Augmentation Strategy for Bupropion After SSRI Failures
When bupropion (Wellbutrin) is being used after sertraline (Zoloft) and escitalopram (Lexapro) have failed, the most evidence-supported approach is to augment bupropion with either buspirone or continue bupropion as monotherapy, rather than adding another agent to it. However, the clinical context suggests you may be asking about what to add to an existing bupropion regimen—in which case, adding an SSRI back (creating combination therapy) or augmenting with lithium are the evidence-based options.
Understanding the Clinical Scenario
The question implies a patient has failed two SSRIs (sertraline and escitalopram) and is now on bupropion. The key decision point is whether bupropion alone is insufficient, requiring augmentation.
Primary Recommendation: SSRI + Bupropion Combination
The strongest evidence supports combining bupropion with an SSRI when either agent alone has been inadequate 1, 2. This approach:
- Targets multiple neurotransmitter systems: Bupropion inhibits dopamine/norepinephrine reuptake while SSRIs enhance serotonin 3, 4
- Shows superior efficacy to switching strategies: In treatment-resistant depression, combining citalopram with bupropion-SR produced greater SIGH-SAD score improvement (-14.8 vs -10.1, p<0.04) and higher remission rates (28% vs 7%, p<0.05) compared to switching to monotherapy 5
- Well-tolerated combination: Multiple studies demonstrate no greater side effect burden than monotherapy 4, 5
Specific SSRI Options to Combine with Bupropion:
Citalopram or Escitalopram are preferred choices:
- Citalopram 20-40 mg/day combined with bupropion-SR 150-300 mg/day showed 70% response rates in partial responders 4, 5
- Well-tolerated with manageable drug interactions 6
Sertraline is an alternative:
- Less effect on CYP450 metabolism compared to other SSRIs 7
- Can be combined with bupropion 150-300 mg/day 8, 4
Avoid paroxetine and fluoxetine in combination with bupropion due to:
- Strong CYP2D6 inhibition by bupropion increases SSRI levels 6
- Higher risk of drug-drug interactions
- Paroxetine has more anticholinergic effects 7
Alternative Augmentation Strategy: Lithium
Lithium augmentation (150-300 mg/day) targeting blood levels of 0.2-0.6 mEq/L is an evidence-based option for treatment-resistant depression 7. This approach:
- Enhances antidepressant response through different mechanisms
- Requires monitoring of blood levels and thyroid/renal function
- Particularly useful if there's mood cycling or bipolar spectrum features
Secondary Option: Buspirone Augmentation
Moderate-certainty evidence shows buspirone augmentation is comparable to bupropion augmentation when added to an SSRI 1. However, since the patient is already on bupropion, this would mean:
- Adding buspirone 15-60 mg/day to existing bupropion
- Less evidence for this specific combination
- May take 2-4 weeks to show effect 7
Dosing Considerations
Bupropion Dosing:
- Start 150 mg SR once daily in morning
- Increase to 150 mg twice daily after 3-7 days
- Maximum 400 mg/day (given as 200 mg twice daily) 7
- Give second dose before 3 PM to minimize insomnia 7
When Adding an SSRI to Bupropion:
- Start with lower SSRI doses due to CYP2D6 inhibition by bupropion 6
- Citalopram: Start 10-20 mg/day, maximum 40 mg/day
- Escitalopram: Start 5-10 mg/day, maximum 20 mg/day
- Sertraline: Start 25-50 mg/day, maximum 200 mg/day
Critical Safety Considerations
Drug Interactions:
- Bupropion inhibits CYP2D6, increasing levels of SSRIs metabolized by this pathway (paroxetine, fluoxetine) 6
- Monitor for serotonin syndrome when combining (though risk is low with bupropion)
- Avoid MAOIs—contraindicated with bupropion 6
Seizure Risk:
- Bupropion lowers seizure threshold (dose-dependent) 7, 6
- Risk increases with doses >400 mg/day
- Avoid in patients with seizure disorders, eating disorders, or abrupt alcohol/benzodiazepine withdrawal 7
Monitoring Parameters:
- Assess response at 4-8 weeks minimum 7
- Monitor for activation, agitation, insomnia
- Screen for treatment-emergent suicidal ideation
- Check blood pressure (bupropion can increase BP)
What NOT to Do
Do not add another bupropion formulation—this increases seizure risk without additional benefit 6.
Do not combine with MAOIs—absolute contraindication due to hypertensive crisis risk 6.
Avoid combining with multiple antidepressants simultaneously without clear rationale—increases adverse effects without proven benefit.
Timeline for Assessment
- Week 2-4: Assess tolerability, adjust doses if needed
- Week 6-8: Evaluate therapeutic response; if inadequate, consider dose optimization
- Week 12: Decision point—if <50% improvement, consider alternative augmentation strategy or switch 2, 1
When This Strategy Fails
If combination therapy with bupropion + SSRI fails after adequate trial (12 weeks at therapeutic doses):