What are the guidelines for using lamotrigine and bupropion (Wellbutrin) together?

Lamotrigine and Bupropion Interaction

Bupropion does not significantly affect lamotrigine pharmacokinetics and the combination can be used safely together, but monitor for additive seizure risk and neuropsychiatric effects. 1, 2

Pharmacokinetic Interaction

No clinically significant drug interaction exists between these medications. The FDA label for bupropion explicitly states that "multiple oral doses of bupropion had no statistically significant effects on the single-dose pharmacokinetics of lamotrigine in 12 healthy volunteers." 1 This finding is corroborated by a dedicated pharmacokinetic study showing that steady-state bupropion 150 mg twice daily caused no clinically relevant changes in lamotrigine exposure, with all pharmacokinetic parameters remaining within acceptable ranges. 2

Critical Safety Considerations

Seizure Risk Management

Both medications lower the seizure threshold, requiring careful patient selection and monitoring. 3, 4

• Absolute contraindications for bupropion include: active seizure disorder, brain metastases, stroke history, or any condition that increases seizure risk 3, 4
• Bupropion carries a 0.1% seizure risk at therapeutic doses, which increases with higher doses (maximum 300 mg/day for immediate release, 400 mg/day for sustained release) 4, 5
• When combining these agents, start with low doses and titrate gradually to minimize additive seizure risk 4
• Avoid in patients with eating disorders (bulimia/anorexia) due to elevated seizure risk 3

Neuropsychiatric Monitoring

Monitor closely for worsening depression, suicidal ideation, and behavioral changes, particularly in patients under 24 years old. 3, 4

• Bupropion carries a black box warning for suicidal behavior/ideation in young adults with depression 4
• Both medications can affect mood stability, though lamotrigine does not typically destabilize mood 6
• Serious neuropsychiatric adverse events are rare but require immediate discontinuation if they occur 3, 4

Cardiovascular Monitoring

Check blood pressure and heart rate regularly, as bupropion can cause elevations. 3, 4

• Contraindicated in uncontrolled hypertension 3, 4
• Monitor particularly during the first 8 weeks of treatment 3

Lamotrigine-Specific Concerns

The interaction concern with lamotrigine primarily involves combined oral contraceptives (COCs), not bupropion. 3

• COCs significantly decrease lamotrigine levels by 50% or more, potentially causing breakthrough seizures 3
• This is NOT a concern with bupropion combination therapy 1, 2

Clinical Advantages of Combination

This combination may offer therapeutic benefits for treatment-resistant depression without sexual side effects or weight gain. 5, 7

• Bupropion is commonly added to other antidepressants to boost response in refractory cases 7
• Lamotrigine is effective for bipolar depression without causing mood destabilization 6, 8
• Neither agent typically causes sexual dysfunction or significant weight gain 5, 6

Practical Dosing Approach

Initiate each medication separately and titrate according to standard protocols:

• Bupropion: Start 150 mg once daily, increase to 150 mg twice daily after 3-7 days if tolerated; maximum 300 mg/day 3
• Lamotrigine: Requires slow titration over weeks to minimize rash risk (0.1% incidence of serious rash) 6
• Do not take the second bupropion dose after 3 PM to minimize insomnia risk 3

Additional Contraindications for Bupropion

• Concurrent MAO inhibitor use or within 14 days of discontinuation 3
• Concurrent opioid therapy (if using naltrexone-bupropion formulation) 3, 4
• Moderate to severe hepatic impairment requires dose reduction 3
• End-stage renal disease 3