Inter- und intraindividuelle Variabilität der Clozapin-Serumspiegel von an Schizophrenie erkrankten Jugendlichen

Einleitung Clozapin (CLZ) ist in der Behandlung therapieresistenter juveniler Schizophrenie anderen Antipsychotika überlegen. Es liegen nur begrenzt Daten über Serumkonzentrationen und hierauf einflussnehmende Variablen vor. Therapeutisches Drug Monitoring (TDM) wird empfohlen, um die Compliance be...

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Bibliographic Details
Main Author: Haberhausen, Michael
Contributors: Remschmidt, Helmut (Prof. Dr. Dr.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2015
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Introduction In treating youth with refractory early onset schizophrenia, Clozapine (CLZ) demonstrated superior efficacy compared to other antipsychotics, but data on the serum clozapine concentrations and its influencing factors are limited. Therapeutic drug monitoring is recommended to assess toxicity and adherence while providing assistance in judging therapeutic response based on serum levels of CLZ. Methods Dose-related steady-state serum concentrations of CLZ and its metabolites were assessed by high-performance liquid chromatography in 272 child and adolescent psychiatric patients diagnosed with schizophrenia (age at first as-sessment: mean +- SD, 17.3 +- 1.6 years; range, 10.1-19.9 years; 166 male, 106 female). The first steady-state concentration of each patient was included for analysis of interindividual variability and in addition a total of 2578 steady-state CLZ serum concentrations (2 to 58 measurements per patient) was analyzed for intraindividual variation. Results The patients received CLZ doses between 12.5 to 1000.0 mg (mean +- SD, 260.0 +- 136.2 mg). The CLZ serum concentration (mean +- SD) was 298.8 +- 218.3 ng/ml. CLZ concentration-to-dose (C/D) ratio (mean +- SD) was 1.4 +- 1.2 (ng/ml)/(mg/d). Females had higher CLZ concentrations und CLZ concentration-to-dose (C/D) ratios than males (p < 0.001). CLZ concentration-to-dose (C/D) ratio was lower in smokers and patients with CLZ monotherapy. Linear mixed model analysis shows significant influences of daily CLZ dose, gender, smoking and presence of co-medications on the CLZ serum concentration (p < 0.001). Patients who were additionally taking the SSRI fluvoxamine received lower CLZ doses and exhibited lower CLZ concentration-to-dose (C/D) ratios than patients without fluvoxamine as a co-medication. Intraindividual variability of CLZ serum concentration accounted for 49.8 % of total variance. Discussion The serum concentrations of CLZ and CLZ metabolites in adolescents with schizophrenia show high inter- and intraindividual variability, comparable to that seen in adults. Repeated serum concentration measurements are recommended to obtain a more precise estimate of the intraindividual variability of serum concentrations