title: A link between serotonin-related gene polymorphisms, amygdala activity, and placebo-induced relief from social anxiety.
abstract: 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.
authors.affiliation: Department of Psychology, Uppsala University, Uppsala, Sweden. tomas.furmark@psyk.uu.se
authors.forename: Tomas
authors.initials: T
authors.lastname: Furmark
authors.forename: Lieuwe
authors.initials: L
authors.lastname: Appel
authors.forename: Susanne
authors.initials: S
authors.lastname: Henningsson
authors.forename: Fredrik
authors.initials: F
authors.lastname: Ahs
authors.forename: Vanda
authors.initials: V
authors.lastname: Faria
authors.forename: Clas
authors.initials: C
authors.lastname: Linnman
authors.forename: Anna
authors.initials: A
authors.lastname: Pissiota
authors.forename: Orjan
authors.initials: O
authors.lastname: Frans
authors.forename: Massimo
authors.initials: M
authors.lastname: Bani
authors.forename: Paolo
authors.initials: P
authors.lastname: Bettica
authors.forename: Emilio Merlo
authors.initials: EM
authors.lastname: Pich
authors.forename: Eva
authors.initials: E
authors.lastname: Jacobsson
authors.forename: Kurt
authors.initials: K
authors.lastname: Wahlstedt
authors.forename: Lars
authors.initials: L
authors.lastname: Oreland
authors.forename: Bengt
authors.initials: B
authors.lastname: Långström
authors.forename: Elias
authors.initials: E
authors.lastname: Eriksson
authors.forename: Mats
authors.initials: M
authors.lastname: Fredrikson
mesh_terms: D000328:Adult; D000679:Amygdala / Q000000981:diagnostic imaging / Q000378:metabolism*; D001008:Anxiety Disorders / Q000000981:diagnostic imaging / Q000235:genetics* / Q000628:therapy; D004252:DNA Mutational Analysis; D004311:Double-Blind Method; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D015990:Placebo Effect; D011110:Polymorphism, Genetic / Q000235:genetics; D049268:Positron-Emission Tomography; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics*; D013315:Stress, Psychological / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism; D014365:Tryptophan Hydroxylase / Q000235:genetics*; D055815:Young Adult
chemical_list: D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin; D014365:Tryptophan Hydroxylase