Combining Wellbutrin (Bupropion) with an SSRI
Yes, bupropion can be safely combined with SSRIs like sertraline for treatment-resistant depression or to manage SSRI-induced sexual dysfunction, but requires specific dosing limits, seizure risk assessment, and close monitoring for serotonin syndrome, particularly in the first 2 weeks of treatment. 1
When This Combination Is Appropriate
The combination of bupropion and SSRIs is recognized by the American Academy of Family Physicians as commonly used in clinical practice for: 1
- Treatment-resistant depression where monotherapy with either agent has failed 1, 2
- Bipolar depression as an augmentation strategy 1, 2
- SSRI-induced sexual dysfunction requiring reversal 3
Clinical data show that 70% of patients with partial response to monotherapy improved with combination therapy, though this was primarily in those receiving augmentation for inadequate response rather than side effect management 4
Absolute Contraindications
Do not combine bupropion with SSRIs in patients with: 1
- Active seizure disorder or conditions lowering seizure threshold 1
- Concurrent MAOI use (requires 14-day washout period) 5, 6
- Uncontrolled hypertension 1
- Brain metastases 1
Critical Dosing Requirements
Bupropion must not exceed 300 mg per day when combined with SSRIs to minimize seizure risk. 1 The FDA label specifically notes that bupropion inhibits CYP2D6, which metabolizes sertraline and other SSRIs, potentially increasing SSRI blood levels. 6
Start conservatively: 1
- Bupropion 150 mg once daily initially
- Increase to 150 mg twice daily after 3-7 days if tolerated
- Consider reducing SSRI dose when adding bupropion, particularly for drugs with narrow therapeutic index 6
Serotonin Syndrome Risk and Monitoring
While serotonin syndrome risk is minimal with this combination, one case report documents its occurrence when bupropion was combined with sertraline, likely due to bupropion's CYP2D6 inhibition increasing SSRI levels. 7 The earliest manifestations were misinterpreted as worsening depression, leading to addition of venlafaxine and clinical deterioration. 7
Monitor closely in the first 24-48 hours after starting or dose changes for: 5, 1
- Mental status changes (confusion, agitation, anxiety)
- Neuromuscular hyperactivity (tremors, clonus, hyperreflexia, muscle rigidity)
- Autonomic symptoms (hypertension, tachycardia, diaphoresis, diarrhea)
Required Baseline and Ongoing Assessments
Before prescribing, screen for: 1
- History of seizures or risk factors lowering seizure threshold
- Current medications that lower seizure threshold (antipsychotics, other antidepressants, theophylline, systemic corticosteroids) 6
- Cardiac conduction abnormalities
- Blood pressure status
During treatment, assess periodically: 1
- Vital signs including blood pressure
- Signs of serotonin syndrome
- Neuropsychiatric effects including suicidal ideation
- Seizure activity, particularly with dose escalation
Common Pitfalls to Avoid
Do not exceed 300 mg/day total bupropion dose - this is the single most important safety measure to prevent seizures. 1
Do not misinterpret early serotonin syndrome symptoms as worsening depression and add additional serotonergic agents, as occurred in the documented case report. 7
Do not combine with MAOIs - sertraline is contraindicated with MAOIs, requiring a 14-day washout. 5, 6
Do not ignore drug interactions - bupropion increases levels of CYP2D6 substrates including sertraline, fluoxetine, and paroxetine, potentially requiring SSRI dose reduction. 6
Expected Tolerability and Efficacy
Open-label studies demonstrate this combination is generally well tolerated, even in geriatric and medically frail patients. 8 The most common adverse effects (>10% incidence) include sexual dysfunction (41%), insomnia (22%), anergy (15%), and tremor (11%), with no seizures reported in clinical series using conservative dosing. 4
Response rates of 56-70% have been documented in treatment-resistant patients, with synergistic effects attributed to combined serotonergic, dopaminergic, and noradrenergic mechanisms. 8, 2, 4