Abstract
Corticolimbic circuitry has been implicated in generalized social anxiety disorder (gSAD) by several neuroimaging symptom provocation studies. However, there are limited data regarding resting state or treatment effects on regional cerebral metabolic rate of glucose uptake (rCMRglu). Given evidence for anxiolytic effects conferred by tiagabine, a γ-aminobutyric acid (GABA) reuptake inhibitor, the present [18F] fluorodeoxyglucose-positron emission tomography (18FDG-PET) study sought to (1) compare resting rCMRglu between healthy control (HC) and pretreatment gSAD cohorts, (2) examine pre- to post-tiagabine treatment rCMRglu changes in gSAD, and (3) determine rCMRglu predictors of tiagabine treatment response. Fifteen unmedicated individuals with gSAD and ten HCs underwent a baseline (pretreatment) resting-state 18FDG-PET scan. Twelve of the gSAD individuals completed an open, 6-week, flexible dose trial of tiagabine, and underwent a second (posttreatment) resting-state 18FDG-PET scan. Compared to the HC subjects, individuals with gSAD demonstrated less pretreatment rCMRglu within the anterior cingulate cortex and ventral medial prefrontal cortex (vmPFC) at baseline. Following tiagabine treatment, vmPFC rCMRglu increased significantly in the gSAD group. Further, the magnitude of treatment response was inversely correlated with pretreatment rCMRglu within vmPFC. Taken together the present findings converge with neuroimaging findings from studies of social cognition in healthy individuals and symptom provocation in gSAD to support a role for the vmPFC in the pathophysiology of gSAD. Given the pharmacological profile of tiagabine, these findings suggest that its therapeutic effects in gSAD may be mediated by GABAergic modulation within the vmPFC.
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Acknowledgements
The study was supported by a grant from Cephalon Inc. Dr Evans was supported by the Clinical Investigator Training Program (Harvard/MIT/HST-BIDMC, in collaboration with Pfizer Inc. and Merck & Co Inc.), the American Psychiatric Research Institute for Research and Education/Merck & Co Early Academic Career Research Award and NIH grants MH T32 19126 and EB T32 1632-03. Dr Rauch was supported in part by NIMH R01 grants MH60219, MH074848, and MH070730. We thank the research participants as well as Diana Fischmann, Elizabeth Scannell, and Steve Weise, for technical assistance.
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Previously presented in part as a poster at the 2006 American College of Neuropsychopharmacology Annual Meeting.
DISCLOSURES/CONFLICTS OF INTEREST
This study was supported by an investigator-initiated grant from Cephalon. Additional disclosures from the individual authors are listed below.
Karleyton C Evans
Participation in sponsored clinical trials: Cephalon, Cyberonics, Northstar Neuroscience, Pfizer
Unrestricted research fellowship support: Janssen, Merck, Pfizer
Naomi M Simon
Participation in sponsored clinical trials: NIMH, NARSAD, Astra Zeneca, Cephalon, Forest Laboratories, GlaxoSmithKline, Lilly, Pfizer, UCB-Pharma, Sepracor
Advisory Boards and Consulting: Solvay
Darin D Dougherty
Participation in sponsored clinical trials: McNeil, Cyberonics, Forest Laboratories, Lilly, Medtronics, Northstar Neuroscience
Speaker's Bureau for CME and other presentations: Cyberonics, McNeil
Elizabeth A Hoge
Participation in sponsored clinical trials: Astra Zeneca, Cephalon, Forest Laboratories, GlaxoSmithKline, Janssen, Lilly, Pfizer, UCB-Pharma, Sepracor
Unrestricted research fellowship support: Merck, Pfizer
John J Worthington
Participation in sponsored clinical trials: Abbott Laboratories, Alkermes, Aspect Medical Systems, Astra-Zeneca, Bristol-Myers Squibb Company, Cephalon, Eli Lilly, Forest Pharmaceuticals Inc., GlaxoSmithkline, J & J Pharmaceuticals, Lichtwer Pharma GmbH, Lorex Pharmaceuticals, Novartis, Organon Inc., PamLab, LLC, Pfizer Inc., Pharmavite, Roche, Sanofi-Aventis, Sepracor, Solvay Pharmaceuticals Inc., UCB Pharma and Wyeth-Ayerst Laboratories
Speaker's Bureau for CME and other presentations: Bristol-Myers Squibb Company, Eli Lilly, Forest Pharmaceuticals Inc., GlaxoSmithKline, Pfizer Inc., Sanofi-Aventis and Wyeth-Ayerst Laboratories
Candice Chow
No financial interests to disclose.
Rebecca E Kaufman
No financial interests to disclose.
Andrea L Gold
Participation in sponsored clinical trials: Cephalon
Alan J Fischman
Participation in sponsored clinical trials: Cephalon, GlaxoSmithKline, McNeil Inc., Shire Pharmaceuticals Group
Mark H Pollack
Advisory Boards and Consulting: AstraZeneca, Brain Cells Inc., Bristol Myers Squibb, Cephalon, Forest Laboratories, GlaxoSmithKline, Janssen, Jazz Pharmaceuticals, Eli Lilly, Medavante, Neurocrine, Neurogen, Novartis, Otsuka Pharmaceuticals, Pfizer, Predix, Roche, Sanofi, Sepracor, Solvay, Tikvah Therapeutics, Transcept Inc., UCB Pharma, Wyeth
Research Grants: Bristol Myers Squibb, Cephalon, Forest Laboratories, GlaxoSmithKline, Janssen, Eli Lilly, NARSAD, NIDA NIMH, Pfizer, Sepracor, UCB Pharma, Wyeth
Speaker's Bureau for CME and other presentations: Bristol Myers Squibb, Forest Laboratories, GlaxoSmithKline, Janssen, Lilly, Pfizer, Solvay, Wyeth
Equity: Medavante, Mensante Corporation
Scott L Rauch
Consulting: Novartis, Neurogen, Sepracor
Participation in sponsored clinical trials: Cephalon, Cyberonics, Medtronic Inc.
Speaker's Bureau for CME and other presentations: Novartis
Unrestricted research support of laboratory fellows: Pfizer
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Evans, K., Simon, N., Dougherty, D. et al. A PET Study of Tiagabine Treatment Implicates Ventral Medial Prefrontal Cortex in Generalized Social Anxiety Disorder. Neuropsychopharmacol 34, 390–398 (2009). https://doi.org/10.1038/npp.2008.69
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DOI: https://doi.org/10.1038/npp.2008.69
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