Prediction of the Therapeutic Response in Depression Based on 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.

Eligibility Criteria:
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