Summary

Fluoxetine can significantly increase brexpiprazole plasma concentrations through CYP2D6 inhibition, potentially leading to enhanced side effects. This moderate-severity interaction requires dose adjustment and careful monitoring when these medications are used together.

Introduction

Brexpiprazole (Rexulti) is an atypical antipsychotic medication primarily used to treat schizophrenia and as adjunctive therapy for major depressive disorder. It works as a partial agonist at dopamine D2 and serotonin 5-HT1A receptors. Fluoxetine (Prozac) is a selective serotonin reuptake inhibitor (SSRI) antidepressant commonly prescribed for depression, anxiety disorders, and obsessive-compulsive disorder. Both medications are frequently used in psychiatric practice and may be prescribed together for patients with complex mental health conditions.

Mechanism of Interaction

The interaction between brexpiprazole and fluoxetine occurs through cytochrome P450 enzyme inhibition. Fluoxetine is a potent inhibitor of CYP2D6, the primary enzyme responsible for metabolizing brexpiprazole. When fluoxetine blocks CYP2D6 activity, it significantly reduces brexpiprazole clearance, leading to increased plasma concentrations and prolonged half-life. This pharmacokinetic interaction can result in brexpiprazole levels that are 2-3 times higher than normal, potentially increasing the risk of dose-related adverse effects.

Risks and Symptoms

The primary clinical risks of this interaction include increased incidence of brexpiprazole-related side effects such as extrapyramidal symptoms, sedation, weight gain, and metabolic changes. Patients may experience enhanced dopaminergic blockade effects, including akathisia, tremor, and tardive dyskinesia risk. Additionally, there may be increased risk of QT prolongation, orthostatic hypotension, and cognitive impairment. While rare, the combination may also slightly increase serotonin syndrome risk due to both drugs' effects on serotonin pathways, though this is more theoretical than clinically significant.

Management and Precautions

When co-administering brexpiprazole and fluoxetine, reduce the brexpiprazole dose by half (50% dose reduction) to compensate for increased exposure. Monitor patients closely for signs of increased side effects, particularly extrapyramidal symptoms and sedation. Regular assessment of metabolic parameters, including weight, glucose, and lipid levels, is recommended. Consider ECG monitoring if other QT-prolonging medications are involved. If fluoxetine is discontinued, gradually increase brexpiprazole back to the original dose over several weeks, as fluoxetine's long half-life means the interaction effects may persist for weeks after discontinuation.

Brexpiprazole interactions with food and lifestyle

Alcohol: Brexpiprazole may enhance the sedative effects of alcohol. Patients should avoid or limit alcohol consumption while taking brexpiprazole as it can increase drowsiness, dizziness, and impair cognitive and motor functions. This combination may also increase the risk of falls and accidents.

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.