TDM-Guided Treatment With SSRIs in Hospitalized Adults and Children

Condition(s) studied

Investigational drug(s) / intervention(s)

Fluoxetine: Oral fluoxetine administered once daily in the morning. Dosing is stratified by age: Children/adolescents (12-17 years) and elderly (\>64 years) start at 10 mg/day; adults (18-64 years) start at 20 mg/day. If clinical improvement is \<25% after 3 weeks, the dose is escalated to 20 mg/day for children/elderly and 40 mg/day for adults. Treatment duration is 8 weeks, with therapeutic drug monitoring (TDM) performed weekly to assess plasma concentrations.

Escitalopram: Oral escitalopram administered once daily in the morning. Dosing is stratified by age: Children/adolescents (12-17 years) and elderly (\>64 years) start at 5 mg/day; adults (18-64 years) start at 10 mg/day. If clinical improvement is \<25% after 3 weeks, the dose is escalated to 10 mg/day for children/elderly and 20 mg/day for adults. Treatment duration is 8 weeks, with therapeutic drug monitoring (TDM) performed weekly to assess plasma concentrations.

Sertralin: Oral sertraline administered once daily in the morning. Dosing is stratified by age: Children/adolescents (12-17 years) and elderly (\>64 years) start at 25 mg/day; adults (18-64 years) start at 50 mg/day. If clinical improvement is \<25% after 3 weeks, the dose is escalated to 50 mg/day for children/elderly and 100 mg/day for adults. Treatment duration is 8 weeks, with therapeutic drug monitoring (TDM) performed weekly to assess plasma concentrations.

Study 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.

Eligibility

Primary outcome measure(s)

• Change in Depression Severity (CDI) — Baseline and Week 8
  Change in depression severity score from Baseline to Week 8 using the Children's Depression Inventory (CDI) for adolescents (12-17 years). The CDI is a 27-item scale. Total scores range from 0 to 54. Higher scores indicate more severe depressive symptoms (a worse outcome).
• Change in Depression Severity (MADRS) — Baseline and Week 8
  Change in depression severity score from Baseline to Week 8 using the Montgomery-Asberg Depression Rating Scale (MADRS) for adults. The MADRS is a 10-item questionnaire. Total scores range from 0 to 60. Higher scores indicate greater depression severity (a worse outcome).

Trial sites (1)

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