This research protocol seeks to learn more about bipolar disorder in children and adolescents ages 6-17. Researchers will describe the moods and behaviors of children with bipolar disorder and use specialized testing and brain imaging to learn about specific brain changes associated with the disorder. This protocol studies children who have been diagnosed with bipolar disorder, and those who have a sibling or parent with bipolar disorder and are thus considered "at risk" for developing the disorder.

Objective:

For this protocol we define Bipolar Spectrum disorders (BSD) as the propensity to have a manic episode by having Bipolar Disorder or Substance/Medication-Induced Bipolar and Related Disorder. BSD in children and adolescents is receiving increased research attention, but important questions remain about its developmental trajectory, phenomenology and behavioral correlates, and little is known about its underlying neural mechanisms. In its study of youth with BSD, this study has three objectives:

1. to use longitudinal techniques to characterize the clinical and physiological manifestations of pediatric BSD, and to use cross-sectional techniques (e.g., comparing children and adults with BSD on these measures) to provide preliminary data to guide such longitudinal studies
2. to identify and follow longitudinally behavioral, neuropsychological, neurophysiological, and neuroanatomical correlates of pediatric BSD, and compare to children with chronic irritability and hyperarousal symptoms (severe mood dysregulation, SMD, as outlined in protocol 02-M-0021), youth with attention deficit hyperactivity disorder (ADHD), and typically developing youth.
3. to examine genetic and familial correlates of pediatric BSD

Study population:

There are 11 separate populations being studied in this protocol:

1. Children and adolescents between the ages of 6-17 years old who meet criteria for BSD.
2. Adults between the ages of 18-58 years old who meet criteria for BD, including those age 18-25 with BSD.
3. Control populations of: a) Healthy volunteer children and adolescents between the ages of 3-17 years old, b) Parents of healthy volunteer children or healthy adults in research, c) Children 8-17 years old with attention deficit hyperactivity disorder (ADHD), who do not have a mood disorder.
4. First and second-degree biological relatives of those in (B.1) or (B.2), above, and are between 3-58 years old.
5. A subgroup of these cohorts will be Old Order Amish individuals who fulfill eligibility for (1), (2), (3a), (3b), or (4).

Design:

For children and adolescents with BSD (i.e. Bipolar Disorder or those with Substance/Medication-Induced Bipolar and Related Disorder), this study is an outpatient characterization and longitudinal follow-along design. Once determined to be eligible, individuals come for an initial assessment, and then at varying intervals they return for clinical interviews, behavioral tasks, and structural and functional MRI.

For children and adolescents who are relatives of individuals with BSD, this is an outpatient follow-along design during which individuals come for an outpatient assessment and at 2-year intervals for clinical interviews, behavioral tasks, and structural and functional MRI.

For healthy volunteer children, children with only ADHD, adults with BD, and parents of healthy volunteer children, this study is an outpatient cross-sectional study that includes clinical interviews, behavioral tasks, and structural and functional MRI.

For all others, individuals come to NIH for clinical interviews, behavioral tasks, and MRI.

For most individuals in the Amish community, the investigation occurs in the field, where they receive clinical interviews and behavioral tasks. Some may choose to come to the NIH to participate in behavioral testing and MRI.

For all individuals, genetic material from saliva or blood is obtained under protocol 01-M-0254.

Outcome measures:

This study will examine between group differences in clinical, behavioral, genetic, neuroanatomical, and neurophysiological variables in individuals with BSD, their relatives, and healthy volunteers. Findings in children with BSD will also be compared to those with severe mood dysregulation, sometimes called a broad phenotype of pediatric BD, recruited under protocol 02-M-0021 (Nottelman, 2001).

Longitudinal clinical, behavioral, and neuroanatomical data will also be obtained.

• INCLUSION AND EXCLUSION CRITERIA:

Inclusion and exclusion criteria for each group are outlined below. The total accrual ceiling is 2050, including subjects of both sexes, made up of the following 11 populations:

Pediatric patients with bipolar disorder or SMIBRD:

INCLUSION CRITERIA:

• Age 6-17
• Meet DSM criteria for BD
• Have a primary caregiver who can accompany him or her on trips to NIMH and provide reliable history and information.
• Have a psychiatrist who provides clinical care for their BSD.
• Be able to complete self-rating forms and to cooperate with other study procedures.

EXCLUSION CRITERIA:

• I.Q. < 70
• Autistic disorder or more than mild autism spectrum disorder;
• Psychosis that interferes with the child s capacity to understand and comply with study procedures
• Unstable medical illness (e.g. severe asthma)
• Medical illness that could cause the symptoms of BSD (e.g. multiple sclerosis, thyroid disease)
• Pregnancy
• Substance abuse within two months of the initial evaluation, since alcohol and abused substances interfere with interpretation of fMRI and cognitive task data.
• NIMH IRP Employee family member

Adults with BD participating as individuals or as parents of at- risk children:

INCLUSION CRITERIA:

• DSM Bipolar Disorder
• Age 18-58
• Be able to complete self-rating forms and to cooperate with other study procedures.
• Medically safe to perform MRI

EXCLUSION CRITERIA:

• Diagnosis of schizophrenia or other current psychosis.
• Claustrophobia or anxiety that prevents participation in MRI
• Any serious medical illness, such as heart, liver, or kidney disease.
• A history of drug or alcohol abuse in the past 90 days.
• Current or past seizure disorder
• Currently unstable hyperthyroidism or hypothyroidism
• Currently receiving medical treatment that would affect mood, such as steroids
• Pregnant or breast-feeding.
• Active suicidal or homicidal thoughts or plans
• NIMH IRP Employee/family member

Healthy volunteer children and adolescents:

INCLUSION CRITERIA:

• Age- and sex- matched to the bipolar patients.
• Have an identified primary care physician.
• Speaks English

EXCLUSION CRITERIA

• I.Q. < 70
• Any serious medical condition or condition that interferes with fMRI scanning
• Pregnancy
• 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.
• Substance abuse within two months prior to study participation or present substance abuse
• History of sexual abuse.
• Parent or sibling with Bipolar Disorder, recurrent MDD, or any disorder with psychosis.
• NIMH IRP Employee family member

Parents of healthy volunteer children (Amish and Non-Amish) and Healthy Adults (not parents):

INCLUSION CRITERIA:

• For healthy adults (not parents): Healthy adults age 25-58
• For parents of healthy volunteers: Parents of control subjects as outlined in B above
• Age 25-58
• Speaks English

EXCLUSION CRITERIA:

• IQ< 70
• Any current psychiatric diagnosis
• NIMH IRP Employee/family member

Control subjects with ADHD but not BD:

INCLUSION CRITERIA:

• Age 8-17
• Currently meets DSM-IV criteria for ADHD
• t score >65 on the Connors Parent scales
• Subjects with other 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

EXCLUSION CRITERIA

• IQ<70
• Pregnancy
• Ongoing medical illness or neurological disorder other than ADHD
• Any condition that would interfere with the participants ability to perform fMRI or other research tasks
• Current Major Depression
• Any past or present manic or hypomanic episode.
• NIMH IRP Employee family member

First- and Second-degree relatives of patients with BD:

INCLUSION CRITERIA:

• First degree relatives (parent or sibling) or second-degree relative (grandparent, grandchild, uncle, aunt, nephew, niece, half-sibling) of patients with BD
• Age 3-58

EXCLUSION CRITERIA:

• Active psychosis
• Dementia
• IQ < 70
• Any clinical condition in need of immediate care
• Any chronic medical illness resulting in impaired CNS function
• Any condition that interferes with the participants ability to perform research tasks
• NIMH IRP Employee/family member

Amish Community children with BD:

INCLUSION CRITERIA:

• Age 8-17
• Meet DSM-IV criteria for BD
• Have a primary caregiver who can provide a reliable history
• Be able to complete self-rating forms and to cooperate with other study procedures.

EXCLUSION CRITERIA:

• IQ<70
• Active psychosis
• Any clinical condition in need of immediate care
• Any chronic medical illness resulting in impaired CNS function
• Any condition that would interfere with the participants ability to perform behavioral research tasks
• Limitations with English that would interfere with understanding consent/assent, interview, or task instructions.
• NIMH IRP Employee family member

Amish Community Adults with BD:

INCLUSION CRITERIA:

• DSM-IV Bipolar Disorder
• Age 18-58
• Be able to complete self-rating forms and to cooperate with other study procedures.

EXCLUSION CRITERIA:

• Diagnosis of schizophrenia or other current psychosis.
• Any serious medical illness, such as heart, liver, or kidney disease.
• A history of drug or alcohol abuse in the past 90 days.
• Current or past seizure disorder
• Currently unstable hyperthyroidism or hypothyroidism
• Currently receiving medical treatment that would affect mood, such as steroids
• Active suicidal or homicidal thoughts or plans
• Limitations with English that would interfere with understanding consent/assent, interview, or task instructions.
• NIMH IRP Employee/family member

Amish Community at-risk subjects:

INCLUSION CRITERIA:

• Age 8-17
• Parent or sibling (first-degree relative) diagnosed with BD

EXCLUSION CRITERIA:

• IQ<70
• Active psychosis
• Any clinical condition in need of immediate care
• Any chronic medical illness resulting in impaired CNS function
• Any condition that would interfere with the participants ability to perform behavioral research tasks
• Limitations with English that would interfere with understanding consent/assent, interview, or task instructions.
• NIMH IRP Employee family member

Amish Community healthy volunteer children & adolescents:

INCLUSION CRITERIA:

• Age 8-17
• No serious physical or neurological symptoms or disorder by history

EXCLUSION CRITERIA:

• I.Q. < 70
• Ongoing medical illness
• Neurological disorder (including seizures)
• Past or present substance abuse
• History of sexual abuse
• Limitations with English that would interfere with understanding consent/assent, interview or task instructions
• Past or present psychopathology in control subject or their first-degree relative
• NIMH IRP Employee family member

Amish Community adults who are parents of healthy volunteer children & adolescents, healthy spouses of Amish adults with BD, or parents of adolescents with BD:

INCLUSION CRITERIA:

• Age 18-58
• No serious physical or neurological symptoms or disorder by history
• For Parents of child with BD or spouses of patient with BD: Spouse or offspring with BD

EXCLUSION CRITERIA:

• I.Q. < 70
• Ongoing medical illness
• Neurological disorder (including seizures)
• Past or present substance abuse
• History of sexual abuse
• Limitations with English that would interfere with understanding consent/assent, interview or task instructions
• NIMH IRP Employee/family member
• For Healthy volunteers: Past or present psychopathology in participant or their first-degree relative
• For Parents of healthy volunteer children: Past or present psychopathology as in (4) above.

In addition, children with BD (Section B.1.) who wish to receive treatment, including discontinuation of medication while inpatients on the pediatric behavioral health unit at NIH, may be eligible for treatment if they meet the following additional criteria:

All inclusion criteria for B.1 (above)

Treatment failure as defined by current CGAS score <60

The child s psychiatrist/treating physician agrees that a change in medication regimen is appropriate

EXCLUSION CRITERIA:

All exclusion criteria for B.1 (above)

Any contraindications for MRI scanning, plus claustrophobia or extreme separation anxiety

EXCLUSIONS for MRI Scanning:

• Pregnancy
• Substance abuse within two months of the initial evaluation, since alcohol and abused substances interfere with interpretation of fMRI and cognitive task data.
• Claustrophobia or anxiety that prevents participation in MRI
• Any serious medical condition or condition that interferes with fMRI scanning
• Metal in body which would make having an MRI scan unsafe, such as pacemakers, stimulators, pumps, aneurysm clips, metallic prostheses, artificial heart valves, cochlear implants or shrapnel fragments, or if you were a welder or metal worker, since there may be

small metal fragments in the eye

- Unable to lie comfortably on back for up to 90 minutes

There are 11 separate populations being studied in this protocol: 1. Children and adolescents between the ages of 6-17 years old who meet criteria for BSD. 2. Adults between the ages of 18-58 years old who meet criteria for BD, including those age 18-25 with BSD. 3. Control populations of: a) Healthy volunteer children and adolescents between the ages of 3-17 years old, b) Parents of healthy volunteer children or healthy adults in research, c) Children 8-17 years old with attention deficit hyperactivity disorder (ADHD), who do not have a mood disorder. 4. First and second-degree biological relatives of those in (B.1) or (B.2), above, and are between 3-58 years old. 5. A subgroup of these cohorts will be Old Order Amish individuals who fulfill eligibility for (1), (2), (3a), (3b), or (4).

.We do not plan to make IDP available.