Serotonin Synthesis and Reuptake in Social Anxiety Disorder: A Positron Emission Tomography Study

JAMA Psychiatry. 2015 Aug;72(8):794-802. doi: 10.1001/jamapsychiatry.2015.0125.


Importance: Serotonin is involved in negative affect, but whether anxiety syndromes, such as social anxiety disorder (SAD), are characterized by an overactive or underactive serotonin system has not been established. Serotonin 1A autoreceptors, which inhibit serotonin synthesis and release, are downregulated in SAD, and serotonin transporter availability might be increased; however, presynaptic serotonin activity has not been evaluated extensively.

Objective: To examine the serotonin synthesis rate and serotonin transporter availability in patients with SAD and healthy control individuals using positron emission tomography (PET) with the radioligands 5-hydroxytryptophan labeled with carbon 11 ([11C]5-HTP) and 11C-labeled 3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile [11C]DASB.

Design, setting, and participants: We performed a cross-sectional study at an academic clinical research center. Eighteen patients with SAD (9 men and 9 women; mean [SD] age, 32.6 [8.2] years) and 18 sex- and age-matched healthy controls (9 men and 9 women; mean [SD] age, 34.7 [9.2] years) underwent [11C]5-HTP PET imaging. We acquired [11C]DASB PET images for 26 additional patients with SAD (14 men and 12 women; mean [SD] age, 35.2 [10.7] years) and the same 18 sex- and age-matched healthy controls. Participants were recruited through newspaper advertisements. Data were acquired from March 12, 2002, through March 5, 2012, and analyzed from March 28, 2013, through August 29, 2014.

Main outcomes and measures: The influx rate of [11C]5-HTP as a measure of serotonin synthesis rate capacity and [11C]DASB binding potential as an index of serotonin transporter availability were acquired during rest. We used the Liebowitz Social Anxiety Scale to measure severity of social anxiety symptoms.

Results: The PET data were not available for analysis in 1 control for each scan. Increased [11C]5-HTP influx rate was observed in the amygdala, raphe nuclei region, caudate nucleus, putamen, hippocampus, and anterior cingulate cortex of patients with SAD compared with healthy controls (P < .05 corrected), supporting an enhanced serotonin synthesis rate. Increased serotonin transporter availability in the patients with SAD relative to healthy controls was reflected by elevated [11C]DASB binding potential in the raphe nuclei region, caudate nucleus, putamen, thalamus, and insula cortex (P < .05 corrected).

Conclusions and relevance: Neurotransmission in SAD is characterized by an overactive presynaptic serotonin system, with increased serotonin synthesis and transporter availability. Our findings could provide important new insights into the etiology of anxiety disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5-Hydroxytryptophan
  • Adult
  • Anxiety Disorders / metabolism*
  • Benzylamines
  • Brain / metabolism*
  • Carbon Radioisotopes
  • Case-Control Studies
  • Cross-Sectional Studies
  • Female
  • Functional Neuroimaging
  • Humans
  • Male
  • Phobic Disorders / metabolism*
  • Positron-Emission Tomography
  • Serotonin / biosynthesis
  • Serotonin / metabolism*
  • Serotonin Plasma Membrane Transport Proteins / metabolism*
  • Social Behavior*
  • Young Adult


  • Benzylamines
  • Carbon Radioisotopes
  • N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine
  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin
  • 5-Hydroxytryptophan