Clinical Trial of Fluoxetine in Anxiety and Depression in Children, and Associated Changes in the Brain
Condition: Anxiety Disorders; Major Depressive Disorder
MeSH terms: Anxiety Disorders; Depressive Disorder; Depressive Disorder, Major
Study type: Interventional
Phase: Phase 2

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 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: 
      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.
    

Intervention name(s): Active Attention Bias Modification Training; Fluoxetine
Intervention type(s): Behavioral; Drug
Intervention description(s): Computer-based attention bias modification training administered at weekly CBT session aimed at re-training attentional biases; Randomized assignment
Intervention MeSH terms: Fluoxetine
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention 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 (Participant, Investigator)
Primary purpose: Treatment
Keywords: CBT; Emotion; fMRI; Magnetic Resonance Imaging; Normal Volunteers