Double-Blind Randomized Controlled Trial of Acute-Course of Ketamine Versus Midazolam for Recurrence of Suicidality in Adolescents

The study design is a double-blind, randomized, active-control trial of adolescents (ages 13-18 years) with recent suicidal behaviors (suicide attempt or increased suicidal ideation). all participants must be receiving standard of care treatment which may range broadly from both outpatient and inpatient programs which include clinically indicated psychosocial and/or psychopharmacological treatments. Ketamine/midazolam treatment will occur twice weekly during the first two weeks of the study, followed by weekly assessments through week 12. SCReeninG: all potential participants will undergo a screening visit where informed consent will be obtained. Participants will be interviewed to assess psychiatric diagnoses. in addition, severity measures of suicidality, depression, mania, anxiety, and substance use will be obtained, as well as baseline measure of adverse events to monitor subsequent safety outcomes. Participants will also undergo a physical examination, safety labs (including a urine drug screen and if applicable, pregnancy testing), an eeG and eCG will also be obtained at screening. TReaTMenT: infusion Treatment Visits. Treatment visits will occur on days 0, 3, 7, 10 ((+-)1 day to allow for holidays, weekends, and missed visits). Participants will be required to be fasting prior to administration of study drug. Fasting will be nil per orally (nPo) for eight hours; clear liquid (water) will be permitted until 2 hour before the infusion to prevent dehydration. These visits will occur at the uT Southwestern Clinical Research unit (CRu) or Children's Medical Center (CMC). aSSeSSMenT anD FoLLoW uP: all participants will be assessed weekly (twice weekly during the first two weeks of treatments) for 12 weeks. This will allow for continued follow-up 11 weeks after the end of study drug (ketamine/midazolam) treatment. Generally, assessments from days 21-77 will be conducted remotely, unless the participant prefers to meet in person for the follow-up. if applicable, the parent/guardian of the participant will also complete self-report measures during this phase. Visit 5 (Day 14) and final study visit (Day 84) will be conducted in person. RanDoMiZaTion: Participants will be randomized in a 1:1 fashion to either intravenous ketamine (0.5mg/kg) or midazolam (0.02 mg/kg) for 4 infusions during the first two weeks (days 0, 3, 7, 10) of study participation. The weight of the participant collected at baseline will be the value used when preparing drug infusion. a total dose of 60mg of ketamine or 2.4 mg of midazolam will not be exceeded, regardless of weight. if participants exceed 120 kilograms at any time during the treatment period, they will be removed from the treatment portion of the study. Randomization will use blocking with a variable block size and will be stratified by presence of a suicide attempt, as well as age group (13-14 years and 15-18 years). The randomization list will be created by the statistician using a random number generating program (SaS Proc Plan). each drug is dissolved in 0.9% sodium chloride in a total volume of 100 mL and administered with an infusion pump at a constant rate. Study medication will be prepared and blinded by the uT Southwestern Research Pharmacy, and will be administered within 12 hours after preparation. all participants must also be receiving standard of care treatment, which includes clinically indicated psychopharmacological and/or psychosocial interventions, for the duration of the study. all study personnel and participants will be blinded, included those collecting and entering outcome data. Randomization codes are maintained by the Research Pharmacy and the identity of study drug can be made available if needed in the rare event of an emergency. a copy of the codes will also be provided to the CDRC Research Clinic Manager, who is available 24 hours per day in the event of an emergency after hours when the pharmacy is unavailable.