Neurofunctional Predictors of Escitalopram Treatment Response in Adolescents With Anxiety

The long-term goal of this study is to explore the neurobiological basis of generalized
anxiety disorder (GAD) using a validated functional MRI (fMRI) paradigm and functional
connectivity analyses with a cohort of GAD patients and healthy subjects and generating
feasibility and preliminary data regarding treatment-related effects of escitalopram on brain
functional activation and Fc patterns in pediatric GAD. An additional goal is to identify
biological markers in saliva and urine that will predict treatment response in pediatric
subjects with GAD. The central hypothesis of this proposal is that core dysfunction within
the prefrontal-amygdala network, which the investigators and others have observed in GAD,
will be normalized by successful treatment. The rationale underlying this hypothesis is that,
despite the high prevalence of GAD, there is a need to understand its neurobiology and to
identify biomarkers of treatment response and the mechanisms by which selective serotonin
reuptake inhibitors (SSRIs) putatively effect changes in the neurocircuitry of pediatric GAD.

Inclusion Criteria:

Inclusion - Anxiety Subjects:

- Diagnostic and Statistical Manual-IV (Text Revision) criteria for generalized anxiety
disorder diagnosed by the Anxiety Disorders Interview Schedule (ADIS-IV)

- Baseline Pediatric Anxiety Rating Scale (PARS) score ≥15 at baseline

- Ages 12-17 years 11 months old

- Fluent in English

- Provision of written informed consent by a legal guardian and written assent by the
subject

- Tanner scale stages II-V, in order to include only post-pubescent subjects and
minimize brain changes associated with the onset of puberty

- Does not have a history of intolerance, non-response or hypersensitivity to
escitalopram

- No co-occurring Diagnostic and Statistical Manual-IV (Text Revision) diagnosis mood
(except dysthymia, depression not otherwise specified), eating, pervasive
developmental disorder or psychotic disorders

- Subjects will be excluded if there are any lifetime diagnosis of mental retardation
(intelligence quotient < 70)

- Subjects with any history of alcohol or drug dependence or any alcohol abuse within
the past 6 months (nicotine dependence is permitted) will be excluded

- No new psychotherapy will be permitted during study participation and if the patient
is engaged in psychotherapy, it must have been stable for 1 month prior to baseline

- Females will not be eligible to participate if pregnant, breast feeding or lactating.

Inclusion - Healthy Subjects:

- Ages of 12-17 years and 11 months

- No history of any Diagnostic and Statistical Manual-IV (Text Revision) Axis I
disorders (nicotine dependence is permitted)

- No first-degree relatives with an affective or psychotic disorder

- No medications with central nervous system effects within 5 half-lives

- Fluent in English

- Tanner stage II-V

- Provision of informed consent and assent.

Exclusion Criteria:

Exclusion - Generalized Anxiety Disorder Patients & Healthy Subjects:

- Contraindication to an magnetic resonance imaging (MRI) scan (e.g., braces or
claustrophobia)

- An unstable medical or neurological illness that could influence fMRI or magnetic
resonance spectroscopy results

- Subjects will be excluded if there are any lifetime diagnosis of mental retardation or
intelligence quotient < 70)

- A positive pregnancy test

- Adolescents will be excluded for treatment with a medication with central nervous
system effects that requires more than 5 days of a screening period in order to
minimize the length of time between screening and baseline and maximize patient
safety, while recognizing that a longer taper period is required of some medications

- Adolescents with any history of major medical or neurological disorders that may
result in neurofunctional or neurochemical abnormalities including loss of
consciousness for >10 minutes will be excluded

- No co-occurring Diagnostic and Statistical Manual-IV (Text Revision) diagnosis mood
(other than dysthymia or Depression Not Otherwise Specified), eating, pervasive
developmental disorder or psychotic disorders

- Subjects will be excluded if there are any lifetime diagnosis of mental retardation or
intelligence quotient < 70

- Subjects with any history of alcohol or drug dependence or any alcohol abuse within
the past 6 months (nicotine dependence is permitted) will be excluded

- No new psychotherapy will be permitted during study participation and if the patient
is engaged in psychotherapy, it must have been stable for 1 month prior to baseline

- Females will not be eligible to participate if pregnant, breast feeding or lactating

- The patient lives >100 miles from the University of Cincinnati or is not able to
attend follow-up visits