Clinical Trial of Fluoxetine in Anxiety and Depression in Children, and Associated Brain Changes
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| ClinicalTrials.gov Identifier: NCT00018057 |
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Recruitment Status :
Recruiting
First Posted : July 2, 2001
Last Update Posted : June 7, 2023
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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 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 |
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 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 |
| Arm | Intervention/treatment |
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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.
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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. |
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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. |
- Pediatric Anxiety Rating Scale [ Time Frame: Weekly ]Clinician-rated report
- Clinician Global Impression Scale [ Time Frame: Weekly ]Clinician-rated report
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| Ages Eligible for Study: | 8 Years to 65 Years (Child, Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | Yes |
- INCLUSION CRITERIA:
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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
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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
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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
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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
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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:
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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
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HEALTHY ADULT SUBJECTS
- Any current psychiatric diagnosis (Assessment relis on SCID)
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
| Contact: Daniel S Pine, M.D. | (301) 594-1318 | daniel.pine@nih.gov |
| United States, Maryland | |
| National Institutes of Health Clinical Center | Recruiting |
| Bethesda, Maryland, United States, 20892 | |
| Principal Investigator: | Daniel S Pine, M.D. | National Institute of Mental Health (NIMH) |
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| 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: | June 7, 2023 |
| Last Verified: | March 28, 2023 |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
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fMRI Emotion Normal Volunteers Magnetic Resonance Imaging CBT |
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Disease Anxiety Disorders Depressive Disorder Depressive Disorder, Major Pathologic Processes Mental Disorders Mood Disorders Fluoxetine Selective Serotonin Reuptake Inhibitors Neurotransmitter Uptake Inhibitors Membrane Transport Modulators |
Molecular Mechanisms of Pharmacological Action Neurotransmitter Agents Serotonin Agents Physiological Effects of Drugs Antidepressive Agents, Second-Generation Antidepressive Agents Psychotropic Drugs Cytochrome P-450 CYP2D6 Inhibitors Cytochrome P-450 Enzyme Inhibitors Enzyme Inhibitors |