For adults with major depressive disorder who have not remitted after an adequate 6–8‑week trial of an SSRI (e.g., citalopram), what does the STAR*D augmentation study recommend as first‑line augmentation options?

STAR*D Augmentation Study Recommendations

Primary First-Line Augmentation Options

The STAR*D augmentation study found that bupropion-SR and buspirone produced similar remission rates (39% vs 33%, not statistically significant) when added to citalopram, but bupropion-SR demonstrated significantly superior tolerability with 12.5% discontinuation due to adverse events compared to 20.6% for buspirone (P < 0.001). 1, 2

Evidence-Based Augmentation Algorithm

Step 1: Verify Adequate Initial SSRI Trial

• Confirm the patient has received at least 6-8 weeks of treatment at therapeutic SSRI doses (e.g., citalopram 40 mg, escitalopram 20 mg) before declaring treatment failure 1, 3
• Assess medication adherence and rule out comorbid conditions (substance use, thyroid dysfunction, bipolar disorder) that may interfere with response 4

Step 2: Choose Augmentation Strategy

• Bupropion-SR 150-400 mg daily is the preferred first-line augmentation agent based on superior tolerability profile and equivalent efficacy to buspirone 1, 2
• Start bupropion-SR at 150 mg once daily in the morning for 3 days, then increase to 150 mg twice daily (total 300 mg/day) if well tolerated 2
• Maximum dose is 400 mg daily in divided doses, with the second dose administered before 3 p.m. to reduce insomnia risk 4

Step 3: Alternative Augmentation Options

• Buspirone 20 mg three times daily (60 mg/day total) is an alternative if bupropion is contraindicated, though it carries higher discontinuation rates 1, 3
• Start buspirone at 5 mg twice daily and titrate to 20 mg three times daily over 2-4 weeks 4
• Cognitive therapy augmentation achieved 31% remission rates, similar to medication augmentation, though time to remission was longer (55 vs 40 days) 3

Critical Contraindications and Safety Considerations

Bupropion-Specific Warnings

• Contraindicated in patients with seizure disorders, eating disorders (anorexia/bulimia), or current use of MAO inhibitors due to increased seizure risk and hypertensive reactions 2, 4
• Avoid in patients with current agitation, as bupropion's activating properties may exacerbate symptoms 4
• May reduce tamoxifen effectiveness; contraindicated in narrow-angle glaucoma 2

Buspirone-Specific Considerations

• Higher rates of treatment-emergent suicidal ideation (13.9%) compared to bupropion-SR (3.6%) in reanalysis of STAR*D data 5
• More frequent discontinuation due to adverse events (20.6% vs 12.5% for bupropion) 1, 3

Expected Outcomes and Monitoring

Remission Rates

• Augmentation strategies achieve approximately 30-39% remission rates in patients who failed initial SSRI monotherapy 1, 3
• Recent reanalysis with protocol fidelity found lower remission rates than originally reported: bupropion-SR 25-29% and buspirone 26% using strict protocol definitions 5
• Sustained remission through 12 months is low (4.9-12.5%), highlighting the need for continued monitoring 5

Timeline for Response

• Allow 6-8 weeks at optimized augmentation doses before declaring treatment failure 1, 3
• Cognitive therapy augmentation requires longer time to remission (55 days) compared to medication augmentation (40 days) 3

Monitoring Protocol

• Assess treatment response every 2-4 weeks using standardized depression rating scales (PHQ-9 or HAM-D) 4
• Monitor specifically for suicidal ideation during the first 1-2 months after augmentation initiation, as suicide risk is greatest during this period 6, 4
• Watch for neuropsychiatric side effects including depression, suicidal thoughts, or behavioral changes 2

Common Pitfalls to Avoid

• Do not augment before ensuring adequate dose and duration of SSRI monotherapy (minimum 6-8 weeks at maximum tolerated dose) 1, 4
• Do not exceed bupropion 400 mg/day or administer doses after 3 p.m. due to insomnia risk 2, 4
• Do not combine multiple serotonergic agents without careful monitoring for serotonin syndrome 4
• Switching versus augmentation strategies showed no significant differences in efficacy, but augmentation may be preferred when partial benefit exists from the initial SSRI 1, 3

Alternative Strategy: Switching

• If augmentation fails or is not tolerated, switching to another antidepressant class is equally valid 1, 3
• STAR*D Level 2 switch options (sertraline 27%, bupropion-SR 26%, venlafaxine-XR 25%) showed no significant differences in remission rates 1, 3
• The American College of Physicians found no significant difference between switching versus augmenting strategies overall, allowing clinician and patient preference to guide selection 1