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

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)