Is it safe to take Wellbutrin (bupropion) and amitriptyline together?

Bupropion and Amitriptyline Combination Safety

The combination of bupropion (Wellbutrin) and amitriptyline should be avoided due to potential safety concerns, particularly the increased risk of seizures and neuropsychiatric effects. 1

Safety Concerns with This Combination

Contraindications and Risks

• Bupropion is contraindicated for use with monoamine oxidase inhibitors (MAOIs) 2, and while amitriptyline is not an MAOI, the combination presents other risks:
  • Both medications can lower seizure threshold, potentially creating an additive risk 1, 3
  • Increased risk of neuropsychiatric effects including anxiety, agitation, and insomnia 1
  • Potential for cardiovascular effects, as both medications can affect heart rate and blood pressure 1

Pharmacological Considerations

• Bupropion acts primarily as a norepinephrine and dopamine reuptake inhibitor with stimulating properties 1
• Amitriptyline is a tricyclic antidepressant with significant anticholinergic effects 4
• The combination may lead to unpredictable interactions due to their different mechanisms of action and side effect profiles 4

Evidence from Clinical Studies

While older studies have examined each medication separately or compared them head-to-head, there is limited recent high-quality evidence specifically supporting their combined use:

• A 1982 study showed that bupropion and amitriptyline have clinically different side effect profiles, with bupropion notably lacking the anticholinergic effects of amitriptyline 4
• A small case series from 1994 reported successful use of bupropion with nortriptyline (a related tricyclic antidepressant) in refractory depression, but this represents very low-quality evidence 5

Alternative Approaches

If treatment for depression is needed, consider these safer alternatives:

1. For patients without significant anxiety:

   • Bupropion monotherapy (starting at lower doses and titrating gradually) 1
   • Maximum recommended dose: 150 mg twice daily 1

2. For patients with anxiety or who cannot tolerate bupropion:

   • SSRI monotherapy (fluoxetine, sertraline, paroxetine) 1
   • Mirtazapine (especially if sleep promotion is desired) 1

3. For treatment-resistant depression:

   • Consider venlafaxine with careful monitoring instead of tricyclic combinations 1
   • Consult with psychiatry for specialized approaches

Monitoring Recommendations

If, despite these concerns, the combination is deemed necessary by a specialist:

• Monitor blood pressure and heart rate regularly, especially during the first 12 weeks 1
• Start with lower doses of both medications 1
• Watch closely for signs of increased anxiety, agitation, insomnia, or seizure activity 1
• Be vigilant for suicidal thoughts, particularly in younger patients 1
• Consider EKG monitoring due to potential cardiac effects of both medications

Practical Considerations

• Dosing should occur earlier in the day to minimize insomnia risk 1
• The combination should be absolutely avoided in patients with:
  • Seizure disorders or conditions lowering seizure threshold
  • Uncontrolled hypertension
  • History of significant anxiety disorders
  • Closed-angle glaucoma 1

This combination carries substantial risks with limited evidence of additional benefit over monotherapy or other combination approaches, making it an unfavorable choice for most patients requiring antidepressant treatment.