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

• ClinicalTrials.gov Identifier: NCT03889756
• Recruitment Status: Active, not recruiting
• First Posted: March 26, 2019
• Last Update Posted: February 11, 2020
• Sponsor: Yale University
• Information provided by (Responsible Party): Yale University

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.

Condition or disease	Intervention/treatment	Phase
Major Depressive Disorder	Drug: Ketamine infusion; Drug: Midazolam infusion	Phase 2; Phase 3

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 24 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Phase 1 is a double-blind, midazolam-controlled parallel design trial; Phase 2 is an open extension.
• Masking: Double (Participant, Outcomes 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.
• Primary Purpose: Treatment
• Official Title: Ketamine for Severe Adolescent Depression: Intermediate-term Safety and Efficacy
• Actual Study Start Date: July 17, 2019
• Estimated Primary Completion Date: September 2022
• Estimated Study Completion Date: November 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Ketamine; 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; 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.
Placebo Comparator: Midazolam; 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; 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.

Outcome Measures

Primary Outcome Measures :

1. Evaluate the efficacy of a multiple-dosing ketamine infusion paradigm (2 infusions per week for 3 weeks) compared to midazolam in adolescents with treatment resistant depression [ Time Frame: Day 18 ]
   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
2. Evaluate the tolerability of a multiple-dosing ketamine infusion paradigm (2 infusions per week for 3 weeks) compared to midazolam in adolescents with treatment resistant depression [ Time Frame: Day 18 ]
   Establish if repeated ketamine will be tolerated as measured by drop-out rates

Eligibility Criteria

• Ages Eligible for Study: 13 Years to 17 Years (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Male or female ages 13-17 years
2. Meet DSM-5 (Diagnostic and Statistical Manual 5 ) criteria for Major Depressive Disorder by structured interview (MINI-KID)
3. Children's Depression Rating Scale, Revised CDRS score ≥40 at screening
4. 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
5. Stable psychiatric medications and doses for the month prior to enrollment. Subjects may continue to engage in any ongoing psychotherapy.
6. Medically and neurologically healthy on the basis of physical examination and medical history.
7. Parents able to provide written informed consent and adolescents must additionally provide assent.

Exclusion Criteria:

1. History of psychotic disorder, manic episode, autism spectrum disorder diagnosed by MINI-KID
2. History of substance dependence diagnosis by MINI-KID (excluding tobacco) or positive urine toxicology.
3. Intellectual disability (IQ<70) per medical history
4. Pregnancy (urine pregnancy tests on the day of infusions for menstruating girls) or lactation
5. Prior treatment with ketamine for depression or prior recreational use of ketamine.
6. Inability to provide written informed consent according to the Yale Human Investigation Committee (HIC) guidelines in English.

Contacts and Locations

Locations

United States, Connecticut

Yale Child Study Center

New Haven, Connecticut, United States, 06520

Sponsors and Collaborators

Yale University

Investigators

• Principal Investigator: Michael H. Bloch, MD; Yale University
• Study Director: Jennifer Dwyer, MD; Yale University

More Information

Publications:

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. Review.

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.

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.

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.

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.

• Responsible Party: Yale University
• ClinicalTrials.gov Identifier: NCT03889756
• Other Study ID Numbers: 2000023857
• First Posted: March 26, 2019
• Last Update Posted: February 11, 2020
• Last Verified: February 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Yale University:

depression, ketamine

Additional relevant MeSH terms:

Depression; Depressive Disorder; Depressive Disorder, Major; Behavioral Symptoms; Mood Disorders; Mental Disorders; Midazolam; Ketamine; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anesthetics, Dissociative; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Central Nervous System Depressants; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Adjuvants, Anesthesia; Hypnotics and Sedatives; Anti-Anxiety Agents; Tranquilizing Agents; Psychotropic Drugs; GABA Modulators; GABA Agents