Brain Markers of Anxiety Disorders and SSRI/CBT Treatment in Children and Adolescents

Anxiety disorders are common and highly disabling conditions of children and adolescence
that often do not remit, and increase the risk of depression, anxiety, substance abuse, and
suicide in adulthood. Available treatments are only modestly successful. When they are
effective, however, early treatment of anxiety disorders can reduce subsequent morbidity.

This study will examine variations in genetics and brain reactivity among children and
adolescents who do and do not respond to SSRIs and Cognitive Behavioral Therapy. Through
this, the study will identify neurological and genetic biomarkers that can predict
responsiveness to SSRI/CBT treatment in those with anxiety disorders.

For SSRI/medication treatment arm:

Although selective serotonin reuptake inhibitors (SSRI) are medications widely prescribed
for children and adolescents with anxiety disorders, little is known about the
neurobiological factors that predict which patients respond to treatment. Current theory
suggests that neurological functioning and genetics may influence a patient's response to
treatment.

Participation in this study will last approximately 14 weeks. Both healthy participants and
participants with anxiety disorders will be recruited to participate. All participants will
complete similar study visits at entry, within 2 weeks of entry, and 12 weeks after that.
The first visit, which will occur at study entry, will include screening questionnaires, an
interview with research staff, a medical screening, and collection of saliva samples for
genotyping. The second visit and the last visit, which will be separated by 12 weeks, will
involve MRI scans and behavioral tasks to be conducted inside and outside the MRI scanner.
Over the 12 weeks between MRI scanning sessions, participants with anxiety disorders will
take sertraline, a common SSRI, on a daily basis. They will also attend nine additional
visits during this time to complete assessments of their symptoms. These visits will occur
0, 1, 2, 3, 4, 6, 8, 10 and 12 weeks after the first scan. Participants with anxiety
disorders will therefore be completing a symptom assessment, MRI scans, and behavioral tasks
all on the final visit, 12 weeks after the second visit. In addition, participants will
complete tasks while connected to an Electroencephalography(EEG) machine before and after
the 12 weeks of treatment, and will have the option of additional EEG's at weeks 2, 4, and
8.

For CBT arm:

Participation in this study will last 16 weeks. All participants will complete similar study
visits at entry, within 2 weeks of entry, and approximately 16 weeks after that. The first
visit, which will occur at study entry, will include screening questionnaires, an interview
with research staff, a medical screening, and collection of saliva samples for genotyping.
The second visit and the last visit, which will be separated by approximately 16 weeks, will
involve MRI scans and behavioral tasks to be conducted inside and outside the MRI scanner.
Over the 16 weeks between MRI scanning sessions, participants with anxiety disorders will
participate in type of talk therapy--Cognitive Behavioral Therapy--on a weekly basis. In
addition, participants will complete tasks while connected to an
Electroencephalography(EEG)machine before and after the 16 weeks of treatment, and will have
the option of additional EEG's at weeks 2, 4, and 8.

Inclusion Criteria:

For anxiety disorder group:

- 7-19 years of age

- Current diagnosis of social anxiety disorder, generalized anxiety disorder and/or
separation anxiety disorder

- Physically healthy, as confirmed by comprehensive medical history, physical exam, and
laboratory testing

For healthy control group:

- 7-19 years of age

- Never been diagnosed with either Axis I or Axis II mental disorders

- Physically healthy, as confirmed by comprehensive medical history, physical exam, and
laboratory testing

Exclusion Criteria for all:

- Clinically significant medical or neurologic condition

- Life history of bipolar disorder, schizophrenia, mental retardation, or pervasive
developmental disorder or current alcohol/drug abuse or dependence

- Severe current depression, as indicated by the Child Depression Inventory, or by the
clinical decision of the rater or doctor

- Current suicidal ideation

- Treatment with psychotropic/psychoactive medications in the past two weeks (4 weeks
for fluoxetine and monoamine oxidase inhibitors) before screening

- Positive urine drug screen results

- Pregnancy

- Clinically significant medical condition that interferes with metabolism of
sertraline

- Multiple drug allergies

- Prior failure of response to sertraline for anxiety, as defined by adequate duration
to achieve a clinical response

- Refusing to attend school because of anxiety

Additional exclusion criteria for the functional MRI studies:

- Presence of ferrous-containing metals within the body, such as aneurysm clips,
shrapnel, or retained particles

- Claustrophobia