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

NCT ID: NCT06508710

Last Updated: 2025-09-03

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 60 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-10-20
• Study Completion Date: 2026-04-30

Brief Summary

Unipolar major depressive disorder is the leading cause of disability worldwide. The most commonly used treatments for major depressive episodes (MDE) are antidepressant medications. However, they have limited efficacy and their onset of action is long, ranging between 2 to 6 weeks. During this period, hospitalization can become necessary, especially for severe MDE. It is crucial to improve the early effectiveness of treatments for these patients in order to alleviate their suffering, limit complications (suicidal risk), and reduce hospitalization durations (approximately 1000 euros per day). The efficacy of intravenous ketamine has been demonstrated in pharmaco-resistant depression but remains to be proven in non-pharmaco-resistant severe MDE. Additionally, PET imaging using [11C]UCB-J, which allows the in vivo study of synaptic density in the human brain, has shown significant decreases in synaptic density in unipolar patients with severe MDE. Furthermore, a single ketamine infusion was found to enhance synaptogenesis

Conditions

Major Depressive Episode

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Ketamine Group

The patient will receive 3 doses of intravenous ketamine (0,50mg/kg) in addition to the usual venlafaxine treatment

Group Type: EXPERIMENTAL

Ketamine

Intervention Type: DRUG

Patients randomized in this group will receive an intravenous ketamine in addition to venlafaxine for one week (on Days 1, 4 and 7)

Placebo group

The patient will receive 3 doses of intravenous placebo (50mL of NaCl 9‰) in addition to the usual venlafaxine treatment

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Patients randomized in this group will receive an intravenous placebo in addition to venlafaxine for one week (on Days 1, 4 and 7)

Interventions

Ketamine

Patients randomized in this group will receive an intravenous ketamine in addition to venlafaxine for one week (on Days 1, 4 and 7)

Intervention Type: DRUG

Placebo

Patients randomized in this group will receive an intravenous placebo in addition to venlafaxine for one week (on Days 1, 4 and 7)

Intervention Type: DRUG

Other Intervention Names

Ketamine+Venlafaxine; Placebo+Venlafaxine

Eligibility Criteria

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 in the 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 study participation.* (*Combined hormonal contraception (containing estrogen and progestin) 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 with two 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, Lewy body dementia, progressive supranuclear palsy, known prolongation of the QTc interval (>450ms for men and >470ms for women) or congenital long QT syndrome, recent acute myocardial infarction, uncompensated heart failure, history of ventricular arrhythmias or torsades de pointes, uncorrected hypokalemia (K+ < 3. 5 mmol/l), epilepsy, uncontrolled hypertension, porphyria, history of stroke (CVA), intracranial hypertension.
• Contraindication to venlafaxine (hypersensitivity to venlafaxine or excipients, are hereditary conditions of fructose intolerance, glucose-galactose malabsorption syndrome, or sucrase-isomaltase deficiency, unstable hypertension, no indication for venlafaxine treatment in clinician's opinion due to ineffectiveness or tolerability of previous venlafaxine treatment).
• Current or previous treatment with venlafaxine or ketamine in the month prior to study inclusion.
• Need to maintain another antidepressant, MAOI, Millepertuis or benzodiazepines (cyamemazine is permitted). Or potential drug interactions in case of recent cessation 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, in the opinion of the investigator or the sponsor, could compromise the safety of the participant.
• Pregnant or breast-feeding patients (women of childbearing potential must have a negative 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 within the exclusion period following previous research involving the human body, if applicable.
• 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 implantable defibrillator; clip on a brain aneurysm or vascular malformation; intraocular or intracerebral ferromagnetic foreign body; prostheses or objects or mobile ferromagnetic metal fragments; cochlear implants; peripheral stimulator; neurosurgical ventriculoperitoneal shunt valves; automated injection device such as insulin pump, glucose sensor; permanent eyelid or lip makeup; non-removable piercing; claustrophobia.

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Assistance Publique - Hôpitaux de Paris

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Romain COLLE

Role: PRINCIPAL_INVESTIGATOR

Service Hospitalo-Universitaire de Psychiatrie - Hôpital Bicêtre

Locations

Psychiatry unit

Le Kremlin-Bicêtre, France, France

Site Status: RECRUITING

EPS Barthélémy Durand

Étampes, , France

Site Status: NOT_YET_RECRUITING

Bicetre Hospital - CRC

Le Kremlin-Bicêtre, , France

Site Status: NOT_YET_RECRUITING

CEA/SHFJ

Orsay, , France

Site Status: ACTIVE_NOT_RECRUITING

Countries

France

Central Contacts

Romain COLLE

Role: CONTACT

romain.colle@aphp.fr

+33145212524

Emmanuelle CORRUBLE

Role: CONTACT

emmanuelle.corruble@aphp.fr

+33145212524

Facility Contacts

Romain COLLE, MD - PHD

Role: primary

romain.colle@aphp.fr

+33145212524

christian trichard

Role: primary

Christian.Trichard@eps-etampes.fr

01.69.46.86.66

laurent becquemont

Role: primary

laurent.becquemont@aphp.fr

01.45.21.74.51

Other Identifiers

2023-506597-12-00

Identifier Type: CTIS

Identifier Source: secondary_id

APHP220668

Identifier Type: -

Identifier Source: org_study_id