A link between serotonin-related gene polymorphisms, amygdala activity, and placebo-induced relief from social anxiety
Open accessAbstract
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.
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Elevated SLC6A4 methylation is associated with generalized anxiety disorder (GAD) and panic disorder, correlates with increased anxiety traits, social anxiety, and amygdala hyperreactivity.
“Elevated SLC6A4 methylation is also associated with generalized anxiety disorder (GAD) and panic disorder, correlates with increased anxiety traits, social anxiety, and amygdala hyperreactivity”
From The clinical use of epigenetics in psychiatry: a narrative review of epigenetic mechanisms, key candidate genes, and precision psychiatry (2025) · cites this paper as [107]
The Genotyping section examines 5-HTTLPR and TPH2 polymorphisms, not SLC6A4 methylation. The Discussion links those genetic variants to amygdala activity and placebo response in social anxiety disorder; it does not address whether elevated methylation is associated with the conditions or traits claimed. Searches for SLC6A4 methylation and DNA methylation found no relevant passage in our copy. (LLM, conf=0.76)
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- Authors
- Furmark, T., Appel, L., Henningsson, S., Åhs, F., Faria, V., Linnman, C., Pissiota, A., Frans, Ö., Bani, M., Bettica, P., Pich, E. M., Jacobsson, E., Wahlstedt, K., Oreland, L., Långström, B., Eriksson, E., & Fredrikson, M.
- Affiliations
- Uppsala University (SE)
- University of Gothenburg (SE)
- GlaxoSmithKline (Italy) (IT)
- Corresponding author
- Furmark, Tomas
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2008-12-03
- Volume
- 28
- Issue
- 49
- Pages
- 13066-13074
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6671592
- OpenAlex
- W2161011520
- Cited by
- 210
- References
- 60
- Citations by year
- 2026: 1 · 2025: 8 · 2024: 1 · 2023: 3 · 2022: 10 · 2021: 8 · 2020: 14 · 2019: 5 · 2018: 11 · 2017: 13 · 2016: 17 · 2015: 14 · 2014: 25 · 2013: 15 · 2012: 18
- FWCI
- 7.82
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- GlaxoSmithKline
- Vetenskapsrådet
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Pain Management and Placebo Effect
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
- Keywords
- placebo response, social anxiety disorder, serotonin, 5-HTTLPR, tryptophan hydroxylase 2, amygdala activity, genetic polymorphism, public speaking stress, serotonergic modulation
- MeSH terms
- Adult, Amygdala, Anxiety Disorders, DNA Mutational Analysis, Double-Blind Method, Female, Gene Frequency, Genetic Testing, Genotype, Humans, Male, Middle Aged, Neuropsychological Tests, Polymorphism, Genetic, Serotonin, Stress, Psychological, Tryptophan Hydroxylase, Placebo Effect, Genetic Predisposition to Disease, Positron-Emission Tomography, Serotonin Plasma Membrane Transport Proteins, Young Adult
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