 1. Phase I: the double-blind crossover. After patients will have been deemed eligible to participate in the study, blood will be drawn for genotyping and various assays BDNF ValMet, BDNF, morning melatonin and salivary cortisol, C-reactive protein, IL-1β, IL-2, IL-6, IL-8, IL-12, IFN-γ, TNF-α, and anti-inflammatory factors IL-4 and IL-10, as previously done in our laboratory.101-102 They will be randomized to receive intravenously either 0.5 mgkg of ketamine the readily available racemic mixture or 30 μgkg of midazolam as a 250 ml infusion prepared in our unit over 40 minutes, given by a research nurse in the presence of a study physician. Their antidepressant drug regimen will not be altered throughout the study. A clinician will evaluate their clinical status prior to the infusion, using the Montgomery-Asberg Depression Rating Scale MADRS103 and the Clinical Global Intensity-Severity CGI-S104 and the patients will rate themselves using the Quick Inventory Depressive Symptoms-Self-report QIDS-SR105 and a self-report questionnaire rating suicidality. The patients will be assessed using the Brief Psychiatric Rating Scale-positive symptom scale106 at baseline before the infusion, time 0 immediately after infusion is complete, then at 60 and 120 minutes post time 0. The CGI-Improvement CGI-I104 will be used to obtain a clinical evaluation of overall change of their condition after two hours before discharging the patients two hours after the infusion. The patients will come in the next day for an evaluation using the MADRS, CGIs, and the QIDS-SR and will be asked to guess what drug they received. Four days after the infusion, the patients will repeat the QIDS-SR at home, and they will come in for an evaluation at day 7. If the patients did not respond, or if they returned to 80 of their MADRS score before the infusion, they will receive either ketamine or midazolam to complete the crossover protocol. If the patients are maintaining more than a 20 improvement of their baseline MADRS score, they will be asked to come in on a weekly basis for an assessment, and will be asked to complete a QIDS-SR twice a week at days 10, 14, 18, 21, and so on in order to assess how long the therapeutic effect lasts. Patients who have not response to their second infusion or those found to have relapsed during the weekly follow-up visits, will continue into phase II. Patients who are unable, ineligible, or unwilling to enter phase II will be given a recommended treatment plan and returned to their family physician with a consultation plan, or additionalalternative treatment options at the discretion of the study physician. 