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

Major Depressive Disorder Clinical Trial

— SAD-KIDS  

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03889756
• Other study ID #: 2000023857
• Status: Terminated
• Phase: Phase 2/Phase 3
• Start date: July 17, 2019
• Est. completion date: January 5, 2023

Study information

• Verified date: March 2023
• Source: Yale University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 3
• Est. completion date: January 5, 2023
• Est. primary completion date: December 18, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 13 Years to 17 Years

Eligibility

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.

Related Conditions & MeSH terms

• Depression
• Depressive Disorder
• Depressive Disorder, Major
• Major Depressive Disorder

Intervention

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.
• 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.

Locations

Country	Name	City	State
United States	Yale Child Study Center	New Haven	Connecticut

Sponsors (1)

Lead Sponsor	Collaborator
Yale University

Country where clinical trial is conducted

United States, 

References & Publications (5)

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. — View 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. — View 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. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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