From the Guidelines
Bupropion should not be used with fluoxetine without caution and medical supervision due to potential increased risks of seizures and serotonin syndrome. When considering the combination of bupropion (Wellbutrin) and fluoxetine (Prozac), it's crucial to weigh the potential benefits against the risks, particularly the increased risk of seizures and serotonin syndrome, as both medications can affect serotonin levels and lower the seizure threshold 1. Key points to consider include:
- The potential for increased side effects such as anxiety, insomnia, and agitation when these medications are used together.
- The importance of medical supervision and potential dosage adjustments to mitigate risks.
- The need for patients to be aware of the signs of serotonin syndrome and to report any unusual symptoms promptly to their healthcare provider.
- The consideration of alternative treatment options that may have a more favorable risk-benefit profile, as suggested by guidelines that recommend discussing treatment effects, adverse effect profiles, cost, accessibility, and preferences with the patient 1. Given the information from the American College of Physicians guideline on nonpharmacologic versus pharmacologic treatment of adult patients with major depressive disorder, it is essential to approach the use of bupropion with fluoxetine with caution, considering the potential for adverse effects and the importance of patient-physician discussion on treatment options 1.
From the FDA Drug Label
Drugs Metabolized by CYP2D6 Bupropion and its metabolites (erythrohydrobupropion, threohydrobupropion, hydroxybupropion) are CYP2D6 inhibitors Therefore, coadministration of bupropion hydrochloride extended-release tablets (XL) with drugs that are metabolized by CYP2D6 can increase the exposures of drugs that are substrates of CYP2D6. Such drugs include certain antidepressants (e.g., venlafaxine, nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, and sertraline), When used concomitantly with bupropion hydrochloride extended-release tablets (XL), it may be necessary to decrease the dose of these CYP2D6 substrates, particularly for drugs with a narrow therapeutic index.
Bupropion may not be entirely safe to use with fluoxetine, as it can increase the exposure of fluoxetine due to its inhibition of the CYP2D6 enzyme. To minimize potential risks, it may be necessary to decrease the dose of fluoxetine when used concomitantly with bupropion. 2
From the Research
Safety of Bupropion with Fluoxetine
- The combination of bupropion and fluoxetine has been associated with a risk of serotonin syndrome, a potentially fatal complication 3, 4.
- A study published in 2004 reported a case of serotonin syndrome in a patient taking bupropion and sertraline, which was misinterpreted as an aggravation of depression 3.
- Another study published in 2023 reported a case of serotonin syndrome in a patient taking fluoxetine and bupropion, which was successfully treated with cyproheptadine and supportive care 4.
Efficacy of Bupropion with Fluoxetine
- A double-blind study published in 1991 compared the efficacy and safety of bupropion and fluoxetine in depressed outpatients, and found no statistically significant differences between treatments on any of the efficacy variables 5.
- A study published in 1997 found that combining bupropion with a serotonin reuptake inhibitor (including fluoxetine) resulted in greater symptomatic improvement in 70% of patients with affective disorders who were partial responders to monotherapy 6.
- A preliminary report published in 2002 found that combining bupropion SR with fluoxetine resulted in a clinically significant benefit in 78% of partial responders or nonresponders, and improved sexual dysfunction in some patients 7.