Double-Blind, Placebo-Controlled Trial of Ketamine Therapy in Treatment-Resistant Depression (TRD)

Inclusion Criteria: * Male or female, 18-70 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 centralized 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 subject's participation in the study. Exclusion Criteria: * 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 Axis I disorder that is the principal focus of treatment and MDD the secondary focus of 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 * Subject is considered at significant risk for suicidal behavior during the course of their participation in the study * Has failed to respond to electroconvulsive therapy (ECT) during the current depressive episode * Has received vagus nerve stimulation (VNS) at any time prior to screening * Has 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 * Current episode of: 1. Hypertension, Stage 1 as defined by a systolic blood pressure ≥140mmHg or diastolic blood pressure ≥90 mmHg at screening on two of three measurements (standing and supine) at least 15 minutes apart. 2. Hypertension, Stage 1 as defined by a systolic blood pressure ≥155 mmHg or diastolic blood pressure ≥99 mmHg at the Baseline Visit (Visit 1) within 1.5 hours prior to randomization on two of three measurements (standing and supine) at least 15 minutes apart. 3. Recent myocardial infarction (within one year) or a history of myocardial infarction. 4. Syncopal event within the past year. 5. Congestive heart failure (CHF) New York Heart Association Criteria \>Stage 2 6. Angina pectoris. 7. Heart rate \<50 or \>105 beats per minute at screening or randomization (Baseline Visit). 8. QTcF (Fridericia-corrected) ≥450 msec at screening or randomization (Baseline Visit). * Current history of hypertension, or on antihypertensives for the purpose of lowering blood pressure, who have either had an increase in antihypertensive dose or increase in the number of antihypertensive drugs used to treat hypertension over the last 2 months. * Chronic lung disease excluding asthma. * 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 any of the following lab abnormalities: 1. Thyroid stimulating hormone outside of the normal limits and clinically significant as determined by the investigator. Free thyroxine (T4) levels may be measured if TSH level is high. Subject will be excluded if T4 level is clinically significant. 2. Patients with diabetes mellitus fulfilling any of the following criteria: i. Unstable diabetes mellitus defined as glycosylated hemoglobin (HbA1c) \>8.5% at screening ii. Admitted to hospital for treatment of diabetes mellitus or diabetes mellitus related illness in the past 12 weeks iii. Not under physician care for diabetes mellitus iv. 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. c. 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 2 months prior to screening. (Subjects on a stable dosage of thyroid replacement medication for at least 2 months or more prior to screening are eligible for enrollment.) * 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 subject at risk or interfere with study results interpretation * History of positive screening urine test for drugs of abuse at screening * Patients with exclusionary laboratory values, or requiring treatment with exclusionary concomitant medications * Patients on exclusionary concomitant psychotropic medications, the half-life of which would not allow sufficient time for patients to have been free of the medication post-taper for five half-lives within the maximum screening period (28 days). * Patient who have participated in studies of ketamine or AZD6765 or other NMDA receptor antagonists for depression and received active treatment. * 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