Clinical Predictors of Intravenous Ketamine Response in Treatment-Resistant Depression

For patients with treatment-resistant depression (TRD), a single low dose of intravenous (IV) ketamine can help relieve symptoms as quickly as 24 hours later.The main problem with IV ketamine for TRD is that the effect is short-lived, lasting only days to 1 or 2 weeks. Furthermore, IV ketamine is a resource-intensive treatment, and the safety of long-term, repeated use for depression is unknown. To provide this treatment in a safe and cost-effective way, Investigators must allocate it efficiently to those patients who have the greatest need and probability of benefit. Therefore, this project aims to find clinical features (signs, symptoms, and parts of a patient's history) that will help predict which patients are most likely to respond to a single dose of IV ketamine for TRD. This will help guide patient selection and triaging.Investigators will recruit 40 participants with TRD over one year, and randomize them to one of two conditions (ketamine followed by an active placebo 3-weeks later, or vice versa). With clinical data collected through detailed interviews and questionnaires, this study design will let us evaluate how well such factors predict (A) rapid response at 24-hours, and (B) sustained response at 7 and 14 days.

Inclusion Criteria:Able to fluently read in English with or without optical correctionNative English speaker (to ensure appropriateness for neurocognitive paradigms)Ability to understand and comply with the study requirementsThis is determined by the investigatorsProvision of written informed consentDocumented diagnosis of MDD meeting DSM-5 criteria (as confirmed by the Diagnostic Assessment Research Tool), currently in a single or recurrent episode without psychotic featuresFailure 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 enrolmentAND commitment to using an appropriate birth control method of their choice throughout the duration of the study, includingintrauterine deviceoral contraceptivelong-term injectable contraceptivedouble-barrier methodimplantdermal contraceptiontubal ligationAbstinence from grapefruit juice consumption on the day of infusionAbstinence from benzodiazepine use within 24 hours of infusionAdherence to maintaining current antidepressant managementExclusion Criteria:Substance related exclusion criteria:Concomitant use of naltrexone or narcoticsPositive 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 naltrexoneHistory of electroconvulsive therapyComorbid DSM-5 personality disorder with a major impact on mental statusSecondary depressive disordersE.g. secondary to stroke, cancer, or other somatic pathologySubjects who will be starting psychotherapy during the trial period, or have only recently started psychotherapy within 2 months of the trialMedical comorbidity related exclusion criteria:Evidence on history or chart review of any of the following:EpilepsyRenal or hepatic impairmentMyocardial infarct within a year prior to initial randomizationCerebrovascular disease,Viral hepatitis B or CAcquired immunodeficiency syndrome.Abnormal liver function tests.Liver enzymes three times the upper normal limit at screeningCurrent 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