What is the recommended titration schedule for aripiprazole and bupropion when used together?

Titration Schedule for Aripiprazole and Bupropion When Used Together

When using aripiprazole and bupropion together, start with low doses of both medications and titrate slowly due to the significant pharmacokinetic interaction that increases aripiprazole exposure by more than 5-fold.

Understanding the Interaction

Bupropion is a moderate to strong CYP2D6 inhibitor, while aripiprazole is extensively metabolized by CYP2D6 and CYP3A4 enzymes 1. This creates an important drug interaction:

• Bupropion inhibits the metabolism of aripiprazole, increasing aripiprazole plasma concentrations
• Research shows bupropion can increase aripiprazole exposure by 5.65-fold 1
• This interaction affects both aripiprazole and its active metabolite dehydroaripiprazole

Recommended Titration Schedule

For Bupropion:

1. Start with 100-150 mg daily for the first week 2
2. Increase to 150 mg twice daily in week 2 if tolerated
3. Maximum dose: 300-450 mg daily in divided doses (lower than typical maximum due to interaction)
4. Allow 2-3 weeks at stable dose before adding aripiprazole

For Aripiprazole (when adding to established bupropion therapy):

1. Start with a significantly reduced dose: 2-2.5 mg daily
2. Maintain this dose for at least 2 weeks to assess tolerability
3. If needed and tolerated, increase by 2.5 mg increments no more frequently than every 2 weeks
4. Target dose: 5-10 mg daily (much lower than standard dosing due to interaction)
5. Maximum dose: 15 mg daily (approximately 1/3 of typical maximum due to interaction)

Monitoring Parameters

• Assess for aripiprazole-related side effects weekly during the first month:
  • Akathisia (most common)
  • Extrapyramidal symptoms
  • Sedation
  • Metabolic changes
• Monitor blood pressure and heart rate (both medications can affect these)
• Evaluate for anxiety, insomnia, or agitation (potential side effects of both medications)
• Check weight and metabolic parameters at baseline and periodically

Special Considerations

• If initiating both medications simultaneously (not recommended), start bupropion first and establish tolerability before adding aripiprazole 3, 4
• If patient is already on aripiprazole, reduce the dose by at least 50-75% before adding bupropion 1
• Patients with hepatic or renal impairment require even lower starting doses and more gradual titration
• Avoid this combination in patients with seizure disorders, eating disorders, or uncontrolled hypertension 5

Evidence of Efficacy

The combination of aripiprazole and bupropion has shown efficacy in treatment-resistant depression:

• Adjunctive aripiprazole has demonstrated rapid improvement in depressive symptoms in patients not responding to bupropion monotherapy 4
• Long-term treatment with this combination has shown similar symptom improvement compared to aripiprazole with SSRIs/SNRIs 3

Common Pitfalls to Avoid

1. Starting with standard doses - This can lead to aripiprazole toxicity due to the significant interaction
2. Titrating too quickly - Allow adequate time between dose increases to assess for side effects
3. Ignoring early signs of akathisia - This is a common side effect that may require dose reduction
4. Overlooking the need for lower maintenance doses - The final aripiprazole dose should be much lower than typically used in monotherapy
5. Failing to monitor for metabolic changes - Both medications can affect weight and metabolic parameters

By following this structured titration approach and careful monitoring, the combination of aripiprazole and bupropion can be used safely and effectively despite their significant pharmacokinetic interaction.