Generalized Anxiety Disorder (GAD) is among the most common anxiety disorders in youth, often emerges during adolescence, and is associated with significant morbidity as well as an increased risk of suicide attempts. Importantly, understanding the relationship between psychopharmacologic treatments for pediatric GAD and functional activity and functional connectivity among several anterior limbic structures (e.g., amygdala, ventrolateral prefrontal cortex) may identify biomarkers of treatment response. The present study will combine double-blind, placebo-controlled treatment with the selective serotonin reuptake inhibitor escitalopram and in vivo neuroimaging techniques (i.e., functional MRI and functional connectivity analyses [Fc]) in adolescents with GAD. Additionally, this study will evaluate early, treatment-related changes in functional activity of the ventrolateral prefrontl cortex and the amygdala, as well as the Fc of these structures, to elucidate predictors of treatment response which precede clinical improvement in youth with GAD. The applicant, a board-certified, child and adolescent psychiatrist, will seek to accomplish several goals and objectives over the course of this four year K23 award. In this regard, the long-term goal of this award is to foster the applicant's research career as an independent investigator focusing on the neurophysiology and neuropharmacology of pediatric anxiety disorders. More immediate objectives of this K23 proposal are to: (1) secure training in the neurodevelopment of GAD;(2) develop expertise in fMRI and Fc analyses;(3) become proficient at longitudinal study design, integrating psychopharmacologic interventions and neurophysiology;and (4) enhance the applicant's knowledge of biostatistics. Additional objectives include exploring the neurobiological basis of GAD using a validated fMRI paradigm and Fc analyses with a cohort of GAD patients and healthy subjects, and generating preliminary data regarding treatment-related effects of escitalopram on brain functional activation and Fc patterns in pediatric GAD. The central hypothesis of this proposal is that core dysfunction within the anterior limbic network, which we and others have observed in GAD, will be normalized by successful treatment. Finally, the rationale underlying this hypothesis is that, despite the high prevalence of GAD, there is a need to understand its neurobiology and to identify biomarkers of treatment response and the mechanisms by which SSRIs putatively effect changes in the neurocircuitry of pediatric GAD.
The proposed research is relevant to public health because Generalized Anxiety Disorder (GAD) is a debilitating psychiatric disorder with a lifetime prevalence of up to 5% in the general adolescent population, yet only about half of patients respond to standard-of-care treatments. The project fits well with the mission of the NIH. In this regard, we propose a brain imaging study to determine if specific patterns of brain activity-that occur following treatment with the antidepressant escitalopram-can predict treatment response in adolescents with GAD.