What is the potential interaction between lurasidone, fluoxetine (Selective Serotonin Reuptake Inhibitor - SSRI), and bupropion?

From the Guidelines

The combination of lurasidone, fluoxetine, and bupropion is not recommended due to the increased risk of serotonin syndrome, seizures, and other adverse effects, and alternative medications should be considered when possible. The use of fluoxetine, a strong CYP3A4 inhibitor, can increase lurasidone blood levels by approximately 1.5-fold, potentially increasing the risk of side effects like sedation, dizziness, and extrapyramidal symptoms 1. Additionally, the combination of fluoxetine and bupropion can increase the risk of seizures and serotonin syndrome, characterized by agitation, confusion, rapid heart rate, high blood pressure, dilated pupils, and muscle rigidity 1.

Some key points to consider when evaluating the interaction between these medications include:

• The potential for increased risk of serotonin syndrome when combining serotonergic medications, such as fluoxetine and bupropion 1
• The importance of monitoring for signs of serotonin syndrome, increased side effects, and changes in mental status when using this combination 1
• The need to start with lower doses of each medication and gradually titrate upward to minimize adverse effects 1
• The consideration of alternative medications when possible, especially in patients with a history of seizures or other risk factors for adverse effects 1

It is essential to weigh the potential benefits of using this combination against the potential risks and to carefully monitor patients for any adverse effects. If this combination is necessary, the lurasidone dose should be reduced to half the usual dose when used with fluoxetine, and patients should be closely monitored for signs of serotonin syndrome, increased side effects, and changes in mental status 1.

From the FDA Drug Label

2 Potential for Bupropion Hydrochloride Extended-Release Tablets (XL) to Affect Other Drugs 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), antipsychotics (e.g., haloperidol, risperidone, and thioridazine), beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone, and flecainide). 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.

• Lurasidone is an antipsychotic that is metabolized by CYP3A4, but it can also be a substrate of CYP2D6 to a lesser extent.
• Fluoxetine is an antidepressant that is metabolized by CYP2D6.
• Bupropion is a CYP2D6 inhibitor.

The coadministration of bupropion with fluoxetine may increase the exposure of fluoxetine due to the inhibition of CYP2D6 by bupropion. The coadministration of bupropion with lurasidone may also increase the exposure of lurasidone, although to a lesser extent, due to the inhibition of CYP2D6 by bupropion. It may be necessary to decrease the dose of fluoxetine and monitor for adverse effects when used concomitantly with bupropion. The dose of lurasidone may also need to be adjusted when used concomitantly with bupropion, although the extent of the interaction is less clear 2.

From the Research

Interaction Check

The interaction between lurasidone, fluoxetine, and bupropion is a complex one, involving both pharmacokinetic and pharmacodynamic aspects.

• Lurasidone is a second-generation antipsychotic that has been studied in combination with various antidepressants, including fluoxetine 3.
• Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) that can interact with lurasidone, potentially leading to increased risk of serotonin syndrome 4.
• Bupropion is another antidepressant that can interact with lurasidone, and the combination of these two medications may increase the risk of pharmacodynamic interactions, particularly in terms of serotonin syndrome 3.

Pharmacokinetic Interactions

• The study by 3 suggests that the combination of fluoxetine and lurasidone may require dose correction factors, although more studies are needed to establish this.
• There is limited information available on the pharmacokinetic interactions between bupropion and lurasidone, although it is known that bupropion can interact with other medications, including antipsychotics 3.

Pharmacodynamic Interactions

• The combination of lurasidone and fluoxetine may lead to beneficial pharmacodynamic interactions, particularly in the treatment of obsessive-compulsive disorder (OCD) and depressive symptoms 5.
• However, the combination of these medications can also increase the risk of serotonin syndrome, a potentially life-threatening condition 4.
• The addition of bupropion to this combination may further increase the risk of pharmacodynamic interactions, particularly in terms of serotonin syndrome 3.

Clinical Implications

• Clinicians should be aware of the potential interactions between lurasidone, fluoxetine, and bupropion, and monitor patients closely for signs of serotonin syndrome or other adverse effects 3, 4.
• Further studies are needed to fully understand the interactions between these medications and to establish safe and effective dosing regimens 3, 5.