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Amygdala Subregions Tied to SSRI and Placebo Response in Patients with Social Anxiety Disorder
Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology. Department of Psychology and Neuroscience, Duke University, Durham, NC, USA.
P.A.I.N. Group, Department of Anesthesia, Children's Hospital, Boston, MA, USA.
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2012 (English)In: Neuropsychopharmacology, ISSN 0893-133X, E-ISSN 1740-634X, Vol. 37, no 10, 2222-2232 p.Article in journal (Refereed) Published
Abstract [en]

The amygdala is a key structure in the pathophysiology of anxiety disorders, and a putative target for anxiolytic treatments, Selective serotonin reuptake inhibitors (SSRIs) and placebo seem to induce anxiolytic effects by attenuating amygdala responsiveness. However, conflicting amygdala findings have also been reported. Moreover, the neural profile of responders and nonresponders is insufficiently characterized and it remains unknown whether SSRIs and placebo engage common or distinct amygdala subregions or different modulatory cortical areas. We examined similarities and differences in the neural response to SSRIs and placebo in patients with social anxiety disorder (SAD). Positron emission tomography (PET) with oxygen-15-labeled water was used to assess regional cerebral blood flow (rCBF) in 72 patients with SAD during an anxiogenic public speaking task, before and after 6-8 weeks of treatment under double-blind conditions. Response rate was determined by the Clinical Global Impression-Improvement scale. Conjunction analysis revealed a common rCBF-attenuation from pre- to post-treatment in responders to SSRIs and placebo in the left basomedial/basolateral and right ventrolateral amygdala. This rCBF pattern con-elated with behavioral measures of reduced anxiety and differentiated responders from nonresponders. However, nonanxiolytic treatment effects were also observed in the amygdala. All subgroups, including nonresponders, showed deactivation of the left lateral part of the amygdala. No rCBF differences were found between SSRI responders and placebo responders. This study provides new insights into the brain dynamics underlying anxiety relief by demonstrating common amygdala targets for pharmacologically and psychologically induced anxiety reduction, and by showing that the amygdala is functionally heterogeneous in anxiolysis.

Place, publisher, year, edition, pages
Nature Publishing Group, 2012. Vol. 37, no 10, 2222-2232 p.
Keyword [en]
amygdala, SSRIs, placebo, SAD, subregions, PET
National Category
Medical and Health Sciences
Research subject
URN: urn:nbn:se:uu:diva-181544DOI: 10.1038/npp.2012.72ISI: 000307796600005OAI: oai:DiVA.org:uu-181544DiVA: diva2:556650
Available from: 2012-09-25 Created: 2012-09-25 Last updated: 2014-12-01Bibliographically approved
In thesis
1. Mind really does matter: The Neurobiology of Placebo-induced Anxiety Relief in Social Anxiety Disorder
Open this publication in new window or tab >>Mind really does matter: The Neurobiology of Placebo-induced Anxiety Relief in Social Anxiety Disorder
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The placebo effect, a beneficial effect attributable to a treatment containing no specific properties for the condition being treated, has been demonstrated in a variety of medical conditions. This thesis includes four studies aimed at increasing our knowledge on the neurobiology of placebo. Study I, a review of the placebo neuroimaging literature, suggested that the anterior cingulate cortex (ACC) may be a common site of action for placebo responses. However, because placebo neuroimaging studies in clinical disorders are largely lacking, the clinical relevance of this needs further clarification. The subsequent three empirical studies were thus designed from a clinical perspective. Using positron emission tomography (PET) these studies investigated the underlying neurobiology of sustained placebo responses in patients with social anxiety disorder (SAD), a disabling psychiatric condition that nonetheless may be mitigated by placebo interventions. Study II demonstrated that serotonergic gene polymorphisms affect anxiety-induced neural activity and the resultant placebo phenotype. In particular, anxiety reduction resulting from placebo treatment was tied to the attenuating effects of the TPH2 G-703T polymorphism on amygdala activity. Study III further compared the neural response profile of placebo with selective serotonin reuptake inhibitors (SSRIs), i.e the first-line pharmacological treatment for SAD. A similar anxiety reduction was noted in responders of both treatments. PET-data further revealed that placebo and SSRI responders had similar decreases of the neural response in amygdala subregions including the left basomedial/basolateral (BM/BLA) and the right ventrolateral (VLA) sections. To clarify whether successful placebo and SSRI treatments operate via similar or distinct neuromodulatory pathways, study IV focused on the connectivity patterns between the amygdala and prefrontal cortex that may be crucial for normal emotion regulation. In responders of both treatment modalities, the left amygdala (BM/BLA) exhibited negative coupling with the dorsolateral prefrontal cortex and the rostral ACC as well as a shared positive coupling with the dorsal ACC. This may represent shared treatment mechanisms involving improved emotion regulation and decreased rumination. This thesis constitutes a first step towards better understanding of the neurobiology of placebo in the treatment of anxiety, including the neural mechanisms that unite and segregate placebo and SSRI treatment.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 92 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Social Sciences, ISSN 1652-9030 ; 82
Placebo effect, anxiolysis, SAD, PET, TPH2 G-703T polymorphism, SSRIs, amygdala subregions, prefrontal cortex.
National Category
Research subject
urn:nbn:se:uu:diva-181548 (URN)978-91-554-8478-1 (ISBN)
Public defence
2012-11-09, Auditorium Minus, Gustavianum, Akademigatan 3, Uppsala, 13:15 (English)
Available from: 2012-10-19 Created: 2012-09-25 Last updated: 2013-01-23Bibliographically approved

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