Augmentation Strategy for Treatment-Resistant Depression
Based on the strongest available evidence, I recommend augmenting with bupropion SR (starting at 150 mg daily, increasing to 150 mg twice daily) rather than increasing buspirone dose, as this combination showed superior tolerability and comparable efficacy to buspirone augmentation in the STAR*D trial. 1
Rationale for This Recommendation
Your patient is on sertraline 200 mg (maximum dose) with buspirone 5 mg BID (subtherapeutic dose for augmentation). You have two options: optimize buspirone or switch augmentation strategies.
Why Bupropion Over Buspirone Optimization
The STAR*D trial—the largest and highest-quality study of second-step depression treatments—directly compared buspirone augmentation versus bupropion SR augmentation of citalopram (another SSRI like sertraline) 1. Key findings:
- No difference in efficacy: Response and remission rates were similar between bupropion SR and buspirone augmentation 2, 1
- Superior tolerability: Discontinuation due to adverse events was significantly lower with bupropion SR (12.5%) versus buspirone (20.6%, p<0.001) 1
- Faster onset: Bupropion showed possible rapid improvement of energy level 3
Buspirone Dosing Concerns
If you choose to continue buspirone, the current dose of 5 mg BID is inadequate:
- Therapeutic augmentation range: 20-60 mg/day in divided doses 3
- Maximum dose: 20 mg three times daily 3
- Takes 2-4 weeks to become effective 3
The patient would need at least 30 mg/day (15 mg BID or 10 mg TID) to achieve therapeutic augmentation effect 4, 5.
Practical Implementation
Option 1: Switch to Bupropion SR (Preferred)
- Start bupropion SR 150 mg every morning
- Continue sertraline 200 mg daily
- Taper buspirone over 1-2 weeks (not abruptly)
- After 3-4 days, increase bupropion SR to 150 mg twice daily (give second dose before 3 PM to minimize insomnia) 3
- Assess response at 4-6 weeks 1
Option 2: Optimize Buspirone (Alternative)
- Increase buspirone to 15 mg BID (30 mg/day total)
- Continue sertraline 200 mg daily
- Further increase to 20 mg BID if tolerated and needed
- Wait 2-4 weeks for full effect 3
- Monitor for dizziness, lightheadedness, and GI side effects
Important Contraindications and Cautions
Bupropion should NOT be used if the patient has:
- History of seizures or seizure disorder
- Current or prior diagnosis of bulimia or anorexia nervosa
- Abrupt discontinuation of alcohol or benzodiazepines
- Significant agitation or psychomotor agitation 3
Drug interactions to monitor:
- Buspirone is metabolized by CYP3A4; sertraline has minimal effect on this pathway, so the current combination is safe 3, 6
- Bupropion inhibits CYP2D6 but sertraline is less dependent on this pathway than other SSRIs 3
Alternative Augmentation Strategies
If both bupropion and buspirone fail or are contraindicated, consider these evidence-based alternatives in order:
Aripiprazole 2.5-5 mg daily: Low-dose augmentation showed significant improvement in depression scores within 1-2 weeks 7, 8
Lithium 150-300 mg daily: Target blood level 0.2-0.6 mEq/L; well-established augmentation strategy 3
Mirtazapine 7.5-30 mg at bedtime: Can be added to sertraline; promotes sleep and appetite 3
Timeline for Assessment
- Week 1-2: Monitor for tolerability and early side effects
- Week 4: Assess for partial response; if none, consider dose adjustment
- Week 6-8: Full therapeutic trial complete; if <50% improvement, consider switching augmentation strategy 1
The evidence strongly supports that switching to bupropion augmentation offers better tolerability with equivalent efficacy compared to optimizing buspirone, making it the preferred choice for this patient already on maximum-dose sertraline.