DEPRESSION AND ANXIETY 29:328–339 (2012) Review ESTABLISHING THE NEUROBIOLOGIC BASIS OF TREATMENT IN CHILDREN AND ADOLESCENTS WITH GENERALIZED ANXIETY DISORDER Jeffrey R. Strawn, M.D., 1,2∗ Anna M. Wehry, 1 Melissa P. DelBello, M.D., 1,2 Moira A. Rynn, M.D., 3 and Stephen Strakowski, M.D. 1 Generalized anxiety disorder (GAD) is associated with significant morbidity in children and adolescents, yet only recently have the neuropharmacology and neu- rophysiology of this condition been studied in youth. Accumulating data suggest structural and functional abnormalities within the brain’s fear networks in youth with GAD. Additionally, seven studies examined the efficacy of medications that modulate this system and, in some cases, the direct effects of these medications on structures within these networks (e.g. amygdala, ventrolateral prefrontal cor- tex [VLPFC]). In this review, we summarize the extant functional, functional connectivity, and structural neuroimaging data in children and adolescents with GAD. In addition, data concerning selective serotonin reuptake inhibitors (SS- RIs), selective serotonin norepinephrine reuptake inhibitors (SSNRIs), atypical anxiolytics, benzodiazepines, and psychotherapy are reviewed in the context of the neurophysiology of pediatric GAD. The existing data suggest abnormal ac- tivity within the amygdala, VLPFC, and anterior cingulate cortex, as well as the possibility of impaired connectivity among these brain regions. In addition to numerous cognitive behavioral therapy (CBT) trials, five randomized, controlled psychopharmacologic trials primarily in youth with GAD suggest that SSRIs and SSNRIs are effective for this condition. These findings also raise the possibility that functional activity within the amygdala and VLPFC may be altered follow- ing successful treatment. Depression and Anxiety 29:328–339, 2012. C  2012 Wiley Periodicals, Inc. Key words: GAD; fMRI; anxiety disorders; anterior limbic network; youth; SSRI 1 Department of Psychiatry and Behavioral NeuroscienceUni- versity of Cincinnati, College of Medicine, Cincinnati, Ohio 2 Cincinnati Children’s Hospital Medical Center, Department of Psychiatry, Cincinnati, Ohio 3 Department of Psychiatry and New York State Psychiatric In- stitute (NYSPI),Columbia University, New York, New York Disclosures: Dr. Strawn has received research support from Eli Lilly and Shire and from the American Academy of Child & Adoles- cent Psychiatry. Dr. DelBello has received research support from AstraZeneca, Eli Lilly, Johnson & Johnson, Shire, Janssen, Pfizer, Bristol-Myers Squibb, Repligen, Martek, Somerset, GlaxoSmithK- line, and Sumitomo; has participated in lecture bureaus for Bristol- Myers Squibb and Merck; and has consulted for GlaxoSmithKline, Eli Lilly, Merck, and Bristol-Myers Squibb. Dr. Rynn has received research support from Eli Lilly and Shire. Dr. Strakowski reports research support from Eli Lilly, Janssen, AstraZeneca, Martek Bio- sciences, Nutrition 21, and Repligen; and has consulted for CME Outfitters, Adamed, Consensus Medical Communications (CME through the University of Minnesota; unrestricted grant from Ortho McNeil/Janssen) and Web MD. Ms. Wehry reports no biomedical conflicts of interest. ∗ Correspondence to: Jeffrey R. Strawn, M.D., Dept. of Psychiatry, University of Cincinnati, Box 670559, Cincinnati, OH 45267-0559. E-mail: strawnjr@uc.edu Received for publication 9 September 2011; Revised 29 November 2011; Accepted 4 December 2011 DOI 10.1002/da.21913 Published online in Wiley Online Library (wileyonlinelibrary.com). C  2012 Wiley Periodicals, Inc.