RESIST : Administration of MAP4343 in Antidepressant Non-Responders Patients Experiencing a Major Depressive Episode

Inclusion Criteria:

1. TRD level from to 2 to 4 inclusive according to the Thase & Rush classification;

2. Patient experiencing a Major Depressive Episode (MDE) according to DSM-5 criteria.MDE can be isolated or recurrent. The diagnosis is based on Mini-InternationalNeuropsychiatric Interview (MINI) test;

3. Patient who received a previous antidepressant treatment (AD-Y) in monotherapy withvortioxetine, duloxetine or venlafaxine) at optimized dosages during 6 weeks priorto randomization, associated or not to AD-potentiator (quetiapine), are eligible.

4. Hamilton Depression Rating Scale (HDRS) score > 21;

5. Clinical Global Impressions scale (CGI) ≥ 4;

6. Male or female patient, aged 18 to 80 years inclusive;

7. Females of childbearing potential/Sexually active males with partner of childbearingpotential: commitment to consistently and correctly use an acceptable method ofbirth control (oral, transdermal, systemic or implant contraception birth control,intrauterine devices, diaphragm or condoms) for the duration of the trial and for 4months after the last study drug administration; Females of non-childbearingpotential: either surgically sterilized or at least 1 year postmenopausal (amenorrhea duration at least 12 months);

8. Negative pregnancy test at screening baseline;

9. Body Mass Index (BMI) between 18 and 32 kg/m2 inclusive;

10. Laboratory parameters within the normal range of the laboratory (hematological,blood chemistry tests, urinalysis, hormonology). Individual values out of the normalrange can be accepted if judged clinically non relevant by the Investigator;

11. Normal ECG recording on a 12-lead ECG at the screening visit:

• 120 < PR < 210 ms

• QRS < 120 ms

• QTcF ≤ 430 ms for male and < 450 ms for female,

• No sign of any trouble of sinusal automatism,

• Or considered NCs by investigators;

12. Normal Blood Pressure (BP) and Heart Rate (HR) at the screening visit after 10minutes in supine position:

• 95 mmHg ≤ Systolic Blood Pressure (SBP) ≤ 140 mmHg,

• 50 mmHg ≤ Diastolic Blood Pressure (DBP) ≤ 90 mmHg,

• 50 bpm ≤ HR ≤ 80 bpm,

• Or considered NCs by investigators;

13. Signing a written informed consent prior to selection;

14. Covered by Health Insurance System and/or in compliance with the recommendations ofNational Law in force relating to biomedical research.

Exclusion Criteria:

1. MDE with mood congruent or not congruent psychotic characteristics;

2. Patient hospitalized following the procedures: Psychiatric care at the request ofanother person (soins psychiatriques à la demande d'un tiers) or Psychiatric care atthe request of the state representative (soins psychiatriques sur décision dureprésentant de l'Etat);

3. Suicidal risk in the last month before randomization (C-SSRS: answer yes to the item 3 and/or answer yes to section suicidal behavior; MINI 5.00; suicidal risk sectionor item 3 of HDRS ≥ 3);

4. History of other psychiatric disorder than DME except global anxiety, social phobia,panic troubles that should be accepted. In particular, patients who experienced adepressive state in bipolar disorder 1 or 2, schizophrenic or schizoaffectivedisorder should not be included;

5. Presence or history of drug hypersensitivity, or certain allergic-prone conditiondiagnosed that could represent a risk factor for an allergic shock;

6. Presence or history of hypersensitivity to vortioxetine, duloxetine, venlafaxine orone of their excipients;

7. Any history or presence of severe hepatic insufficiency and/or of hepatic diseasewhich could lead to hepatic insufficiency;

8. Patients who are pregnant or breastfeeding. Patients should not be enrolled if theyplan to become pregnant during the time of study participation;

9. Any drug intake during the last month prior to the first administration excepttreatments for concomitant pathologies which are stable since at least 3 months;Benzodiazepine-type anxiolytics, hydroxyzine chlorhydrate, and add-on treatments areauthorized within limits described in Section 5.3; For the previous drug intake, theinvestigator should consider the time needed to sufficiently eliminate a drug frombody system, e.g. 5 half-lives of the drug;

10. Subjects who received MAOI in monotherapy right before the selection (as ttX);

11. General anesthesia within 3 months before administration;

12. Major surgery within 28 days prior to randomization or major surgery planned duringthe next 6 months;

13. Positive HBs antigen or anti HCV antibody, or positive results for HIV 1 or 2 tests;

14. Significant renal disease, defined as a history of chronic renal failure requiringdialysis or kidney transplant, calculated creatinine clearance ≤ 60 mL/min;

15. Blood donation (including in the frame of a clinical trial) within 2 months beforeadministration;

16. Subject who, in the judgment of the Investigator, is likely to be non-compliant oruncooperative during the study, or unable to cooperate because of a languageproblem, poor mental development;

17. Medical history which in the opinion of the investigator would make the patientunsuitable for participation in the study (including, but not limited, to patientswith coronary insufficiency, thromboembolism diseases);

18. Exclusion period of a previous study;

19. No possibility of contact in case of emergency;

20. History or presence of drug or alcohol abuse (alcohol consumption > 40 g/day);

21. Administrative or legal supervision.