What are the guidelines for taking Wellbutrin (bupropion) and sertraline together?

Combining Wellbutrin (Bupropion) and Sertraline

Combining bupropion and sertraline is a clinically supported strategy for treatment-resistant depression and can be used together safely with appropriate monitoring, though caution is warranted due to potential drug interactions and rare risk of serotonin syndrome.

Pharmacologic Interaction and Safety Considerations

Drug Interaction Profile

• Bupropion inhibits the CYP2D6 enzyme pathway, which metabolizes sertraline and other SSRIs, potentially increasing sertraline blood levels 1.
• This interaction requires awareness but does not contraindicate combination use—sertraline is noted to have less effect on metabolism of other medications compared to other SSRIs, making it a relatively favorable choice for combination therapy 2.
• The FDA label specifically lists sertraline among antidepressants whose concentrations can be increased by bupropion's CYP2D6 inhibition, recommending consideration of dose reduction when combining these agents 1.

Serotonin Syndrome Risk

• A rare case report documented serotonin syndrome in a patient taking therapeutic doses of bupropion and sertraline together 3.
• The syndrome manifested with myoclonic jerks, confusion, gait difficulties, and dysautonomia, which resolved after medication discontinuation 3.
• This risk appears related to bupropion's CYP2D6 inhibition increasing SSRI blood levels rather than direct serotonergic effects 3.
• Clinicians should monitor for early signs including tremor, myoclonus, confusion, and autonomic instability—symptoms that can be mistaken for worsening depression 3.

Clinical Efficacy Evidence

Treatment-Resistant Depression

• Open-label evidence demonstrates that combining bupropion with sertraline is effective for treatment-refractory depression in patients who failed adequate trials of each medication separately 4.
• Four patients with chronic depression and multiple failed treatments achieved remission with the combination, with no adverse effects reported 4.
• The efficacy likely results from synergistic effects on serotonergic, dopaminergic, and noradrenergic systems 4.
• A 2006 review supports combination treatment with bupropion and SSRIs as generally well-tolerated, capable of boosting antidepressant response in SSRI-refractory patients 5.

Augmentation Strategy Context

• Low-quality evidence from the American College of Physicians shows no difference in response or remission when augmenting citalopram with bupropion versus buspirone, though bupropion decreased depression severity more 2.
• Moderate-quality evidence showed discontinuation due to adverse events was lower with bupropion augmentation than buspirone 2.

Sexual Dysfunction Management

• Bupropion is significantly superior to sertraline in preserving sexual function: only 15% of men and 7% of women on bupropion developed sexual dysfunction versus 63% of men and 41% of women on sertraline 6.
• Bupropion is effective in reversing SSRI-associated sexual dysfunction when added to ongoing SSRI treatment 5.
• Sexual dysfunction with sertraline appears as early as day 7 at 50 mg/day and persists throughout treatment 6.

Practical Implementation Algorithm

When to Consider Combination Therapy

1. Partial response to sertraline monotherapy after adequate trial (4-8 weeks at therapeutic dose) 2
2. Treatment-refractory depression with prior failed trials of both agents separately 4
3. SSRI-associated sexual dysfunction requiring intervention 5

Dosing Approach

• Start bupropion at 37.5 mg every morning, increasing by 37.5 mg every 3 days to minimize insomnia risk 2.
• Maximum bupropion dose is 150 mg twice daily; give second dose before 3 PM to avoid insomnia 2.
• Consider reducing sertraline dose when adding bupropion due to CYP2D6 inhibition, though specific dose adjustments are not definitively established 1.
• Sertraline dosing typically ranges from 25-50 mg initially to maximum 200 mg daily 2.

Monitoring Requirements

• Assess for serotonin syndrome symptoms weekly during first month: myoclonus, tremor, confusion, agitation, autonomic instability 3.
• Monitor for seizure risk factors: bupropion should not be used in patients with seizure disorders or eating disorders 2.
• Evaluate blood pressure: both medications can affect cardiovascular parameters 2.
• Screen for suicidal ideation, particularly in patients under 24 years old 2.

Critical Pitfalls to Avoid

• Do not misinterpret early serotonin syndrome symptoms as worsening depression—this can lead to inappropriate dose escalation 3.
• Avoid bupropion in agitated patients—it has activating properties that may worsen agitation 2.
• Do not exceed maximum bupropion doses (150 mg twice daily for immediate release formulations) to minimize seizure risk 2.
• Recognize that bupropion can cause false-positive urine amphetamine tests 1.

Comparative Context

• Both bupropion and sertraline show similar antidepressant efficacy as monotherapy in moderate-to-severe depression 6, 7.
• When switching between agents (rather than combining), moderate-quality evidence shows no difference in response between bupropion, sertraline, or venlafaxine 2.
• Sertraline causes significantly more nausea (31%), diarrhea (26%), and somnolence (17%) than bupropion 7.