Clinical trial NCT06508710: Early Effects of Ketamine vs Placebo With Venlafaxine in Severe Depression Patients
Official title: Early Efficacy of Ketamine Compared With Placebo as Adjunctive Therapy With Venlafaxine in Severely Unipolar Depressed Inpatients
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Major Depressive Episode
Keywords: depression
ketamine
synaptogenesis
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2024-07-18
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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


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)

Primary outcomes:
measure: the early efficacy on depressive symptomatology
timeFrame: at day 0 and day 7
Secondary outcomes:
measure: The efficacy of ketamine on HDRS overall score
timeFrame: at day 1,4,7,14, 28 and 42 following the initiation of treatment by venlafaxine
measure: The efficacy of Ketamine on HDRS response rate
timeFrame: at day 1,4,7,14, 28 and 42 following the initiation of treatment by venlafaxine
measure: The efficacy of Ketamine on HDRS remission rate
timeFrame: 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
measure: The efficacy of ketamine on BDI overall score
timeFrame: at day 1,4,7,14, 28 and 42 following the initiation of treatment by venlafaxine
measure: The efficacy of ketamine on CGI scale
timeFrame: at day 1,4,7,14, 28 and 42 following the initiation of treatment by venlafaxine
measure: Duration of hospitalization
timeFrame: 42 days
measure: Reduction of suicidal ideation
timeFrame: at day 0 and day 7
measure: Clinical improvement on HDRS overall score
timeFrame: at day 7, 14, 28 and 42
measure: Clinical improvement on HDRS response rate
timeFrame: at day 7, 14, 28 and 42
measure: Clinical improvement on HDRS remission rate
timeFrame: at day 7, 14, 28 and 42
measure: Clinical improvement on BDI overall score
timeFrame: at day 7, 14, 28 and 42
measure: Clinical improvement on CGI scale
timeFrame: at day 7, 14, 28 and 42
measure: Tolerance on blood pressure
timeFrame: Day 1, 4, 7
measure: Tolerance on heart rate
timeFrame: Day 1, 4, 7
measure: Tolerance on respiratory rate
timeFrame: Day 1, 4, 7
measure: Tolerance on nausea and vomiting
timeFrame: Day 1, 4, 7
measure: Tolerance on dissociation
timeFrame: Day 1, 4, 7
measure: Tolerance on headaches
timeFrame: Day 1, 4, 7
measure: The consumption of anxiolytic treatments
timeFrame: During all the study
measure: Biomarkers
timeFrame: Day 1 and 14
Other outcomes:
measure: Synaptic density variation in the whole brain
timeFrame: Day 0 and 14
measure: synaptic density variation in the cingulate cortex
timeFrame: Day 0 and 14
measure: synaptic density variation in the prefrontal cortex
timeFrame: Day 0 and 14
measure: synaptic density variation in the hippocampus
timeFrame: Day 0 and 14
measure: Relationship between ketamine efficacy and synaptogenesis
timeFrame: Day 0 and 14
Locations:
city: Le Kremlin Bicêtre
country: France
facility: Psychiatry unit
city: Le Kremlin-Bicêtre
country: France
facility: Bicetre Hospital - CRC
city: Orsay
country: France
facility: CEA/SHFJ
city: Étampes
country: France
facility: EPS Barthélémy Durand
Study officials:
affiliation: Service Hospitalo-Universitaire de Psychiatrie - Hôpital Bicêtre
name: Romain COLLE
role: PRINCIPAL_INVESTIGATOR
References: