This is an application for a FIRST Award (R29) with the overall purpose of furthering knowledge of therapeutics for three childhood anxiety disorders: social phobia, separation anxiety, and generalized anxiety disorder. Several consideraitons contribute to the importance of this research. First, as a group, these disorders are exceedingly common and associated with considerable childhood distress. Second, many children and adolescents with these disorders face period s of prolonged impairment, with potential ramifications for adulthood mental health. Third, these childhood disorders are often treated with medication, yet there is lottle empirical basis for this practice. The serotonin re-uptake inhibitors (SSRIs) are often used, given their safety and efficacy in a broad array of adult anziety disorders. As a result, there is a compelling need to evaluate the safety and efficacy of the SSRIs in childhood anxiety disorders. Pilot data from open studies suggest that fluoxetine holds promise as a treatment for childhood social phobia, separation anziety, and generalized anxiety disorders. The primary aim of this study is to follow-up these pilot findings through an eight-week double-blind placebo-controlled random assignment clinical eficacy and safety study of fluoxetine in 100 children and adolescents with either social phobia, separation anxiety, or generalized anxiety disorders. The hypothesis will be tested that fluoxetine is superior to placebo in reducing anxiety symptoms and impairment. Beyond lack of knowledge in therapeutics, there is limited understanding of drug action mechanisms in childhood anziety disorders. Studies in adults show that SSRIs may influence anxiety symptoms through effects on a dysregulated respiratory system. Pilot data suggest that the respiratory system is affected in a group of childhood anxiety disorders much as it is affected in a group of adult anxiety disorders. As in adults with panic disorder, children with either social phobia, separation anxiety, or generalized anxiety disorder exhibit irregular ventilatory patterns while breathing room air and CO2 hyper-sensitivity, manifested as increased ventilation and anxiery, while breathing CO2. In adults, these respiratory abnormalities respond to SSRIs. As a result, an examination of fluoxetine's effect on respiration in childhood anziety disorders may provide important data on drug action mechanisms in children. The secondary aim of this study is to examine thenormalizing effect of fluoxetine on irregular ventilatory patterns, ventilatory hypersensitivity, and the anxiety response to CO2 challenge in children and adolescents with anxiety disorders. The hypothesis will be tested that fluoxetine reduces irregular breathing, ventilatory hypersensitivity to CO2, and the anxiety response to CO2.
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