clozapine and fluoxetine

Fluoxetine inhibits CYP2D6 and CYP3A4, which are involved in the metabolism of clozapine. This reduces clozapine clearance and increases its plasma concentration.

Elevated clozapine levels increase the risk of dose-related adverse effects such as sedation, orthostatic hypotension, tachycardia, metabolic disturbances, seizures, agranulocytosis, and QT prolongation. Toxicity can occur at standard clozapine doses.

Avoid co-prescription if feasible. If necessary, use a lower clozapine dose, monitor plasma clozapine concentrations, and watch for signs of toxicity. Consider alternative antidepressants that do not inhibit CYP2D6 or CYP3A4.

Well established through pharmacokinetic studies and case reports. Fluoxetine has been shown to significantly increase clozapine levels, sometimes by twofold or more.