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

From the Guidelines

Combining lurasidone, fluoxetine, and modafinil poses a significant interaction risk, necessitating cautious use and close medical supervision. The primary concern arises from fluoxetine's ability to inhibit CYP2D6 and moderately inhibit CYP3A4, which can substantially increase lurasidone blood levels, potentially leading to enhanced side effects such as sedation, dizziness, and extrapyramidal symptoms 1. Furthermore, the addition of modafinil, which can induce CYP3A4 enzymes, complicates this interaction by potentially reducing lurasidone levels while also affecting fluoxetine metabolism 1.

Key Considerations

• Fluoxetine's strong inhibition of CYP2D6 and moderate inhibition of CYP3A4 can increase lurasidone levels, enhancing the risk of side effects.
• Modafinil's induction of CYP3A4 can decrease lurasidone levels and affect fluoxetine metabolism, further complicating the interaction.
• If this combination is necessary, reducing the lurasidone dosage (typically by 50% when used with moderate CYP3A4 inhibitors) and close monitoring for increased side effects or decreased effectiveness are recommended.
• Symptoms of concern include unusual drowsiness, muscle stiffness, tremors, significant mood changes, or cardiac symptoms.

Monitoring and Management

• Close medical supervision is crucial when combining these medications to mitigate potential risks.
• Patients should be monitored for signs of serotonin syndrome, a potentially life-threatening condition caused by elevated brain serotonin levels, characterized by mental status changes, neuromuscular hyperactivity, and autonomic hyperactivity 1.
• Regular assessment of treatment response and adjustment of medication dosages as needed are vital to optimize the benefit-to-harm ratio and achieve remission.

Special Prescribing Considerations

• Each SSRI, including fluoxetine, has unique prescribing considerations, such as the potential for discontinuation syndrome and drug-drug interactions 1.
• The potential for drug-drug interactions varies among SSRIs, with fluvoxamine having a greater potential for such interactions due to its inhibition of multiple CYP enzymes 1.

From the FDA Drug Label

In vitro data demonstrated that modafinil is a weak inducer of CYP3A activity in a concentration-related manner. CYP2C19 is also reversibly inhibited, with similar potency, by a circulating metabolite, modafinil sulfone Although the maximum plasma concentrations of modafinil sulfone are much lower than those of parent modafinil, the combined effect of both compounds could produce sustained partial inhibition of the enzyme. The Potential of Modafinil Tablets to Alter the Metabolism of Other Drugs by Enzyme Induction or Inhibition Drugs Metabolized by CYP3A4/5 In vitro data demonstrated that modafinil is a weak inducer of CYP3A activity in a concentration-related manner. Therefore, the blood levels and effectiveness of drugs that are substrates for CYP3A enzymes (e. g., steroidal contraceptives, cyclosporine, midazolam, and triazolam) may be reduced after initiation of concomitant treatment with modafinil tablets CYP2C19 also provides an ancillary pathway for the metabolism of certain tricyclic antidepressants (e.g., clomipramine and desipramine) and selective serotonin reuptake inhibitors that are primarily metabolized by CYP2D6.

The interaction between lurasidone, fluoxetine, and modafinil is as follows:

• Lurasidone is metabolized by CYP3A4. Modafinil is a weak inducer of CYP3A4, which may decrease the levels of lurasidone.
• Fluoxetine is metabolized by CYP2D6 and to a lesser extent by CYP2C19 and CYP3A4. Modafinil is a reversible inhibitor of CYP2C19, which may increase the levels of fluoxetine.
• However, the clinical significance of these interactions is not well established, and the effects may vary depending on the individual patient and the specific doses used. 2 2

From the Research

Interaction Check

• The interaction between lurasidone, fluoxetine, and modafinil is complex and involves multiple neurotransmitter systems.
• Lurasidone has a high affinity for serotonin 5-HT(1A), 5-HT(2A), 5-HT₇, dopamine D₂, and adrenergic α(2C) receptors 3.
• Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) that increases extracellular serotonin levels 4.
• Modafinil promotes wakefulness and has been shown to enhance the increase of extracellular serotonin levels induced by fluoxetine and imipramine 4.

Mechanism of Action

• Lurasidone's mechanism of action involves the inhibition of 5-HT7R, which contributes to its therapeutic advantages in the treatment of schizophrenia and bipolar depression 5, 3.
• Fluoxetine's mechanism of action involves the inhibition of serotonin reuptake, which increases extracellular serotonin levels 4.
• Modafinil's mechanism of action is not fully understood, but it may involve the inhibition of cortical γ-aminobutyric acid (GABA) release via serotonergic mechanisms 6.

Clinical Relevance

• Lurasidone is FDA-approved for the treatment of schizophrenia and bipolar depression, and has been shown to have a minimal propensity for weight gain and metabolic disruption 7.
• Fluoxetine is FDA-approved for the treatment of depression, and has been shown to be effective in increasing extracellular serotonin levels 4.
• Modafinil is FDA-approved for the treatment of narcolepsy, and has been shown to enhance the increase of extracellular serotonin levels induced by fluoxetine and imipramine 4.

Potential Interactions

• The combination of lurasidone, fluoxetine, and modafinil may have additive or synergistic effects on serotonin levels and may be useful in the treatment of depression or other psychiatric disorders 4.
• However, the potential interactions between these medications are complex and require further study to fully understand their clinical relevance 5, 3, 7, 4.