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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00018057
Recruitment Status : Recruiting
First Posted : July 2, 2001
Last Update Posted : July 7, 2020
Sponsor:
Collaborators:
University of Minnesota
University of Oregon
University of Maryland, College Park
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Mental Health (NIMH) )

Brief Summary:

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 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 Disorder Major Depressive Disorder Behavioral: Attention Bias Modification Training 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 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.

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Study Type : Interventional  (Clinical Trial)
Estimated 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 : October 2, 2001
Estimated Primary Completion Date : January 1, 2029
Estimated Study Completion Date : January 1, 2029

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Anxiety

Arm Intervention/treatment
Active Comparator: 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 controlinvention 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.

Sham 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 controlinvention 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.




Primary Outcome Measures :
  1. Pediatric Anxiety Rating Scale [ Time Frame: Weekly ]
    Clinician-rated report

  2. Clinician Global Impression Scale [ Time Frame: Weekly ]
    Clinician-rated report



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   8 Years to 50 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria
  • 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: 18-50
    • 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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00018057


Contacts
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Contact: Daniel S Pine, M.D. (301) 594-1318 daniel.pine@nih.gov

Locations
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United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: Stefanie Sequeira    301-402-8225    sequeirasl@mail.nih.gov   
University of Maryland, College Park Recruiting
College Park, Maryland, United States, 20742
Contact: Nathan Fox, Ph.D.    Not Listed      
United States, Tennessee
Vanderbilt University Recruiting
Nashville, Tennessee, United States, 37232
Contact: Jennifer Blackford    Not Listed    jenni.blackford@vanderbilt.edu   
United States, Wisconsin
University of Wisconsin Recruiting
Madison, Wisconsin, United States, 53792
Contact: Lisa Williams    Not Listed    lewilliams4@wisc.edu   
Sponsors and Collaborators
National Institute of Mental Health (NIMH)
University of Minnesota
University of Oregon
University of Maryland, College Park
Investigators
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Principal Investigator: Daniel S Pine, M.D. National Institute of Mental Health (NIMH)
Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: National Institute of Mental Health (NIMH)
ClinicalTrials.gov Identifier: NCT00018057    
Other Study ID Numbers: 010192
01-M-0192
First Posted: July 2, 2001    Key Record Dates
Last Update Posted: July 7, 2020
Last Verified: June 19, 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute of Mental Health (NIMH) ):
fMRI
Emotion
Normal Volunteers
Magnetic Resonance Imaging
CBT
Additional relevant MeSH terms:
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Disease
Anxiety Disorders
Depressive Disorder
Depressive Disorder, Major
Pathologic Processes
Mental Disorders
Mood Disorders