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The Journal of Neuroscience, December 3, 2008, 28(49):13066-13074; doi:10.1523/JNEUROSCI.2534-08.2008

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Behavioral/Systems/Cognitive
A Link between Serotonin-Related Gene Polymorphisms, Amygdala Activity, and Placebo-Induced Relief from Social Anxiety

Tomas Furmark,¹ Lieuwe Appel,² Susanne Henningsson,³ Fredrik Åhs,¹ Vanda Faria,¹ Clas Linnman,¹ Anna Pissiota,¹ Örjan Frans,¹ Massimo Bani,⁴ Paolo Bettica,⁴ Emilio Merlo Pich,⁴ Eva Jacobsson,⁵ Kurt Wahlstedt,⁵ Lars Oreland,⁶ Bengt Långström,^2,7 Elias Eriksson,³ and Mats Fredrikson¹

¹Department of Psychology, Uppsala University, SE-751 42 Uppsala, Sweden, ²Uppsala Imanet, GE Healthcare, SE-751 09 Uppsala, Sweden, ³Department of Pharmacology, Göteborg University, SE-405 30 Göteborg, Sweden, ⁴GlaxoSmithKline, Medicine Research Centre, 37135 Verona, Italy, ⁵Quintiles AB Phase I Services, SE-753 23 Uppsala, Sweden, ⁶Department of Neuroscience, Pharmacology, Uppsala University, SE-751 24 Uppsala, Sweden, and ⁷Department of Biochemistry and Organic Chemistry, Uppsala University, SE-751 23 Uppsala, Sweden

Correspondence should be addressed to Dr. Tomas Furmark, Department of Psychology, Uppsala University, Box 1225, SE-751 42 Uppsala, Sweden. Email: tomas.furmark{at}psyk.uu.se

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.

Key words: placebo; genes; phobia; serotonin; brain; functional neuroimaging

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Received June 4, 2008; revised Sept. 29, 2008; accepted Oct. 22, 2008.

Correspondence should be addressed to Dr. Tomas Furmark, Department of Psychology, Uppsala University, Box 1225, SE-751 42 Uppsala, Sweden. Email: tomas.furmark{at}psyk.uu.se

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