Optimization of Clozapine Treatment: Study of Variables Affecting Response in Uruguayan Patients With Schizophrenia.

Abstract

Purpose/background: Clozapine is the recommended drug for treatment-resistant schizophrenia. Drug response could be affected by numerous factors such as age, sex, body mass index, co-medication, consumption of xanthine-containing beverages, smoking, and genetic variants of the enzymes involved in clozapine metabolism (CYP1A2, CYP3A4, and, to a lesser extent, CYP2C19 and CYP2D6). This study evaluated genetic and nongenetic variables that may affect clozapine plasma concentrations in Uruguayan patients with schizophrenia.

Methods/procedures: Demographic data including sex, age, ethnicity, body weight, smoking habit, concomitant medication, and xanthine consumption were collected through a data collection form. Clozapine and norclozapine concentrations were determined using an HPLC system equipped with a UV detector. Genetic variants were determined through next-generation sequencing using Illumina sequencing technology and a panel of DNA probes.

Findings/results: Fifty patients were included in the study. After evaluation, only tobacco use and obesity had a significant impact on clozapine exposure (P < 0.05). The high prevalence of the genetic variant CYP1A2*1F may account for the significant impact that tobacco smoking has on clozapine concentrations. Some common adverse effects observed in this study depend on clozapine plasma concentrations, such as constipation and sialorrhea.

Implications/conclusions: These types of studies provide the clinician with tools to optimize clozapine therapy, attempting to use the minimum effective dose and attenuating the burden of concentration-dependent adverse reactions.