Positioning of Esketamine Treatment in the Real-world Management of Depression

Study Overview
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Brief Summary
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The goal of this naturalistic, open label, single arm intervention study is to investigate the effects of Esketamine in treating depression.The main aims to answer are: to investigate whether Esketamine is effective when added to ongoing antidepressant treatment to identify patient characteristics that will determine a therapeutic response to Esketamine in real-world practice Participants will: attend the clinic for supervised self-administration of intranasal Esketamine treatment be observed for 2 hours following Esketamine administration including blood pressure monitoring be asked to complete a battery of questionnaires be reimbursed for travel expenses

Detailed Description
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Depression is a common mental illness, and it is one of the leading causes of disease burden worldwide. Fortunately, there are many effective treatments available for depression, including lifestyle changes, psychological treatments, and medications such as antidepressants. However, not all patients will respond to the first treatment prescribed. Some patients may only experience a 'partial response', where a few treatments help their depression somewhat, but they do not achieve a full recovery. Currently, the reasons why some patients do not respond, or only experience a partial response to an antidepressant, is not fully understood. Recently, researchers have been investigating new medications that may help patients recover from depression. One of these new medications is Esketamine, which is a relatively new molecule derived from a drug called Ketamine - an anaesthetic that has been used medically for decades. Researchers have been investigating the antidepressant properties of Ketamine for a long time. It is thought that Ketamine, and its derivative, Esketamine, help to treat depression for a number of reasons. However, it is not yet known which patients benefit most from Esketamine when used in conjunction with conventional antidepressants. In addition, we do not yet understand how the effect of Esketamine is impacted by other treatments that a patient may be taking for their depression. Finally, it has not yet been investigated how patients with a partial response to an antidepressant will benefit from adding Esketamine to their therapeutic regimen without switching to a new baseline antidepressant. Therefore, there are two principle aims of this study 1) to investigate whether Esketamine is effective when added to ongoing antidepressant treatment and 2) to identify patient characteristics that will determine a therapeutic response to Esketamine in real-world practice.

Official Title
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Positioning of Esketamine Treatment in the Real-world Management of Depression

Conditions
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Major Depressive Disorder

Intervention / Treatment
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* Drug: Esketamine Nasal Spray [Spravato]


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults aged 18-65 years old Diagnosis of Major Depressive Disorder (MDD) Currently depressed Had an inadequate response to 2 or more courses of antidepressants (of adequate dose and duration) Able to understand and provide informed consent Exclusion Criteria: Concurrent diagnoses: Participants with other 'Diagnostic and Statistical Manual of Mental Disorders' (DSM-5) including current substance misuse disorders, personality disorders, post-traumatic stress (PTSD) disorder, bipolar disorder, schizophrenia, obsessive-compulsive disorder (OCD), eating disorders and attention-deficit/hyperactivity disorder (ADHD). Participants who are unable to understand the study and therefore unable to provide informed consent Pregnancy: Participants who are pregnant and/or breastfeeding Participants who are not willing to avoid pregnancy for themselves or their partners during the study by using effective birth control methods Current medications: Participants taking a total daily dose of benzodiazepines greater than the equivalent of 6mg/day of lorazepam Participants on complementary and alternative medicine therapies i.e., St John's wort, Chinese medicines, and various herbal and homeopathic treatments Participants taking Stimulants such as methylphenidate, amphetamine, and dextroamphetamine are excluded due to their synergistic effect and can cause increased blood pressure. Medical history: Participants with current or past history of seizures (uncomplicated childhood febrile seizures with no sequelae are not exclusionary) Participants with a history of uncontrolled hypertension Participants with uncontrolled diabetes mellitus Participants with aneurysmal vascular disease including thoracic and abdominal aorta, intracranial and peripheral arterial vessels, or arteriovenous malformation, intracerebral haemorrhage Participants with untreated glaucoma, current penetrating or perforating eye injury, brain injury, hypertensive encephalopathy, intrathecal therapy with ventricular shunts, or any other condition associated with increased intracranial pressure or increased intraocular pressure or planned eye surgery Participants who have received treatment with electroconvulsive therapy (ECT) or vagal nerve stimulation (VNS) or deep brain stimulation (DBS) in the current episode of depression Ketamine history: Participants with a lifetime history of ketamine, phencyclidine (PCP), lysergic acid diethylamide (LSD), or 3,4-methylenedioxy-methamphetamine (MDMA), or other hallucinogen use history Participants with hypersensitivity to Esketamine, Ketamine, or any of the excipients

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Participants with Major Depressive Disorder<br>Intranasal esketamine to be self-administered by participants under direct supervision of a healthcare professional. First initial dose is 56mg and subsequent doses will be 56mg or 84mg. Esketamine will be administered twice weekly for weeks 1-4, once weekly for weeks 5-8, and once weekly/once fortnightly/once monthly as clinically indicated for weeks 9-25. After each treatment phase, participants will be re-assessed through a comprehensive battery of assessments and dose adjustments will be performed by the study psychiatrist base on tolerability, treatment response, and ongoing consent. | Drug: Esketamine Nasal Spray [Spravato]<br>* This is an uncontrolled, single arm, naturalistic study. There will be three treatment phases: Phase 1 - Acute treatment phase (weeks 1-4); Phase 2 - Maintenance treatment phase (weeks 5-8); Phase 3 - Continuation treatment phase (Weeks 9-25). Phase 1 is the critical component of our study as it determines our primary outcomes.<br>* Other names: Spravato;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of treatment responders determined by a 50% reduction on the Hamilton Depression Rating Scale (HAM-D) 17-Item scoring. | Hamilton Depression Rating Scale (HAM-D) 17-Item scoring | At the end of week 4 | 
| Mean depression score on the Quick Inventory of Depressive Symptomatology Self-report (QIDS-SR) 16-Item. | Quick Inventory of Depressive Symptomatology Self-report (QIDS-SR) 16-Item. | Baseline, at the end of weeks 1,2,3, and 4 (primary time point); and further after week 8 and week 12 after Esketamine was commenced. | 
| Global functioning determined by Clinical Global Impression (CGI) score. | Clinical Global Impression (CGI) | Baseline, week 1, week 2, week 3, week 4 (primary time point), week 8 and week 12 after Esketamine was commenced. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in mood symptom scores assessed using the visual analogue scale (self-reported) | Visual analogue scale (self-reported) | Baseline, after treatment day 1 and day 3 of each week until Esketamine is ceased. | 
| Depressive symptoms assessed using the Beck Depression Inventory (BDI) 21-Item. | Beck Depression Inventory (BDI) 21-Item. | Baseline and at week 4 after Esketamine was commenced. | 
| Anxiety symptoms assessed using the State-Trait Anxiety Inventory (STAI) | State-Trait Anxiety Inventory (STAI) | Baseline and at week 4 after Esketamine was commenced. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Depression