Male or female patients, 21‐65 years of age
Female individuals who are not of childbearing potential (i.e. surgically sterile, post‐menopausal for at least one year) or using a medically accepted reliable means of contraception. Women using oral contraceptive medication for birth control must also be using a barrier contraceptive. Women of childbearing potential must also have a negative serum B‐HCG at screening and at pre‐infusion
Participants must fulfil DSM‐IV criteria for Major Depression without psychotic features, based on clinical assessment by a study psychiatrist and confirmed by a structured diagnostic interview, the Structured Clinical Interview for DSM‐IV TR Axis I Disorders, Patient Edition (SCID‐P)
Participants must have a history of at least one previous episode of depression prior to the current episode (recurrent MDD) or have chronic MDD (of at least two years' duration)
Participants have not responded to two or more adequate trials of an antidepressant as determined by Antidepressant Treatment History Form (ATHF) criteria (score >= 3)
Current Major Depressive Episode of at least moderate severity, defined as a QIDS‐SR score ≥ 14 and a CGI‐S score of ≥ 4;Current major depressive episode is of at least 4 weeks duration
Each participant must have a level of understanding sufficient to agree to all tests and examinations required by the protocol and must sign an informed consent document
Each participant must be able to identify a family member, physician, or friend who will participate in the Treatment Contract
Lifetime history of psychotic features, diagnosis of schizophrenia or any other psychotic disorder, or diagnosis of bipolar disorder
Lifetime histories of autism, mental retardation, pervasive developmental disorders, or Tourette's syndrome
Current diagnosis of OCD or eating disorder (bulimia nervosa or anorexia nervosa)
Particpants with DSM‐IV drug or alcohol abuse/dependence within the preceding 2 years
Patients with schizotypal or antisocial personality disorder, or any clinically significant axis II disorder that would, in the investigator's judgment, preclude safe study participation
Patients judged clinically to be at serious and imminent suicidal or homicidal risk
Women who are either pregnant or nursing
Serious, unstable medical illnesses including hepatic, renal impairment, gastroenterologic (including gastro‐oesophageal reflux disease), respiratory (including obstructive sleep apnoea, or history of difficulty with airway management during previous aesthetics), cardiovascular (including Ischaemic heart disease and uncontrolled hypertension), endocrinologic, neurologic (including history of severe head injury), immunologic, or hematologic disease
Clinically significant abnormal findings of laboratory parameters, physical examination, or ECG
Patients who have a positive urine toxicology for illicit substances at screening and within 24 hours of the infusion
Patients with one or more seizures without a clear and resolved etiology
Treatment with an irreversible MAOI within 2 weeks prior to randomisation or fluoxetine within 4 weeks prior to randomisation
Treatment with other antidepressants within one week of randomisation
Previous recreational use of PCP or ketamine
Hypertension (systolic BP > 160 mm Hg or diastolic BP > 90 mm Hg) not controlled by diuretic or beta‐blocker therapy alone or in combination
A blood pressure reading over 160/90 or two separate readings over 140/90 at screening or baseline visits
Renal impairment, as reflected by a BUN > 20 mg/dL and/or creatinine clearance of > 1.3 mg/dL
Thyroid impairment, as reflected by a TSH > 4.2 mu/L
Cardiac disease, as reflected by an EKG that is abnormal and of concern for cardiac disease
Any anticipated change in medications that could affect fluid or salt balance, including the following antihypertensive agents: ACE inhibitor, loop diuretics, calcium channel blockers, thiazide diuretics, angiotensin II receptor blockers
