What are the next steps for a patient with persistent depression symptoms despite being on duloxetine (90mg), buspirone (15mg twice a day), and bupropion (Wellbutrin 150mg)?

Treatment Optimization for Persistent Depression on Current Regimen

Your patient requires immediate optimization of the bupropion dose to 300 mg daily (150 mg twice daily) before considering any additional interventions, as the current 150 mg daily dose is subtherapeutic. 1, 2

Immediate Action: Dose Optimization

Increase bupropion SR to 150 mg twice daily (300 mg total daily dose), as the standard therapeutic dose for major depressive disorder is 300 mg daily, not 150 mg daily. 1, 2 The current regimen includes:

• Duloxetine 90 mg (already at therapeutic dose) 2
• Buspirone 15 mg BID (30 mg total - adequate dose)
• Bupropion 150 mg (subtherapeutic - needs increase to 300 mg) 1, 2

Dosing Instructions for Bupropion Increase

• Administer 150 mg in the morning and 150 mg before 3 PM to minimize insomnia risk 1, 2
• Allow 6-8 weeks at this therapeutic dose before determining treatment response 1, 2
• Do not exceed 450 mg daily due to seizure risk (approximately 0.1% at therapeutic doses) 1

If Inadequate Response After 6-8 Weeks at Optimized Doses

Evidence-Based Augmentation Strategy

Consider aripiprazole augmentation (2.5-5 mg daily) as the next step, which demonstrates superior efficacy with 55.4% remission rates and provides approximately 8 depression-free day-equivalents of benefit after accounting for tardive dyskinesia risk. 2 This is particularly appropriate for patients with BMI <25 and age <85. 2

Alternative Combination Evidence

The combination of duloxetine and bupropion has demonstrated effectiveness in treatment-resistant depression:

• A retrospective study showed significant CGI-S score reduction (4.4 to 2.1, P <0.0001) with 30% achieving remission and 60% responding 3
• The combination addresses complementary mechanisms (serotonergic via duloxetine, noradrenergic/dopaminergic via bupropion) 3
• Common side effects include nausea, dry mouth, jitteriness/agitation, and blood pressure elevation 3

Critical Safety Monitoring Required

Before Dose Increase

• Screen for seizure history or conditions predisposing to seizures (absolute contraindication) 1, 2
• Verify no current MAOI use or within 14 days of discontinuation 1
• Assess for eating disorders (bulimia/anorexia - absolute contraindication) 1
• Check for abrupt discontinuation of alcohol, benzodiazepines, or antiepileptic drugs (absolute contraindication) 1
• Verify creatinine clearance >30 mL/min for duloxetine continuation 2

Ongoing Monitoring

• Monitor blood pressure at each visit, as both duloxetine and bupropion can cause hypertension 2, 3
• Assess for suicidal ideation at 1-2 weeks, particularly if patient is under 24 years old (black box warning for bupropion) 1, 2
• Monitor for neuropsychiatric symptoms including agitation, restlessness, and behavioral changes 1
• Watch for increased agitation given bupropion's activating properties 1

Clinical Decision Algorithm

1. Optimize bupropion to 300 mg daily (150 mg twice daily, second dose before 3 PM) 1, 2
2. Wait 6-8 weeks for adequate trial at therapeutic doses 1, 2
3. If inadequate response, add aripiprazole 2.5-5 mg daily (if appropriate based on age/BMI) 2
4. Monitor closely for side effects and therapeutic response 2, 3

Common Pitfalls to Avoid

• Do not add aripiprazole or other augmentation agents before optimizing bupropion dose - the patient is currently on a subtherapeutic dose 2
• Do not discontinue treatment before 6-8 weeks unless significant adverse effects occur 1, 2
• Do not exceed bupropion 450 mg daily due to increased seizure risk 1, 2
• Do not use duloxetine if creatinine clearance <30 mL/min 2
• Do not ignore blood pressure monitoring - both medications can cause hypertension 2, 3

Supporting Evidence for Current Combination

The duloxetine-bupropion combination has theoretical synergism through distinct mechanisms involving serotonergic, dopaminergic, and noradrenergic systems. 4, 3 In treatment-resistant depression, switching to antidepressants with different mechanisms of action (like this combination) shows response rates of 60-70% and remission rates of 30-40%. 5