Summary

The combination of fluoxetine and selegiline represents a potentially dangerous drug interaction that can lead to serotonin syndrome. This interaction occurs due to fluoxetine's serotonin reuptake inhibition and selegiline's monoamine oxidase inhibition, creating a risk of excessive serotonin accumulation.

Introduction

Fluoxetine (brand name Prozac) is a selective serotonin reuptake inhibitor (SSRI) commonly prescribed for depression, anxiety disorders, and obsessive-compulsive disorder. It works by blocking the reuptake of serotonin in the brain, increasing serotonin availability. Selegiline (brand names Eldepryl, Zelapar) is a monoamine oxidase inhibitor (MAOI) primarily used to treat Parkinson's disease and sometimes depression. At low doses, selegiline selectively inhibits MAO-B, but at higher doses or when combined with certain medications, it can also inhibit MAO-A, affecting serotonin metabolism.

Mechanism of Interaction

The interaction between fluoxetine and selegiline occurs through complementary mechanisms that can lead to dangerous serotonin accumulation. Fluoxetine blocks the serotonin transporter, preventing serotonin reuptake and increasing synaptic serotonin levels. Simultaneously, selegiline inhibits monoamine oxidase enzymes responsible for breaking down serotonin and other neurotransmitters. When used together, these mechanisms create a "double block" effect - serotonin levels increase due to reduced reuptake while simultaneously being prevented from normal enzymatic breakdown. This can result in excessive serotonin activity and potentially life-threatening serotonin syndrome.

Risks and Symptoms

The primary risk of combining fluoxetine and selegiline is serotonin syndrome, a potentially fatal condition characterized by altered mental status, autonomic instability, and neuromuscular abnormalities. Symptoms may include confusion, agitation, hyperthermia, diaphoresis, tremor, muscle rigidity, hyperreflexia, and cardiovascular instability. The risk is particularly elevated because fluoxetine has a long half-life (4-6 days) and its active metabolite norfluoxetine has an even longer half-life (4-16 days), meaning the interaction risk persists for weeks after discontinuation. Additional risks include hypertensive crisis, seizures, and cardiovascular complications. The interaction is considered contraindicated in most clinical guidelines.

Management and Precautions

Fluoxetine interactions with food and lifestyle

Alcohol: Fluoxetine may increase the sedative effects of alcohol and impair cognitive and motor performance. Patients should avoid or limit alcohol consumption while taking fluoxetine. Grapefruit juice: May increase fluoxetine blood levels, though this interaction is generally considered minor. St. John's Wort: Should be avoided as it may increase the risk of serotonin syndrome when combined with fluoxetine.

Selegiline interactions with food and lifestyle

Selegiline requires strict dietary restrictions due to its interaction with tyramine-containing foods. Patients taking selegiline must avoid high-tyramine foods including aged cheeses, cured meats, fermented foods, certain wines, and overripe fruits, as these can cause dangerous hypertensive crises. Alcohol consumption should be limited or avoided, particularly red wine and beer, which contain tyramine. Patients should also avoid certain medications and supplements containing sympathomimetics. These dietary and lifestyle restrictions are critical for patient safety and are emphasized in all major clinical guidelines for selegiline therapy.