Prediction of the Therapeutic Response in Depression Based on Neuro-computational Modeling Assessment of Motivation (STRATIDEP)

Prediction of the Therapeutic Response in Depression Based on Neuro-computational Modeling Assessment of Motivation

Prediction of the Therapeutic Response in Depression Based on an Early Neuro-computational Modeling Assessment of Motivation

This study aims to better understand the mechanisms of action of antidepressants, but also the neural correlates of motivation deficits. One hundred patients with a moderate to severe major depressive episode will be enrolled in this prospective multicenter study. The objective will be to predict the therapeutic response to two first-line antidepressants on the basis of an early neurocomputational assessment of motivation. Antidepressant treatment will be administered as monotherapy after randomization between two drugs: escitalopram and vortioxetine. Patients will undergo six visits and follow-up for one year. The investigators will combine computer modeling and functional MRI to identify motivational deficits and elucidate their brain correlates before initiation, after 7 days and after 6 months of treatment. 36 healthy volunteers will also be included to allow comparison with patients with depression. They will not receive any treatment.

One hundred patients with a moderate to severe major depressive episode will be enrolled in this prospective multicenter study. Six visits will be scheduled within a year: V0 (inclusion visit): verification of inclusion and exclusion criteria, information, and consent. V1 (before randomization - baseline state): Clinical evaluation using validated questionnaires for the severity of depression, quality of life, anhedonia, apathy, and cognitive dysfunction. Neuro-cognitive evaluation using a battery of tests to explore motivation, emotion processing, belief construction, and their updating. Part of the tests will be performed during the functional MRI session. Structural (anatomical) and functional MRI, ASL. Blood samples. Randomization and introduction of the new antidepressant will occur immediately after V1. To maximize acceptability by referring psychiatrists, dosage and co-prescriptions will be at the discretion of the psychiatrist in charge, but the assigned treatment will not be changed for 4 weeks (until V3). V2 (7 days after the beginning of the new antidepressant - 'early response visit'): o Similar to V1. V3 (28 days after the beginning of the new antidepressant - 'conventional response visit'): Clinical evaluation using validated questionnaires for the severity of depression, quality of life, anhedonia, apathy, and cognitive dysfunction. Blood samples V4 (6 months after the beginning of the new antidepressant - 'remission visit'): Clinical evaluation using validated questionnaires for the severity of depression, quality of life, anhedonia, apathy, and cognitive dysfunction. Cognitive evaluation using a battery of tests to explore motivation, emotion processing, belief construction, and their updating. Structural (anatomical) MRI, ASL Blood samples V5 (one year after the beginning of the new antidepressant - 'functional remission visit'): Clinical evaluation using validated questionnaires for the severity of depression, quality of life, anhedonia, apathy, and cognitive dysfunction. 36 healthy volunteers without a history of neurologic or psychiatric disorder, matched for age, gender, and education will be included. They will perform V0-V2 (without MRI and blood sample at V2). Healthy volunteers will not receive any treatment as part of the research.

Randomization and introduction of the new antidepressant will occur immediately after V1. Patients will receive an antidepressant as monotherapy after randomization between two strategies: escitalopram and vortioxetine. To maximize acceptability by referring psychiatrists, dosage and co-prescriptions will be at the discretion of the psychiatrist in charge, but the allocated treatment will not be changed for 4 weeks (until V3). After 4 weeks, the treatment can be adapted by the refeering psychiatrist exactly as if the patient had not been included in the trial.

The strategy will not be modified for a period of 4 weeks. Dosage adjustment and co-prescriptions will be at the discretion of the refeering psychiatrist.

The strategy will not be modified for a period of 4 weeks. Dosage adjustment and co-prescriptions will be at the discretion of the refeering psychiatrist.

Patients will receive an antidepressant strategy : escitalopram. The strategy will not be modified for a period of 4 weeks. Dosage adjustment and co-prescriptions will be at the discretion of the refeering psychiatrist. After 4 weeks, the strategy can be adapted by the refeering psychiatrist exactly as if the patient had not been included in the trial.

Patients will receive an antidepressant strategy : vortioxetine. The strategy will not be modified for a period of 4 weeks. Dosage adjustment and co-prescriptions will be at the discretion of the refeering psychiatrist. After 4 weeks, the treatment strategy can be adapted by the refeering psychiatrist exactly as if the patient had not been included in the trial.

Prediction of the therapeutic response (MADRS score) 28 days after the introduction of the antidepressant strategy (V3) based on the early changes (differences between V1 and V2) of the computational phenotype of depressed patients.

The therapeutic response will be measured with the Montgomery-Asberg Depression Rating Scale (MADRS). The MADRS is a 10- item scale widely used in depression research to assess the severity of depression. Response will be defined by a score divided by 2 compared to baseline MADRS score, while remission will be defined by a score < 7 (symptom absent) 28 days after the initiation of the antidepressant strategy. The "computational phenotype" is the outcome of the computationnal analysis of behavior. It is expressed in abstract unit. The change in computationnal phenotype between V1 and V2 will be entered in logistic regression aiming to predict clinical response at 28 days, measured with the MADRS score.

Baseline state (before the start of antidepressant strategy), V2 (after 7 days of antidepressant) and V3 (after 28 days of antidepressant)

Prediction of the therapeutic response (MADRS score) 28 days after the introduction of the antidepressant strategy (V3) based on the early changes (differences between V1 and V2) of the neuro-computational phenotype of depressed patients

Same than outcome 1 but using brain imaging on top of behavior (neurocomputational modeling) to predict clinical response.

Baseline state (before the start of antidepressant strategy), V2 (after 7 days of antidepressant) and V3 (after 28 days of antidepressant)

Prediction of the therapeutic response (MADRS score) 28 days after the introduction of the antidepressant strategy (V3) based on the initial (baseline state- V1) neuro-computational phenotype of depressed patients

Same than Outcome 2 but using only V1 instead of the change between V1 and V2 to predict clinical response.

Baseline state (before the start of antidepressant strategy), and V3 (after 28 days of antidepressant)

Prediction of long-term remission (V4) based on the early changes (differences between V1 and V2) of the neuro-computationnal phenotype of depressed patients

Baseline state (before the start of antidepressant strategy), V2 (after 7 days of antidepressant), V4 (6 months after the start of antidepressant)

Prediction functional remission (V5) based on the early changes (differences between V1 and V2) of the neuro-computationnal phenotype of depressed patients

Baseline state (before the start of antidepressant strategy), V2 (after 7 days of antidepressant), V5 (1 year after the start of antidepressant)

Prediction of relapse at one year (V5) based on the computationnal phenotype of remitted patients at 6 months (V4).

Same than Outcome 1 but using computational phenotype at V4 to predict predict functional remission at V5.

Comparison of the brain functional statistical maps of patient with depression and healthy volunteers at V1.

Description of the evolution of motivation deficit of depressed patients after one week of antidepressant treatment

Description of the evolution of the neural correlates of motivation deficits after one week of antidepressant treatment

Baseline state (before the start of antidepressant strategy), V4 (6 months after the start of antidepressant)

Description of the evolution of the structural neural correlates of depression after 6 months of treatment

Baseline state (before the start of antidepressant strategy), V4 (6 months after the start of antidepressant)

Description of the evolution of the functional neural correlates of depression after 6 months of treatment

Baseline state (before the start of antidepressant strategy) V4 (6 months after the start of antidepressant)

Serum tubes will be drowned along the study (V1, V2, V3 and V4 for patients - V1 for healthy volunteers) prepared and stored.

Baseline state (before the start of antidepressant strategy), V2 (after 7 days of antidepressant) and V3 (after 28 days of antidepressant), V4 (6 months after the start of antidepressant)

Patients with major depressive disorder Inclusion Criteria: Meeting DSM-5 criteria for major depressive disorder (single or recurrent episodes) With a MADRS score >= 24 For which a new line of treatment is needed No previous line of antidepressant for this episode or wash-out long-enough to avoid carry-over effects Valid health care insurance Exclusion Criteria: Treatment-resistant depression (defined as insufficient response despite at least 2 trials of antidepressant prescribed at adequate dose and duration) Subjects with a trial of escitalopram and/or vortioxetine for the current episode, or with contra-indication to one of these two drugs Subjects with a diagnostic of persistent depressive disorder, bipolar disorder or schizophrenia, neurodeveloppemental disorder, unremitted substance abuse disorder other than tobacco, personality disorder severe enough to compromise the follow-up (based on investigator's appreciation). Subject with a history of neurological disorder: parkinson's disease, dementia Contraindications to MRI scanning: pregnancy, claustrophobia, metallic implants Pregnant or breastfeeding women involuntary hospitalisation and legal protection measures Healthy volunteers Inclusion Criteria: - Valid health care insurance Exclusion Criteria: Subjects with a diagnostic of persistent depressive disorder, bipolar disorder or schizophrenia, neurodeveloppemental disorder, unremitted substance abuse disorder other than tobacco, personality disorder severe enough to compromise the follow-up (based on investigator's appreciation). Subject with a history of neurological disorder: parkinson's disease, dementia Contraindications to MRI scanning: pregnancy, claustrophobia, metallic implants Pregnant or breastfeeding women

Groupe hospitalo-universitaire Assistance Publique, hôpital Pitié Salpêtrière - Hôpitaux de Paris Sorbonne Université

The data obtained from medical visits (clinical informations, biological assessments, cognitive data) and brain MRIs will be kept, coded and archived for a period of two years after the last publication of the research results or until the final research report is signed. These can be used later for collaborative research (academic and/or industrial partners) in the European Union (EU) and/or abroad exclusively for scientific purposes. In case of transfer of the anonymized database resulting from this research abroad (outside the EU), the sponsor undertakes to ensure a level of security equivalent to French or European Union law.

The data obtained from medical visits (clinical informations, biological assessments, neurocognitive data)and brain MRIs will be kept, coded and archived for a period of two years after the last publication of the research results or until the final research report is signed.

The data can be used for collaborative research (academic and/or industrial partners) in the European Union (EU) and/or abroad exclusively for scientific purposes. In case of transfer of the anonymized database resulting from this research abroad (outside the EU), the sponsor undertakes to ensure a level of security equivalent to French or European Union law.

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