What could be causing daily afternoon headaches in a patient with depression, anxiety, and Attention Deficit Hyperactivity Disorder (ADHD) who recently started taking Wellbutrin (bupropion) 100mg SR for anxiety and depression, in addition to Adderall (amphetamine) IR and XR for ADHD, and Guanfacine (guanfacine) at night?

Afternoon Headaches in Patient on Wellbutrin and Stimulants

The afternoon headaches are most likely caused by the Wellbutrin (bupropion) itself, as headache is a common adverse effect that typically emerges within the first few weeks of treatment, and the timing corresponds with the 12-day initiation period. 1, 2

Primary Cause: Bupropion-Induced Headache

Bupropion commonly causes headaches as a direct adverse effect, particularly during the initial weeks of treatment. 2, 3 The temporal relationship—starting 12 days after Wellbutrin initiation—strongly suggests medication-induced headache rather than other causes. 4

Why the Afternoon Timing?

The afternoon timing is clinically significant and points to several potential mechanisms:

• The patient is taking 100 mg Wellbutrin SR once daily, but the standard therapeutic dose is 150 mg twice daily (300 mg total). 1 This subtherapeutic single daily dose may create fluctuating drug levels that manifest as afternoon headaches when levels peak or trough.
• The second dose of Adderall XR (15 mg in the afternoon) may be interacting with bupropion levels, as both medications affect dopaminergic and noradrenergic systems. 3, 5
• Stimulant medications themselves can cause headaches, and the combination of Adderall IR in the morning plus Adderall XR in the afternoon creates overlapping stimulant effects that may be exacerbated by bupropion. 6

Critical Dosing Error

The current Wellbutrin dosing regimen (100 mg SR once daily) is incorrect and subtherapeutic. 1 The American Family Physician recommends:

• Starting with 150 mg once daily for 3 days
• Then increasing to 150 mg twice daily (300 mg total)
• The second dose should be taken before 3 PM to minimize insomnia risk 1

Taking only 100 mg once daily may create unstable drug levels that contribute to afternoon headaches. 1

Immediate Management Strategy

Step 1: Treat the Headache Symptomatically

Use NSAIDs (ibuprofen, naproxen sodium, or aspirin) as first-line treatment for the headaches. 7 These have the strongest evidence for medication-induced headaches. 8, 7

• Acetaminophen alone is ineffective and should not be used as monotherapy. 7
• Limit acute headache medication use to no more than 2 days per week to prevent medication-overuse headache. 7, 9

Step 2: Correct the Bupropion Dosing

The patient needs proper dose titration of Wellbutrin SR:

• Increase to 150 mg once daily first
• After 3-7 days, advance to 150 mg twice daily (morning and early afternoon before 3 PM) 1
• This proper dosing may paradoxically resolve the headaches by providing more stable drug levels

Step 3: Monitor for 6-8 Weeks

Allow 6-8 weeks at the therapeutic dose (300 mg/day) before determining if bupropion is effective or if the headaches persist. 1 Most adverse effects, including headaches, often resolve after the initial adjustment period. 3

Alternative Considerations

Stimulant-Related Factors

The unusual Adderall dosing pattern (10 mg IR morning + 15 mg XR afternoon) may be contributing:

• This creates overlapping stimulant effects in the afternoon when both medications are active
• Stimulants can cause headaches independently, and the combination with bupropion may be additive 6
• Consider consolidating to a single extended-release formulation taken in the morning

Medication Overuse Risk

If the patient is using any acute headache medications (analgesics, triptans) more than 2 days per week, this could be causing medication-overuse headache. 7, 9

• Daily use of symptomatic medications results in chronic daily headache 9
• Completely avoid medications containing barbiturates, caffeine, butalbital, or opioids as these carry the highest risk 7

When to Consider Preventive Therapy

If headaches persist after proper bupropion dosing and continue for 2 or more attacks per month producing disability for 3+ days per month, start preventive therapy. 7

First-line preventive option: Amitriptyline 30-150 mg/day has the strongest evidence and is particularly beneficial when psychiatric comorbidity exists (depression, anxiety). 7

Critical Safety Monitoring

Monitor for neuropsychiatric adverse effects, especially:

• Worsening depression or anxiety
• Suicidal ideation (highest risk in first 1-2 months and in patients under 24 years) 1, 2
• Agitation, irritability, or mood changes 2
• Blood pressure elevation, as bupropion can cause hypertension, particularly when combined with stimulants 2

Common Pitfall to Avoid

Do not discontinue bupropion prematurely due to headaches. 1 Many adverse effects resolve after the initial weeks, and the patient is on a subtherapeutic dose. Proper dose titration to 300 mg/day divided into two doses may actually resolve the afternoon headaches by providing more stable drug levels throughout the day.