Adding Wellbutrin (Bupropion) to Cymbalta (Duloxetine)
The combination of bupropion and duloxetine is generally safe and well-tolerated for treatment-resistant depression, with evidence supporting enhanced antidepressant response, but requires careful monitoring for seizure risk, blood pressure elevation, and suicidality, particularly in younger patients. 1
Key Safety Considerations
Absolute Contraindications
- Seizure disorders or conditions lowering seizure threshold - bupropion reduces seizure threshold with a 0.1% seizure risk even at therapeutic doses 1
- Concurrent MAOI use - must allow at least 14 days between discontinuation of MAOIs and initiation of this combination due to serotonin syndrome risk 1
- Brain metastases with seizure history - the combination should be avoided in these patients 1
- Uncontrolled hypertension - both medications can elevate blood pressure 2
Serotonin Syndrome Risk
While bupropion primarily affects dopamine and norepinephrine systems, serotonin toxicity can occur with bupropion, particularly at higher doses or when combined with serotonergic agents like duloxetine 3, 4. The mechanism involves bupropion's inhibition of cytochrome P450 2D6, which can increase duloxetine levels 3. However, controlled studies demonstrate this combination is generally well-tolerated when used at therapeutic doses 5.
Clinical Benefits
Efficacy Data
- Open-label studies show this combination is effective for treatment-refractory depression when patients have failed either medication alone 6, 5
- The combination may provide synergistic effects through distinct mechanisms: duloxetine enhances serotonin and norepinephrine, while bupropion affects dopamine and norepinephrine systems 1, 6
- Bupropion can reduce SSRI/SNRI-associated sexual dysfunction, a common reason for augmentation 5
Monitoring Protocol
Initial Assessment (Before Starting)
- Baseline blood pressure and pulse 1
- Screen for seizure history, eating disorders, abrupt alcohol/benzodiazepine withdrawal 1
- Consider baseline liver function tests given duloxetine's hepatic effects 1
- Assess suicide risk, particularly in patients under age 24 1
Ongoing Monitoring
- Week 1-2: Assess for neuropsychiatric symptoms (agitation, anxiety, insomnia, irritability) 1
- Monthly for first 2 months: Monitor for suicidality, particularly during initial treatment period 1
- Each visit: Check blood pressure and pulse due to cardiovascular effects 1
- Watch for: Signs of serotonin syndrome (confusion, myoclonus, hyperthermia, autonomic instability), hepatic dysfunction (jaundice, abdominal pain, elevated transaminases), hypomania/mania, abnormal bleeding 1
Dosing Strategy
Starting Doses
- Duloxetine: 30-60 mg daily 1
- Bupropion: 150 mg daily (SR formulation 100-150 mg twice daily; XL formulation 150-300 mg once daily) 1
Titration
- Start with lower doses when combining to assess tolerability 5
- Typical maintenance: duloxetine 60-120 mg daily, bupropion 150-300 mg daily 2, 1
Common Adverse Effects to Anticipate
- Neuropsychiatric: Insomnia, agitation, anxiety, irritability (most common) 1
- Gastrointestinal: Nausea, dry mouth, constipation 1
- Cardiovascular: Increased blood pressure and heart rate 1
- Other: Headache, dizziness 2
Discontinuation
Both medications require gradual tapering - abrupt discontinuation can cause withdrawal symptoms, particularly with duloxetine which has a shorter half-life than some SSRIs 1. Taper over at least 1-2 weeks when discontinuing 2.