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Article

Therapeutic Drug Monitoring in Children and Adolescents: Findings on Fluoxetine from the TDM-VIGIL Trial

by
Michael Frey
1,2,*,†,
Lukasz Smigielski
3,†,
Elvira Tini
3,
Stefanie Fekete
4,
Christian Fleischhaker
5,
Christoph Wewetzer
6,
Andreas Karwautz
7,
Christoph U. Correll
8,9,10,
Manfred Gerlach
4,
Regina Taurines
4,
Paul L. Plener
7,11,
Uwe Malzahn
12,
Selina Kornbichler
2,
Laura Weninger
2,
Matthias Brockhaus
13,
Su-Yin Reuter-Dang
14,
Karl Reitzle
15,
Hans Rock
16,
Hartmut Imgart
17,
Peter Heuschmann
12,18,
Stefan Unterecker
19,
Wolfgang Briegel
4,20,
Tobias Banaschewski
21,
Jörg M. Fegert
11,
Tobias Hellenschmidt
22,
Michael Kaess
23,24,
Michael Kölch
25,26,
Tobias Renner
27,
Christian Rexroth
28,
Susanne Walitza
3,29,30,
Gerd Schulte-Körne
2,
Marcel Romanos
4 and
Karin Maria Egberts
4,*
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1
Faculty of Applied Healthcare Science, Deggendorf Institute of Technology, 94469 Deggendorf, Germany
2
Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital, LMU Munich, 80097 Munich, Germany
3
Department of Child and Adolescent Psychiatry and Psychotherapy, Psychiatric University Hospital Zurich, University of Zurich, 8032 Zürich, Switzerland
4
Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Center for Mental Health, University Hospital of Wuerzburg, 97080 Wuerzburg, Germany
5
Department of Child and Adolescent Psychiatry and Psychotherapy, University Medical Center Freiburg, 79104 Freiburg, Germany
6
KIRINUS Tagesklinik Kinder und Jugendliche, 80639 Munich, Germany
7
Department of Child and Adolescent Psychiatry, Medical University Vienna, 1090 Vienna, Austria
8
Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany
9
Department of Psychiatry, The Zucker Hillside Hospital, Northwell Health, Glen Oaks, NY 11004, USA
10
Department of Psychiatry and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549, USA
11
Department of Child and Adolescent Psychiatry/Psychotherapy, University Hospital Ulm, 89075 Ulm, Germany
12
Clinical Trial Center Wuerzburg, University Hospital Wuerzburg, 97080 Wuerzburg, Germany
13
Max-Planck-Institut für Psychiatry, 80804 Munich, Germany
14
Specialist Practice and Medical Care Centre for Child and Adolescent Psychiatry Munich, Dr. Epple & Dr. Reuter-Dang, 81241 Munich, Germany
15
Specialist Practice and Medical Care Center for Child and Adolescent Psychiatry Munich, 81241 Munich, Germany
16
Central Information Office, Department of Neurology, Philipps University of Marburg, 35112 Marburg, Germany
17
Parkland-Clinic, Clinic for Psychosomatics and Psychotherapy, Academic Teaching Hospital for the University Gießen, 34537 Bad Wildungen, Germany
18
Institute of Clinical Epidemiology and Biometry, University of Wuerzburg, 97080 Wuerzburg, Germany
19
Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Wuerzburg, 97080 Wuerzburg, Germany
20
Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Leopoldina Hospital, 97422 Schweinfurt, Germany
21
Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, 68159 Mannheim, Germany
22
Department of Child and Adolescent Psychiatry, Psychotherapy and Psychosomatic medicine, Vivantes Clinic Berlin Neukölln, 12351 Berlin, Germany
23
Clinic for Child and Adolescent Psychiatry, Center for Psychosocial Medicine, University Hospital Heidelberg, 69115 Heidelberg, Germany
24
University Hospital of Child and Adolescent Psychiatry and Psychotherapy, University of Bern, 3000 Bern, Switzerland
25
Department of Child and Adolescent Psychiatry and Psychotherapy, Brandenburg Medical School Brandenburg, 16816 Neuruppin, Germany
26
Department of Child and Adolescent Psychiatry, Neurology, Psychosomatics, and Psychotherapy, University Medical Center Rostock, 18147 Rostock, Germany
27
Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Psychiatry and Psychotherapy Tuebingen, Center of Mental Health Tuebingen, 72076 Tuebingen , Germany
28
Clinic for Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University of Regensburg at the Regensburg District Hospital, Medbo KU, 93053 Regensburg, Germany
29
Zurich Center for Integrative Human Physiology, University of Zurich, 8057 Zürich, Switzerland
30
Neuroscience Center Zurich, University of Zurich and ETH, 8057 Zürich, Switzerland
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Pharmaceutics 2023, 15(9), 2202; https://doi.org/10.3390/pharmaceutics15092202
Submission received: 19 July 2023 / Revised: 18 August 2023 / Accepted: 19 August 2023 / Published: 25 August 2023

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; steady-state concentration; reference range TDM; adolescents; depression; antidepressants; selective serotonin reuptake inhibitors; pharmacovigilance; steady-state concentration; reference range

Share and Cite

MDPI and ACS Style

Frey, M.; Smigielski, L.; Tini, E.; Fekete, S.; Fleischhaker, C.; Wewetzer, C.; Karwautz, A.; Correll, C.U.; Gerlach, M.; Taurines, R.; et al. Therapeutic Drug Monitoring in Children and Adolescents: Findings on Fluoxetine from the TDM-VIGIL Trial. Pharmaceutics 2023, 15, 2202. https://doi.org/10.3390/pharmaceutics15092202

AMA Style

Frey M, Smigielski L, Tini E, Fekete S, Fleischhaker C, Wewetzer C, Karwautz A, Correll CU, Gerlach M, Taurines R, et al. Therapeutic Drug Monitoring in Children and Adolescents: Findings on Fluoxetine from the TDM-VIGIL Trial. Pharmaceutics. 2023; 15(9):2202. https://doi.org/10.3390/pharmaceutics15092202

Chicago/Turabian Style

Frey, Michael, Lukasz Smigielski, Elvira Tini, Stefanie Fekete, Christian Fleischhaker, Christoph Wewetzer, Andreas Karwautz, Christoph U. Correll, Manfred Gerlach, Regina Taurines, and et al. 2023. "Therapeutic Drug Monitoring in Children and Adolescents: Findings on Fluoxetine from the TDM-VIGIL Trial" Pharmaceutics 15, no. 9: 2202. https://doi.org/10.3390/pharmaceutics15092202

APA Style

Frey, M., Smigielski, L., Tini, E., Fekete, S., Fleischhaker, C., Wewetzer, C., Karwautz, A., Correll, C. U., Gerlach, M., Taurines, R., Plener, P. L., Malzahn, U., Kornbichler, S., Weninger, L., Brockhaus, M., Reuter-Dang, S.-Y., Reitzle, K., Rock, H., Imgart, H., ... Egberts, K. M. (2023). Therapeutic Drug Monitoring in Children and Adolescents: Findings on Fluoxetine from the TDM-VIGIL Trial. Pharmaceutics, 15(9), 2202. https://doi.org/10.3390/pharmaceutics15092202

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