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

Sponsor

National Institute of Mental Health (NIMH) (NIH)

Overall Status

Recruiting

CT.gov ID

NCT00018057

Collaborator

University of Minnesota (Other), University of Oregon (Other), University of Maryland (Other)

2,530

Enrollment

Location

Arms

327

Anticipated Duration (Months)

7.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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 attentiontraining 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.

Condition or Disease	Intervention/Treatment	Phase
Anxiety Disorders Major Depressive Disorder	Behavioral: Attention Bias Modification Training Drug: Fluoxetine	Phase 2

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

2530 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Oct 2, 2001

Anticipated Primary Completion Date :

Jan 1, 2029

Anticipated Study Completion Date :

Jan 1, 2029

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Active 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: Attention Bias Modification Training The intervention is computer-based. The active and control treatments have two components. In one component of the active intervention, subjects are asked to indicate the identity of a letter that appears behind a neutral face, opposite from an angry face. In another component of the active intervention, subjects are asked to identify numbers that are hidden within a puzzle, in locations distal from angry faces. In both components of the active intervention, subjects implicitly learn to shift their attention away from angry faces. This is because the faces are systematically arranged to be far removed from letters and numbers that need to be identified. The control arm of the intervention involves similar components. However, unlike in the intervention arm, angry faces appear in various locations near letters and numbers. Therefore, attention is not shaped in the control arm. This intervention requires five minutes per session and is administered before weekly psychotherapy sessions. Drug: Fluoxetine Randomized assignment.
Placebo Comparator: Control 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: Attention Bias Modification Training The intervention is computer-based. The active and control treatments have two components. In one component of the active intervention, subjects are asked to indicate the identity of a letter that appears behind a neutral face, opposite from an angry face. In another component of the active intervention, subjects are asked to identify numbers that are hidden within a puzzle, in locations distal from angry faces. In both components of the active intervention, subjects implicitly learn to shift their attention away from angry faces. This is because the faces are systematically arranged to be far removed from letters and numbers that need to be identified. The control arm of the intervention involves similar components. However, unlike in the intervention arm, angry faces appear in various locations near letters and numbers. Therefore, attention is not shaped in the control arm. This intervention requires five minutes per session and is administered before weekly psychotherapy sessions.

Arm

Intervention/Treatment

Experimental: Active

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: Attention Bias Modification Training

The intervention is computer-based. The active and control treatments have two components. In one component of the active intervention, subjects are asked to indicate the identity of a letter that appears behind a neutral face, opposite from an angry face. In another component of the active intervention, subjects are asked to identify numbers that are hidden within a puzzle, in locations distal from angry faces. In both components of the active intervention, subjects implicitly learn to shift their attention away from angry faces. This is because the faces are systematically arranged to be far removed from letters and numbers that need to be identified. The control arm of the intervention involves similar components. However, unlike in the intervention arm, angry faces appear in various locations near letters and numbers. Therefore, attention is not shaped in the control arm. This intervention requires five minutes per session and is administered before weekly psychotherapy sessions.

Drug: Fluoxetine

Randomized assignment.

Placebo Comparator: Control

Behavioral: Attention Bias Modification Training

Outcome Measures

Primary Outcome Measures

Pediatric Anxiety Rating Scale [Weekly]
Clinician-rated report
Clinician Global Impression Scale [Weekly]
Clinician-rated report

Eligibility Criteria

Criteria

Ages Eligible for Study:

8 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

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 have complete physical examination and 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 relis on SCID)