Pharmaceutics (Aug 2023)
Therapeutic Drug Monitoring in Children and Adolescents: Findings on Fluoxetine from the TDM-VIGIL Trial
- Michael Frey,
- Lukasz Smigielski,
- Elvira Tini,
- Stefanie Fekete,
- Christian Fleischhaker,
- Christoph Wewetzer,
- Andreas Karwautz,
- Christoph U. Correll,
- Manfred Gerlach,
- Regina Taurines,
- Paul L. Plener,
- Uwe Malzahn,
- Selina Kornbichler,
- Laura Weninger,
- Matthias Brockhaus,
- Su-Yin Reuter-Dang,
- Karl Reitzle,
- Hans Rock,
- Hartmut Imgart,
- Peter Heuschmann,
- Stefan Unterecker,
- Wolfgang Briegel,
- Tobias Banaschewski,
- Jörg M. Fegert,
- Tobias Hellenschmidt,
- Michael Kaess,
- Michael Kölch,
- Tobias Renner,
- Christian Rexroth,
- Susanne Walitza,
- Gerd Schulte-Körne,
- Marcel Romanos,
- Karin Maria Egberts
Affiliations
- Michael Frey
- Faculty of Applied Healthcare Science, Deggendorf Institute of Technology, 94469 Deggendorf, Germany
- Lukasz Smigielski
- Department of Child and Adolescent Psychiatry and Psychotherapy, Psychiatric University Hospital Zurich, University of Zurich, 8032 Zürich, Switzerland
- Elvira Tini
- Department of Child and Adolescent Psychiatry and Psychotherapy, Psychiatric University Hospital Zurich, University of Zurich, 8032 Zürich, Switzerland
- Stefanie Fekete
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Center for Mental Health, University Hospital of Wuerzburg, 97080 Wuerzburg, Germany
- Christian Fleischhaker
- Department of Child and Adolescent Psychiatry and Psychotherapy, University Medical Center Freiburg, 79104 Freiburg, Germany
- Christoph Wewetzer
- KIRINUS Tagesklinik Kinder und Jugendliche, 80639 Munich, Germany
- Andreas Karwautz
- Department of Child and Adolescent Psychiatry, Medical University Vienna, 1090 Vienna, Austria
- Christoph U. Correll
- Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany
- Manfred Gerlach
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Center for Mental Health, University Hospital of Wuerzburg, 97080 Wuerzburg, Germany
- Regina Taurines
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Center for Mental Health, University Hospital of Wuerzburg, 97080 Wuerzburg, Germany
- Paul L. Plener
- Department of Child and Adolescent Psychiatry, Medical University Vienna, 1090 Vienna, Austria
- Uwe Malzahn
- Clinical Trial Center Wuerzburg, University Hospital Wuerzburg, 97080 Wuerzburg, Germany
- Selina Kornbichler
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital, LMU Munich, 80097 Munich, Germany
- Laura Weninger
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital, LMU Munich, 80097 Munich, Germany
- Matthias Brockhaus
- Max-Planck-Institut für Psychiatry, 80804 Munich, Germany
- Su-Yin Reuter-Dang
- Specialist Practice and Medical Care Centre for Child and Adolescent Psychiatry Munich, Dr. Epple & Dr. Reuter-Dang, 81241 Munich, Germany
- Karl Reitzle
- Specialist Practice and Medical Care Center for Child and Adolescent Psychiatry Munich, 81241 Munich, Germany
- Hans Rock
- Central Information Office, Department of Neurology, Philipps University of Marburg, 35112 Marburg, Germany
- Hartmut Imgart
- Parkland-Clinic, Clinic for Psychosomatics and Psychotherapy, Academic Teaching Hospital for the University Gießen, 34537 Bad Wildungen, Germany
- Peter Heuschmann
- Clinical Trial Center Wuerzburg, University Hospital Wuerzburg, 97080 Wuerzburg, Germany
- Stefan Unterecker
- Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Wuerzburg, 97080 Wuerzburg, Germany
- Wolfgang Briegel
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Center for Mental Health, University Hospital of Wuerzburg, 97080 Wuerzburg, Germany
- Tobias Banaschewski
- Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, 68159 Mannheim, Germany
- Jörg M. Fegert
- Department of Child and Adolescent Psychiatry/Psychotherapy, University Hospital Ulm, 89075 Ulm, Germany
- Tobias Hellenschmidt
- Department of Child and Adolescent Psychiatry, Psychotherapy and Psychosomatic medicine, Vivantes Clinic Berlin Neukölln, 12351 Berlin, Germany
- Michael Kaess
- Clinic for Child and Adolescent Psychiatry, Center for Psychosocial Medicine, University Hospital Heidelberg, 69115 Heidelberg, Germany
- Michael Kölch
- Department of Child and Adolescent Psychiatry and Psychotherapy, Brandenburg Medical School Brandenburg, 16816 Neuruppin, Germany
- Tobias Renner
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Psychiatry and Psychotherapy Tuebingen, Center of Mental Health Tuebingen, 72076 Tuebingen , Germany
- Christian Rexroth
- Clinic for Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University of Regensburg at the Regensburg District Hospital, Medbo KU, 93053 Regensburg, Germany
- Susanne Walitza
- Department of Child and Adolescent Psychiatry and Psychotherapy, Psychiatric University Hospital Zurich, University of Zurich, 8032 Zürich, Switzerland
- Gerd Schulte-Körne
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital, LMU Munich, 80097 Munich, Germany
- Marcel Romanos
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Center for Mental Health, University Hospital of Wuerzburg, 97080 Wuerzburg, Germany
- Karin Maria Egberts
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Center for Mental Health, University Hospital of Wuerzburg, 97080 Wuerzburg, Germany
- DOI
- https://doi.org/10.3390/pharmaceutics15092202
- Journal volume & issue
-
Vol. 15,
no. 9
p. 2202
Abstract
Fluoxetine is the recommended first-line antidepressant in many therapeutic guidelines for children and adolescents. However, little is known about the relationships between drug dose and serum level as well as the therapeutic serum reference range in this age group. Within a large naturalistic observational prospective multicenter clinical trial (“TDM-VIGIL”), a transdiagnostic sample of children and adolescents (n = 138; mean age, 15; range, 7–18 years; 24.6% males) was treated with fluoxetine (10–40 mg/day). Analyses of both the last timepoint and all timepoints (n = 292 observations), utilizing (multiple) linear regressions, linear mixed-effect models, and cumulative link (mixed) models, were used to test the associations between dose, serum concentration, outcome, and potential predictors. The receiver operating curve and first to third interquartile methods, respectively, were used to examine concentration cutoff and reference values for responders. A strong positive relationship was found between dose and serum concentration of fluoxetine and its metabolite. Higher body weight was associated with lower serum concentrations, and female sex was associated with lower therapeutic response. The preliminary reference ranges for the active moiety (fluoxetine+norfluoxetine) were 208–328 ng/mL (transdiagnostically) and 201.5–306 ng/mL (depression). Most patients showed marked (45.6%) or minimal (43.5%) improvements and reported no adverse effects (64.9%). This study demonstrated a clear linear dose–serum level relationship for fluoxetine in youth, with the identified reference range being within that established for adults.
Keywords
- TDM
- adolescents
- depression
- antidepressants
- selective serotonin reuptake inhibitors
- pharmacovigilance
