Ketamine in the Treatment of Depression

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.