Can Bupropion (Wellbutrin) and Amitriptyline Be Prescribed Together?
Yes, you can prescribe bupropion and amitriptyline together—this combination has been studied since the 1980s and demonstrates comparable efficacy to monotherapy with either agent, though you must carefully screen for seizure risk factors and monitor for additive side effects. 1, 2
Evidence Supporting the Combination
The combination of bupropion with tricyclic antidepressants like amitriptyline has historical precedent and clinical utility:
Direct comparative trials from the 1980s showed bupropion (300-750 mg/day) was equally effective as amitriptyline (75-225 mg/day) for depression, with both agents producing significant improvement on Hamilton Depression Scale scores. 2, 3
Bupropion demonstrated a more favorable side effect profile than amitriptyline in head-to-head studies, with notably fewer anticholinergic, antihistaminic, and antiadrenergic effects. 3, 4
Case series from 1994 documented successful treatment of refractory depression using bupropion combined with the tricyclic nortriptyline (a metabolite of amitriptyline), supporting the safety and efficacy of combining these drug classes. 5
Critical Safety Screening Before Prescribing
Absolute Contraindications to Bupropion
Screen for these conditions that prohibit bupropion use:
- History of seizure disorder, stroke, brain tumor, head trauma, or brain metastases 6, 7
- Current or recent MAOI use (within 14 days of discontinuation) 8, 7
- Active eating disorders (bulimia or anorexia nervosa) 7
- Abrupt discontinuation of alcohol, benzodiazepines, or antiepileptic drugs 7
- Uncontrolled hypertension 8, 9
- Moderate to severe hepatic impairment (reduce dose to maximum 150 mg daily if mild-moderate impairment) 7
Seizure Risk Amplification
Both bupropion and amitriptyline can lower seizure threshold, making careful adherence to maximum dosing essential when combining these agents. 8, 7
- Bupropion carries a 0.1% (1 in 1,000) seizure risk at standard doses of 300 mg/day, which increases substantially above 450 mg/day. 6, 7
- The maximum bupropion dose is 450 mg/day for XL formulation and 400 mg/day for SR formulation—never exceed these limits. 7
Recommended Dosing Strategy
Bupropion Initiation and Titration
Start bupropion at 37.5-150 mg once daily in the morning, then increase by 37.5-75 mg every 3 days as tolerated, targeting 300 mg/day as the therapeutic dose for depression. 8, 7
- For bupropion SR: Begin 150 mg once daily for 3 days, then increase to 150 mg twice daily (300 mg total). 6, 7
- For bupropion XL: Begin 150 mg once daily, then increase to 300 mg once daily. 7
- Administer the second SR dose before 3 PM to minimize insomnia risk, as bupropion has activating properties. 8, 7
Amitriptyline Dosing Considerations
Standard amitriptyline dosing for depression ranges from 75-225 mg/day, as used in comparative trials with bupropion. 2, 3
Monitoring Requirements
First 1-2 Weeks
Monitor for worsening depression, suicidal ideation (especially in patients <24 years), and increased agitation, as bupropion is an activating medication. 8, 7
Throughout Treatment
- Blood pressure and heart rate monitoring, especially during the first 12 weeks, as bupropion can cause elevations. 8, 9
- Watch for anticholinergic side effects from amitriptyline (dry mouth, constipation, urinary retention, blurred vision). 3, 4
- Monitor weight changes: bupropion typically causes slight weight loss while amitriptyline causes weight gain. 3, 4
Assess Treatment Response
Allow 6-8 weeks at therapeutic doses before determining adequacy of response; if inadequate, consider dose adjustment or alternative augmentation strategies. 8, 7
Complementary Mechanisms and Clinical Advantages
This combination addresses depression through complementary pathways: amitriptyline via serotonin/norepinephrine reuptake inhibition and bupropion via norepinephrine/dopamine modulation. 8
- Bupropion may counteract amitriptyline-induced sedation and weight gain through its activating, weight-neutral properties. 3, 4
- The combination may be particularly beneficial for patients with depression plus low energy, apathy, or hypersomnia. 8
- Bupropion has significantly lower rates of sexual dysfunction compared to other antidepressants, potentially offsetting any sexual side effects. 8, 7
Common Pitfalls to Avoid
- Never combine with MAOIs or within 14 days of MAOI discontinuation due to hypertensive crisis risk. 8, 9
- Do not exceed maximum bupropion doses (450 mg/day XL or 400 mg/day SR) to maintain seizure risk at 0.1%. 7
- Avoid in patients with uncontrolled hypertension without first achieving blood pressure control. 8, 9
- Screen carefully for alcohol or benzodiazepine use—abrupt discontinuation while on bupropion dramatically increases seizure risk. 7
- Reduce bupropion dose by 50% in moderate-to-severe renal impairment (GFR <90 mL/min). 7