i-CBT and IV Ketamine for Suicidality in Treatment-Resistant Depression: A Randomized, Midazolam-Controlled Clinical Trial

Inclusion Criteria: 1. Provide written, voluntary informed consent prior to study enrollment. Substitute decision makers will not be allowed to consent to study on a potential patient's behalf. 2. Male or female between the age of 21 to 65, inclusive. 3. Meets DSM-5 criteria for Major Depressive Disorder, currently experiencing a Major Depressive Episode (MDE) without psychotic features. Diagnosis will be confirmed using the Mini-International Neuropsychiatric Interview (MINI) conducted by a delegated physician or trained research study staff. 4. Must present with a moderate to severe depressive episode, as determined by the MADRS score greater than 21. 5. Must be at risk for suicide, operationalized as a response of 'yes' to items 1 or 2 on the Suicidal Ideation subscale or 'yes to any item of the Suicidal Behaviour subscale on the C-SSRS. 6. Current MDE has inadequate response to two or more adequate first-line treatment trials for MDD, as per the 2016 CANMAT Depression Guidelines. 7. Access to reliable internet for the entire study period and an internet-based device (i.e., a smartphone, laptop, desktop or tablet). 8. Must have the ability to speak and read English. This is due to the i-CBT modules only being offered in English presently. Exclusion Criteria: 1. Currently has symptoms of mania or hypomania or mixed state bipolar, as determined by the Young Mania Rating Scale (YMRS) score greater than 12. 2. Current symptoms of psychosis or a substance use disorder within the past 3 months. Past history of psychotic features during a mood episode will not be excluded. Other secondary psychiatric comorbidities (e.g. anxiety disorders, trauma related disorders, etc.) will not be excluded. 3. Lifetime history of a primary psychotic disorder (including, but not limited to, schizophrenia or schizoaffective disorder). 4. Lifetime history of ketamine use disorder. 5. History of neurological disorders (including, but not limited to, uncontrolled seizure disorder, history of stroke within past 12 months, major head injuries, aneurysmal vascular disease \[including thoracic and abdominal aorta, intracranial, and peripheral arterial vessels\], arteriovenous malformation, or intracerebral hemorrhage). 6. Presence a relative or absolute contraindication to ketamine or midazolam, including a drug allergy, stroke history, uncontrolled hypertension, low or labile blood pressure (as defined by a baseline systolic blood pressure \> 140 mmHg and/or diastolic blood pressure \> 90 mmHg), recent myocardial infarction within past 12 months, cardiac arrhythmia, severe coronary artery disease, heart failure or moderate to severe hepatic impairment (defined as a Child-Pugh score of B or C) or severe renal impairment (glomerular filtration rate (GFR) \< 45 milliliters/min). 7. Pregnant or breastfeeding women or women who intend to get pregnant. Patients who are sexually active must agree to use a highly effective contraceptive method. 8. Use of prohibited concomitant medications, which includes other forms of ketamine including racemic ketamine and esketamine, benzodiazepines, monoamine oxidase inhibitors, stimulants or medical cannabis of any form. All other medications will be permitted. 9. Currently receiving CBT or CBT-related interventions (e.g., Dialectical Behavioural Therapy). 10. Changes in medication or non-CBT psychotherapy one month prior to study enrollment.