What are the next treatment options for a patient with major depressive disorder who has failed an adequate 6–8‑week trial of bupropion (Wellbutrin) and a selective serotonin reuptake inhibitor (SSRI) at therapeutic doses?

Treatment Options After Failed Bupropion and SSRI Trials

After failing both bupropion and an SSRI, you should switch to a different antidepressant class—specifically an SNRI (venlafaxine or duloxetine) or mirtazapine—as this provides a modest but statistically significant advantage over switching to another SSRI. 1, 2

Confirm Adequate Treatment Trials First

Before proceeding, verify that both previous trials were truly adequate:

• Duration: Each medication must have been tried for at least 6–8 weeks at therapeutic doses 1, 2
• Dosing: Confirm maximum recommended or tolerated doses were achieved (e.g., bupropion up to 450 mg/day, SSRI at FDA-approved maximum) 2
• Adherence: Verify medication adherence through patient interview and pharmacy refill records 2
• Exclude confounders: Rule out bipolar disorder, active substance use, or personality disorders that could impair treatment response 2

Primary Recommendation: Switch to a Different Antidepressant Class

Preferred Options (in order of evidence strength):

1. Venlafaxine Extended Release (SNRI)

• Demonstrated efficacy in the landmark STAR*D trial for patients who failed initial antidepressant therapy 2
• Particularly advantageous if the patient has comorbid chronic pain, where SNRIs achieve higher remission rates (≈49% vs 42% with SSRIs) 3
• Monitor blood pressure, as SNRIs can cause dose-dependent hypertension 3

2. Duloxetine (SNRI)

• Another evidence-based SNRI option from STAR*D showing similar efficacy to venlafaxine 1
• Also beneficial for comorbid pain conditions 3

3. Mirtazapine

• Supported by moderate-quality evidence as an effective switch strategy 1
• Useful when insomnia or poor appetite are prominent symptoms, though sedation and weight gain are common 1

4. Bupropion SR/XR (if not already tried at adequate dose)

• Only consider if the previous bupropion trial was inadequate in dose or duration 2
• Advantage: lowest sexual dysfunction rates among antidepressants 3, 2, 4

Alternative Strategy: Augmentation

If switching is not preferred or feasible, augmentation strategies have similar efficacy to switching:

Augment the Current SSRI with Bupropion

• The STAR*D trial showed augmenting an SSRI with bupropion SR achieved similar remission rates to switching strategies 1
• Bupropion augmentation has lower discontinuation rates due to adverse events (12.5%) compared to buspirone augmentation (20.6%) 1
• Open-label studies show 50–62% response rates when bupropion is added to SSRIs 5, 6
• Typical dosing: bupropion SR 150–400 mg/day added to existing SSRI 5, 6

Add Cognitive Behavioral Therapy (CBT)

• The American College of Physicians strongly recommends adding CBT to ongoing pharmacotherapy for treatment-resistant depression 3
• Combination therapy nearly doubles remission rates (≈57% vs 31% with medication alone) in severe depression 3
• CBT augmentation showed similar efficacy to medication augmentation in STAR*D 1

Critical Monitoring After Treatment Change

• Week 1–2: Assess for emergent suicidal ideation, agitation, or unusual behavioral changes, as suicide risk peaks during the first 1–2 months of any new antidepressant 3
• Week 6–8: If symptom reduction is <50% on validated scales (PHQ-9, HAM-D, MADRS), this constitutes a second treatment failure and meets criteria for treatment-resistant depression 3, 2

When Two Adequate Trials Have Failed: Treatment-Resistant Depression

After documenting two failed trials (different mechanisms, adequate dose ≥4 weeks each, within current episode), the patient meets criteria for treatment-resistant depression (TRD) 2. At this point, consider:

• Ketamine or esketamine augmentation: Produces rapid symptom reduction within 24 hours, supported by high-quality evidence for TRD 3
• Lithium augmentation: Evidence-based strategy requiring baseline thyroid, renal function, and serum level monitoring 3
• Repetitive transcranial magnetic stimulation (rTMS) or electroconvulsive therapy (ECT) for multiple treatment failures 3

Common Pitfalls to Avoid

• Switching to another SSRI: No significant difference in response rates when switching between SSRIs after initial SSRI failure 1, 2—switch to a different class instead
• Inadequate trial duration: Declaring failure before 6–8 weeks at therapeutic dose 1, 2
• Not verifying adherence: Up to 50% of patients demonstrate non-adherence, which can masquerade as treatment resistance 3
• Premature discontinuation: Continue successful treatment for 4–9 months after first episode, ≥1 year for recurrent depression 3

Treatment Duration After Successful Response

• First episode: Continue for 4–9 months after achieving remission 3
• Recurrent depression (≥2 prior episodes): Maintain for ≥1 year or longer 3