title: Relationship between clozapine dose, serum concentration, and clinical outcome in children and adolescents in clinical practice.
abstract: Information on dose- and concentration-related clinical effects of clozapine treatment in children and adolescents is scarce. This study aimed to examine the relationship between dose, serum concentration, and clinical outcome as well as the influencing factors thereof in paediatric patients treated with clozapine. Data from a routine Therapeutic Drug Monitoring (TDM) service between 2004 and 2014 were studied in 68 patients, aged 11-18 years. Severity of illness, therapeutic effectiveness and adverse drug reactions (ADRs) were assessed by standardized means. A relationship between the daily dose (mean 319 mg, 4.9 mg/kg) and serum concentration (mean 387 ng/ml) of clozapine was found with the variation in dose explaining 30 % of the variability in clozapine serum concentrations. Also gender contributed to the variability, however, no influence of age or concomitant medications was detected. Furthermore, a significant association was found between clozapine serum concentration and the occurrence of ADRs. Patients without ADRs had a lower mean serum concentration than those with mild (261.4 vs 407.3 ng/ml, P = 0.018) and moderate ADRs (261.4 vs 416.3 ng/ml, P = 0.028). As clozapine was estimated to be effective in lower blood concentrations, guidance on a possibly lower therapeutic range of clozapine serum levels in paediatric patients is provided. With ADRs increasing under higher concentrations, TDM is strongly recommended in paediatric clozapine therapy for individualized dosing. Dose adjustment in females also might be reasonable according to gender-related differences in serum concentrations. However, regarding the limitations of this study results should be validated in larger studies with more standardized designs.
authors.affiliation: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Centre for Mental Health, University Hospital of Würzburg, Würzburg, Germany. E_Wohkitte_C@ukw.de.
authors.forename: Christopher
authors.initials: C
authors.lastname: Wohkittel
authors.affiliation: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Centre for Mental Health, University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Gerlach
authors.affiliation: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Centre for Mental Health, University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Regina
authors.initials: R
authors.lastname: Taurines
authors.affiliation: Clinics of the City Cologne GmbH, Clinic for Child and Adolescent Psychiatry and Psychotherapy, Cologne, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Wewetzer
authors.affiliation: Department of Psychiatry, Psychosomatics and Psychotherapy, Centre for Mental Health, University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Unterecker
authors.affiliation: Department of Psychiatry, Psychosomatics and Psychotherapy, Centre for Mental Health, University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Burger
authors.affiliation: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Centre for Mental Health, University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Diana
authors.initials: D
authors.lastname: Schreck
authors.affiliation: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Centre for Mental Health, University Hospital of Würzburg, Würzburg, Germany.|HEMERA Private Hospital for Mental Health, Adolescents and Young Adults, Bad Kissingen, Germany.|Department of Child and Adolescent Psychiatry and Psychotherapy, University Hospital of Ulm, Ulm, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Mehler-Wex
authors.affiliation: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Centre for Mental Health, University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Marcel
authors.initials: M
authors.lastname: Romanos
authors.affiliation: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Centre for Mental Health, University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Egberts
mesh_terms: D000293:Adolescent; D014150:Antipsychotic Agents / Q000097:blood* / Q000627:therapeutic use*; D002648:Child; D003024:Clozapine / Q000097:blood / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D001523:Mental Disorders / Q000097:blood / Q000188:drug therapy*; D012189:Retrospective Studies; D016896:Treatment Outcome
chemical_list: D014150:Antipsychotic Agents; D003024:Clozapine
keywords: Adverse drug reactions; Clinical effectiveness; Pharmacotherapy; Psychiatry; Therapeutic drug monitoring