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.

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.

Inclusion Criteria:

• Be male or female, aged between 18 and 55 years of age inclusive.
• Have a diagnosis of MDD, Bipolar 1 or Bipolar 2 depression and fulfil criteria for TRD depression. TRD patients are defined as having inadequately responded to at least two courses of antidepressants, given in a therapeutic dose and duration (Fekadu et al., 2018).
• Have moderate to severe depression symptoms as demonstrated by a MADRS score greater than 20.
• Be physically healthy, defined as having no clinically relevant abnormalities identified by a detailed medical history and full examination including blood pressure and pulse rate measurement, 12-lead ECG and clinical laboratory tests
• Have a good command of the English language.
• Have no or very little knowledge of the Chinese language.
• Provide a personally signed and dated informed consent document indicating that the participant has been informed of and agrees to comply with all aspects of the study.
• Be willing and able to comply with scheduled visits, dosing plan, laboratory trials and any other necessary procedures.

Exclusion Criteria:

• Have a current diagnosed psychiatric disorder, except MDD, Bipolar 1 and Bipolar 2 disorders and comorbid generalised anxiety disorder (GAD), social anxiety and/or social phobia.
• Have a current or previously diagnosed psychotic disorder: Schizophrenia, Schizoaffective Disorder, Delusional disorder, Schizophreniform disorder, Schizotypal (personality) disorder, or Brief psychotic disorder.
• Have previously failed Ketamine as an antidepressant treatment given at a therapeutic dose.
• Have previously experienced an adverse response to ketamine and/or midazolam.
• Have scored 70 or lower in the WASI at the screening visit.
• Have one or more immediate family members with a current or previously diagnosed psychotic disorder.
• Have a medically significant condition which renders them unsuitable for the study (e.g., diabetes, severe cardiovascular disease, severe respiratory disease (e.g. COPD), hepatic or renal failure etc.).
• Be pregnant or breastfeeding, if female.
• Have any MR contra-indications (e.g., metal implants, pacemakers, claustrophobia etc.) which would render them unsuitable for the study.
• Currently consume alcohol in excess of 28 units a week or more than 6 cups of caffeinated drinks per day.
• Smoke more than 5 cigarette per day
• Have taken illicit drugs 7 days prior to admission or current use of drugs of abuse including amphetamines, MDMA, cannabis and opioids Have taken any other medication during the course of the study that has not been discussed. This should be documented by the investigators. (As an exception, 1g paracetamol/24 hours may be taken up to 24 hours prior to any visit).
• Have consumed alcohol or caffeine within 12h and/or nicotine 4h hours prior to the screening visit, study day 1, 2 and 3 and each infusion visit until discharged at the end of each of those visits.
• Have consumed grapefruit juice or Seville oranges-containing products 24 hours prior to admission.
• Have used any prescribed medication in the 3 weeks prior to enrolment or non-prescription medication (other than paracetamol) in the previous 7 days, excluding medication prescribed for bipolar I and II and MDD.
• Have a significant history of drugs of abuse (including benzodiazepines) or positive drugs of abuse test.
• Have received another new chemical entity in the 1 month before dosing or taken part in another research study using drugs within 1 month before dosing.
• Have an acute illness within 2 weeks before the start of study.
• Have any clinically significant abnormalities in clinical chemistry (including liver function tests), haematology or urinalysis results.
• Have self-reported HIV, hepatitis B or hepatitis C
• Have a definite or suspected personal or family history of intolerance or hypersensitivity to drugs and/or their excipients, judged to be clinically relevant by the investigator.
• Have a history or presence of gastrointestinal, hepatic or renal disease or other condition known to interfere with absorption, distribution, metabolism or excretion of drugs.
• Have uncontrolled hypertension, or supine systolic BP outside of the range of 90 to 140 mmHg and a supine diastolic BP outside the range of 40 to 90 mmHg, after a period of acclimatisation.
• Have a decrease in systolic BP of > 25 mmHg or a decrease in diastolic BP of > 15 mmHg when going from resting in bed to standing position, with or without symptoms such as dizziness or light- headedness. (For determination of orthostatic hypotension, lying and standing BP will be recorded after the subject has rested for 10 minutes and has had resting BP recorded followed by measurements 5 minutes after standing)
• Have had treatment in the previous 3 months with any drug known to have a well-defined potential for hepatotoxicity (e.g., halothane).
• Have a risk of suicide according to the investigator's clinical judgment (eg, per C-SSRS positive answer on question 5 within 6 months or has made a suicide attempt within 6 months prior to screening visit).
• Have started a course of hormone replacement therapy within 8 weeks prior to the screening visit.
• Be a subject who, in the opinion of the investigator, should not participate in the study for reasons of safety.
• Have a score of more than 20 on the YMRS at study day 1 and at each subsequent assessment
• Be a subject who, in the opinion of the investigator, has a significant history of mixed episodes.