A link between serotonin-related gene polymorphisms, amygdala activity, and placebo-induced relief from social anxiety.
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.
Furmark
Tomas
T
Department of Psychology, Uppsala University, Uppsala, Sweden. tomas.furmark@psyk.uu.se
Appel
Lieuwe
L
Henningsson
Susanne
S
Ahs
Fredrik
F
Faria
Vanda
V
Linnman
Clas
C
Pissiota
Anna
A
Frans
Orjan
O
Bani
Massimo
M
Bettica
Paolo
P
Pich
Emilio Merlo
EM
Jacobsson
Eva
E
Wahlstedt
Kurt
K
Oreland
Lars
L
Långström
Bengt
B
Eriksson
Elias
E
Fredrikson
Mats
M
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
D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin; D014365:Tryptophan Hydroxylase