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): 7.0-60.0,  Mood Disorder for children with DMDD, subthreshold DMDD: 1.1.1 Ages 7-17 at the time of recruitment; will be followed in the longitudinal component of the study until age 25. 1.1.2 Abnormal mood (specifically, anger, sadness, and/or irritability), present at least half of the day most days (or at least half the day at least one day per week for subthreshold), and of sufficient severity to be noticeable by people in the child s environment (e.g. parents, teachers, peers). 1.1.3 Compared to his/her peers, the child exhibits markedly increased reactivity to negative emotional stimuli that is manifest verbally or behaviorally. For example, the child responds to frustration with extended temper tantrums (inappropriate for age and/or precipitating event), verbal rages, and/or aggression toward people or property. Such events occur, on average, at least three times a week. For subthreshold DMDD such tantrums occur on average at least once per month. 1.1.4 The symptoms in # 1.1.2, and 1.1.3 above are currently present and have been present for at least 12 months without any symptom-free periods exceeding three months. 1.1.5 The onset of symptoms must be prior to age 10 years. 1.1.6 For DMDD the symptoms are severe in at least in one setting (e.g. violent outbursts, assaultiveness at home, school, or with peers) and at least mild (distractibility, intrusiveness) in a second setting. For subthreshold DMDD, there must be evidence of impairment causing distress to the child or to those around him/her in at least one setting. 2. Parents of children and adolescents with DMDD or subthreshold DMDD enrolled in 02-M-0021 2.1.1. Are capable of performing behavioral tasks and/or scanning. 2.1.2. Speaks English 3. Healthy Volunteer (Control) Children 3.1.1. Control subjects will be group matched to the patients. 3.1.2. Have an identified primary care physician. 3.1.3. Speaks English 4. Healthy Volunteer Adults 4.1.1 Control subjects will be group matched to the patients. 4.1.2. They will have normal physical and neurological examinations by history or checklist 4.1.3. Have an identified primary care physician. 4.1.4 Speaks English 5. Children with Major Depressive Disorder (MDD) (all must be met): 5.1.1 Ages 11-17 at the time of recruitment; will be followed in the longitudinal component of the study until age 25. 5.1.2. DSM-IV or DSM-5 Major Depressive Disorder 5.1.2.1 Five or more of the following symptoms have been present during the same 2-week period and represent a change from previous functioning; at one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure. 5.1.2.1.1 Depressed mood most of the day, nearly every day, as indicated by either subjective report (e.g., feeling sad, blue, down in the dumps, or empty) or observation made by others (e.g., appears tearful or about to cry). (In children and adolescents, this may present as an irritable or cranky, rather than sad, mood.) 5.1.2.1.2 Markedly diminished interest or pleasure in all, or almost all, activities every day, such as no interest in hobbies, sports, or other things the person used to enjoy doing. 5.1.2.1.3. Significant weight loss when not dieting or weight gain (e.g., a change of more than 5 percent of body weight in a month), or decrease or increase in appetite nearly every day. 5.1.2.1.4. Insomnia (inability to get to sleep or difficulty staying asleep) or hypersomnia (sleeping too much) nearly every day 5.1.2.1.5. Psychomotor agitation (e.g., restlessness, inability to sit still, pacing, pulling at clothes or clothes) or retardation (e.g., slowed speech, movements, quiet talking) nearly every day 5.1.2.1.6. Fatigue, tiredness, or loss of energy nearly every day (e.g., even the smallest tasks, like dressing or washing, seem difficult to do and take longer than usual). 5.1.2.1.7. Feelings of worthlessness or excessive or inappropriate guilt nearly every day (e.g., ruminating over minor past failings). 5.1.2.1.8. Diminished ability to think or concentrate, or indecisiveness, nearly every day (e.g. appears easily distracted, complains of memory difficulties). 5.1.2.1.9. Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideas without a specific plan, or a suicide attempt or a specific plan for committing suicide 5.1.2.1.10 Symptoms cause clinically significant distress or impairment in social, occupational/academic, or other important areas of functioning. 5.1.2.1.11. The episode is not attributable to the physiological effects of a substance or to another medical condition. 5.1.3. Youth with MDD who are continuing in research as adults must also be receiving psychiatric care for their MDD, if it is ongoing 6. Children with Attention-Deficit/Hyperactivity Disorder (ADHD) 6.1.1. Age 8-17 6.1.2. Currently meets DSM-IV or DSM-5 for ADHD 6.1.3. Subjects with other primary psychiatric disorders including anxiety disorders, dysthymic disorder, past major depression, oppositional defiant disorder, tic disorders, and the learning, communication, and elimination disorders may be accepted 6.1.4. Have an identified primary care physician. 6.1.5. Speaks English  for those with DMDD: 1.3.1 The individual exhibits any of these cardinal bipolar symptoms: 1.3.1.1 Elevated or expansive mood 1.3.1.2 Grandiosity or inflated self-esteem 1.3.1.3 Decreased need for sleep 1.3.1.4 Increase in goal-directed activity (this can result in the excessive involvement in pleasurable activities that have a high potential for painful consequences) 1.3.1.5. Has BD symptoms in distinct periods lasting more than 1 day. 1.3.2. Meets for schizophrenia, schizophreniform disorder, schizoaffective illness, PDD, or PTSD. 1.3.3. IQ< 70 1.3.4. The symptoms are due to the direct physiological effects of a drug of abuse, or to a general medical or neurological condition. 1.3.5. Currently pregnant or lactating 1.3.6. Meets for alcohol or substance abuse with the last three months 1.3.7. NIMH IRP Employees/staff and immediate family members will be excluded from the study per NIMH policy. 2. of parents of children and adolescents with DMDD or subthreshold DMDD 2.1Are an NIMH IRP Employees/staff 2.2Have an I.Q. < 70 2.3 Have any serious medical condition or condition that interferes with participation 3.2 Healthy Volunteer 2.1. I.Q. < 70; 3.2.2. Any serious medical condition or condition that interferes with fMRI scanning pregnant or lactating; 3.2.3. Past or current diagnosis of any anxiety disorder (panic disorder, GAD, Separation Anxiety Disorder, Social Phobia), mood disorder (manic or hypomanic episode, major depression), OCD, PTSD, Conduct Disorder, psychosis, current suicidal ideation, Tourette Disorder, Autism Spectrum Disorder or ADHD. 3.2.4. Substance abuse within two months prior to study participation or present substance abuse 3.2.5. History of sexual abuse. 3.2.6. Parent or sibling with Bipolar Disorder, recurrent MDD, or any disorder with psychosis. 3.2.7. NIMH IRP Employees/staff and immediate family members will be excluded from the study per NIMH policy. 4.2 Healthy Volunteer Adult 2.1. IQ< 70 4.2.2. Pregnant 4.2.3. Any past or current history of Bipolar Disorder (any manic or hypomanic episode), recurrent MDD, or any disorder with psychosis 4.3.3 NIMH IRP Employees/staff and immediate family members will be excluded from the study per NIMH policy. 5.3<TAB> for those with MDD: 5.3.1<TAB>The individual exhibits any of these cardinal bipolar symptoms: 5.3.1.1<TAB>Elevated or expansive mood 5.3.1.2<TAB>Grandiosity or inflated self-esteem 5.3.1.3<TAB>Decreased need for sleep 5.3.1.4<TAB>Increase in goal-directed activity (this can result in the excessive involvement in pleasurable activities that have a high potential for painful consequences) 5.3.1.5. Has BD symptoms in distinct periods lasting more than 1 day. 5.3.2. Meets for schizophrenia, schizophreniform disorder, schizoaffective illness, PDD, or PTSD. 5.3.3. IQ< 70 5.3.4.<TAB>The symptoms are due to the direct physiological effects of a drug of abuse, or to a general medical or neurological condition. 5.3.5.<TAB>Currently pregnant or lactating 5.3.6.<TAB>Meets for alcohol or substance abuse with the last three months 5.3.7.<TAB>NIMH IRP Employees/staff and immediate family members will be excluded from the study per NIMH policy. 6.2.<TAB> for those with ADHD: 6.2.1. IQ<70 6.2.2.<TAB>Pregnancy (excludes for scanning only) 6.2.3.<TAB>Ongoing medical illness or neurological disorder other than ADHD 6.2.4.<TAB>Any condition that would interfere with the participants ability to perform research tasks 6.2.5. Current Major Depression 6.2.6. Any past or present manic or hypomanic episode For all groups: NIMH employees are excluded