What are the considerations for using a combination of Wellbutrin (bupropion) and duloxetine in a patient with major depressive disorder who has not responded to monotherapy with either medication?

Combination of Wellbutrin (Bupropion) and Duloxetine for Treatment-Resistant Depression

For patients with major depressive disorder who have not responded to monotherapy with either bupropion or duloxetine, combining these two medications is a reasonable and potentially effective strategy, with preliminary evidence showing 60-90% response rates and generally manageable side effects. 1, 2

Evidence for the Combination

Efficacy Data

The combination of duloxetine and bupropion has shown promising results in treatment-resistant depression:

• In patients who failed monotherapy with either agent, adding the other medication resulted in significant clinical improvement, with CGI-Severity scores decreasing from 4.4 to 2.1 (P <.0001) after 8.8 weeks of combination treatment 1

• Response rates of 60% and remission rates of 30% were achieved in patients with treatment-resistant MDD who had previously failed adequate trials of either bupropion (330 mg for 20.5 weeks) or duloxetine (90 mg for 18 weeks) 1

• In atypical depression with treatment resistance, the combination showed 26.1% response rates, though this was not significantly different from duloxetine plus placebo (21.7%) in a small 6-week trial 2

Mechanistic Rationale

This combination targets complementary neurotransmitter systems: duloxetine inhibits serotonin and norepinephrine reuptake, while bupropion inhibits dopamine and norepinephrine reuptake, providing broader monoaminergic coverage than either agent alone 3, 4

Practical Implementation

Dosing Strategy

Start with the medication the patient has already been taking at therapeutic doses, then add the second agent at lower doses and titrate as tolerated:

• If starting with bupropion as the base: Use 300-330 mg/day, then add duloxetine starting at 30-60 mg/day, titrating to 60-120 mg/day 1, 2

• If starting with duloxetine as the base: Use 60-120 mg/day, then add bupropion starting at 150 mg/day, titrating to 300 mg/day 1, 2

• Mean effective adjunctive doses in clinical practice: duloxetine 60 mg and bupropion 175 mg when added to existing therapy 1

Monitoring Requirements

Assess response within 1-2 weeks of initiating combination therapy and continue monitoring regularly 5:

• Evaluate for treatment response by 6-8 weeks; if inadequate response, consider further treatment modifications 5

• Monitor blood pressure closely, as both agents can increase blood pressure, particularly in combination 1

• Screen for activation symptoms including jitteriness, agitation, and insomnia, which occurred in 20% of patients on combination therapy 1

Safety Considerations

Common Side Effects

The most frequently reported adverse effects with the combination include 1:

• Nausea (20%)
• Dry mouth (20%)
• Jitteriness/agitation (20%)
• Fatigue/drowsiness (20%)
• Increased blood pressure (10%)
• Insomnia, headache, increased sweating, sexual dysfunction (each 10%)

Critical Safety Warnings

Bupropion lowers the seizure threshold; avoid in patients with epilepsy or conditions that increase seizure risk 5

Monitor for suicidal thoughts and behaviors, especially in the first 1-2 months of treatment, as all antidepressants carry this risk 5

The combination may be particularly useful for patients with sexual dysfunction, as bupropion is associated with significantly lower rates of sexual adverse events compared to SSRIs 5

Alternative Strategies if Combination Fails

If the patient does not respond adequately to the duloxetine-bupropion combination within 6-8 weeks, consider 5:

• Switching to a different second-generation antidepressant class (though evidence shows no clear superiority of one agent over another in treatment-resistant cases) 5

• Augmentation with cognitive behavioral therapy, which has shown equivalent efficacy to medication augmentation strategies 5

• Note that 38% of patients do not achieve treatment response and 54% do not achieve remission even with multiple medication trials 5

Special Populations

For elderly patients, both bupropion and duloxetine are acceptable options, though close monitoring for blood pressure changes and drug interactions is essential 5

The combination may be particularly beneficial for patients with comorbid pain, as duloxetine has demonstrated efficacy for pain associated with MDD 5

Consider this combination preferentially for patients with depressed mood who also need smoking cessation support, as the bupropion component may assist with nicotine reduction 5