Patient description: A 46-year-old Asian woman with MDD complains of persistent feelings of sadness and loss of interest in daily activities. She states that her mood is still depressed most of the days. She complains of loss of energy and feelings of worthlessness nearly every day. She is on anti-depressants for the past 6 months, but the symptoms are still present. She does not drink alcohol or smoke. She used to exercise every day for at least 30 min., but she doesn't have enough energy to do so for the past 3 weeks. She also has some digestive issues recently. She is married and has 4 children. She is menopausal. Her husband was diagnosed with colon cancer a year ago and is undergoing chemotherapy. Her past medical history is unremarkable. Her family history is negative for any psychologic problems. Her HAM-D score is 20.

Clinical trial eligibility criteria: eligible ages (years): 18.0-65.0,  Depression Mood Disorders Major Depresssion General patient 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 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 for substudy 4 (patients with MDD) 1. Age of onset less than 40 years of age. 2. Subjects with MDD must fulfill DSM-IV 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. for healthy control subjects (Substudy 4 only) 1. Age 18-65 years. 2. Written informed consent completed  General patient 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 for substudy 2 (patients with MDD) 1. Previous treatment with ketamine or hypersensitivity to amantadine. Additional 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 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