Medication Adjustment for Worsening Depression on Bupropion 100mg TID
For a patient on bupropion 100mg three times daily (300mg total) with worsening depression, the best medication adjustment is to augment with an SSRI such as sertraline (50-200mg daily) or escitalopram (10-20mg daily) rather than switching medications entirely. 1
Rationale for Augmentation Strategy
The current regimen of bupropion 100mg TID represents an unconventional dosing schedule. The FDA-approved formulations are sustained-release (SR) dosed twice daily or extended-release (XL) dosed once daily, not immediate-release three times daily 2. However, the total daily dose of 300mg is within therapeutic range.
Worsening depression after 6-8 weeks at an adequate dose indicates treatment failure requiring intervention. 1 Since this patient is already on a therapeutic dose of bupropion, augmentation is preferred over dose escalation.
Specific Augmentation Recommendations
Add one of the following SSRIs to the existing bupropion regimen:
- Sertraline 50-200mg daily - weight-neutral with long-term use and favorable tolerability profile 1
- Escitalopram 10-20mg daily - weight-neutral with favorable tolerability profile 1
The combination addresses depression through complementary mechanisms: sertraline/escitalopram affects serotonin pathways while bupropion works via noradrenergic/dopaminergic pathways 3. Evidence shows that augmenting SSRIs with bupropion (or vice versa) decreases depression severity more effectively than other augmentation strategies 1.
Why Keep Bupropion in the Regimen
Bupropion has significantly lower rates of sexual dysfunction compared to SSRIs alone (fluoxetine or sertraline), which favors maintaining it in combination therapy 1. Additionally, bupropion's activating properties may benefit patients with comorbid apathy or low energy 3.
Critical Monitoring Requirements
Assess response within 1-2 weeks of adding the SSRI, then regularly thereafter: 1
- Monitor for suicidal ideation, agitation, irritability, and unusual behavioral changes (especially critical in patients under 24 years) 1
- Evaluate depressive symptoms and functional improvement 1
- Screen for treatment-emergent adverse effects including serotonin syndrome when combining agents 1
The risk for suicide attempts is greatest during the first 1-2 months of treatment. 3
Important Safety Considerations
Bupropion lowers seizure threshold with a risk of 0.1% at doses ≤450mg/day. 1 The current 300mg daily dose is well below this threshold, but counsel patients to:
- Minimize alcohol use 1
- Avoid abrupt discontinuation of alcohol, benzodiazepines, or antiepileptic drugs 2
Monitor blood pressure and heart rate periodically, especially during the first 12 weeks, as bupropion can cause elevations in both 3.
Timeline for Response Assessment
Allow 6-8 weeks at the augmented regimen before determining treatment response. 3, 1 If no adequate response occurs by this timeframe, consider further treatment modifications 1.
Once adequate response is achieved, continue antidepressant therapy for 4-9 months minimum. 1
Alternative Consideration: Dose Optimization
If the patient is currently taking immediate-release bupropion 100mg TID, consider switching to bupropion SR 150mg twice daily (same 300mg total daily dose) for improved adherence and more stable drug levels 4, 3. The second dose should be given before 3 PM to minimize insomnia risk 3.
The maximum FDA-approved dose for bupropion SR is 400mg daily 4, 2, so there is room for dose escalation to 200mg twice daily if augmentation is not preferred. However, augmentation with an SSRI is the stronger evidence-based approach for treatment-resistant depression. 1