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

Phase 3RecruitingNCT06508710

Assistance Publique - Hôpitaux de Paris60 enrolled

Overview

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

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

Conditions

Major Depressive Episode

Interventions

Eligibility

Sex: ALLMin age: 18 YearsMax age: 65 Years

Medical Language ↔ Plain English

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)

Outcomes

Primary Outcomes

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

Time frame: at day 0 and day 7

Secondary Outcomes

The efficacy of ketamine on HDRS overall score

To compare the efficacy of ketamine as adjunctive therapy, after the early adjunctive treatment phase, and placebo, by assessing changes in overall score obtained on the HDRS 17-items.

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

The efficacy of Ketamine on HDRS response rate

To compare the efficacy of ketamine as adjunctive therapy, after the early adjunctive treatment phase, and placebo, by assessing HDRS response rate (improvement of 50% or more in the overall HDRS score) between groups

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

The efficacy of Ketamine on HDRS remission rate

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

Time frame: 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

To compare the efficacy of ketamine as adjunctive therapy, after the early adjunctive treatment phase, and placebo, by assessing changes in overall score obtained on the short form of the Beck Depression Inventory (BDI)

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

The efficacy of ketamine on CGI scale

To compare the efficacy of ketamine as adjunctive therapy, after the early adjunctive treatment phase, and placebo, by assessing changes in Clinical Global Impression (CGI) scale

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

Duration of hospitalization

Evaluate whether ketamine as adjunctive therapy reduces the length of hospital stay, noting the number of days spent in hospital (including re-hospitalization) The discharge from hospitalization will be decided by the treatment-blinded clinician responsible for the patient

Time frame: 42 days

Reduction of suicidal ideation

Evaluate whether adjunctive ketamine reduces early suicidal ideation, by assessement of overall Columbia-Suicide Severity Rating Scale (C-SSRS) score, after 7 days of treatment by venlafaxine

Time frame: at day 0 and day 7

Clinical improvement on HDRS overall score

Evaluate whether ultra-early improvement (at D1 or D4 of treatment by venlafaxine) predicts clinical improvement at D7, D14, D28 and D42 by tracking changes in overall score obtained on the 17-item Hamilton Depression Rating Scale (HDRS)