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Ketamine for Severe Adolescent Depression: Intermediate-term Safety and Efficacy (SAD-KIDS)

Primary Purpose

Major Depressive Disorder

Status

Terminated

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Ketamine infusion

Midazolam infusion

About this trial

This is an interventional treatment trial for Major Depressive Disorder focused on measuring depression, ketamine

Eligibility Criteria

13 Years - 17 Years (Child)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Yale Child Study Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Ketamine

Midazolam

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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.

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.

Secondary Outcome Measures

Full Information

NCT ID

NCT03889756

First Posted

March 22, 2019

Last Updated

March 31, 2023

Sponsor

Yale University

1. Study Identification

Unique Protocol Identification Number

NCT03889756

Brief Title

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

Acronym

SAD-KIDS

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

March 2023

Overall Recruitment Status

Terminated

Why Stopped

No more funding available to continue since we could not recruit throughout the pandemic.

Study Start Date

July 17, 2019 (Actual)

Primary Completion Date

December 18, 2019 (Actual)

Study Completion Date

January 5, 2023 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Yale University

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

5. Study Description

Brief Summary

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

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Major Depressive Disorder

Keywords

depression, ketamine

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2, Phase 3

Interventional Study Model

Parallel Assignment

Model Description

Phase 1 is a double-blind, midazolam-controlled parallel design trial; Phase 2 is an open extension.

Masking

ParticipantOutcomes Assessor

Masking Description

Participants will not be told what medication they are receiving; physicians absent from the infusion paradigm will perform blinded clinical efficacy ratings.

Allocation

Randomized

Enrollment

3 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Ketamine

Arm Type

Experimental

Arm Description

Arm Title

Midazolam

Arm Type

Placebo Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

Ketamine infusion

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Midazolam infusion

Intervention Description

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.

Primary Outcome Measure Information:

Title

Description

Time Frame

Day 18

Title

Tolerability of a Multiple-dosing Ketamine Infusion Paradigm (2 Infusions Per Week for 3 Weeks) Compared to Midazolam in Adolescents With Treatment Resistant Depression

Description

Establish if repeated ketamine will be tolerated as measured by drop-out counts.

Time Frame

Day 18

10. Eligibility

Sex

All

Minimum Age & Unit of Time

13 Years

Maximum Age & Unit of Time

17 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Michael H. Bloch, MD

Organizational Affiliation

Yale University

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Jennifer Dwyer, MD

Organizational Affiliation

Yale University

Official's Role

Study Director

Facility Information:

Facility Name

Yale Child Study Center

City

New Haven

State/Province

Connecticut

ZIP/Postal Code

06520

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

16012257

Citation

Richmond TK, Rosen DS. The treatment of adolescent depression in the era of the black box warning. Curr Opin Pediatr. 2005 Aug;17(4):466-72. doi: 10.1097/01.mop.0000166347.53102.e7.

Results Reference

background

PubMed Identifier

8122957

Citation

Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, Heninger GR, Bowers MB Jr, Charney DS. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry. 1994 Mar;51(3):199-214. doi: 10.1001/archpsyc.1994.03950030035004.

Results Reference

background

PubMed Identifier

16894061

Citation

Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, Charney DS, Manji HK. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006 Aug;63(8):856-64. doi: 10.1001/archpsyc.63.8.856.

Results Reference

background

PubMed Identifier

23982301

Citation

Murrough JW, Iosifescu DV, Chang LC, Al Jurdi RK, Green CE, Perez AM, Iqbal S, Pillemer S, Foulkes A, Shah A, Charney DS, Mathew SJ. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry. 2013 Oct;170(10):1134-42. doi: 10.1176/appi.ajp.2013.13030392.

Results Reference

background

PubMed Identifier

28669202

Citation

Wilkinson ST, Toprak M, Turner MS, Levine SP, Katz RB, Sanacora G. A Survey of the Clinical, Off-Label Use of Ketamine as a Treatment for Psychiatric Disorders. Am J Psychiatry. 2017 Jul 1;174(7):695-696. doi: 10.1176/appi.ajp.2017.17020239. No abstract available.

Results Reference

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

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