Early Effects of Ketamine vs Placebo With Venlafaxine in Severe Depression Patients

Inclusion Criteria:

• Current MDE in the context of unipolar major depressive disorder (DSM-5 criteria),hospitalized (open care) for this episode, with a minimum HDRS score of 24 and inthe context of an indication for the introduction of venlafaxine treatment.

• Patient aged between 18 and 65.

• Signed free and informed consent

• Membership of a social security scheme

• For women of childbearing age, effective contraception throughout studyparticipation.* (*Combined hormonal contraception (containing estrogen andprogestin) associated with ovulation inhibition: (oral, intravaginal, transdermal),Progestin-only hormonal contraception associated with ovulation inhibition: (oral,injectable, implantable), Intrauterine device (IUD), Hormonal intrauterine system (IUS), Bilateral tubal occlusion, Vasectomized partner, Sexual abstinence.)

Exclusion Criteria:

• Criteria relating to associated pathologies entailing particular risks:pharmaco-resistant CDE (failure of at least two properly conducted treatments withtwo different antidepressant treatment classes), CDE with psychotic features,psychotic disorder, bipolar disorder, current (<1 month) substance use disorder (excluding tobacco).

• Liver impairment (AST and/or ALT > 3 ULN, PAL and/or GGT and/or bilirubin > 2 ULN).

• Severe renal insufficiency (GFR <30ml/min with Cockcroft's formula).

• Bradycardia less than 55 beats per minute.

• Contraindication to ketamine : Hypersensitivity to active substance or excipients,comatose state, central nervous system (CNS) depression, Parkinson's disease, Lewybody dementia, progressive supranuclear palsy, known prolongation of the QTcinterval (>450ms for men and >470ms for women) or congenital long QT syndrome,recent acute myocardial infarction, uncompensated heart failure, history ofventricular arrhythmias or torsades de pointes, uncorrected hypokalemia (K+ < 3. 5mmol/l), epilepsy, uncontrolled hypertension, porphyria, history of stroke (CVA),intracranial hypertension.

• Contraindication to venlafaxine (hypersensitivity to venlafaxine or excipients, arehereditary conditions of fructose intolerance, glucose-galactose malabsorptionsyndrome, or sucrase-isomaltase deficiency, unstable hypertension, no indication forvenlafaxine treatment in clinician's opinion due to ineffectiveness or tolerabilityof previous venlafaxine treatment).

• Current or previous treatment with venlafaxine or ketamine in the month prior tostudy inclusion.

• Need to maintain another antidepressant, MAOI, Millepertuis or benzodiazepines (cyamemazine is permitted). Or potential drug interactions in case of recentcessation of these treatments (based on the Summary of Product Characteristics (SmPC) of the respective medication(s) and their half-life).

• Any other unspecified reason (clinically significant illness or anomaly) which, inthe opinion of the investigator or the sponsor, could compromise the safety of theparticipant.

• Pregnant or breast-feeding patients (women of childbearing potential must have anegative urine or blood test for human chorionic gonadotropin prior to trial entry).Planned pregnancy within three months of enrolment

• Adult under guardianship, curatorship or safeguard of justice

• Participating in other interventional research involving the human body or withinthe exclusion period following previous research involving the human body, ifapplicable.

• Social insurance

Additional criteria for inclusion in the ancillary study :

• Contraindications to [11C]UCB-J PET-MRI

1. Absolute contraindications: Pacemaker or neurosensorial stimulator or implantabledefibrillator; clip on a brain aneurysm or vascular malformation; intraocular orintracerebral ferromagnetic foreign body; prostheses or objects or mobileferromagnetic metal fragments; cochlear implants; peripheral stimulator;neurosurgical ventriculoperitoneal shunt valves; automated injection device such asinsulin pump, glucose sensor; permanent eyelid or lip makeup; non-removablepiercing; claustrophobia.

2. Relative contraindications: Dental prostheses and orthodontic material; certainintrauterine devices; certain tattoos; certain transdermal patch implants; certainmetal implants far from the examined area. (The investigator physician and/orradiology operator will always conduct a precise questionnaire before theexamination to ensure perfect safety and absence of MRI danger)