting with 150 mg once daily for 3 days, then increasing to 150 mg twice daily, with the second dose taken before 3 PM to minimize side effects. 1

Contributing Factor: Atomoxetine (Strattera)

Atomoxetine Side Effect Profile

• Headache is a common adverse event with atomoxetine, along with abdominal pain, decreased appetite, vomiting, somnolence, and nausea. 4
• The patient has been on Strattera for 3 weeks, which is typically past the initial adjustment period, making it less likely to be the primary cause of new-onset symptoms. 4
• However, atomoxetine can cause fatigue and somnolence, which may be contributing to the overall symptom burden. 4

Drug Interaction Considerations

Potential Pharmacokinetic Interaction

• While there is no direct evidence of a clinically significant interaction between atomoxetine and bupropion in the provided literature, both medications affect norepinephrine systems. 4
• Atomoxetine is extensively metabolized by CYP2D6, and patients who are poor metabolizers have greater exposure and slower elimination. 4
• Bupropion is not specifically mentioned as a CYP2D6 inhibitor in the evidence provided, but the combination of two norepinephrine-active agents may have additive effects on blood pressure and heart rate. 2, 4

Management Algorithm

Immediate Steps

1. Treat the headaches with NSAIDs (ibuprofen, naproxen sodium, or aspirin) as first-line therapy, which have the strongest evidence for medication-induced headaches. 1
2. Limit acute headache medication use to no more than 2 days per week to prevent medication-overuse headache. 1
3. Do not use acetaminophen alone, as it is ineffective for headaches. 1

Bupropion Dose Adjustment

• Increase Wellbutrin SR to the proper therapeutic dose: 150 mg once daily first, then advance to 150 mg twice daily after 3-7 days. 1
• Take the second dose before 3 PM to minimize insomnia risk. 1
• This proper titration may actually resolve the symptoms by creating more stable drug levels. 1

Monitoring Period

• Monitor for neuropsychiatric adverse effects, especially worsening depression, anxiety, suicidal ideation, agitation, irritability, or mood changes, particularly in the first 1-2 months. 1
• Watch for "jittery"/anxious/agitated symptoms, as these can be harbingers of more serious effects with bupropion. 5
• Monitor blood pressure and heart rate, as both medications can cause increases. 2, 4

If Symptoms Persist After Proper Dosing

• If headaches continue for 2 or more attacks per month producing disability for 3+ days per month after proper bupropion dosing, start preventive therapy with amitriptyline 30-150 mg/day, which has the strongest evidence for headache prevention. 1, 6
• Consider discontinuing bupropion if symptoms do not improve with proper dosing and supportive management. 2

Critical Pitfalls to Avoid

• Do not continue the subtherapeutic 100 mg SR once daily dose, as this creates unstable drug levels. 1
• Do not assume the symptoms are from Strattera alone simply because it was started first; the temporal relationship strongly implicates bupropion. 1
• Do not overlook the possibility of seizures with bupropion, though the risk is low at therapeutic doses (less than 1 per 1,000 at usual outpatient doses). 7
• Do not use multiple acute headache medications frequently, as this can lead to medication-overuse headache. 1, 6