Co-Administration of Elavil (Amitriptyline) and Wellbutrin (Bupropion)
Yes, amitriptyline and bupropion can be safely co-administered together, with both drugs demonstrating comparable efficacy to their individual use and no pharmacokinetic interactions that preclude combination therapy. 1, 2, 3
Evidence Supporting Safe Combination
Historical Clinical Trial Data
Direct comparison studies from the 1980s established that bupropion and amitriptyline are equally effective antidepressants, with both achieving significant improvement on Hamilton Depression Scale scores, Clinical Global Impressions, and other validated depression measures after 2-4 weeks of treatment. 1, 2
Bupropion (300-750 mg/day) demonstrated equivalent efficacy to amitriptyline (75-225 mg/day) in controlled trials of depressed inpatients and outpatients, with no evidence of dangerous interactions when the drugs were studied head-to-head. 1, 2, 4
Modern Combination Therapy Evidence
Contemporary literature supports combining bupropion with other antidepressants (including tricyclics like amitriptyline) to enhance antidepressant response in treatment-resistant depression, with open-label and controlled studies demonstrating that combination treatment is generally well-tolerated and can boost therapeutic response. 3
The combination addresses depression through complementary mechanisms: amitriptyline works primarily through serotonin and norepinephrine reuptake inhibition plus anticholinergic effects, while bupropion operates via noradrenergic/dopaminergic pathways without anticholinergic activity. 5, 3
Critical Safety Screening Before Initiating Combination
Absolute Contraindications to Bupropion
Seizure disorders or any condition predisposing to seizures (prior head trauma, brain tumor, stroke, brain metastases) – bupropion lowers seizure threshold with documented risk of approximately 0.1% (1 in 1,000) at therapeutic doses. 5, 6
Current or recent MAOI use (within 14 days of discontinuation) – risk of hypertensive crisis. 5, 6
Eating disorders (bulimia, anorexia nervosa) – markedly increased seizure risk. 5
Abrupt discontinuation of alcohol, benzodiazepines, or antiepileptic drugs – precipitates withdrawal seizures that are potentiated by bupropion. 5
Uncontrolled hypertension – bupropion can elevate blood pressure and heart rate. 5, 6
Relative Contraindications to Amitriptyline
Uncontrolled narrow-angle glaucoma – anticholinergic effects worsen intraocular pressure.
Recent myocardial infarction or unstable cardiac disease – tricyclics carry cardiotoxic risk, whereas bupropion is notably non-cardiotoxic. 2, 4
Urinary retention or severe prostatic hypertrophy – anticholinergic effects of amitriptyline exacerbate these conditions.
Dosing Strategy for Combination Therapy
Bupropion Dosing
Start bupropion SR at 150 mg once daily for 3 days, then increase to 150 mg twice daily (300 mg total) if tolerated. 5
Maximum dose is 300 mg/day when combined with other CNS-active medications to maintain seizure risk at 0.1%; never exceed 450 mg/day under any circumstances. 5, 7
Administer the first dose in the morning and any second dose before 3 PM to minimize insomnia risk, as bupropion has activating properties. 5
Amitriptyline Dosing
Typical therapeutic range is 75-225 mg/day, with most patients responding to 150 mg/day given as a single bedtime dose to leverage sedating effects. 1, 2
Start at 25-50 mg at bedtime and titrate by 25 mg every 3-7 days as tolerated, monitoring for anticholinergic side effects (dry mouth, constipation, urinary retention, blurred vision).
Dose Adjustments for Special Populations
Hepatic impairment (moderate to severe): Limit bupropion to 150 mg daily; reduce amitriptyline dose by 50%. 5, 6
Renal impairment (eGFR <90 mL/min): Reduce bupropion dose by 50%; amitriptyline requires no adjustment but monitor for increased side effects. 5
Older adults (≥65 years): Start bupropion at 37.5 mg every morning, increase by 37.5 mg every 3 days; start amitriptyline at 10-25 mg at bedtime. 5
Monitoring Protocol
First 1-2 Weeks (Weekly Visits)
Screen for suicidal ideation, agitation, irritability, or unusual behavioral changes – the risk of suicide attempts is highest during the first 1-2 months of antidepressant therapy, especially in patients <24 years. 5, 6, 7
Measure blood pressure and heart rate at each visit, as bupropion can cause elevations. 5, 6
Assess for anticholinergic toxicity from amitriptyline: dry mouth, constipation, urinary retention, confusion (especially in elderly), blurred vision.
Monitor for activation or insomnia from bupropion – if present, ensure second dose is given before 3 PM or reduce dose. 5
Weeks 2-8 (Every 2-4 Weeks)
Continue blood pressure monitoring monthly for the first 12 weeks. 5
Assess therapeutic response using standardized depression scales (e.g., PHQ-9, Hamilton Depression Scale).
Monitor weight: Bupropion typically causes slight weight loss, while amitriptyline causes weight gain; the combination may result in weight neutrality. 1, 2
Efficacy Assessment Timeline
Allow 6-8 weeks at therapeutic doses before determining treatment response. 5, 6, 7
Early improvement in energy may be observed with bupropion within the first few weeks, but definitive response assessment should wait until 6-8 weeks. 5, 7
If inadequate response occurs by 6-8 weeks, modify the treatment approach by adjusting doses, adding augmentation therapy (e.g., lithium, thyroid hormone), or switching to alternative agents. 5, 6
Clinical Advantages of This Combination
Complementary Side-Effect Profiles
Bupropion has notably absent anticholinergic side effects, whereas amitriptyline is highly anticholinergic – the combination may allow lower amitriptyline doses while maintaining efficacy. 2, 4
Bupropion is non-sedating and activating, which can counteract amitriptyline's sedation and may improve energy, motivation, and apathy. 5, 2
Bupropion is associated with significantly lower rates of sexual dysfunction compared to SSRIs and does not worsen the sexual side effects sometimes seen with tricyclics. 5, 3
Bupropion is non-cardiotoxic, providing a safety advantage over using two tricyclic antidepressants together. 2, 4
Mechanistic Synergy
The combination targets distinct neurotransmitter systems: amitriptyline inhibits serotonin and norepinephrine reuptake, while bupropion enhances dopamine and norepinephrine activity through different mechanisms. 5, 3
This dual mechanism may be particularly beneficial for patients with treatment-resistant depression, low energy, apathy, or comorbid conditions such as smoking cessation needs. 5, 3
Critical Safety Warnings and Common Pitfalls
Seizure Risk Management
Never exceed 300 mg/day of bupropion when combined with other CNS-active medications – seizure risk rises markedly above 450 mg/day and is dose-dependent. 5, 7
Avoid rapid dose escalation of bupropion – titrate gradually over 3-7 days to minimize seizure risk. 7
Screen for all seizure risk factors before initiating: eating disorders, alcohol withdrawal, head trauma history, structural brain lesions, concurrent medications that lower seizure threshold. 5, 6, 7
Cardiovascular Monitoring
Baseline ECG is recommended before starting amitriptyline in patients >40 years or with any cardiac history, as tricyclics can prolong QTc interval and cause arrhythmias.
Monitor blood pressure regularly, especially in the first 12 weeks, as bupropion can elevate blood pressure. 5, 6
Drug Interaction Considerations
Bupropion inhibits CYP2D6, which can modestly increase amitriptyline levels, but this is not clinically significant at standard doses and does not require dose adjustment. 6
Both medications lower seizure threshold – avoid adding tramadol, meperidine, or other medications that further reduce seizure threshold. 6
Discontinuation Strategy
Do not discontinue either medication abruptly – taper gradually to minimize withdrawal symptoms. 7
Amitriptyline requires a slow taper (reduce by 25 mg every 1-2 weeks) to avoid cholinergic rebound (nausea, headache, malaise).
Bupropion can be tapered more rapidly but should still be reduced gradually over 1-2 weeks to minimize potential withdrawal symptoms. 5
When to Avoid This Combination
Patients with uncontrolled hypertension should not receive bupropion until blood pressure is controlled. 5, 6
Patients with recent myocardial infarction or unstable angina should avoid amitriptyline; consider bupropion monotherapy or an SSRI instead. 4
Patients with severe hepatic impairment require dose reduction of both agents and close monitoring. 5, 6
Patients taking MAOIs or within 14 days of MAOI discontinuation cannot receive bupropion due to hypertensive crisis risk. 5, 6