TDM-Guided Treatment With SSRIs in Hospitalized Adults and Children

Summary

Depression in childhood and adolescence is a serious and increasing public-health problem associated with profound short- and long-term consequences, including impaired social and educational functioning, increased risk of somatic illness and substance use, and elevated mortality from suicide. Up to half of depressive disorders beginning in youth persist into adulthood, and the COVID-19 pandemic, with its attendant social isolation, has further increased the incidence of clinically significant depressive illness in children and young adults. Despite the high burden of disease, pharmacotherapeutic guidance for pediatric depression remains limited. Selective serotonin reuptake inhibitors (SSRIs) are first-line agents, yet dosing recommendations for youth do not adequately account for major sources of variability such as developmental pharmacokinetics, body size, age, comorbid diagnoses, and pharmacogenetic differences. Fluoxetine is commonly recommended in pediatric populations largely for historical reasons, while newer SSRIs such as escitalopram and sertraline are increasingly prescribed off-label without robust comparative evidence. This randomized clinical trial evaluates therapeutic drug monitoring (TDM)-guided treatment with fluoxetine, sertraline, or escitalopram in children and adults diagnosed with Major Depressive Disorder. TDM procedures will be implemented across all randomized arms to capture drug exposure and enable dose adjustments according to predefined safety and efficacy criteria. Treatments will be initiated at the lower end of recommended pediatric doses and titrated if prespecified clinical nonresponse or tolerability thresholds are met, allowing evaluation of dose-response dynamics while prioritizing patient safety. The study combines prospective, randomized comparative effectiveness methodology with intensive pharmacokinetic/pharmacodynamic (PK/PD) assessment. Repeated plasma concentration measurements will be collected at multiple timepoints to characterize within- and between-patient PK variability for each SSRI. Standardized clinical instruments will be used longitudinally to assess depressive symptom severity, response and remission rates, time to onset of therapeutic effect, adverse events (including early activation and worsening of suicidal ideation), treatment adherence, and functional outcomes (academic performance, social functioning, and quality of life). Pharmacogenetic testing will be performed to evaluate the contribution of genetic variants (including but not limited to CYP enzymes, serotonin transporter and MAO-A related polymorphisms) to PK parameters and clinical response. Integrated population PK and PK/PD modeling will (1) quantify concentration-effect and concentration-adverse-effect relationships over time, (2) identify demographic, clinical and genetic moderators of exposure and response, (3) evaluate nonlinearity in PK (e.g., dose-dependent absorption or clearance patterns), and (4) derive evidence-based therapeutic concentration ranges and individualized dosing algorithms for pediatric practice. Secondary objectives include head-to-head comparison of efficacy, tolerability, time to response, and persistence on treatment between the three SSRIs, as well as exploratory analyses of diagnostic subtypes and comorbidities that may influence outcomes. By filling critical gaps in controlled PK/PD data for the most commonly prescribed SSRIs in youth, this trial aims to move beyond meta-analytic inference toward actionable, individualized dosing recommendations. The expected outcomes are earlier identification of atypical pharmacokinetics, safer and more effective dose optimization, reduced adverse events and early discontinuation, shortened time to symptomatic improvement, and ultimately improved functional recovery and quality of life for children and young adults with depression. The study's translational PK/PD outputs will inform clinical TDM protocols, pediatric dosing guidelines, and future precision-medicine strategies in adolescent psychopharmacology.

Timeline

Start

2025-04-03

Primary completion

2027-11-30

Completion

2027-11-30

Publications

• Background Al Kadhi O, Melchini A, Mithen R, Saha S. Development of a LC-MS/MS Method for the Simultaneous Detection of Tricarboxylic Acid Cycle Intermediates in a Range of Biological Matrices. J Anal Methods Chem. 2017;2017:5391832. doi: 10.1155/2017/5391832. Epub 2017 Sep 18.
• Background Dziurkowska E, Wesolowski M. Isolation of Antidepressants and Their Metabolites from Saliva Using Supported Liquid Extraction (SLE). Biomedicines. 2023 Feb 25;11(3):708. doi: 10.3390/biomedicines11030708.
• Background Mas S, Blazquez A, Rodriguez N, Boloc D, Lafuente A, Arnaiz JA, Lazaro L, Gasso P. Pharmacogenetic study focused on fluoxetine pharmacodynamics in children and adolescent patients: impact of the serotonin pathway. Pharmacogenet Genomics. 2016 Nov;26(11):487-496. doi: 10.1097/FPC.0000000000000240.
• Background Zwolinska W, Dmitrzak-Weglarz M, Slopien A. Biomarkers in Child and Adolescent Depression. Child Psychiatry Hum Dev. 2023 Feb;54(1):266-281. doi: 10.1007/s10578-021-01246-y. Epub 2021 Sep 29.
• Background Dwyer JB, Stringaris A, Brent DA, Bloch MH. Annual Research Review: Defining and treating pediatric treatment-resistant depression. J Child Psychol Psychiatry. 2020 Mar;61(3):312-332. doi: 10.1111/jcpp.13202. Epub 2020 Feb 4.
• Background Sultana J, Spina E, Trifiro G. Antidepressant use in the elderly: the role of pharmacodynamics and pharmacokinetics in drug safety. Expert Opin Drug Metab Toxicol. 2015 Jun;11(6):883-92. doi: 10.1517/17425255.2015.1021684. Epub 2015 Mar 3.
• Background Lin S, Huang L, Luo ZC, Li X, Jin SY, Du ZJ, Wu DY, Xiong WC, Huang L, Luo ZY, Song YL, Wang Q, Liu XW, Ma RJ, Wang ML, Ren CR, Yang JM, Gao TM. The ATP Level in the Medial Prefrontal Cortex Regulates Depressive-like Behavior via the Medial Prefrontal Cortex-Lateral Habenula Pathway. Biol Psychiatry. 2022 Aug 1;92(3):179-192. doi: 10.1016/j.biopsych.2022.02.014. Epub 2022 Feb 22.
• Background Cao T, Xu B, Li S, Qiu Y, Chen J, Wu H, Cai H. Bioenergetic biomarkers as predictive indicators and their relationship with cognitive function in newly diagnosed, drug-naive patients with bipolar disorder. Transl Psychiatry. 2025 Apr 14;15(1):148. doi: 10.1038/s41398-025-03367-7.
• Background Bousman CA, Stevenson JM, Ramsey LB, Sangkuhl K, Hicks JK, Strawn JR, Singh AB, Ruano G, Mueller DJ, Tsermpini EE, Brown JT, Bell GC, Leeder JS, Gaedigk A, Scott SA, Klein TE, Caudle KE, Bishop JR. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6, CYP2C19, CYP2B6, SLC6A4, and HTR2A Genotypes and Serotonin Reuptake Inhibitor Antidepressants. Clin Pharmacol Ther. 2023 Jul;114(1):51-68. doi: 10.1002/cpt.2903. Epub 2023 May 30.
• Background Tini E, Smigielski L, Romanos M, Wewetzer C, Karwautz A, Reitzle K, Correll CU, Plener PL, Malzahn U, Heuschmann P, Unterecker S, Scherf-Clavel M, Rock H, Antony G, Briegel W, Fleischhaker C, Banaschewski T, Hellenschmidt T, Imgart H, Kaess M, Kolch M, Renner T, Reuter-Dang SY, Rexroth C, Schulte-Korne G, Theisen F, Fekete S, Taurines R, Gerlach M, Egberts KM, Walitza S. Therapeutic drug monitoring of sertraline in children and adolescents: A naturalistic study with insights into the clinical response and treatment of obsessive-compulsive disorder. Compr Psychiatry. 2022 May;115:152301. doi: 10.1016/j.comppsych.2022.152301. Epub 2022 Feb 26.
• Background Cellini L, De Donatis D, Zernig G, De Ronchi D, Giupponi G, Serretti A, Xenia H, Conca A, Florio V. Antidepressant efficacy is correlated with plasma levels: mega-analysis and further evidence. Int Clin Psychopharmacol. 2022 Mar 1;37(2):29-37. doi: 10.1097/YIC.0000000000000386.
• Background Stolfi F, Abreu H, Sinella R, Nembrini S, Centonze S, Landra V, Brasso C, Cappellano G, Rocca P, Chiocchetti A. Omics approaches open new horizons in major depressive disorder: from biomarkers to precision medicine. Front Psychiatry. 2024 Jun 13;15:1422939. doi: 10.3389/fpsyt.2024.1422939. eCollection 2024.
• Background Cui L, Li S, Wang S, Wu X, Liu Y, Yu W, Wang Y, Tang Y, Xia M, Li B. Major depressive disorder: hypothesis, mechanism, prevention and treatment. Signal Transduct Target Ther. 2024 Feb 9;9(1):30. doi: 10.1038/s41392-024-01738-y.
• Background Fabiano N, Stubbs B. Creatine as a treatment for depression: A brain bioenergetics perspective. Eur Neuropsychopharmacol. 2025 Jul;96:3-4. doi: 10.1016/j.euroneuro.2025.03.014. Epub 2025 Apr 11. No abstract available.

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