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,  Healthy Volunteer Major Depressive Disorder Depression All Subjects (Main Study) 1. 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. All subjects must have undergone a screening assessment under either protocol 01-M-0254, "The Evaluation of Patients with Mood and Anxiety Disorders and Healthy Volunteers" or protocol 17-M-0181 ("Recruitment and Characterization of Research Volunteers for NIMH Intramural Studies"). 4. Agree to be hospitalized Additional Patients with MDD (Main Study) 1. At the initial study enrollment, subjects must have fulfilled DSM-IV or DSM-V for Major Depression, single episode or recurrent. Subjects must be experiencing a current major depressive episode of at least 2 weeks duration. 2. At the initial screening and beginning of Phases II and III, subjects must have a baseline score on the MADRS greater than or equal to 20 and YMRS of < 12. 3. Current or past history of lack of response to one adequate antidepressant trial, operationally defined using the Antidepressant Treatment History Form (ATHF); a failed adequate trial of ECT would count as an adequate antidepressant trial. Ketamine Metabolites Substudy Healthy Volunteers 1. 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. All subjects must have undergone a screening assessment under either protocol 01-M-0254, "The Evaluation of Patients with Mood and Anxiety Disorders and Healthy Volunteers") or 17-M-0181 ("Recruitment and Characterization of Research Volunteers for NIMH Intramural Studies"). 4. Agree to be hospitalized  Additional Patients with MDD (Main Study) 1. Current diagnosis of Bipolar Disorder including Bipolar I, Bipolar II, or Bipolar NOS diagnoses. 2. Current psychotic features or a diagnosis of Schizophrenia or any other psychotic disorder as defined in the DSM-IV or DSM-V. 3. Subjects with a history of DSM-IV or DSM-V drug or alcohol dependency or abuse (except for caffeine or nicotine dependence) within the preceding 3 months. In addition, subjects who currently are using drugs (except for caffeine or nicotine) must not have used illicit substances or known drugs of abuse in the 2 weeks prior to screen and must have a negative alcohol and drug urine test (except for prescribed benzodiazepines or stimulants) urine test at screening. 4. Treatment with a reversible MAOI within two weeks prior to Phase II. 5. Subjects who, in the investigator s judgment, pose a current serious suicidal or homicidal risk All Subjects (Main Study) 1. Pregnant or nursing women or women who plan to become pregnant. Women who are able to get pregnant must be willing to use at least one form of effective birth control during the entire period of study participation (or until last clinical labs and rating) and have a negative pregnancy test that was obtained no more than 24 hours prior to MRI and infusion of ketamine. 2. Serious, unstable illnesses including hepatic, renal, gastroenterologic, respiratory, cardiovascular (including ischemic heart disease, coronary artery disease, atherosclerotic ischemic stroke, and atrial fibrillation), endocrinologic, neurologic, immunologic, or hematologic disease. 3. Clinically significant abnormal laboratory tests. 4. Subjects with one or more seizures without a clear and resolved etiology or current use of medication known to lower seizure threshold. History of seizure (regardless of age or etiology), history of epilepsy in self or first-degree relatives, stroke, brain surgery, head injury, or known structural brain lesion will be excluded from the TMS procedures. 5. Treatment with any other concomitant medication 14 days prior to Phase II. An exception of this would be necessary for those who are taking Fluoxetine or Aripiprazole. Prior to Phase II, treatment with Fluoxetine must be discontinued for at least 5 weeks and treatment with Aripiprazole must be discontinued for at least 3 weeks. 6. Any use of opioid medication in the past 3 months 7. Presence of metallic (ferromagnetic) implants (e.g, heart pacemaker, aneurysm clip) (for subjects doing imaging component of the study only). 8. Presence of any medical illness likely to alter brain morphology and/or physiology (e.g., hypertension, diabetes) even if controlled by medications. 9. Subjects who have hearing loss that has been clinically evaluated and diagnosed 10. Participants who are uncomfortable in small closed spaces (have claustrophobia), unable to lie comfortably supine for up to 90 minutes, and would feel uncomfortable in the MRI machine (for subjects doing imaging component of the study only). 11. Positive HIV test 12. Weight > 119 kg 13. A current NIMH employee/staff or their immediate family member 14. [for participants undergoing NPU Threat Test with Auditory Startle] Known history of hearing loss Additional Healthy Volunteers (Main Study) 1. Current or past history of any DSM-IV or DSM-V Axis I disorder based on clinical assessment and confirmed by a structured diagnostic interview (SCID). Ketamine Metabolites Substudy Healthy Volunteers 1. Current or past history of any DSM-IV or DSM-V Axis I disorder based on clinical assessment and confirmed by a structured diagnostic interview (SCID). 2. Current (within the past 3 months) or past alcohol or substance abuse or dependence diagnosis (except for nicotine or caffeine) 3. Pregnant or nursing women or women who plan to become pregnant. Women who are able to get pregnant must be willing to use at least one form of effective birth control during the 4-days of the study participation (or until last clinical labs and rating) and have a negative pregnancy test that was obtained no more than 24 hours prior to infusion of ketamine. 4. Serious, unstable illnesses including hepatic, renal, gastroenterologic, respiratory, cardiovascular (including ischemic heart disease, coronary artery disease, atherosclerotic ischemic stroke, and atrial fibrillation), endocrinologic, neurologic, immunologic, or hematologic disease. 5. Clinically significant abnormal laboratory tests. 6. Subjects with one or more seizures without a clear and resolved etiology or current use of medication known to lower seizure threshold. 7. Treatment with any other concomitant medication. 8. Any use of opioid medication in the past 3 months 9. Positive HIV test 10. Weight > 119 kg 11. A current NIMH employee/staff or their immediate family member 12. Presence of metallic (ferromagnetic) implants (e.g, heart pacemaker, aneurysm clip) (for subjects doing neuroimaging component of the study only). 13. Participants who are uncomfortable in small closed spaces (have claustrophobia), unable to lie comfortably supine for up to 90 minutes, and would feel uncomfortable in the MRI machine (for subjects requiring clinical MRI scans for safety and/or structural MRI scans for MEG coregistration)