Do fluoxetine and lamotrigine contribute to serotonin syndrome?

From the Guidelines

Both fluoxetine and lamotrigine can potentially contribute to serotonin syndrome, though with different levels of risk, and their combination requires careful monitoring for symptoms of serotonin syndrome, as noted in the clinical practice guideline for the assessment and treatment of children and adolescents with anxiety disorders 1. The risk of serotonin syndrome is a significant concern when combining serotonergic medications, and fluoxetine, as a selective serotonin reuptake inhibitor (SSRI), carries a higher risk due to its direct increase of serotonin levels in the brain by blocking its reuptake. Lamotrigine, primarily an anticonvulsant and mood stabilizer, poses a lower risk but may still contribute to serotonin syndrome, particularly when combined with other serotonergic medications like fluoxetine. Some key points to consider when prescribing these medications together include:

• Starting the second non-MAOI serotonergic drug at a low dose, increasing the dose slowly, and monitoring for symptoms, especially in the first 24 to 48 hours after dosage changes, as recommended by the clinical practice guideline 1.
• Being aware of the potential for drug-drug interactions, particularly with fluoxetine, which may interact with drugs metabolized by CYP2D6, and lamotrigine, which may have a lower risk of interactions but still requires caution when combined with other medications 1.
• Monitoring patients closely for symptoms of serotonin syndrome, which can include agitation, confusion, rapid heart rate, dilated pupils, muscle rigidity, tremor, excessive sweating, high fever, and seizures, and seeking immediate medical attention if these symptoms develop 1.
• Informing patients about the potential risks and the importance of reporting all medications they are taking to prevent potentially dangerous drug interactions, as emphasized in the clinical practice guideline 1. The underlying mechanism of serotonin syndrome involves excessive serotonin activity in the central nervous system, which can occur through additive effects when multiple serotonergic agents are combined, highlighting the need for careful prescribing and monitoring practices, as discussed in the pharmacokinetic pharmacogenetic prescribing guidelines for antidepressants 1.

From the Research

Serotonin Syndrome and Fluoxetine and Lamotrigine

• Serotonin syndrome is a potentially life-threatening condition associated with increased serotonergic activity in the central nervous system 2.
• It can occur after initiation of a single serotonergic drug or increasing the dose of a serotonergic drug in individuals who are particularly sensitive to serotonin 2.
• The combination of two or more serotonergic drugs can cause serotonin syndrome, and lamotrigine, especially in combination with other serotonergic drugs, should be considered a cause of serotonin toxicity 3.

Fluoxetine and Serotonin Syndrome

• Fluoxetine, a serotonin reuptake inhibitor, has been associated with serotonin syndrome, particularly when combined with other serotonergic agents or when used in high doses 4, 5.
• A case report described a patient who developed serotonin syndrome after beginning treatment with fluoxetine, highlighting the potential risk of this condition with selective serotonin reuptake inhibitors (SSRIs) 4.
• Another case report described a patient who developed delayed-onset serotonin syndrome after ingesting a mixture of fluoxetine and other serotonergic agents, including serotonin antagonists 5.

Lamotrigine and Serotonin Syndrome

• Lamotrigine has been implicated in serotonin syndrome, particularly when used in combination with other serotonergic agents 3, 2.
• A case report described a patient who developed serotonin toxicity after ingesting lamotrigine and citalopram, highlighting the potential risk of this condition with lamotrigine and other serotonergic agents 3.
• Another case report described a patient who developed serotonin syndrome after ingesting higher than prescribed doses of lamotrigine and aripiprazole, in addition to cocaine abuse 2.

Combination of Fluoxetine and Lamotrigine

• While there is no direct evidence on the combination of fluoxetine and lamotrigine, the available data suggest that both drugs can contribute to serotonin syndrome, particularly when used in combination with other serotonergic agents 3, 2, 4, 5.
• Therefore, caution should be exercised when using fluoxetine and lamotrigine together, and patients should be monitored closely for signs and symptoms of serotonin syndrome 3, 2, 4, 5.