Clinical Trial of Fluoxetine in Anxiety and Depression in Children, and Associated Changes in the Brain

Study Overview
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Brief Summary
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Objective: This protocol uses functional magnetic resonance imaging (fMRI) to examine neuro-cognitive correlates of pediatric and adult mood and anxiety disorders. The primary goal of the project is to document, in pediatric anxiety disorders and major depression, perturbations in brain systems mediating attention biases, fear conditioning, emotional memory, and response to various forms of motivational stimuli. As one secondary goal, the project measures the relationship between these factors and treatment response to either fluoxetine, a specific serotonin reuptake inhibitor (SSRI), cognitive behavioral therapy (CBT), or interpersonal psychotherapy (IPT). Another secondary goal examines similar associations in adults. Study Population: A total of 2530 children, adolescents, and adults will be recruited. Most subjects will not be able to complete all procedures. We seek to comprehensively study 150 juveniles with only a current anxiety disorder, 60 juveniles with current major depression, 150 juveniles with no psychiatric disorder, 100 adults with major depression, 60 adults with an anxiety disorder, and 150 adults with no psychiatric disorder. To achieve this, we are recruiting 2530 individuals. Design: Subjects will be tested using fMRI paradigms designed to examine brain regions engaged when processing motivationally salient stimuli, as assessed during attention, memory, social interaction, reward, and fear-conditioning paradigms. After these initial fMRI tests, subjects with depression or an anxiety disorder receive treatment. Treatment will comprise open treatment with either fluoxetine or CBT, augmented with computer-based attention retraining, delivered in a randomized-controlled design, with random assignment to either active or placebo attention training regimens. Adolescent subjects then will be re-tested after eight-weeks using only the attention, memory, and conditioning paradigms. Outcome Measures: Prior imaging studies note that tasks requiring attention modulation, emotional memory, social interchange, and fear conditioning engage brain regions previously implicated in adult mood and anxiety disorders. These regions include most consistently the amygdala and ventral prefrontal cortex. Moreover, imaging studies of reward function implicate the striatum and prefrontal cortex in adult mood disorders. As a result, we hypothesize that attention, memory, social interaction, reward, and conditioning paradigms will engage the amygdala, ventral prefrontal cortex and striatum in both psychiatrically healthy and impaired subjects. Moreover, we hypothesize that these healthy and psychiatrically impaired groups will differ in the degree of engagement. Juvenile subjects also will be treated for eight-weeks, and a subset will be re-tested with fMRI. We predict that pre-treatment abnormalities in neural circuitry will predict response to treatment, such that increased amygdala and prefrontal activation will occur in individuals who show the strongest response to treatment. Moreover, we hypothesize that effective treatment will normalize abnormalities in attention and emotional memory, as manifest in fMRI.

Detailed Description
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Objective: This protocol uses functional magnetic resonance imaging (fMRI) to examine neuro-cognitive correlates of pediatric and adult mood and anxiety disorders. The primary goal of the project is to document, in pediatric anxiety disorders and major depression, perturbations in brain systems mediating attention biases, fear conditioning, emotional memory, and response to various forms of motivational stimuli. As one secondary goal, the project measures the relationship between these factors and treatment response to either fluoxetine, a specific serotonin reuptake inhibitor (SSRI), cognitive behavioral therapy (CBT), or interpersonal psychotherapy (IPT). Another secondary goal examines similar associations in adults. Study Population: A total of 2530 children, adolescents, and adults will be recruited. Most subjects will not be able to complete all procedures. We seek to comprehensively study 150 juveniles with only a current anxiety disorder, 60 juveniles with current major depression, 150 juveniles with no psychiatric disorder, 100 adults with major depression, 60 adults with an anxiety disorder, and 150 adults with no psychiatric disorder. To achieve this, we are recruiting 2530 individuals. Design: Subjects will be tested using fMRI paradigms designed to examine brain regions engaged when processing motivationally salient stimuli, as assessed during attention, memory, social interaction, reward, and fear-conditioning paradigms. After these initial fMRI tests, subjects with depression or an anxiety disorder receive treatment. Treatment will comprise open treatment with either fluoxetine or CBT, augmented with computer-based attention retraining, delivered in a randomized-controlled design, with random assignment to either active or placebo attention-training regimens. Adolescent subjects then will be re-tested after eight-weeks using only the attention, memory, and conditioning paradigms. Outcome Measures: Prior imaging studies note that tasks requiring attention modulation, emotional memory, social interchange, and fear conditioning engage brain regions previously implicated in adult mood and anxiety disorders. These regions include most consistently the amygdala and ventral prefrontal cortex. Moreover, imaging studies of reward function implicate the striatum and prefrontal cortex in adult mood disorders. As a result, we hypothesize that attention, memory, social interaction, reward, and conditioning paradigms will engage the amygdala, ventral prefrontal cortex and striatum in both psychiatrically healthy and impaired subjects. Moreover, we hypothesize that these healthy and psychiatrically impaired groups will differ in the degree of engagement. Juvenile subjects also will be treated for eight-weeks, and a subset will be re-tested with fMRI. We predict that pre-treatment abnormalities in neural circuitry will predict response to treatment, such that increased amygdala and prefrontal activation will occur in individuals who show the strongest response to treatment. Moreover, we hypothesize that effective treatment will normalize abnormalities in attention and emotional memory, as manifest in fMRI.

Official Title
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Fluoxetine's Effects on Attention and Emotional Memory in Anxious and Depressed Youth and Adults

Conditions
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Anxiety Disorders, Major Depressive Disorder

Intervention / Treatment
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* Behavioral: Active Attention Bias Modification Training
* Drug: Fluoxetine


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: ALL JUVENILE SUBJECTS: Age: 8 - 17 (subjects who consent as 17- year-olds but turn 18 during the course of the study will be eligible to complete all procedures completed by other subjects who consent as 17- year- olds but do not turn 18). Consent: can give consent/assent (Parents will provide consent; minors will provide assent) IQ: all subjects will have IQ > 70 (Assessment relies on WASI) Language: all subjects will speak English ALL ADULT SUBJECTS Age: 18-65 Consent: can give consent IQ: all subjects will have IQ>70 (Assessment relies on WASI) Language: all subjects will speak English ALL SUBJECTS WITH AN ANXIETY DISORDER Diagnosis: Current Diagnosis of Social Phobia, Separation Anxiety, Generalized Anxiety Disorder, or Panic Disorder (Based on K-SADS (juveniles) or SCID (adults)) Symptom Severity: Clinically significant, ongoing anxiety symptoms Clinical Impairment: Clinically significant, ongoing distress or impairment from anxiety ALL SUBJECTS WITH A MOOD DISORDER Diagnosis: Current Diagnosis of Major Depression (Based on K-SADS (juveniles) or SCID (adults)) Clinical Impairment: Clinically significant, ongoing distress or impairment from depressive symptoms Symptom Severity: Clinically significant, ongoing depressive symptoms ALL PREVIOUSLY ENROLLED ADOLESCENT PATIENTS, HEALTHY VOLUNTEERS, AND HEALTHY VOLUNTEERS TURNED PATIENTS Diagnosis: Current Diagnosis of Social Phobia, Separation Anxiety, Generalized Anxiety Disorder, or Panic Disorder; No current diagnosis (Based on K-SADS (juveniles) or SCID (adults)) Clinical Impairment (as applicable): Clinically significant, ongoing symptoms (This will be documented by clinician review with patients and their families during at least two visits with families.) Symptom Severity (as applicable): Clinically significant, ongoing symptoms (This will be documented by clinician review with patients and their families during at least two visits with families.) EXCLUSION CRITERIA: ALL SUBJECTS Any serious medical condition or condition that interferes with fMRI scanning, and for patients electing medication, any condition that increases risk of SSRI treatment. (All patients will complete a medical history. Healthy volunteer participants will be medication- free and have no current serious medical conditions, based on a review of their medical history.) Pregnancy Current use of any psychoactive substance; current suicidal ideation; current diagnosis of attention deficit hyperactivity disorder (ADHD) of sufficient severity to require pharmacotherapy. Current diagnoses Tourette's Disorder, OCD, post-traumatic distress disorder, conduct disorder Past or current history of mania, psychosis, or severe pervasive developmental disorder Recent use of an SSRI; all subjects must have been free of any SSRI-use for at least one month (fluoxetine six months) and must not have been treated with an SSRI for their current depressive episode. NIMH employees and staff and their immediate family members will be excluded from the study per NIMH policy HEALTHY ADULT SUBJECTS --Any current psychiatric diagnosis (Assessment relies on SCID)

Ages Eligible for Study
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Minimum Age: 8 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A group of healthy subjects and patients with anxiety disorders are assessed on a number of mental health and biological variables. A subset of the patients who can agree to attend regular psychotherapy sessions are randomized to receive cognitive behavioral therapy with computer-based augmentation. In one study arm, these patients receive cognitive behavioral therapy with an active form of a computer game. In the other treatment arm, subjects receive cognitive behavioral therapy with a control treatment.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active ABMT<br>Subjects in both treatment arms receive cognitive behavioral therapy (CBT) for a 12-week period. In the final eight weeks of the trial, the subjects complete either the active-intervention arm or the control invention arm. In these arms, either the active or control treatment is administered immediately before a CBT session. | Behavioral: Active Attention Bias Modification Training<br>* Computer-based attention bias modification training administered at weekly CBT session aimed at re-training attentional biases<br>Drug: Fluoxetine<br>* Randomized assignment<br>|
| Placebo Comparator: Placebo<br>Subjects in both treatment arms receive cognitive behavioral therapy (CBT) for a 12-week period. In the final eight weeks of the trial, the subjects complete either the active-intervention arm or the control invention arm. In these arms, either the active or control treatment is administered immediately before a CBT session. | Behavioral: Active Attention Bias Modification Training<br>* Computer-based attention bias modification training administered at weekly CBT session aimed at re-training attentional biases<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Pediatric Anxiety Rating Scale (PARS) | Clinician-rated report | Weekly | 
| Clinical Global Impression Scale (CGI) | Clinician-rated report | Weekly | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CBT, Emotion, fMRI, Magnetic Resonance Imaging, Normal Volunteers