Evaluation of the Initial Prescription of Ketamine and Milnacipran in Depression in Patients With a Progressive Disease

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Evaluation of the Initial Prescription of Ketamine and Milnacipran Forin Depression in Patients With a Progressive Disease

Conditions
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Depression

Intervention / Treatment
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* Drug: Ketamine
* Drug: Milnacipran
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Milnacipran + Ketamine<br>Ketamine 0,5mg/kg single intravenous perfusion during 40 minutes. Milnacipran dosage depending of glomerular filtration rate of patient, during 16 days (doses of 25 or 50 mg or 100mg per day) | Drug: Ketamine<br>* One single perfusion of 0.5 mg/kg during 40 minutes at the beginning of the inclusion<br>Drug: Milnacipran<br>* One or two caps per day from the beginning of the inclusion. Milnacipran dosage depending of glomerular filtration rate of patient, during 16 days (doses of 25 or 50 mg or 100mg per day)<br>|
| Active Comparator: Milnacipran + Placebo<br>Placebo single intravenous perfusion during 40 minutes. Milnacipran dosage depending of glomerular filtration rate of patient, during 16 days (doses of 25 or 50 mg or 100mg per day) | Drug: Milnacipran<br>* One or two caps per day from the beginning of the inclusion. Milnacipran dosage depending of glomerular filtration rate of patient, during 16 days (doses of 25 or 50 mg or 100mg per day)<br>Drug: Placebo<br>* One single perfusion during 40 minutes at the beginning of the inclusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MADRS Score | Measure of the change of Depression Intensity | At day 1, At day 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| EUROHIS-QOL 8 | Measure of the improvement of quality of life after 15 days of treatment. EUROHIS-QOL 8-item index, a shortened version of the World Health Organization Quality of Life Instrument-Abbreviated Version (WHOQOL-BREF). | at day 0, at day 15 | 
| Number of request of early death (suicidal intentions or euthanasia or physician-assisted suicide) | measure request of suicidal intentions made by the patient on explicit request of the clinician. | at day 0, at day 1, at day 2, at day 4, at day 8, at day 15 | 
| Hospital Anxiety and Depression scale (HAD) | The items of the scale limit confounding factors related to physical comorbidity . The answers are simple and quick . It is a wide choice and recommended for depression studies in palliative care. | at day 0, at day 1, at day 2, at day 4, at day 8, at day 15 | 
| MADRS Score | The MADRS scale quantifies the intensity of depressive symptoms, determine the number of responders (reduction in the initial score greater than or equal to 50%) and the number of patients in remission (score less than 7). | at day 0, at day 4, at day 8, at day 15 | 
| Clinical Global Impression (CGI) Score | These hetero fast and well validated assessments help to complete the assessment by the clinician on the severity of the patient's situation and overall improvement | at day 0, at day 1, at day 2, at day 4, at day 8, at day 15 | 
| Global Assessment Scale Operation (EGF) | Global Assessment of Functioning is a numerical scale ( from 0 to 100) used to evaluate the psychological, social and work of an individual . | at day 0, at day 15 | 
| Edmonton Symptom Assessment System ( ESAS ) | Symptom Assessment Scale | at day 0, at day 1, at day 2, at day 4, at day 8, at day 15 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ketamine, Palliative care, Supportive care, Early palliative care, Fast acting antidepressant, End of life care, Cancer, psychological distress, antidepressant, serotonin norepinephrine reuptake inhibitors