A PET Study of Tiagabine Treatment Implicates Ventral Medial Prefrontal Cortex in Generalized Social Anxiety Disorder

Department of Psychiatry, Psychiatric Neuroscience Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology (Impact Factor: 7.05). 07/2008; 34(2):390-8. DOI: 10.1038/npp.2008.69
Source: PubMed


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 gamma-aminobutyric acid (GABA) reuptake inhibitor, the present [(18)F] fluorodeoxyglucose-positron emission tomography ((18)FDG-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 (18)FDG-PET scan. Twelve of the gSAD individuals completed an open, 6-week, flexible dose trial of tiagabine, and underwent a second (posttreatment) resting-state (18)FDG-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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Available from: Darin D Dougherty, Mar 24, 2014
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    • "We had previously shown that acute OXT exerted effects on the amygdala and mPFC/ACC during the processing of threat and other negative emotions (Labuschagne et al, 2010, 2011). Both the amygdala and rostral ACC/mPFC are putative neural 'targets' of psychosocial and pharmacological treatments known to be effective in GSAD (Evans et al, 2009; Goldin et al, 2013; Klumpp et al, 2013a; Phan et al, 2013). Furthermore, our correlation analysis found that in GSAD patients, the magnitude of change induced by OXT (from PBO) in left amygdala-ACC/mPFC is correlated with the severity of social interactional anxiety such that those with the highest levels of anxiety may benefit the most from OXT treatment. "
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    ABSTRACT: Generalized social anxiety disorder (GSAD) is characterized by aberrant patterns of amygdala-frontal connectivity to social signals of threat and at rest. The neuropeptide oxytocin (OXT) modulates anxiety, stress and social behaviors. Recent functional neuroimaging studies suggest these effects are mediated through OXT's effects on amygdala reactivity and/or amygdala-frontal connectivity. The aim of the current study was to examine OXT's effects on amygdala-frontal resting-state functional connectivity (rsFC) in GSAD patients and healthy controls (HC). In a randomized, double-blind, cross-over design, 18 GSAD and 18 HC participants received intranasal OXT (24 IU or 40.32 μg) or placebo prior to resting-state functional magnetic resonance imaging. In individuals with GSAD, OXT enhanced rsFC of the left and right amygdala with rostral ACC/mPFC, and in doing so, reversed (i.e., 'normalized') the reduced amygdala-frontal connectivity observed relative to HCs evident on placebo. Higher social anxiety severity in GSAD subjects correlated with lower amygdala-ACC/mPFC connectivity on placebo and higher social anxiety also correlated with greater enhancement in amygdala-frontal connectivity induced by OXT. These findings show that OXT modulates a neural circuit known for social threat processing and emotion regulation, suggesting a neural mechanism by which OXT may play a role in the pathophysiology and treatment of social anxiety disorder.Neuropsychopharmacology accepted article preview online, 5 March 2014; doi:10.1038/npp.2014.53.
    Full-text · Article · Mar 2014 · Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology
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    • "In a PET-FDG study, Evans and colleagues [87] found no significant voxelwise correlations between pre-treatment rCMRglu in their regions of interest (which included mPFC/ACC, amygdala, hippocampus, parahippocampal gyrus, insula) and symptomatic improvement after treatment with tiagabine. However, categorical group comparisons revealed that treatment responders had lower pre-treatment rCMRglu in subcallosal gyrus compared to healthy control subjects. "
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    ABSTRACT: Although several psychological and pharmacological treatment options are available for anxiety disorders, not all patients respond well to each option. Furthermore, given the relatively long duration of adequate treatment trials, finding a good treatment fit can take many months or longer. Thus, both clinicians and patients would benefit from the identification of objective pre-treatment measures that predict which patients will best respond to a given treatment. Recent studies have begun to use biological measures to help predict symptomatic change after treatment in anxiety disorders. In this review, we summarize studies that have used structural and functional neuroimaging measures to predict treatment response in obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD), generalized anxiety disorder (GAD), and social anxiety disorder (SAD). We note the limitations of the current studies and offer suggestions for future research. Although the literature is currently small, we conclude that pre-treatment neuroimaging measures do appear to predict treatment response in anxiety disorders, and future research will be needed to determine the relative predictive power of neuroimaging measures as compared to clinical and demographic measures.
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    • "Findings from functional imaging have been fairly consistent. Individuals with SAD demonstrate increased activation of the amygdala and connecting frontal-striatal cortices when exposed to negative or threatening facial expressions (Yoon et al., 2007; Evans et al., 2009; Shah et al., 2009; Klumpp et al., 2010; Schmidt et al., 2010). "
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    ABSTRACT: Social anxiety disorder (SAD) is one of the most common and disabling anxiety disorders, yet much remains to be learned about its psychobiology. Although functional imaging has emphasized the role of the amygdala and other limbic structures in the neurobiology of SAD, structural and connectivity imaging techniques have emphasized the possibility of abnormalities in other regions and in whole-brain networks. The involvement of a broad range of networks in SAD is consistent with current understandings of the neuroanatomy of emotion and of social processing. Copyright © 2012 John Wiley & Sons, Ltd.
    No preview · Article · Jan 2013 · Human Psychopharmacology Clinical and Experimental
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