Reducing Adolescent Suicide Risk: Safety, Efficacy, and Connectome Phenotypes of Intravenous Ketamine

Adolescent Depression Clinical Trial

Official title:

Reducing Adolescent Suicide Risk: Safety, Efficacy, and Connectome Phenotypes of Intravenous Ketamine

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04613453
• Other study ID #: 2000029003
• Secondary ID: 1R01MH125203-01
• Status: Recruiting
• Phase: Phase 2
• Start date: January 21, 2022
• Est. completion date: March 2025

Study information

• Verified date: August 2023
• Source: Yale University
• Contact: Brooke Rivera, LMSW
• Phone: 203-785-7880
• Email: brooke.rivera[@]yale.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to determine if intravenous ketamine reduces suicidal thinking compared to an active placebo (midazolam) in adolescents who have treatment resistant depression and a recent history of a suicide event (defined as a suicide attempt, emergency room evaluation for suicidal thinking, or a transition to inpatient care for suicidality in the past 120 days).

The primary objective of this study is to determine whether ketamine reduces suicidal ideation (as measured via the C-SSRS, recent ideation scale) relative to an active control, midazolam, 48-hours after first administration in adolescents with TRD at high suicide risk.

Description:

The main purpose of the study is to examine the safety, efficacy, response predictors, and post-treatment trajectory of adolescents with TRD and high suicide risk following a highly conservative repeat dosing ketamine infusion paradigm (four infusions of 0.5mg/kg each over two weeks) compared to an active control, midazolam. Those who are randomized to midazolam and remain ill have the option to cross-over to ketamine in the open phase. All participants will be followed closely for four months post-treatment and treated with standard of care depression treatment (medication management and cognitive behavioral therapy). Brain-based predictors of anti-suicidal responses will be assessed via connectome predictive modeling (CPM), examining functional brain circuits via fMRI before and after treatment.

Given the unregulated use of ketamine in the community at widely varying doses and frequencies, the safety data gathered from this highly conservative repeat dosing paradigm is critical to inform the field about potential risks. Efficacy data at rapid, short-term, and intermediate-term (4 month) timepoints will be critical to determining whether a larger study is warranted in this population. The assessment of brain-based predictors of response through the integration of functional neuroimaging adds an important measure of biological engagement that will inform subsequent studies and stands to contribute towards the goal of personalized medicine (i.e. determining not only if a treatment works, but in whom).

Aim 1: To evaluate the safety of treating adolescents with TRD at high suicide risk with a conservative repeat-dosing ketamine paradigm followed by standard of care treatment over 4 months. Hypothesis: We anticipate no untoward effects on medical outcomes (cardiovascular function and bladder health) or cognitive function (measured via Cogstate).

Aim 2: To evaluate the 48-hour impact of ketamine on suicidal ideation compared to midazolam, and to identify connectome phenotypes predictive of ideation post-treatment. Hypothesis: Ketamine will reduce suicidal thinking (Columbia Suicide Rating Scale, recent ideation subscale) compared to midazolam. CPM will identify networks predictive of ideation, validated via k-fold or leave-one-out cross-validation within the sample. The network measures obtained at this fixed ketamine dose will inform the design of larger clinical trials.

Aim 3 (exploratory): To describe the trajectory of suicidal thinking, depressive symptoms, and use of mental health resources in both ketamine responders and non-responders over 4 months.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 66
• Est. completion date: March 2025
• Est. primary completion date: December 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 13 Years to 17 Years

Eligibility

Inclusion Criteria:

1. Ages 13-17 years, inclusive

2. Meet DSM-5 criteria for Major Depressive Disorder by structured interview (MINI-KID+)

3. Children's Depression Rating Scale, Revised (CDRS-R) score =45 at screening

4. Continued clinically significant depressive symptoms despite an SRI trial (e.g. SSRI or SNRI) of adequate dose and duration, meaning at least 6 weeks at therapeutic dosing, including at least 4 weeks of stable dosing

5. Suicide event within the past 120 days (i.e. a suicide attempt (defined as an act of potentially self-injurious behavior with explicit or inferred intent to die) -OR- degree of suicidal ideation requiring an emergency evaluation or a transition to higher level of care (e.g. intensive outpatient program, partial hospital program, inpatient)

6. Columbia Suicide Severity Rating Scale ideation score of = 1 at screening

7. Medically and neurologically healthy on the basis of physical examination, medical history, and the clinical judgement of the evaluating physician.

8. Parents able to provide written informed permission and adolescents must additionally provide assent.

9. Stated willingness to comply with all study procedures and availability for the duration of the study

10. Provision of signed and dated parental permission and adolescent assent form. If there are two parents or guardians, both must provide permission and each must sign a separate permission form.

Exclusion Criteria:

1. History of psychotic disorder, manic episode, or 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 participation in a ketamine study, prior clinical psychiatric treatment with ketamine, or prior recreational use of ketamine

6. Pre-existing cardiovascular disease or untreated or unstable hypertension

7. Body weight greater than 80 kgs

8. Currently taking benzodiazepines or other medications that may cause respiratory depression, or lamotrigine, which is hypothesized to interfere with ketamine's mechanism of action

9. Inability to provide written informed consent according to the Yale Human Investigation Committee (HIC) guidelines in English.

For participation in the fMRI scans only (participants with contraindications to fMRI may still participate in all other portions of the trial, providing they meet all other inclusion/exclusion criteria):

10. Any contraindication to MRI including severe claustrophobia, or metal in the body (including mental dental braces)

Related Conditions & MeSH terms

• Adolescent Depression
• Adolescent Suicide
• Suicide

Intervention

Drug:
• Ketamine Infusion
Participants will receive four Ketamine infusions over two weeks, each 0.5mg/kg over 40 minutes.
• Midazolam Infusion
Participants will receive four Midazolam infusions over two weeks, each 0.045mg/kg over 40 minutes.

Locations

Country	Name	City	State
United States	Yale New Haven Hospital	New Haven	Connecticut

Sponsors (2)

Lead Sponsor	Collaborator
Yale University	National Institute of Mental Health (NIMH)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Columbia-Suicide Severity Rating Scale (C-SSRS)	The C-SSRS is an assessment of suicidal ideation and behavior in clinical and research settings. The C-SSRS consists of 16 questions that ask about suicidal ideation and behaviors (the first 10 questions comprise the ideation subscale and the last 6 comprise the behavior subscale). This 5-item subscale ranges from a minimum of 0 (corresponding to no suicidal ideation) to a maximum of 5 (representing active suicidal ideation with plan and intent).	2 days
Secondary	Montgomery Asberg Depression Rating Scale	Montgomery Asberg Depression Rating Scale is an 10-item scale examines depressive symptoms and will be assessed at baseline (prior to any experimental treatment), prior to each experimental treatment, and weekly during the open phase of the trial. This 10-item scale ranges from 0 to 60, with higher values representing more intensive depressive symptoms.	2 days
Secondary	Change in Children's Depression Rating Scale	Children's Depression Rating Scale-Revised is a 17-item scale examines depressive symptoms in children and adolescents using the combined report of the adolescent and the parent, synthesized by a clinician. It will be administered at baseline (prior to any experimental treatment), at the end of the blinded phase of the trial (Day 11), and monthly during the open phase of the trial. This 17-item clinical scale creates scores that range from 17 to 113, with higher scores representing more intensive depressive symptoms	Baseline to Day 11