KetaPal is a placebo-controlled randomized trial designed to demonstrate the antidepressant action of ketamine in palliative care situations. Half of participants will receive Ketamine and Milnacipran in combination, while the other half will receive a Placebo and Milnacipran in combination.

Ketamine, a molecule mainly used as an analgesic in palliative care, turns out to be an excellent fast acting antidepressant. By acting as an NMDA receptor antagonist, its mechanism of action is complementary to classical and long acting antidepressants like Selective Serotonin Reuptake Inhibitors (SSRI). In particular, ketamine is able to boost synaptogenesis in only a few hours whereas long-term prescription of SSRI can stimulate neurogenesis.

The purpose of this study is to evaluate a new therapeutic strategy that could integrate ketamine in the same time than SSRI, to control depression symptoms faster and optimize patient's quality of life complementary to treatments of cancer.

Inclusion Criteria:

• Inpatient
• Supported by a functional palliative care unit
• Having a severe and progressive disease diagnosed
• Meet the criteria for major depressive disorder as defined by DSM in its version 5
• MADRS > 19 ( moderate to severe)
• No antidepressant treatment or treatment introduced for more than four weeks
• In ability to receive clear information and give consent
• Beneficiary of a social security scheme

Exclusion Criteria:

• upper weight or equal to 100 kg
• ultimate phase (about 24 to 72 hours prior to death)
• unstable patient on cardiovascular diseases, including uncontrolled hypertension
• severe renal impairment (renal clearance less than 15 ml / min)
• psychiatric comorbidity: schizophrenia and schizoaffective disorder
• neurological comorbidity: recent cerebrovascular accident (Less than one month), Parkinson's disease, dementia
• treatment with ketamine received in the four weeks preceding the inclusion
• impaired judgment, cognitive or massive sensory impairment not allowing to receive clear information
• oral antidepressant treatment introduced less than four weeks ago
• dosage of oral antidepressant treatment upper than the marketing authorization for more than four weeks
• patient not covered by the social security system
• refusal to sign the consent
• minor patient or guardianship
• pregnant women (implementation of a urine pregnancy test before inclusion for women of childbearing age)
• lactating women
• intolerance or allergic reaction to ketamine or milnacipran.
• contraindications to the association of ketamine or milnacipran with the patient's usual treatment

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