Ketamine for Severe Adolescent Depression: Intermediate-term Safety and Efficacy

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the intermediate-term efficacy and tolerability of a multiple-dosing ketamine infusion paradigm for the treatment of medication-refractory major depressive disorder (MDD). We are using a two-phase design. The first phase is a 3-week double blind parallel design clinical trial comparing 6 infusions of ketamine compared to 6 infusions of midazolam in 24 adolescents with treatment resistant depression. The primary outcome of this phase will be Children's Depression Rating Scale (CDRS) score at Day 18. The second phase is a 6-month open phase in which patients who received midazolam and remain depressed with be offered open ketamine treatment (6 infusions over 3 weeks). All participants will be followed weekly for 6 months and tracked for time to relapse.

Detailed Description
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The purpose of this study is to evaluate the intermediate-term efficacy and tolerability of a multiple-dosing ketamine infusion paradigm for the treatment of medication-refractory major depressive disorder (MDD). The specific aims of the study are: To evaluate the efficacy and tolerability of a multiple-dosing ketamine infusion paradigm (2 infusions per week for 3 weeks) compared to midazolam in adolescents with treatment resistant depression (TRD), . To test these aims we have designed a two-phase trial. The first phase is a 3-week double blind parallel design clinical trial comparing 6 infusions of ketamine compared to 6 infusions of midazolam in 24 adolescents with TRD. The primary outcome of this phase will be Children's Depression Rating Scale (CDRS) score at Day 18. The second phase is a 6-month open phase in which patients who received midazolam and remain depressed with be offered open ketamine treatment (6 infusions over 3 weeks). All participants will be followed weekly for 6 months and tracked for time to relapse. In those who initially responded to ketamine, symptom triggered maintenance infusions will be offered during this 6-month time period. All participants will receive standard of care treatment in addition to experimental procedures, and will be tracked monthly with extensive neurocognitive assessments.

Official Title
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Ketamine for Severe Adolescent Depression: Intermediate-term Safety and Efficacy

Conditions
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Major Depressive Disorder

Intervention / Treatment
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* Drug: Ketamine infusion
* Drug: Midazolam infusion


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female ages 13-17 years Meet DSM-5 (Diagnostic and Statistical Manual 5 ) criteria for Major Depressive Disorder by structured interview (MINI-KID) Children's Depression Rating Scale, Revised CDRS score ≥40 at screening Failure to achieve remission with at least 2 antidepressant trials (e.g. SSRI, SNRI or TCA), meaning at least 6 weeks at therapeutic dosing, including at least 4 weeks of stable dosing Stable psychiatric medications and doses for the month prior to enrollment. Subjects may continue to engage in any ongoing psychotherapy. Medically and neurologically healthy on the basis of physical examination and medical history. Parents able to provide written informed consent and adolescents must additionally provide assent. Exclusion Criteria: History of psychotic disorder, manic episode, autism spectrum disorder diagnosed by MINI-KID History of substance dependence diagnosis by MINI-KID (excluding tobacco) or positive urine toxicology. Intellectual disability (IQ<70) per medical history Pregnancy (urine pregnancy tests on the day of infusions for menstruating girls) or lactation Prior treatment with ketamine for depression or prior recreational use of ketamine. Inability to provide written informed consent according to the Yale Human Investigation Committee (HIC) guidelines in English.

Ages Eligible for Study
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Minimum Age: 13 Years
Maximum Age: 17 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
Interventional Model Description: Phase 1 is a double-blind, midazolam-controlled parallel design trial; Phase 2 is an open extension.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ketamine<br>Ketamine is an FDA-approved anesthetic agent that is commonly used to induce surgical anesthesia due to its low incidence of significant respiratory depression and hypotension. It as a N-methyl-D-aspartate (NMDA) receptor antagonist and glutamatergic modulator, and has been demonstrated in multiple controlled clinical trials to have rapidly acting antidepressant and anti-suicidal effects in adults. | Drug: Ketamine infusion<br>* The dose of ketamine established in prior research (0.5 mg/kg over 40 minutes) will be used in this study to minimize risks. The maximum total single dose allowed in this study will be 40mg, corresponding to a weight of 80kg.<br>|
| Placebo Comparator: Midazolam<br>Midazolam, the active control in this study, is a medication that is approved by the Food and Drug Administration as a sedative for both children and adults.It is a benzodiazepine with a short half-life that was chosen so as to blind the psychotomimetic effects of Ketamine. | Drug: Midazolam infusion<br>* The weight-based midazolam dosing established in prior ketamine trials in adults (0.045mg/kg) will be used to minimize risks, as this is considered a very low dose compared to the sedation literature. The maximum total dose allowed in this study will be 3.6mg per infusion, corresponding to a weight of 80kg.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of a Multiple-dosing Ketamine Infusion Paradigm (2 Infusions Per Week for 3 Weeks) Compared to Midazolam in Adolescents With Treatment Resistant Depression Using the Children's Depression Rating Scale (CDRS) | Establish if repeated ketamine will be efficacious medically and psychiatrically, as measured by a significant reduction in CDRS score in those treated with ketamine at the end of the dosing paradigm. The Children's Depression Rating Scale (CDRS) is a clinician-rated instrument with 17 items scored on a 1 to 5 or 1 to 7 scale. A rating of 1 indicates normal, thus the minimum score is 17. The maximum score is 113. Scores of 20-30 suggest borderline depression. Scores of 40-60 indicate moderate depression. | Day 18 | 
| Tolerability of a Multiple-dosing Ketamine Infusion Paradigm (2 Infusions Per Week for 3 Weeks) Compared to Midazolam in Adolescents With Treatment Resistant Depression | Establish if repeated ketamine will be tolerated as measured by drop-out counts. | Day 18 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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depression, ketamine