SSRI Selection for Augmentation of Wellbutrin (Bupropion) Monotherapy
Sertraline or escitalopram are the preferred SSRIs to add to bupropion monotherapy, with sertraline having slightly more supporting evidence for combination use and a favorable side effect profile when combined with bupropion.
Primary Recommendation
Sertraline is the most evidence-based choice for augmenting bupropion, as it was specifically studied in combination with bupropion SR and demonstrated good tolerability with low discontinuation rates 1, 2, 3
Escitalopram represents a strong alternative, with open-label data showing 50% remission rates when combined with bupropion SR, though this evidence is less robust than for sertraline 1
Rationale for Sertraline as First Choice
Complementary mechanisms: Bupropion provides dopamine-norepinephrine reuptake inhibition while sertraline adds serotonergic activity, targeting different neurotransmitter systems simultaneously 4, 3
Sexual dysfunction mitigation: When combined with bupropion, the sexual dysfunction commonly associated with sertraline monotherapy (41% in women, 63% in men) is significantly reduced, as bupropion counteracts SSRI-induced sexual side effects 2, 3
Proven safety profile in combination: Studies specifically evaluating bupropion SR plus sertraline showed similar adverse event rates to monotherapy, with headache being the most common side effect (30-40%) 3
Dosing Strategy
Start sertraline at 50 mg daily while maintaining therapeutic bupropion doses, as this was the starting dose in combination studies 2, 3
Titrate sertraline to 50-200 mg daily based on response, using 1-2 week intervals for dose adjustments 5, 3
For escitalopram alternative: Begin at 10 mg daily and titrate to maximum 20 mg daily, with mean effective doses around 18 mg daily in combination studies 1
Alternative SSRI Considerations
Fluoxetine is generally NOT recommended as a first choice due to its long half-life requiring 3-4 week intervals between dose adjustments, which delays optimization 5
Citalopram may be considered as it has a shorter half-life similar to sertraline, allowing 1-2 week titration intervals, though specific combination data with bupropion is lacking 5, 6
Paroxetine should be avoided due to higher rates of sexual dysfunction (compared to other SSRIs) and weight gain, which would counteract bupropion's advantages 5
Critical Safety Monitoring
Monitor for serotonin syndrome when combining any SSRI with bupropion, particularly in the first 24-48 hours after dose changes, watching for mental status changes, neuromuscular hyperactivity, and autonomic instability 7
Assess for increased nausea risk: Sertraline causes nausea in 31% of patients, which may be additive with bupropion's gastrointestinal effects 3
Screen for seizure risk factors: Bupropion carries seizure risk, so avoid doses above 400 mg daily of bupropion SR and ensure no other seizure risk factors are present 5, 4
Expected Outcomes
Response rates of 62% and remission rates of 50% were achieved with escitalopram-bupropion combination in open-label studies, substantially higher than typical SSRI monotherapy (where 38% fail to respond and 54% fail to achieve remission) 5, 1
Sexual function improvement: Patients switching from SSRI monotherapy to bupropion or adding bupropion show significant improvement in sexual functioning within 2-4 weeks 8
Time to effect: Allow 6-8 weeks at optimized doses before determining treatment failure, though some improvement should be evident by 2-4 weeks 5
Common Pitfalls to Avoid
Don't use fluoxetine-risperidone combinations as a model for SSRI selection with bupropion, as this addresses a different clinical scenario (OCD augmentation) 7
Avoid excessive polypharmacy: While combination therapy is appropriate, ensure each medication serves a distinct therapeutic purpose 5
Don't overlook weight considerations: Sertraline and bupropion both cause minimal weight changes (sertraline -0.79 kg, bupropion -1.06 kg), making this combination weight-neutral unlike paroxetine or mirtazapine 5, 3