Clinical Predictors of Intravenous Ketamine Response in Treatment-Resistant Depression

Inclusion Criteria: Able to fluently read in English with or without optical correction Native English speaker (to ensure appropriateness for neurocognitive paradigms) Ability to understand and comply with the study requirements This is determined by the investigators Provision of written informed consent Documented diagnosis of MDD meeting DSM-5 criteria (as confirmed by the Diagnostic Assessment Research Tool), currently in a single or recurrent episode without psychotic features Failure of at least two antidepressant medications from different pharmacological classes, as well as at least one augmentation agent, each of which must have been given at adequate doses for at least 6 weeks during the present episode (recorded using the Antidepressant Treatment History Form - Short Form). Augmentation strategies include those listed in the 2016 Canadian Network for Mood and Anxiety Treatments (CANMAT) depression guidelines, including a 12-week course of cognitive behavioural therapy or interpersonal therapy. MADRS score of ≥25 at initial assessment and randomization, and no more than 20% improvement between those visits. For premenopausal females who are currently sexually active with male partners: Negative urine pregnancy test at enrolment AND commitment to using an appropriate birth control method of their choice throughout the duration of the study, including intrauterine device oral contraceptive long-term injectable contraceptive double-barrier method implant dermal contraception tubal ligation Abstinence from grapefruit juice consumption on the day of infusion Abstinence from benzodiazepine use within 24 hours of infusion Adherence to maintaining current antidepressant management Exclusion Criteria: Substance related exclusion criteria: Concomitant use of naltrexone or narcotics Positive urine drug screen or history of DSM-5 substance use disorder (except caffeine or nicotine) Psychiatric exclusion criteria: Previous ketamine use (therapeutic or recreational) Concurrent use of naltrexone History of electroconvulsive therapy Comorbid DSM-5 personality disorder with a major impact on mental status Secondary depressive disorders E.g. secondary to stroke, cancer, or other somatic pathology Subjects who will be starting psychotherapy during the trial period, or have only recently started psychotherapy within 2 months of the trial Medical comorbidity related exclusion criteria: Evidence on history or chart review of any of the following: Epilepsy Renal or hepatic impairment Myocardial infarct within a year prior to initial randomization Cerebrovascular disease, Viral hepatitis B or C Acquired immunodeficiency syndrome. Abnormal liver function tests. Liver enzymes three times the upper normal limit at screening Current uncorrected thyroid pathology or recent correction within 30 days (correction of thyroid function for longer than 1 month is admissible). Any unstable somatic pathology or clinically significant investigational abnormality (biochemical, ECG) that investigators believe would be negatively impacted by study procedures or that would negatively impact study procedures