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

NCT03889756 | Terminated Phase 2 Results FDA Drug

• 1 other identifier: 2000023857
• Study Type: interventional
• Target: 3
• Locations: 1 country
• Sites: 1

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.

Conditions

Major Depressive Disorder

Keywords

depression, ketamine

Outcome Measures

Primary Outcomes (2)

• 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

Study Arms (2)

Ketamine

EXPERIMENTAL

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

Midazolam

PLACEBO COMPARATOR

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

Interventions

Ketamine infusion DRUG

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.

Ketamine

Midazolam infusion DRUG

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.

Midazolam

Eligibility Criteria

• Age: 13 Years - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Yale University: lead

Study Sites (1)

Yale Child Study Center

New Haven, Connecticut, 06520, United States

Location

Related Publications (5)

• 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.

  PMID: 16012257 BACKGROUND

• 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.

  PMID: 8122957 BACKGROUND

• 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.

  PMID: 16894061 BACKGROUND

• 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.

  PMID: 23982301 BACKGROUND

• 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.

  PMID: 28669202 BACKGROUND

MeSH Terms

Conditions

Depressive Disorder, Major; Depression

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders; Behavioral Symptoms; Behavior

Limitations and Caveats

The study was only able to enroll 3 participants before the pandemic started and then ran out of funding to finish the trial. Presented are summary data and to avoid revealing any identifying information of participants, data is presented overall where applicable (e.g. baseline characteristics).

Results Point of Contact

• Title: Dr. Michael Bloch
• Organization: Yale University

michael.bloch@yale.edu

203 7374809

Study Officials

• Michael H. Bloch, MD

  Yale University

  PRINCIPAL INVESTIGATOR

• Jennifer Dwyer, MD

  Yale University

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, OUTCOMES ASSESSOR
• Masking Details: Participants will not be told what medication they are receiving; physicians absent from the infusion paradigm will perform blinded clinical efficacy ratings.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

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

Study Record Dates

• First Submitted: March 22, 2019
• First Posted: March 26, 2019
• Study Start: July 17, 2019
• Primary Completion: December 18, 2019
• Study Completion: January 5, 2023
• Last Updated: April 24, 2023
• Results First Posted: April 24, 2023

Record last verified: 2023-03

Locations

US (1)