Predictors of Intravenous Ketamine Response in TRD

Inclusion Criteria: * Able to fluently read in English with or without optical correction * Ability to understand and comply with the study requirements * This is determined by the investigators * Provision of written informed consent * Documented diagnosis of MDD or bipolar disorder meeting DSM-5 criteria (as confirmed by the Diagnostic Assessment Research Tool), currently in a single or recurrent episode without psychotic features * Failure of at least two antidepressant medications from different pharmacological classes, as well as at least one augmentation agent, each of which must have been given at adequate doses for at least 6 weeks (recorded using the Antidepressant Treatment History Form - Short Form). * Augmentation strategies include those listed in the 2016 Canadian Network for Mood and Anxiety Treatments (CANMAT) depression guidelines, including a 12-week course of cognitive behavioural therapy or interpersonal therapy. * MADRS score of ≥25 at initial assessment and Day -1. * For premenopausal females who are currently sexually active with male partners: * Negative serum beta-HCG test at enrolment * AND commitment to using an appropriate birth control method of their choice throughout the duration of the study, including * Intrauterine device * Oral contraceptive * Long-term injectable contraceptive * Double-barrier method * Implant * Dermal contraception * Tubal ligation * Abstinence from grapefruit juice consumption on the day of infusion * Abstinence from benzodiazepine use within 24 hours of infusion * Adherence to maintaining current antidepressant management Exclusion Criteria: * Pregnant or breastfeeding * Allergies to ketamine or midazolam * Body mass less than 50kg * Concomitant use of medications with the potential for clinically significant interactions with either ketamine or midazolam (e.g., monoamine oxidase inhibitors, methylene blue) * Substance related exclusion criteria: * Concomitant use of naltrexone or narcotics * Positive urine drug screen or history of DSM-5 substance use disorder (SUD) in the past 3 months (except nicotine, and recreational cannabis use that doesn't meet the criteria for DSM-5 substance use disorder). History of SUD with significant severity that investigators believe warrant exclusion based on clinical judgment. * Previous or current benzodiazepine abuse history * Psychiatric exclusion criteria: * Previous ketamine use (therapeutic or recreational) * Comorbid DSM-5 personality disorder with a major impact on mental status * Secondary depressive disorders * E.g. secondary to stroke, cancer, or other somatic pathology * Subjects who will be starting psychotherapy during the trial period, or have only recently started psychotherapy within 2 months of the trial * Participants who have had ECT within 6 weeks prior to enrollment and/or have ECT during the trial period. * Medical comorbidity related exclusion criteria: * Evidence on history or chart review of any of the following: * Epilepsy * Any current or historical occurrence of renal disease * Clinically significant abnormalities of liver function tests (total bilirubin, albumin, prothrombin time and international normalized ratio \[PT/INR\], gamma-glutamyl transferase \[GGT\], alkaline phosphatase \[ALP\]). Clinical significance of any abnormal liver function tests will be evaluated by the study anesthesiologists. Patients with clinically significant abnormalities suggesting hepatic disease will be excluded. * Liver enzymes (AST, ALT) three times the upper normal limit at screening * Exception: of history of acute kidney injury or transient reductions in glomerular filtration rate that have fully resolved for at least three months * Any current or historical occurrence of hepatic disease * Abnormal liver function tests * Liver enzymes three times the upper normal limit at screening * Exception: History of transient elevations of liver enzymes or reduction in liver function that have re-normalized for the past three months (as per criteria above concerning function/enzymes) * Myocardial infarct within a year prior to initial randomization * Chronic obstructive pulmonary disease * Untreated obstructive sleep apnea * Cerebrovascular disease (including history of cerebrovascular accident) * Intracerebral structural lesions * Viral hepatitis B or C * Acquired immunodeficiency syndrome * Interstitial cystitis * Glaucoma * Uncontrolled hypertension * Decompensated heart failure * Current uncorrected thyroid pathology or recent correction within 30 days (correction of thyroid function for longer than 1 month is admissible). * Any unstable somatic pathology or clinically significant investigational abnormality (biochemical, ECG) that investigators believe would be negatively impacted by study procedures or that would negatively impact study procedures