Predictors of Intravenous Ketamine Response in TRD

Study Design: This will be a randomized, double-blinded, midazolam-controlled crossover trial. There is no perfect control agent for studies of subanaesthetic IV ketamine, but midazolam is generally thought to be superior to normal saline since it is not an antidepressant, yet is psychoactive and thus should better preserve blinding. Participants will undergo psychiatric assessment to establish diagnosis and determine suitability. After providing informed consent for participation, participants will wear a GENEActive accelerometer on the non-dominant wrist for the duration of the trial, beginning 21 days prior to the first infusion. Participants will complete a set of rating scales, anhedonia measures and computerized tasks. On Day 0 (infusion day), participants will receive either a single infusion of IV ketamine (KET) (KET; 0.5mg/kg over 40 minutes) or midazolam (MID) (MID; 30μg/kg over 40 minutes) diluted in 0.9% NaCl by an intravenous pump. Investigators will randomize infusion sequences in a 1-to-1 ratio: KET followed by MID (K→M) or vice versa (M→K). Infusions will be administered on Days 0 and 21, separated by a 20-day washout period. This duration balances the need to establish comparable baselines at each crossover phase and the ethical consideration of not allowing depressive symptoms to remain untreated for an unreasonable amount of time. Investigators will obtain objective depression ratings with the Montgomery-Åsberg Depression Rating Scale (MADRS) on Days -1, 1, 7, 14, 20, 22, 28, 35, and 41. Participants will provide weekly self-ratings of depressive symptoms (using the Quick Inventory of Depressive Symptoms 16-item self-rated version; QIDS 16-SR). Weekly symptom monitoring will continue for 20 days following the second infusion. Anhedonia will be measured using both self-reported rating scale measures as well as behavioural task. Patients will provide self-ratings using the Snaith-Hamilton Pleasure Scale - 14 items (SHAPS), the Dimensional Anhedonia Rating Scale - 17 items (DARS), and Positive Valence System Scale - 21 items (PVSS-21). Several aspects of subjective sleep and circadian rhythms will be measured via self-report questionnaires. The Pittsburgh Sleep Quality Index (PSQI) will measure general sleep quality and sleep disturbance, and the Basic Language Morningness Scale (BALM) will be used to measure subjective chronotype (morningness-eveningness) of patients. Both will be completed by participants prior to the first infusion and 14 days after each infusion. Participants will complete the Epworth Sleepiness Scale (ESS) to measure daytime sleepiness symptoms, as well as the Fatigue Scale Severity Scale (FSS) to measure symptoms of fatigue. Both ESS and FSS will be completed the day before and after each infusion, and every 7 days. Study Groups: Participants will receive either (A) 0.5mg/kg of ketamine hydrochloride or (B) 30μg/kg of MID diluted in 0.9 percent Sodium chloride (NaCl) over 40 minutes by an intravenous pump. The KET and MID doses are similar to those used in previous studies, and selected to minimize the possibility of unblinding. Participants must abstain from consuming grapefruit juice or benzodiazepines for 24 hours preceding the infusion since the former is a potent CYP3A4 inhibitor that may reduce the rate of midazolam and ketamine elimination, and the latter reduces the response to ketamine.