Child & Adolescent Bipolar Disorder Brain Imaging and Treatment Study

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