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

NCT06508710 | Recruiting Phase 3 DMC

• 2 other identifiers: APHP2206682023-506597-12-00
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 4

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

Keywords

depression; ketamine; synaptogenesis

Outcome Measures

Primary Outcomes (1)

• the early efficacy on depressive symptomatology

  Evolution of the total score of the Hamilton Depression Rating Scale (HDRS 17 items: scale items are rated from 0 to 2 or from 0 to 4 and the score ranges from 0 to 52) after 7 days of treatment by venlafaxine The HDRS scale will be assessed by a senior psychiatrist or psychologist trained in administering the scales, following a psychiatric interview

  at day 0 and day 7

Secondary Outcomes (20)

• The efficacy of ketamine on HDRS overall score

  at day 1,4,7,14, 28 and 42 following the initiation of treatment by venlafaxine

• The efficacy of Ketamine on HDRS response rate

  at day 1,4,7,14, 28 and 42 following the initiation of treatment by venlafaxine

• The efficacy of Ketamine on HDRS remission rate

  To compare the efficacy of ketamine as adjunctive therapy, after the early adjunctive treatment phase, and placebo, by assessing remission rate (HDRS 17 items ≤ 7) between groups

• The efficacy of ketamine on BDI overall score

  at day 1,4,7,14, 28 and 42 following the initiation of treatment by venlafaxine

• The efficacy of ketamine on CGI scale

  at day 1,4,7,14, 28 and 42 following the initiation of treatment by venlafaxine

Other Outcomes (5)

• Synaptic density variation in the whole brain

  Day 0 and 14

• synaptic density variation in the cingulate cortex

  Day 0 and 14

• synaptic density variation in the prefrontal cortex

  Day 0 and 14

Study Arms (2)

Ketamine Group

EXPERIMENTAL

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

Drug: Ketamine

Placebo group

PLACEBO COMPARATOR

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

Drug: Placebo

Interventions

Ketamine DRUG

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

Also known as: Ketamine+Venlafaxine

Ketamine Group

Placebo DRUG

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

Also known as: Placebo+Venlafaxine

Placebo group

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.)

You may not qualify if:

• 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).
• 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
• Social insurance
• \- Contraindications to \[11C\]UCB-J PET-MRI
• 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.
• 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)

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead

Study Sites (4)

Psychiatry unit

Le Kremlin-Bicêtre, France, 94270, France

RECRUITING

EPS Barthélémy Durand

Étampes, 91152, France

NOT YET RECRUITING

Bicetre Hospital - CRC

Le Kremlin-Bicêtre, 94250, France

NOT YET RECRUITING

CEA/SHFJ

Orsay, 94401, France

ACTIVE NOT RECRUITING

MeSH Terms

Conditions

Depression

Interventions

Ketamine

Condition Hierarchy (Ancestors)

Behavioral Symptoms; Behavior

Intervention Hierarchy (Ancestors)

Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals

Study Officials

• Romain COLLE

  Service Hospitalo-Universitaire de Psychiatrie - Hôpital Bicêtre

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Romain COLLE

CONTACT

+33145212524; romain.colle@aphp.fr

Emmanuelle CORRUBLE

CONTACT

+33145212524; emmanuelle.corruble@aphp.fr

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 15, 2024
• First Posted: July 18, 2024
• Study Start: October 20, 2024
• Primary Completion: March 1, 2026
• Study Completion: April 1, 2026
• Last Updated: September 3, 2025

Record last verified: 2024-12

Locations

FR (4)