Ketamine for Treatment-Resistant Bipolar Disorder

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 Bipolar I or II Disorder, currently experiencing a Major Depressive Episode without psychotic features. Diagnosis will be confirmed using the Mini-International Neuropsychiatric Interview (MINI) conducted by a delegated physician or trained research study while assessing eligibility. 4. Patient must present with a moderate to severe depressive episode, as determined by the MADRS score greater than 21. 5. Current depressive episode has inadequate response to two or more adequate first-line treatment trials for bipolar depression, as per the 2018 CANMAT Bipolar Disorder Guidelines. First line treatment trials include the use of lithium, valproate, carbamazepine, lamotrigine and/or any antipsychotic medication. 6. Patient must be receiving guideline-concordant pharmacotherapy without changes in the last month, including a therapeutic dose of a guideline-concordant mood stabilizer/antipsychotic. Exclusion Criteria 1. Currently exhibiting symptoms of mania, 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. History of psychotic features during a mood episode will not be excluded. 3. 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) 4. Lifetime history of a primary psychotic disorder (including, but not limited to, schizophrenia or schizoaffective disorder) 5. Lifetime history of ketamine use disorder 6. Presence of active suicidality, requiring involuntary inpatient treatment or recent suicide attempts within the past 3 months. 7. Presence of a contraindication to ketamine or midazolam, including a drug allergy, uncontrolled hypertension (baseline systolic blood pressure \> 140 mmHg and/or diastolic blood pressure \> 90 mmHg), low or labile blood pressure, myocardial infarction within past 12 months, cardiac arrhythmia, moderate to severe hepatic impairment (i.e., Child-Pugh score of B or C), moderate or severe renal impairment (glomerular filtration rate (GFR) \< 45 milliliters/min) , heart failure, or coronary artery disease 8. 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 (as outlined in section 5.11). 9. Use of prohibited concomitant medications, including other forms of ketamine or esketamine, benzodiazepines, stimulants, alcohol, and medical or recreational cannabis taken during the trial at a specific prohibited time. 10. Use of ketamine in the 30 days leading up to the patient's entry in the trial. 11. Use of monoamine oxidase inhibitors (MAOIs) at least two weeks prior to receiving study treatment.