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A link between serotonin-related gene polymorphisms, amygdala activity, and placebo-induced relief from social anxiety
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
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2008 (English)In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 28, no 49, 13066-74 p.Article in journal (Refereed) Published
Abstract [en]

Placebo may yield beneficial effects that are indistinguishable from those of active medication, but the factors underlying proneness to respond to placebo are widely unknown. Here, we used functional neuroimaging to examine neural correlates of anxiety reduction resulting from sustained placebo treatment under randomized double-blind conditions, in patients with social anxiety disorder. Brain activity was assessed during a stressful public speaking task by means of positron emission tomography before and after an 8 week treatment period. Patients were genotyped with respect to the serotonin transporter-linked polymorphic region (5-HTTLPR) and the G-703T polymorphism in the tryptophan hydroxylase-2 (TPH2) gene promoter. Results showed that placebo response was accompanied by reduced stress-related activity in the amygdala, a brain region crucial for emotional processing. However, attenuated amygdala activity was demonstrable only in subjects who were homozygous for the long allele of the 5-HTTLPR or the G variant of the TPH2 G-703T polymorphism, and not in carriers of short or T alleles. Moreover, the TPH2 polymorphism was a significant predictor of clinical placebo response, homozygosity for the G allele being associated with greater improvement in anxiety symptoms. Path analysis supported that the genetic effect on symptomatic improvement with placebo is mediated by its effect on amygdala activity. Hence, our study shows, for the first time, evidence of a link between genetically controlled serotonergic modulation of amygdala activity and placebo-induced anxiety relief.

Place, publisher, year, edition, pages
2008. Vol. 28, no 49, 13066-74 p.
Keyword [en]
placebo, genes, phobia, serotonin, brain, functional neuroimaging
National Category
Pharmaceutical Sciences
URN: urn:nbn:se:uu:diva-102680DOI: 10.1523/JNEUROSCI.2534-08.2008ISI: 000261378100005PubMedID: 19052197OAI: oai:DiVA.org:uu-102680DiVA: diva2:216627
Available from: 2009-05-11 Created: 2009-05-11 Last updated: 2013-01-23Bibliographically 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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