A multicenter randomized, controlled, single-blind, adaptive phase IV clinical trial to evaluate the efficiency and effectiveness of a pre-emptive pharmacogenetic strategy for antidepressant selection in patients with depressive disorder: The PREDICT adaptive clinical trial.

The primary objective evaluates the effectiveness of a personalized medicine strategy that incorporates pre-emptive pharmacogenetic testing of biomarkers associated with antidepressant response, along with demographic, clinical, and concomitant medication data, compared to standard clinical practice in patients with depressive disorder who are initiating a new therapy following prior treatment failure. This objective addresses the clinical need to optimize antidepressant selection in patients who have not responded to initial treatment, potentially reducing trial-and-error prescribing and improving therapeutic outcomes through genomically-informed decision-making.

The secondary objectives include:

• To evaluate the efficiency of a personalized medicine strategy that integrates pre-emptive pharmacogenetic testing with clinical, demographic, and concomitant medication data into a web-based clinical decision-support tool, supported by expert pharmacological review, compared to standard clinical practice in patients with depressive disorder who are initiating a new antidepressant treatment following prior treatment failure.

• To evaluate healthcare resource utilization in both study arms.

• To assess clinical improvement or response.

• To evaluate time to remission.

• To assess the cost-effectiveness of a personalized medicine strategy compared to standard clinical practice.

• To calculate the incremental cost of implementing the personalized medicine strategy in routine clinical practice within the National Health System.

• To assess the incidence of adverse drug reactions and treatment discontinuation in both study arms.

The sponsor did not provide information regarding the total number of participants enrolled in this clinical trial. The study population consists of **adult** participants aged 18 years and older, including both **male** and **female** subjects. Participants are **patients** diagnosed with **depressive disorder** who are currently experiencing their first depressive episode and are receiving pharmacological treatment at the time of study inclusion. The trial population was selected based on specific criteria, including confirmed clinical diagnosis according to standardized diagnostic criteria such as **ICD-11** or **DSM-5**, a **Patient Health Questionnaire-9 (PHQ-9)** score of at least 10, and a **Montgomery-Asberg Depression Rating Scale (MADRS)** score of at least 18, both assessed within two weeks prior to study inclusion. Participants must have received no more than one prior **antidepressant** treatment line and must not have undergone prior **genotyping** for specific genes including **CYP3A4**, **SLC6A4**, **HTR2A**, **CYP2D6**, **CYP2B6**, or **CYP2C19**. Women of childbearing potential are required to use highly effective **contraception** or practice sexual abstinence throughout the study. No vulnerable populations are included in this trial.

This is a multicenter, randomized, controlled, single-blind, adaptive phase IV clinical trial designed to evaluate the effectiveness and efficiency of a pre-emptive pharmacogenetic strategy for antidepressant selection in patients with depressive disorder. The trial investigates whether incorporating pharmacogenetic testing of biomarkers associated with antidepressant response, combined with demographic, clinical, and concomitant medication data, improves treatment outcomes compared to standard clinical practice in patients initiating new therapy following prior treatment failure. The study is classified as a low-intervention clinical trial. Multiple antidepressant medications are utilized in the trial, including various formulations of vortioxetine, escitalopram, sertraline, quetiapine, bupropion hydrochloride, clomipramine hydrochloride, venlafaxine hydrochloride, imipramine hydrochloride, fluoxetine, mianserin hydrochloride, duloxetine, agomelatine, amitriptyline hydrochloride, nortriptyline hydrochloride, fluvoxamine maleate, mirtazapine, paroxetine, citalopram hydrobromide, trimipramine maleate, and desvenlafaxine. All investigational products are administered via oral use, with pharmaceutical forms including film-coated tablets, modified-release tablets, coated tablets, prolonged-release capsules, gastro-resistant capsules, and hard capsules. The maximum treatment period for all medicinal products is 16 weeks.

The primary endpoint is symptom remission based on changes in depression severity scores using the Patient Health Questionnaire-9 (PHQ-9) and Montgomery-Asberg Depression Rating Scale (MADRS) following initiation of new antidepressant treatment. Secondary endpoints include the total number of therapeutic adjustments performed within 16 weeks after treatment initiation, encompassing antidepressant switches and dose modifications beyond standard titration. Additional secondary outcomes assess the total number and type of psychotherapeutic appointments such as cognitive behavioral therapy (CBT) and interpersonal therapy (IPT), total hospitalizations, clinical visits (scheduled and unscheduled), and non-scheduled psychiatric consultations in each arm. The trial evaluates incremental cost-effectiveness ratios (ICERs) comparing cost differences relative to clinical efficacy between arms, total costs including pharmacogenetic testing in the intervention arm versus clinical event costs in the control arm, and the incremental cost of pharmacogenetic testing implementation. Safety endpoints include total adverse events, serious adverse events, dropouts due to serious adverse events, and adverse events of special interest including suicidal ideation, suicide attempt, serotonin syndrome, and neuroleptic malignant syndrome. The number of participants with sustained symptom remission at the end of the 16-week follow-up period is also assessed.

Principal inclusion criteria require participants to be at least 18 years of age with the ability to understand the study purpose, provide informed consent, and authorize use of confidential health information according to privacy regulations. Participants must have a current first depressive episode confirmed by clinical diagnosis according to standardized diagnostic criteria such as ICD-11 or DSM-5 as documented in medical records. Eligible participants must be currently receiving pharmacological treatment for depressive disorder with no more than one prior antidepressant treatment line. A PHQ-9 score of 10 or higher and a MADRS score of 18 or higher assessed within two weeks preceding study inclusion are required. Participants must have no prior genotyping for CYP3A4, SLC6A4, HTR2A, CYP2D6, CYP2B6, or CYP2C19 genes. Women of childbearing potential must agree to use highly effective contraception or practice sexual abstinence throughout the study and commit to avoiding pregnancy. Participants must demonstrate ability and willingness to participate and follow the study for the majority of its duration.

The estimated recruitment start date is January 19, 2026, and the estimated end date is January 1, 2029, establishing an overall trial duration of approximately three years. Expected participant involvement spans 16 weeks from initiation of new antidepressant treatment. Conditions that may lead to early termination from the study include occurrence of serious adverse events resulting in dropout, inability to comply with study procedures, withdrawal of informed consent, or other safety concerns as determined by the treating physician or investigator.

This clinical trial investigates multiple antidepressant medications as experimental treatments in patients with depressive disorder. All investigational medicinal products are administered via oral route for a maximum treatment period of 16 weeks. The study evaluates the effectiveness of a personalized medicine strategy incorporating pre-emptive pharmacogenetic testing compared to standard clinical practice.

Vortioxetine is administered as a film-coated tablet formulation at a maximum daily dose of 20 mg, with a maximum total dose of 2240 mg over the treatment period. The active substance is vortioxetine, a chemically synthesized compound.

Escitalopram is provided as film-coated tablets with a maximum daily dose of 20 mg and a maximum total dose of 2240 mg. The medication contains escitalopram as the active pharmaceutical ingredient.

Sertraline is administered in film-coated tablet form at a maximum daily dose of 200 mg, with a maximum total dose of 22400 mg throughout the treatment duration. The active substance is sertraline.

Quetiapine is supplied as film-coated tablets with a maximum daily dose of 600 mg and a maximum total dose of 67200 mg over the 16-week treatment period. The active pharmaceutical ingredient is quetiapine.

Bupropion hydrochloride is administered as modified-release tablets with a maximum daily dose of 300 mg and a maximum total dose of 33600 mg. The formulation contains bupropion hydrochloride as the active substance.

Clomipramine hydrochloride is provided in coated tablet formulation at a maximum daily dose of 250 mg, with a maximum total dose of 28000 mg over the treatment period. The active pharmaceutical ingredient is clomipramine hydrochloride.

Venlafaxine hydrochloride is administered as prolonged-release hard capsules with a maximum daily dose of 375 mg and a maximum total dose of 42000 mg. The active substance is venlafaxine hydrochloride.

Imipramine hydrochloride is supplied as coated tablets at a maximum daily dose of 200 mg, with a maximum total dose of 22400 mg throughout the treatment duration. The medication contains imipramine hydrochloride as the active ingredient.

Fluoxetine is provided in hard capsule formulation with a maximum daily dose of 60 mg and a maximum total dose of 6720 mg over the treatment period. The active pharmaceutical ingredient is fluoxetine.

Mianserin hydrochloride is administered as film-coated tablets at a maximum daily dose of 90 mg, with a maximum total dose of 10080 mg. The active substance is mianserin hydrochloride.

Duloxetine is supplied as gastro-resistant hard capsules with a maximum daily dose of 120 mg and a maximum total dose of 13440 mg throughout the 16-week treatment period. The medication contains duloxetine as the active ingredient.

Agomelatine is provided in film-coated tablet formulation at a maximum daily dose of 50 mg, with a maximum total dose of 5600 mg over the treatment duration. The active pharmaceutical ingredient is agomelatine.

Amitriptyline hydrochloride is administered as film-coated tablets with a maximum daily dose of 150 mg and a maximum total dose of 16800 mg. The active substance is amitriptyline hydrochloride.

Nortriptyline hydrochloride is supplied in tablet formulation at a maximum daily dose of 150 mg, with a maximum total dose of 16800 mg throughout the treatment period. The medication contains nortriptyline hydrochloride as the active ingredient.

Fluvoxamine maleate is provided as film-coated tablets with a maximum daily dose of 300 mg and a maximum total dose of 33600 mg over the 16-week treatment duration. The active pharmaceutical ingredient is fluvoxamine maleate.

Mirtazapine is administered in film-coated tablet formulation at a maximum daily dose of 45 mg, with a maximum total dose of 5040 mg throughout the treatment period. The active substance is mirtazapine.

Paroxetine is supplied as film-coated tablets with a maximum daily dose of 50 mg and a maximum total dose of 5600 mg over the treatment duration. The medication contains paroxetine as the active ingredient.

Citalopram hydrobromide is provided in film-coated tablet formulation at a maximum daily dose of 40 mg, with a maximum total dose of 4480 mg throughout the 16-week treatment period. The active pharmaceutical ingredient is citalopram hydrobromide.

Trimipramine maleate is administered as film-coated tablets with a maximum daily dose of 400 mg and a maximum total dose of 44800 mg over the treatment duration. The active substance is trimipramine maleate.

Desvenlafaxine is supplied in prolonged-release tablet formulation at a maximum daily dose of 200 mg, with a maximum total dose of 22400 mg throughout the treatment period. The medication contains desvenlafaxine as the active ingredient.

Efficacy will be assessed through evaluation of symptom remission based on changes in depression severity scores measured by the Patient Health Questionnaire-9 (PHQ-9) and the Montgomery-Asberg Depression Rating Scale (MADRS) following initiation of a new antidepressant treatment after failure of prior therapy at study entry. Additional efficacy parameters include the total number of therapeutic adjustments performed within 16 weeks after initiation of the new antidepressant treatment, encompassing changes of antidepressant medication (switch) and dose increases or decreases beyond standard titration. The assessment will also evaluate the total number of participants achieving symptom remission at the end of the 16-week follow-up period.

Further efficacy measures include the total number and type of psychotherapeutic appointments such as cognitive behavioral therapy and interpersonal therapy per study arm, the total number of hospitalizations per arm, the total number of clinical visits including both scheduled and unscheduled appointments, and the total number of non-scheduled psychiatric consultations in each arm. Economic efficacy will be assessed through incremental cost-effectiveness ratios comparing cost differences relative to differences in clinical efficacy between the two arms, total costs in the intervention arm including pharmacogenetic testing and clinical event costs versus total costs related to clinical events in the control arm, and the incremental cost of pharmacogenetic testing and associated implementation procedures.