RT Journal Article SR Electronic T1 A Link between Serotonin-Related Gene Polymorphisms, Amygdala Activity, and Placebo-Induced Relief from Social Anxiety JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP 13066 OP 13074 DO 10.1523/JNEUROSCI.2534-08.2008 VO 28 IS 49 A1 Furmark, Tomas A1 Appel, Lieuwe A1 Henningsson, Susanne A1 Åhs, Fredrik A1 Faria, Vanda A1 Linnman, Clas A1 Pissiota, Anna A1 Frans, Örjan A1 Bani, Massimo A1 Bettica, Paolo A1 Pich, Emilio Merlo A1 Jacobsson, Eva A1 Wahlstedt, Kurt A1 Oreland, Lars A1 Långström, Bengt A1 Eriksson, Elias A1 Fredrikson, Mats YR 2008 UL http://www.jneurosci.org/content/28/49/13066.abstract AB 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.