Ketamine Infusion for Adolescent Depression and Anxiety

• ClinicalTrials.gov Identifier: NCT02579928
• Recruitment Status: Completed
• First Posted: October 20, 2015
• Results First Posted: March 16, 2020
• Last Update Posted: July 14, 2020
• Sponsor: Yale University
• Collaborator: American Academy of Child Adolescent Psychiatry.
• Information provided by (Responsible Party): Yale University

Tracking Information

• First Submitted Date: October 16, 2015
• First Posted Date: October 20, 2015
• Results First Submitted Date: December 5, 2019
• Results First Posted Date: March 16, 2020
• Last Update Posted Date: July 14, 2020
• Study Start Date: October 2015
• Actual Primary Completion Date: September 28, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 29, 2020)

Montgomery-Asberg Depression Rating Scale Score 1 Day After Infusion [ Time Frame: 1 day after the 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.

Original Primary Outcome Measures (submitted: October 19, 2015)

Improvement in depressive symptoms [ Time Frame: 1 day after the infusion ]

Our primary outcome will be improvement in depressive symptoms as measured by Children's Depression Rating Scale, revised (CDRS-R) score, 1 day after infusion.

• Current Secondary Outcome Measures: Not Provided

Original Secondary Outcome Measures (submitted: October 19, 2015)

• Ketamine metabolites and D-serine [ Time Frame: 40 minutes (end of the infusion), 80 minutes, 110 minutes, and 230 minutes after each infusion ]
  Plasma levels
• Risk of suicidality [ Time Frame: Scored at Screening, 60 minutes before each infusion, 180 minutes after each infusion,at Day 1 /Day1+14, Day 2/Day 2 +14, Day 3/Day 3 + 14, Day5/ Day 5+14, Day 7/ Day 7+14, Day 10/ Day 10+14 and Day 14/ Day 14 + 14 ]
  Assessment with the Treatment-Emergent Activation and Suicidality Assessment Profile (TEASAP)

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Ketamine Infusion for Adolescent Depression and Anxiety
• Official Title: Efficacy of Rapid-Acting NMDA Antagonist for Treatment of Adolescent Depression and Anxiety Disorders
• Brief Summary: 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: 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.
• Study Type: Interventional
• Study Phase: Phase 4

Study Design

Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention 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 (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:

Midazolam was chosen as an active placebo in keeping with its similar pharmacokinetic profile and precedent as a reasonable comparator for nonspecific behavioral effects of ketamine

Primary Purpose: Treatment

Condition

• Major Depressive Disorder
• Anxiety Disorder

Intervention

• Drug: Ketamine
  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.
  Other Name: Ketalar
• Drug: Midazolam
  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.
  Other Name: Versed

Study Arms

• Experimental: Ketamine
  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).
  Intervention: Drug: Ketamine
• Experimental: Midazolam
  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),
  Intervention: Drug: Midazolam

Publications *

• 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.
• Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, Krystal JH. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000 Feb 15;47(4):351-4.
• 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.
• Niciu MJ, Ionescu DF, Richards EM, Zarate CA Jr. Glutamate and its receptors in the pathophysiology and treatment of major depressive disorder. J Neural Transm (Vienna). 2014 Aug;121(8):907-24. doi: 10.1007/s00702-013-1130-x. Epub 2013 Dec 8. Review.
• Ballard ED, Ionescu DF, Vande Voort JL, Niciu MJ, Richards EM, Luckenbaugh DA, Brutsché NE, Ameli R, Furey ML, Zarate CA Jr. Improvement in suicidal ideation after ketamine infusion: relationship to reductions in depression and anxiety. J Psychiatr Res. 2014 Nov;58:161-6. doi: 10.1016/j.jpsychires.2014.07.027. Epub 2014 Aug 12.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 2, 2020): 17
• Original Estimated Enrollment (submitted: October 19, 2015): 18
• Actual Study Completion Date: September 2019
• Actual Primary Completion Date: September 28, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 13 Years to 17 Years (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02579928
• Other Study ID Numbers: 1506016041
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Yale University
• Original Responsible Party: Same as current
• Current Study Sponsor: Yale University
• Original Study Sponsor: Same as current
• Collaborators: American Academy of Child Adolescent Psychiatry.

Investigators

• Principal Investigator: Michael H. Bloch, MD MS; Yale University

• PRS Account: Yale University
• Verification Date: June 2020