Ketamine Infusion for Adolescent Depression and Anxiety

Study Overview
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Brief Summary
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The purpose of this study is to determine the tolerability and short-term efficacy of a single ketamine infusion for the treatment of adolescents with 1) medication-refractory major depressive disorder (MDD) and/or 2) medication-refractory anxiety disorders (social anxiety disorder, panic disorder, generalized anxiety disorder and/or separation anxiety disorder).

Detailed Description
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We will conduct a crossover trial in which as many as 36 adolescents (18 with MDD and 18 with anxiety disorders) will be given a single infusion of ketamine (study drug) or midazolam (active control). MDD symptoms and anxiety symptoms will be monitored over a two-week period. If applicable, comorbid school refusal symptoms will also be monitored over a two-week period for both cohorts. A 2-week washout period will be required between infusion doses. Our primary outcomes will be 1) improvement in MDD symptoms (measured by Montgomery-Asberg Depression Rating Scale, revised (MADRS) score) 1 day after infusion, for the cohort of subjects enrolled in the MDD arm of this trial and 2) improvement in the anxiety symptoms (measured by the Multimodal Anxiety Scale for Children (MASC) acute physical symptoms subscale) for the cohort of subjects enrolled in the anxiety disorders arm of the trial.

Official Title
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Efficacy of Rapid-Acting NMDA Antagonist for Treatment of Adolescent Depression and Anxiety Disorders

Conditions
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Major Depressive Disorder, Anxiety Disorder

Intervention / Treatment
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* Drug: Ketamine
* Drug: Midazolam


Participation Criteria
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Eligibility Criteria
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Inclusion: MDD Cohort: Meet DSM-5 criteria for Major Depressive Disorder by structured interview (MINI-KID) CDRS-R score >40. Failure to achieve remission with at least 1 adequate prior antidepressant trial (e.g. SSRI, SNRI, or TCA), meaning at least 8 weeks at therapeutic dosing, including at least 4 weeks of stable dosing. Anxiety Cohort: Meet DSM-5 criteria for any of the following anxiety disorders: Social Anxiety Disorders, Generalized Anxiety Disorder, Separation Anxiety Disorder and/or Panic Disorder by structured interview (MINI-KID) ADIS Clinical Severity Rating ≥4 (moderately severe) for any of the 4 included anxiety disorders Failure to achieve remission with at least 1 adequate prior anxiolytic medication trial (e.g. SSRI, SNRI, or TCA), meaning at least 8 weeks at therapeutic dosing, including at least 4 weeks of stable dosing. Failure to achieve remission with previous CBT or subject declines current CBT therapy Both cohorts: 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: Current inpatient hospitalization or active suicidal ideation requiring referral for inpatient hospitalization for safety. History of psychotic disorder or manic episode diagnosed by MINI-KID History of substance dependence diagnosis by MINI-KID (excluding tobacco) or positive urine toxicology. Pregnancy (urine pregnancy tests on the day of scans for menstruating girls). 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: Crossover Assignment
Interventional Model Description: Participants were randomly assigned the treatment order, with participants receiving a single infusion of either ketamine hydrochloride (0.5 mg/kg) or midazolam (0.045 mg/kg) on Day 1, and the alternate compound 2 weeks later.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ketamine<br>Participants were randomly be assigned to receive a dose of 0.5 mg/kg of Ketamine (administered intravenously over 40 minutes with a maximum total dose allowed in this study will be 50mg). | Drug: Ketamine<br>* A single dose of 0.5mg/kg of Ketamine will be administered Intravenously during 40 minutes in the Hospital Research Unit of YNHH. The subject will be monitored continuously during the procedure, and every hour for three hours after the infusion.<br>* Other names: Ketalar;|
| Experimental: Midazolam<br>Participants were randomly assigned to receive a dose of 0.045mg/kg of Midazolam (administered Intravenously over 40 minutes with a the maximum total dose allowed in this study of 4.5mg), | Drug: Midazolam<br>* A single dose of 0.045mg/kg of Midazolam will be administered intravenously during 40 minutes in the Hospital Research Unit of YNHH. The subject will be monitored continuously during the procedure, and every hour for three hours after the infusion.<br>* Other names: Versed;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Montgomery-Asberg Depression Rating Scale Score 1 Day After Infusion | Depressive symptoms (measured by Montgomery-Asberg Depression Rating Scale, revised (MADRS) score) on 1 day after infusion, for the cohort of subjects enrolled in the MDD arm of this trial. Higher MADRS score indicates more severe depression, and each item yields a score of 0 to 6. The overall score ranges from 0 to 60. Usual cutoff points are: 0 to 6 - normal /symptom absent. 7 to 19 - mild depression. 20 to 34 - moderate depression. >34 - severe depression. | 1 day after the infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ketamine, Depression, Major Depressive Disorder, Anxiety, School refusal, Suicide, Generalized Anxiety, Suicidal Ideation