Depressed patients will be offered experimental treatment with a new, potentially fast-acting antidepressant called ketamine while being scanned by magnetic resonance imaging (MRI) to measure the chemical effect of the drug. Ketamine will be given in a dose of 0.0 (placebo), 0.1, 0.2, 0.3, 0.4, or 0.5 mg/kg. If a patient does not respond to ketamine after the first infusion, it may be because s/he received ketamine placebo or the dose of ketamine was too low. In that case, an optional second scan and infusion of active ketamine (0.5 mg/kg) will be offered. This second scan will occur no later than weeks after the first scan/infusion (as scheduling permits). There is no guarantee that the patient will respond to the second ketamine infusion. Patients enrolled in the study are eligible for up to 6 months treatment with their study psychiatrist after the ketamine infusion(s).

Healthy Volunteers: Healthy controls will receive an infusion of ketamine at a single dose (0.5 mg/kg). Volunteers will only receive one MRI scan and infusion.

Major depressive disorder (MDD) is a common illness, affecting over 14 million American adults each year. MDD is a leading cause of disability worldwide, and is responsible for huge workplace and healthcare costs. The several week delay between onset of treatment and improvement in MDD symptoms with currently available treatments further increases the burden of the disorder. Shortening this delay is a major unmet challenge in the treatment of MDD. Studies report that a single intravenous low dose of a drug called ketamine can bring about substantial improvement in depression in hours, even in patients that have not improved with other antidepressant treatments. Certain aspects of ketamine's drug action are fairly well understood, but the question remains of how these properties relate to antidepressant effect. The investigator's preliminary data support the rapid antidepressant benefit from ketamine. The investigators have used a scanner to measure the effects of ketamine on two major brain chemical transmitters and found that it causes a significant increase (more than 60%) in glutamate (Glu) and gamma aminobutyric acid (GABA) levels in the front of the brain. The investigators hypothesize that this increase in Glu and GABA levels, is responsible for the antidepressant action of the medication. Knowing how ketamine works could help to develop better medications that can be used orally and used for maintenance of the improvement seen with ketamine. The objective of the proposed dose finding study is to examine the relationship between the ketamine-induced improvement of MDD and the Glu and GABA responses to ketamine and to compare the Glu and GABA responses to ketamine in MDD and healthy subjects to better understand the pathophysiology of MDD. To achieve these aims this the investigators propose a randomized, placebo-controlled, double blind study with several different doses of ketamine. The investigators will conduct MRI scans to measure Glu and GABA before and during the ketamine treatment.

Patient Inclusion Criteria:

• Patient suffering from a major depressive episode (MDE) as part of an major depressive disorder (MDD). Patients may be psychiatric medication-free or, if on psychiatric medications, not responding adequately.
• Patient scores at least 22 on the Montgomery-Åsberg Depression Rating Scale (MADRS)
• Age range 18-65 years
• Patient is off all psychotropic and other types of drugs likely to interact with glutamate for at least 14 days before starting the study with an exception of chloral hydrate or short acting benzodiazepines for distressing anxiety or insomnia
• Subject is likely to be able to tolerate a medication washout
• Female subjects of child-bearing potential must be using an acceptable method of birth control throughout the study.
• Must be enrolled in New York Psychiatric Institute (NYSPI) study #4815

Patient Exclusion Criteria:

• Lifetime history of schizophrenia,schizoaffective illness, Bipolar Disorder, or psychosis.
• First-degree relative with schizophrenia, schizoaffective disorder, or bipolar disorder if the subject is less than 33 years old
• Significant uncontrolled physical illness particularly if it may affect the brain or glutamatergic system including blood dyscrasias lymphomas, hypersplenism, endocrinopathies, renal failure or severe chronic obstructive lung disease, autonomic neuropathies and active malignancy.
• Subjects will be excluded for baseline hypertension (BP>140/90) or significant history of cardiovascular illness
• Significant ECG abnormalities
• Lacks capacity to consent
• Patients who are actively suicidal as defined by a suicidal ideation score of 4 or 5 or suicidal behavior score > 0 on the Columbia Suicide Severity Rating Scale (C-SSRS) at in-person screening interview will be excluded from participating as outpatients and may only participate as inpatients if the independent inpatient treatment team agrees with the plan to enroll the patient.
• Electroconvulsive therapy (ECT) within the last 3 months for this episode
• Pregnancy or plans to conceive during the course of study participation
• Heart pacemaker, body implant or other metal in body
• A neurological disease or prior head trauma with evidence of cognitive impairment.
• Patients who are responding satisfactorily to antidepressant medications because they will not be washed-out for purposes of this study
• Claustrophobia sufficient to preclude MRI
• Irremovable medicinal patch
• Prior ineffective trial of, or adverse effect to, ketamine
• Subjects judged unlikely to be able to tolerate a psychoactive medication washout of 14 days
• Inadequate understanding of English
• IV drug use or history of ketamine use as a recreational drug ≥ 2 times or an adverse reaction to ketamine

Control Inclusion Criteria:

• Age 18-65
• Physically healthy
• Absence of an Axis I diagnosis (specific phobia acceptable). Absence of Borderline Personality Disorder and Antisocial Personality Disorder.
• Not on any medications known to affect glutamatergic functioning
• Female subjects of child-bearing potential must be using an acceptable method of birth control throughout the study.
• Must be enrolled in NYSPI protocol #4815

Control Exclusion Criteria:

• First degree relative with MDD; first degree relative with Schizophrenia, Schizoaffective Disorder, Bipolar disorder, if the subject is less than 33 years old, and therefore still at significant risk
• Significant active physical illness particularly if it may affect the brain or glutamatergic system including blood dyscrasias lymphomas, hypersplenism, endocrinopathies, renal failure or severe chronic obstructive lung disease,autonomic neuropathies and active malignancy.
• Subjects will be excluded for baseline hypertension (BP>140/90) or significant history of cardiovascular illness.
• Significant ECG abnormalities
• Pregnancy or plans to conceive during the course of study participation
• Heart pacemaker, body implant or other metal in body
• A neurological disease or prior head trauma with evidence of cognitive impairment.
• Claustrophobia sufficient to preclude MRI
• Irremovable Medicinal patch
• Inadequate understanding of English
• Lifetime history of substance dependence,current or past substance abuse will be excluded; IV drug use or history of ketamine use as a recreational drug ≥ 2 times or an adverse reaction to ketamine will be excluded.