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Ketamine in Adolescents With Treatment-Resistant Depression

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02078817
Recruitment Status : Completed
First Posted : March 5, 2014
Results First Posted : January 27, 2020
Last Update Posted : January 27, 2020
Sponsor:
Information provided by (Responsible Party):
University of Minnesota

Tracking Information
First Submitted Date  ICMJE February 27, 2014
First Posted Date  ICMJE March 5, 2014
Results First Submitted Date  ICMJE November 15, 2019
Results First Posted Date  ICMJE January 27, 2020
Last Update Posted Date January 27, 2020
Study Start Date  ICMJE September 2014
Actual Primary Completion Date March 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 24, 2020)
Number of Responders Measured by Clinical Global Impression (CGI) [ Time Frame: 2 weeks ]
Responders will be defined as those with CGI ratings (given by the study clinician) of 1 or 2 (much or very much improved). Patients that are given a scores of 3-7 (minimally improved to very much worse) will be considered non-responders.
Original Primary Outcome Measures  ICMJE
 (submitted: March 3, 2014)
Clinical Global Impression [ Time Frame: 1 week ]
Responders will be defined as those rated by the study clinician as a 1 or 2 (much or very much improved). Patients that are given a 3-7 (minimally improved to very much worse) will be considered non-responders.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 24, 2020)
  • Children's Depression Rating Scale-Revised [ Time Frame: 2 weeks ]
    The CDRS-R measure is given in interview form to child and parent separately. A consensus is then created with best-estimate for 17 items (each with a range of 1-5 or 1-7) using both sources of information. The total score is the sum of 17 item scores, ranging from 17-113 with higher scores indicating greater depression symptoms.
  • Montgomery-Åsberg Depression Rating Scale (MADRS) [ Time Frame: 2 weeks ]
    MADRS is a 10-item clinician-administered inventory measuring depression symptoms. Items are scored on a scare from 0 (none) to 6 (constant). Total scores are a sum of the 10 item scores, ranging from 0 to 60, with higher scores indicating greater symptom severity.
  • Beck Depression Inventory-II (BDI-II) [ Time Frame: 2 weeks ]
    BDI-II is a 21-item self-report multiple-choice inventory that assesses the severity of depressive symptoms over the prior week. Items are rated on a 4-point scale ranging from 0 to 3. Total scores are a sum of the 21 item scores ranging from 0 to 63. Higher scores indicate more severe depression symptoms.
  • Change in Clinician Administered Dissociative States Scale (CADSS) [ Time Frame: baseline, 2 weeks ]
    CADSS is a 27-item instrument measuring symptoms of dissociative stress, with 19 items completed by the patient and 8 items completed by the clinician. Items are rated on a scale of 0 (not at all) to 4 (extreme). Total scores are a sum of the 27 item scores and range from 0 to 108, with higher scores indicating greater symptom severity.
  • Maximum Change in Systolic Blood Pressure [ Time Frame: 2 hours and 40 minutes ]
    Vital signs were measured every 15 minutes, starting from the beginning of the infusion and ending 2 hours after the infusion ended (2 hours, 40 minutes total). Maximum increase of blood pressure compared to baseline was calculated.
  • Maximum Change in Diastolic Blood Pressure [ Time Frame: baseline, 45 minutes post infusion ]
  • Maximum Change in Heart Rate [ Time Frame: 4 hours ]
  • Maximum Decrease in Pulse Oximetry [ Time Frame: 4 hours ]
Original Secondary Outcome Measures  ICMJE
 (submitted: March 3, 2014)
  • Children's Depression Rating Scale-Revised [ Time Frame: 2 weeks ]
  • Montgomery-Åsberg Depression Rating Scale (MADRS) [ Time Frame: 1 week ]
  • Beck Depression Inventory-II [ Time Frame: 2 weeks ]
  • Profile of Mood States Questionaire [ Time Frame: before and after each ketamine treatment ]
    This measure assesses feelings at the moment
  • Clinician Administered Dissociative States Scale [ Time Frame: before and after each ketamine treatment ]
  • Blood Pressure [ Time Frame: 4 hours ]
  • Heart Rate [ Time Frame: 4 hours ]
  • Pulse Oximetry [ Time Frame: 4 hours ]
  • Brief Psychiatric Rating Scale [ Time Frame: 1 week ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Ketamine in Adolescents With Treatment-Resistant Depression
Official Title  ICMJE Open-Label Intravenous Subanesthetic Ketamine for Adolescents With Treatment-Resistant Depression
Brief Summary This study will test the use of ketamine for treatment of depression in adolescents that have not responded to other treatments. We will also examine neurobiological mechanisms of treatment.
Detailed Description

Depression frequently emerges during adolescence and is associated with severe outcomes. Current interventions do not lead to remission for many adolescents. Treatment-resistant depression (TRD) in adolescence is an ominous prognostic indicator for a lifetime of suffering and increased risk for suicide. Efforts should be directed toward novel interventions that could alter this perilous course. Theoretically, restoration of healthy development during this critical window would substantially improve outcomes over the lifespan.

Ketamine is a noncompetitive, high-affinity antagonist of the N-methyl-D-aspartate type glutamate receptor that has long been used for induction and maintenance of anesthesia in children and adults, and recently has been investigated for its rapid antidepressant effects. Randomized, double-blind, saline-controlled trials in adults with TRD have demonstrated that a single, subanesthetic infusion of intravenous (IV) ketamine at 0.5 mg/kg over 40 minutes can produce a rapid (within 2 hours) antidepressant response (Ibrahim et al., 2011; Zarate et al., 2006). Recent evidence suggests that serial doses of ketamine may be even more effective and may lead to more prolonged remission (aan het Rot et al., 2010; Murrough et al., 2012). Our current research at using serial dosing of IV ketamine among adult veterans with TRD over a 2-week period has shown promising results, with a response rate of 92% among the 12 participants to date.

No results from any studies examining effectiveness of either single-dose or serial-dose ketamine have yet been published in adolescents with TRD. Because of the ongoing neurodevelopment in adolescence, which is thought to confer enhanced neuroplasticity, it is possible that adolescents with TRD could show greater responses and more sustained remission than adults with TRD. The biological mechanisms of depression impacted by ketamine are only now being uncovered in adults (Zarate et al., 2013). Characterization of the neural mechanisms underlying ketamine response or non-response in adolescents with TRD will represent a significant advance. The specific aims of this preliminary study are as follows:

Aim #1: To determine the efficacy of repeated-dose subanesthetic IV ketamine among adolescent patients with TRD.

Hypothesis: Based on previous results in adults with TRD, we predict that response rates will improve over the course of six treatments of ketamine.

Aim #2: To explore durability of antidepressant response to repeated dose of IV ketamine in a 4-week observational period.

Hypothesis: Based on the inherent neuroplasticity in adolescence due to ongoing neurodevelopment, adolescents may show a more durable clinical response than has been seen in adults.

Aim #3: To study the neurobiological mechanisms of response to ketamine. We will examine relevant biological systems using several different brain imaging indices and measures of intracellular functioning from peripheral blood.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Major Depressive Disorder
Intervention  ICMJE Drug: Ketamine
IV infusions of 0.5mg/kg of Ketamine hydrochloride over a 40-minute infusion period. Participants will receive a total of 6 doses over a 2-week period.
Study Arms  ICMJE Experimental: ketamine
Intravenous ketamine 0.5 mg/kg over 40 minutes will be given 6 times over 2 weeks.
Intervention: Drug: Ketamine
Publications * Roy AV, Thai M, Klimes-Dougan B, Westlund Schreiner M, Mueller BA, Albott CS, Lim KO, Fiecas M, Tye SJ, Cullen KR. Brain entropy and neurotrophic molecular markers accompanying clinical improvement after ketamine: Preliminary evidence in adolescents with treatment-resistant depression. J Psychopharmacol. 2021 Feb;35(2):168-177. doi: 10.1177/0269881120928203. Epub 2020 Jul 9.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: March 2, 2018)
14
Original Estimated Enrollment  ICMJE
 (submitted: March 3, 2014)
20
Actual Study Completion Date  ICMJE March 2018
Actual Primary Completion Date March 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Male and female adolescents aged 12 to 18 years.
  • Presence of recurrent major depression without psychotic features confirmed by the Kiddie-Schedule for Affective Disorders and Schizophrenia - Parent and Lifetime Version (Kaufman et al., 1997).
  • Current depression severity measured by the Children's Depression Rating Scale (CDRS) (Poznanski, 1985) raw score greater than or equal to 36 at screening and the day ketamine is due to be received for the first time.
  • Current depressive episode resistant to treatment, defined as failure to achieve remission (elimination of symptoms and restoration of pre-morbid psychosocial functioning) from at least 2 antidepressant trials of different pharmacological classes. Systematic evaluation of previous antidepressant trials will be assessed by using the Antidepressant Treatment History Form (Sackeim, 2001).
  • If present, current antidepressant medication treatment must be dose stable for at least 2 months prior to beginning the study. (Patients will continue with current antidepressant treatment throughout the study. Based on our experience in current research at the VA Medical Center using serial ketamine for adult TRD, patients have shown positive results while continuing their current antidepressant treatment.)

Exclusion Criteria:

  • Inability to speak English
  • Inability or unwillingness to provide written informed consent
  • A history of Mental Retardation or any Pervasive Developmental Disorder
  • Current or lifetime diagnosis of schizophrenia, schizoaffective disorder, or psychosis Not Otherwise Specified.
  • Family history with a first degree relative with schizophrenia, schizoaffective disorder, or psychosis Not Otherwise Specified.
  • Diagnosis of seizures or other neurological disorders.
  • Comorbid diagnosis of substance abuse or dependence, current or past.
  • Clinically unstable medical illness.
  • Current use of the following medications: any barbiturates, any narcotics, any non-benzodiazepine hypnotics at doses higher than zolpidem 10 mg qhs or equivalent for insomnia.
  • For women: pregnancy (confirmed by baseline lab test).
  • The presence of any MRI contra-indications such as MRI-incompatible metals in the body or claustrophobia.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 12 Years to 18 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02078817
Other Study ID Numbers  ICMJE 22225
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party University of Minnesota
Study Sponsor  ICMJE University of Minnesota
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account University of Minnesota
Verification Date January 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP