Inclusion Criteria
Study participants must:
1. Be adolescents (aged 13-18 years);
2. Have had a recent suicidal event (suicide attempt or significant suicidal ideation with a plan or intent warranting emergency evaluation or inpatient hospitalization within the past 90 days);
3. Receiving standard of care treatment that includes clinically indicated psychosocial and/or psychopharmacological treatment;
4. Have a current primary diagnosis of a depressive disorder based on the MINI-KID (other psychiatric disorders are acceptable, but must not be primary);
5. Participants must be able to complete assessments in English. However, the parent(s) or legal guardians of minors may either speak English or Spanish
6. Use effective method of contraception during and for 90 days following the end of treatment for female and male participants. Recommended methods of birth control are namely, consistent use of an approved hormonal birth control (pill/patches, rings), an intrauterine device (IUD), contraceptive injection, double barrier methods, sexual abstinence, or sterilization;
Exclusion Criteria
Study participants must not:
1. Have a psychotic disorder, such as lifetime schizophrenia, or a pervasive or intellectual developmental disorder requiring substantial or very substantial support;
2. Have current mania, hypomania, mixed episode, or obsessive-compulsive disorder;
3. Have a primary diagnosis other than a depressive disorder;
4. Have moderate to severe alcohol or substance use disorder within the past six months (based on MINI-KID); If there is a positive urine drug screen at screening, the urine drug screen will be repeated at each infusion visit. Positive urine drug screen will be reviewed by study physician and infusion will proceed as long as no safety risk was identified;
5. If female, be pregnant, lactating, or nursing; Women of childbearing potential must have a negative urine pregnancy test prior to all infusions;
6. Have unstable medical conditions (stable for less than 3 months) or with clinically significant laboratory values or an electrocardiogram (ECG) that would pose significant risk;
7. Be at serious suicidal risk that cannot be managed in the outpatient setting;
8. Have prior treatment for depression with or contraindications to ketamine, esketamine, or, midazolam;
9. Treatment with medications that may alter pharmacokinetics of ketamine, including moderate-to-strong inhibitors or inducers of CYP3A4 and CYP2B6, is exclusionary. Regarding pharmacodynamic interactions, medications that may increase heart rate or blood pressure such as the ADHD stimulant medications will be permitted with last dose at least 24 hours prior to infusion. All concomitant medications will be evaluated by the study physician to determine if the type and dose of concomitant medication requires discontinuation and will be excluded if the concomitant medication could substantially increase the risk of study infusion. A complete list of medications that are Not Allowed is available in Appendix D of the protocol. The study team will not ask the participant to discontinue any treatment (except for not taking ADHD medications for 24 hours before study treatment) just for the sake of taking part in this study;
10. Weigh \>120 kilograms at baseline. If participants are enrolled but exceed 120 kilograms at any time during the treatment period, they will be removed from the treatment portion of the study.
