What are the considerations for using Wellbutrin (bupropion) in patients with bipolar disorder?

Bupropion Use in Bipolar Disorder: Clinical Considerations

Bupropion should be used with extreme caution in bipolar disorder due to its significant risk of triggering manic episodes, even when combined with mood stabilizers, and is contraindicated in patients with bipolar disorder according to FDA labeling.

Risk of Mania/Hypomania

• The FDA drug label explicitly warns that bupropion can precipitate manic, mixed, or hypomanic episodes, with increased risk in patients with bipolar disorder 1
• Clinical evidence shows that even when combined with mood stabilizers, bupropion carries a substantial risk of inducing manic switches in bipolar patients:
  • In one study, 6 out of 11 bipolar patients (55%) experienced manic or hypomanic episodes requiring discontinuation of bupropion, even though 5 of these 6 patients were already stabilized on lithium plus either carbamazepine or valproate 2
  • Case reports document manic shifts in bipolar depression patients when bupropion was added as an adjunct to mood stabilizer treatment 3

Comparative Risk Among Antidepressants

• Some evidence suggests bupropion may have a lower risk of inducing mood switches compared to certain other antidepressants:
  • In a double-blind trial comparing bupropion to desipramine in bipolar depression, mania/hypomania occurred in 5 of 10 desipramine-treated patients versus only 1 of 9 bupropion-treated patients 4
  • However, this reduced risk is relative and not absolute - manic switches still occur with bupropion

Seizure Risk Considerations

• Bupropion lowers the seizure threshold with an incidence of approximately 0.1% at therapeutic doses 5
• This is particularly concerning in bipolar patients who may be on multiple medications that could further lower seizure threshold
• Bupropion should be avoided in patients with:
  • History of seizure disorders
  • Anorexia nervosa or bulimia
  • Current use of other medications that lower seizure threshold 5

Drug Interactions

• Carbamazepine significantly affects bupropion metabolism:
  • Decreases bupropion peak concentrations by 87%
  • Increases hydroxybupropion (active metabolite) concentrations 6
• This interaction may require dosage adjustments but also increases unpredictability of response and side effects

Clinical Decision Algorithm

1. First-line approach: Avoid bupropion in bipolar disorder patients due to FDA contraindication and documented risk of manic switch
2. If considering despite risks:
   • Ensure patient is stabilized on adequate mood stabilizer therapy
   • Start with lowest possible dose (75-100mg daily)
   • Monitor closely for emergence of manic/hypomanic symptoms
   • Implement frequent follow-up during dose titration
   • Never exceed 450mg daily in bipolar patients
   • Discontinue immediately if any signs of mood elevation occur

Special Considerations

• Medication interactions: Exercise extreme caution with concurrent use of:

  • Monoamine oxidase inhibitors (contraindicated)
  • Carbamazepine (significantly alters bupropion levels)
  • Other medications that lower seizure threshold

• Monitoring requirements:

  • Weekly monitoring during initial titration
  • Assess for signs of mood elevation at each visit
  • Monitor blood pressure (bupropion can cause hypertension)
  • Educate patients and families about warning signs of mania and seizures

Conclusion

While bupropion may have theoretical advantages in bipolar depression due to its norepinephrine and dopamine reuptake inhibition mechanism, the documented risk of triggering manic episodes (even with mood stabilizer coverage) and its FDA contraindication in bipolar disorder make it a high-risk option that should generally be avoided. When safer alternatives exist, these should be prioritized to reduce the risk of destabilizing bipolar patients.