Male or female, 18‐65 years old
Able to read, understand, and provide written, dated informed consent prior to screening
Diagnosed with Major Depressive Disorder (MDD), single or recurrent, and currently experiencing a Major Depressive Episode (MDE) of at least eight weeks in duration, prior to screening
Has a history of TRD during the current MDE
Meet the threshold on the total MADRS score of greater than or equal to 20 at both screening and baseline visits (Day ‐7/‐28 and Day 0), as confirmed by the remote centralised MGH CTNI rater between the screen visit and the baseline visit
In good general health
For female participants, status of non‐childbearing potential or use of an acceptable form of birth control
Body mass index between 18‐35 kg/m2
Concurrent psychotherapy will be allowed if the type and frequency of the therapy has been stable for at least three months prior to screening and is expected to remain stable during participation in the study
Concurrent hypnotic therapy will be allowed if the therapy has been stable for at least 4 weeks prior to screening and if it is expected to remain stable during the course of the participant's participation in the study
Female of childbearing potential who is not willing to use one of the specified forms of birth control during the study
Female that is pregnant or breastfeeding
Female with a positive pregnancy test at screening or baseline
History during the current MDE of failure to achieve a satisfactory response to >7 treatment courses of a therapeutic dose of an antidepressant therapy of at least 8 weeks duration during the current episode
Total MADRS score of < 20 at the screen or baseline visits, or as assessed by the remote, independent MGH CTNI rater and reported to the site
Current diagnosis of a Substance Use Disorder (Abuse or Dependence) with the exception of nicotine dependence, at screening or within 6 months prior to screening
Current diagnosis of Axis I disorders other than dysthymic disorder, generalised anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, or specific phobia (unless one of these is comorbid and clinically unstable, and/or the focus of the participant's treatment for the past 6 months or more)
History of bipolar disorder, schizophrenia or schizoaffective disorders, or any history of psychotic symptoms in the current or previous depressive episodes
History of eating disorders within five years of screening
Any Axis I or Axis II Disorder, which at screening is clinically predominant to their MDD or has been predominant at any time within 6 months prior to screening
Particpant is considered at significant risk for suicidal behavior during the course of their participation in the study
Has failed to respond to electroconvulsive therapy during the current depressive episode
Has received vagus nerve stimulation (VNS) at any time prior to screening
Dementia, delirium, amnestic, or any other cognitive disorder
Has a clinically significant abnormality on the screening physical examination
Participation in any clinical trial with an investigational drug or device within the past month or concurrent to study participation
Known history or current episode of: hypertension, Recent myocardial infarction (within one year) or a history of myocardial infarction, Syncopal event within the past year, Congestive heart failure, Angina pectoris, heart rate < 50 or > 105 beats per minute at screening or randomisation, or QTcF greater than or equal to 450 msec at screening or randomisation
Chronic lung disease
Lifetime history of surgical procedures involving the brain or meninges, encephalitis, meningitis, degenerative central nervous system disorder, epilepsy, mental retardation, or any other disease/procedure/accident/intervention associated with significant injury to or malfunction of the central nervous system, or a history of significant head trauma within the past 2 years
Presents with a history of Thyroid stimulating hormone outside of the normal limits and clinically significant as determined by the investigator
Patients with diabetes mellitus fulfilling any of the following criteria: unstable diabetes mellitus defined as glycosylated haemoglobin (HbA1c) > 8.5% at screening; admitted to hospital for treatment of diabetes mellitus or diabetes mellitus related illness in the past 12 weeks; not under physician care for diabetes mellitus; has not been on the same dose of oral hypoglycaemic drug(s) and/or diet for the 4 weeks prior to screening (for thiazolidinediones (glitazones) this period should not be less than 8 weeks); any other clinically significant abnormal laboratory result (as determined after evaluation by study investigator and MGH CTNI medical monitor) at the time of the screening exam
History of hypothyroidism and has been on a stable dosage of thyroid replacement medication for less than 6 months prior to screening. (Particpants on a stable dosage of thyroid replacement medication for at least 6 months or more prior to screening are eligible for enrolment)
History of hyperthyroidism which was treated (medically or surgically) less than six months prior to screening
Any current or past history of any physical condition which in the investigator's opinion might put the participant at risk or interfere with study results interpretation
History of positive screening urine test for drugs of abuse
Patients with exclusionary laboratory values, or requiring treatment with exclusionary concomitant medications
Patients who have participated in studies of ketamine or AZD6765 for depression
Patients with narrow angle glaucoma
Patients with a lifetime history of PCP/Ketamine drug use
Liver function tests higher than 2.5 times upper limit of normal
