Terminated early due to concerns from the NIH DSMB regarding the rate of recruitment and the resulting inability to accomplish the initially approved study aims

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.

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.

In July of this year (2024), the NIMH DSMB determined that Study 2000029003 will not be able to enroll enough individuals to be sufficiently powered to test the efficacy of Ketamine in treating adolescents with Major Depressive Disorder (MDD) and suicidal ideation (the primary aim of the study). Subsequently, the study was closed to enrollment

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)

One participant who was consented but not randomized at the time of study termination was offered unblinded ketamine and was included in the safety data for ketamine for the overall sample but not the efficacy analysis.

4 months