What can be added to a patient's current regimen of Wellbutrin (bupropion) 150mg daily and Cymbalta (duloxetine) 60mg daily for increased depression?

Optimizing Treatment for Increased Depression on Wellbutrin and Cymbalta

The most evidence-based approach is to increase the bupropion (Wellbutrin) dose to 300 mg daily (150 mg twice daily) before adding any additional agents, as the current 150 mg daily dose is subtherapeutic. 1

Immediate Dose Optimization

Your patient is currently on a subtherapeutic dose of bupropion. The standard therapeutic dose for major depressive disorder is 300 mg daily (150 mg twice daily), not 150 mg daily. 1

Titration strategy:

• Increase bupropion SR to 150 mg twice daily (300 mg total daily dose) 1
• Administer the second dose before 3 PM to minimize insomnia risk 1, 2
• Allow 6-8 weeks at this therapeutic dose before determining treatment response 1
• The duloxetine 60 mg daily is already at standard therapeutic dose 2

If Inadequate Response After Dose Optimization

If the patient fails to respond after 6-8 weeks at bupropion 300 mg daily plus duloxetine 60 mg daily, the evidence supports the following options:

Option 1: Augmentation with Aripiprazole (Preferred in Most Cases)

Aripiprazole augmentation is superior to bupropion augmentation alone and offers rapid symptom improvement. 3, 4

• Start aripiprazole 2.5-5 mg daily 4
• Patients typically report rapid improvement in depressive symptoms within days to weeks 4
• One trial showed 55.4% remission with aripiprazole augmentation versus 34% with bupropion augmentation 3
• Critical caveat: In overweight patients (BMI ≥25), the metabolic risks of aripiprazole (weight gain, metabolic syndrome, tardive dyskinesia) may outweigh benefits, reducing net benefit by approximately 22.8 depression-free day-equivalents 5
• In adults under 65 years with normal BMI, aripiprazole offers approximately 8 depression-free day-equivalents of benefit after accounting for tardive dyskinesia risk 5

Option 2: Continue Current Combination (Alternative for Overweight Patients)

In overweight patients or those aged 18-84 years, continuing the bupropion-duloxetine combination (C-BUP strategy) is preferred over aripiprazole augmentation. 5

• The combination of bupropion plus duloxetine offers approximately 20.7 depression-free day-equivalents of benefit compared to switching strategies 5
• This combination addresses depression through complementary mechanisms: duloxetine affects serotonin/norepinephrine, while bupropion works via norepinephrine/dopamine pathways 1
• Bupropion augmentation of SNRIs like duloxetine decreases depression severity more than buspirone augmentation 1

Option 3: Switch Strategies (Not Recommended as First Choice)

The STAR*D trial found no significant differences between various switch strategies (switching to different antidepressants) versus augmentation strategies. 3 Given your patient is already on two agents, augmentation is more practical than switching.

Critical Safety Monitoring

Before making any changes:

• Monitor blood pressure at each visit, as both duloxetine and bupropion can cause hypertension 2, 6
• Assess for suicidal ideation, particularly if patient is under 24 years old (black box warning for bupropion) 1
• Screen for seizure risk factors, as bupropion maximum dose is 450 mg daily to minimize seizure risk 1, 2
• Verify creatinine clearance >30 mL/min for duloxetine continuation 2, 6

Serotonin syndrome risk: While rare, the combination of bupropion with duloxetine carries theoretical risk of serotonin syndrome due to bupropion's CYP2D6 inhibition increasing duloxetine levels. 7 Monitor for myoclonus, confusion, autonomic instability, and agitation.

Clinical Decision Algorithm

1. First step: Increase bupropion to 300 mg daily (if no contraindications) 1
2. Wait 6-8 weeks for adequate trial at therapeutic doses 1
3. If inadequate response:
   • BMI <25 and age <85: Consider aripiprazole 2.5-5 mg daily 4, 5
   • BMI ≥25 or concerns about metabolic effects: Continue optimized bupropion-duloxetine combination and reassess, or consider switching strategies 5
   • Age ≥85: Aripiprazole may be preferred over further dose increases due to fall risk with higher medication burden 5

Common Pitfalls to Avoid

• Do not add aripiprazole before optimizing bupropion dose - the patient is on a subtherapeutic dose 1
• Do not discontinue treatment before 6-8 weeks unless significant adverse effects occur 1
• Do not exceed bupropion 450 mg daily due to seizure risk 1
• Do not misinterpret early serotonin syndrome symptoms (myoclonus, confusion) as worsening depression 7
• Do not use duloxetine if creatinine clearance <30 mL/min 6