Rapid Antidepressant Effects of Ketamine in Major Depression

* INCLUSION CRITERIA: General patient inclusion criteria 1. Male or female subjects, 18 to 65 years of age. 2. Each subject must have a level of understanding sufficient to agree to all required tests and examinations and sign an informed consent document. 3. Subjects must fulfill DSM-IV criteria for Major Depressive Disorder (MDD) without psychotic features, based on clinical assessment and confirmed by a structured diagnostic interview, SCID-P. 4. Subjects must have an initial score of at least 20 on the MADRS at screen and at baseline of study phase I. 5. Subjects must have failed to respond in the past to an adequate dose and duration of at least one antidepressant (SSRI, bupropion, or venlafaxine) during a depressive episode 6. Current depressive episode of at least 4 weeks duration. Additional inclusion criteria for substudy 4 (patients with MDD) 1. Age of onset less than 40 years of age. 2. Subjects with MDD must fulfill DSM-IV criteria for Major Depression single episode or recurrent without psychotic features based on clinical assessment and confirmed by a structured diagnostic interview (SCID-P). 3. A failed adequate trial of ECT would count as an adequate antidepressant trial. 4. In women of childbearing age, a negative pregnancy test within 24 hours of MRI. Inclusion criteria for healthy control subjects (Substudy 4 only) 1. Age 18-65 years. 2. Written informed consent completed. EXCLUSION CRITERIA: General patient exclusion criteria 1. Current or past diagnosis of Schizophrenia or any other psychotic disorder as defined in the DSM-IV. 2. Subjects with a history of DSM-IV drug or alcohol dependency or abuse (except for nicotine or caffeine) within the preceding 3 months. 3. Female subjects who are either pregnant or nursing. 4. Serious, unstable illnesses including hepatic, renal, gastroenterologic, respiratory, cardiovascular (including ischemic heart disease), endocrinologic, neurologic, immunologic, or hematologic disease. 5. Subjects with uncorrected hypothyroidism or hyperthyroidism. 6. Subjects with one or more seizures without a clear and resolved etiology. 7. Treatment with a reversible MAOI within 4 weeks prior to study phase I. 8. Treatment with fluoxetine within 5 weeks prior to study phase I. 9. Treatment with any other concomitant medication not allowed (Appendix A for Substudy 2; Appendix G for Substudy 4) 14 days prior to study phase I. 10. No structured psychotherapy will be permitted during the study. 11. Current NIMH employee/staff or their immediate family member. Additional Exclusion Criteria for substudy 2 (patients with MDD) 1\. Previous treatment with ketamine or hypersensitivity to amantadine. Additional Exclusion Criteria for Substudy 4 (patients with MDD) 1. Subjects who currently are using drugs (except for caffeine or nicotine), must not have used illicit substances in the 2 weeks prior to screen and must have a negative alcohol and drug urine test (except for prescribed benzodiazepines) urine test at screening. 2. Presence of any medical illness likely to alter brain morphology and/or physiology (e.g., hypertension, diabetes) even if controlled by medications. 3. Clinically significant abnormal laboratory tests. 4. For imaging procedures, Presence of metallic (ferromagnetic) implants (e.g, heart pacemaker, aneurysm clip). 5. Subjects who, in the investigator's judgment, pose a current serious suicidal or homicidal risk, or who have a MADRS item 10 score of \>4. Exclusion Criteria for healthy control subjects (Substudy 4 only) 1. Current or past Axis I diagnosis 2. Presence of metallic (ferromagnetic) implants (e.g., heart pacemaker, aneurysm clips). 3. Presence of medical illness likely to alter brain morphology and/or physiology (e.g., hypertension, diabetes) even if controlled by medications. 4. Treatment with any of the exclusionary medications detailed in Appendix G 14 days prior to Phase 1 of the Substudy 4. 5. Current or past alcohol or substance abuse or dependence diagnosis (except for nicotine or caffeine). 6. Presence of psychiatric disorders in first-degree relatives. 7. Female subjects who are either pregnant or nursing. 7.8.Current NIMH employee/staff or their immediate family member.