Ketamine for Treatment-Resistant Bipolar Disorder

Inclusion criteria

• 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.
• Male or female between the age of 21 to 65, inclusive.
• 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.
• Patient must present with a moderate to severe depressive episode, as determined by the MADRS score greater than 21.
• 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.
• 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

• Currently exhibiting symptoms of mania, hypomania, or mixed state bipolar, as determined by the Young Mania Rating Scale (YMRS) score greater than 12.
• 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.
• 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)
• Lifetime history of a primary psychotic disorder (including, but not limited to, schizophrenia or schizoaffective disorder)
• Lifetime history of ketamine use disorder
• Presence of active suicidality, requiring involuntary inpatient treatment or recent suicide attempts within the past 3 months.
• 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
• 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).
• 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.
• Use of ketamine in the 30 days leading up to the patient's entry in the trial.
• Use of monoamine oxidase inhibitors (MAOIs) at least two weeks prior to receiving study treatment.