* INCLUSION CRITERIA:
Patients: In order to be eligible for this study, MDD participants must meet all of the following criteria:
* 18 to 70 years of age.
* Female participants of childbearing potential must be using a medically acceptable means of contraception.
* Be in good general health as evidenced by medical history and physical examination. Stable medical conditions as assessed by their primary care provider (PCP) and/or in-house clinician are permitted to join the study.
* Each participant must have a level of understanding sufficient to agree to all required tests and examinations and sign an informed consent document.
* All participants must have undergone a screening assessment under protocol 01-M-0254, The Evaluation of Patients with Mood and Anxiety Disorders and Healthy Participants .
* Participants must fulfill DSM-5 criteria for major depression (MDD) without psychotic features, as based on clinical assessment and structured diagnostic interview (SCID-P).
* Participants must have an initial score on the MADRS \>= 18 or HAM-D \>= 15 within one week of study entry.
* Participants must be experiencing an MDE lasting at least four weeks.
* All MDD participants must have a PCP or psychiatrist in the community.
* Participants must have their radial artery pulse checked for the presence of adequate ulnar collateral flow and the absence of any metal or foreign objects in both wrists.
* Participants must agree to adhere to the lifestyle considerations.
Healthy Controls: In order to be eligible to participate in this study, control subjects must meet all of the following criteria:
* Aged 18 to 70 years old.
* Female participants of childbearing potential must be using a medically acceptable means of contraception.
* Able to provide informed consent.
* Be in good general health, as evidenced by medical history and physical examination, and have no cognitive impairment.
* Be enrolled in 01M0254, The Evaluation of Participants with Mood and Anxiety Disorders and Healthy Volunteers or 17M0181, Recruitment and Characterization of Healthy Research Volunteers for NIMH Intramural Studies .
* Have their radial artery pulse checked for the presence of adequate ulnar collateral flow and the absence of any metal or foreign objects in both wrists.
* Agree to adhere to the lifestyle considerations.
EXCLUSION CRITERIA:
Participants with MDD who meet any of the following criteria will be excluded from participation in this study:
* Clinically significant abnormalities on EKG or laboratory testing. This includes CBC and acute care panel (Na, K, Cl, CO2, creatinine, glucose, urea nitrogen). Any lab value that is two-times the upper limit or even lower values in the investigator s judgment. Creatinine level \>1.3 mg/dL.
* Participants must be free of all prohibited medications for at least two weeks (5 weeks for aripiprazole, brexpiprazole, fluoxetine) prior to screen visit. These medications include antidepressants, antipsychotics, anxiolytics, psychotropic drugs not otherwise specified
(including herbal products), and sedatives/hypnotics.
* Current psychotic features, a diagnosis of schizophrenia or any other psychotic disorder as defined in the DSM-5.
* Participants with a history of psychiatric inpatient hospitalization within the past year.
* Participants with a history of DSM-5 substance use disorder (except for caffeine or nicotine dependence) within the preceding three months. In addition, participants must not have substance use disorder or alcohol use disorder. However, alcohol or cannabis use by themselves are not exclusion criteria, unless that use impairs function of daily life.
* Participants who, in the investigator s judgment, pose a current serious suicidal or homicidal risk.
* Participants with suicidal ideation within the past 6 months.
* Participants with suicidal behavior within the past 12 months.
* Participants who have a history of aggressive behavior towards others.
* Participants who have an unstable medical condition that, in the opinion of the investigators, makes participation unsafe (e.g., an active infection or untreated malignancy).
* HIV infection.
* Pregnancy.
* Are unable to travel to the NIH.
* Have recent exposure to radiation related to research (e.g., PET from other research) that, when combined with this study, would be above the allowable limits.
* Have an inability to lie flat and/or lie still on the camera bed for at least two hours, including claustrophobia, overweight greater than the maximum for the scanner, and uncontrollable behavioral symptoms, which will be screened by an interview with the participant during the screening visit.
* Are unable to have an MRI scan (e.g., because of pacemakers or other implanted electrical devices, brain stimulators, dental implants, aneurysm clips (metal clips on the wall of a large artery), metallic prostheses (including metal pins and rods, heart valves, and cochlear implants), permanent eyeliner, implanted delivery pumps, shrapnel fragments, or metal fragments in the eye.
* Be NIMH staff or an NIH employee who is a subordinate/relative/co-worker of the investigators.
Healthy controls who meet any of the following criteria will be excluded from participation in this study:
* Clinically significant abnormalities on EKG or laboratory testing. This includes CBC and acute care panel (Na, K, Cl, CO2, creatinine, glucose, urea nitrogen).
* Participants must be free of all prohibited medications or at least two weeks (5 weeks for aripiprazole, brexpiprazole, fluoxetine) prior to screen visit. These medications include antidepressants, antipsychotics, anxiolytics, psychotropic drugs not otherwise specified (including herbal products), and sedatives/hypnotics.
* Participants with a history of DSM-5 substance use disorder (except for caffeine or nicotine dependence) within the preceding three months. In addition, participants must not have substance use disorder or alcohol use disorder. However, alcohol or cannabis use by themselves are not exclusion criteria, unless that use impairs function of daily life.
* Participants who have a history of major depressive disorder.
* Participants who have an unstable medical condition that, in the opinion of the investigators, makes participation unsafe (e.g., an active infection or untreated malignancy).
* HIV infection.
* Pregnancy.
* Are unable to travel to the NIH.
* Have recent exposure to radiation related to research (e.g., PET from other research) that, when combined with this study, would be above the allowable limits.
* Have an inability to lie flat and/or lie still on the camera bed for at least two hours, including claustrophobia, overweight greater than the maximum for the scanner, and uncontrollable behavioral symptoms, which will be screened by an interview with the participant during the screening visit.
* Are unable to have an MRI scan (e.g., because of pacemakers or other implanted electrical devices, brain stimulators, dental implants, aneurysm clips (metal clips on the wall of a large artery), metallic prostheses (including metal pins and rods, heart valves, and cochlear implants), permanent eyeliner, implanted delivery pumps, shrapnel fragments, or metal fragments in the eye.
* Use of cytochrome P450 enzyme inducers (e.g. rifampin, phenobarbital, carbamazepine, phenytoin).
* Be NIMH staff or an NIH employee who is a subordinate/relative/co-worker of the investigator.
