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
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
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.
Parallel
Ketamine
DrugPatients randomized in this group will receive an intravenous ketamine in addition to venlafaxine for one week (on Days 1, 4 and 7)
Placebo
DrugPatients randomized in this group will receive an intravenous placebo in addition to venlafaxine for one week (on Days 1, 4 and 7)
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
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.
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
The efficacy of Ketamine on HDRS remission rate
at day 1,4,7,14, 28 and 42 following the initiation of treatment by venlafaxine
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)
Synaptic density variation in the whole brain
Within-subject variation in synaptic density between day 0 and day 14 following treatment initiation of venlafaxine, estimated by measuring the rate of \[11C\]UCB-J binding to SV2A proteins by PET-MRI in the whole brain
synaptic density variation in the cingulate cortex
Within-subject variation in synaptic density between day 0 and day 14 following treatment initiation of venlafaxine, estimated by measuring the rate of \[11C\]UCB-J binding to SV2A proteins by PET-MRI in the cingulate cortex
synaptic density variation in the prefrontal cortex
Within-subject variation in synaptic density between day 0 and day 14 following treatment initiation of venlafaxine, estimated by measuring the rate of \[11C\]UCB-J binding to SV2A proteins by PET-MRI in the prefrontal cortex
synaptic density variation in the hippocampus
Within-subject variation in synaptic density between day 0 and day 14 following treatment initiation of venlafaxine, estimated by measuring the rate of \[11C\]UCB-J binding to SV2A proteins by PET-MRI in the hippocampus
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