Maintenance Ketamine Infusions for Treatment-Resistant Bipolar Depression

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 confirmed by study psychiatrist at the start of the parent KET-BD randomized clinical trial (RCT).
• Patients in the KET-BD RCT 4a. Patients in the ketamine arm of the KET-BD RCT must have experienced an antidepressant response (i.e. change in MADRS score ≥ 50% at day 14 compared to baseline or Clinical Global Impression-Improvement (CGI-I) = 2 'much improved' or 1 'very much improved') or experienced clinical remission of symptoms (i.e., MADRS score < 12 on day 14) 4b. Patients in the midazolam arm of the KET-BD RCT must present as moderately to severely depressed (MADRS >21) on days 14 and 28 of the parent RCT and must be responders or remitters following four flexibly dosed infusions over 2 weeks.
• 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. Adequate medications confirmed at the start of the parent KET-BD RCT.
• Patient must be receiving guideline-concordant pharmacotherapy without changes in the last month, including a therapeutic dose of a mood stabilizer.

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, 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 5.9).
• Use of prohibited concomitant medications, including other forms of ketamine or esketamine, benzodiazepines, monoamine oxidase inhibitors, stimulants, medical or recreational cannabis of any form.
• Patients in the ketamine-arm of the parent RCT, that did not reasonably tolerate 4 infusions of flexibly-dosed ketamine, as determined by the investigator and/or patient