A double-blind active-placebo crossover design will be used to study a single group of people with TRD to assess the effects of ketamine on brain networks activity versus an active placebo (midazolam). Participants will receive three separate IV infusions of ketamine (0.5mg/kg) followed by three separate IV infusions of an active placebo (midazolam (0.045mg/kg)), or 3 IV infusions of midazolam followed by 3 IV infusions of ketamine. Treatment order will be randomized in a crossover design.~The study will consist of 11 visits including a screening visit, baseline assessments, and two main infusion periods each involving 3 separate IV infusions and a post infusion assessment visit 24 hrs after the third infusion. Ketamine or midazolam will be administered at each of the infusion periods in a crossover design.~Assessment visits will include MRI, EEG and cognitive and clinical assessments.~Up to 50 subjects will be enrolled to ensure that evaluable data is obtained from 45 subjects. The primary comparison will be within-subject between active treatment and placebo.
The main aim of this research is to explore the effects that ketamine has on the functional connectivity of the brain in participants with treatment resistant depression (TRD). This study will investigate the relationship between these changes and response to treatment as measured by clinical scales, as well as examining drug induced changes in reward and emotion based brain activity, structural connectivity, cerebral blood flow, cognition, metabolism and blood markers of brain plasticity.