title: Serotonin Synthesis and Reuptake in Social Anxiety Disorder: A Positron Emission Tomography Study.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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
  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.
authors.affiliation: Department of Psychology, Uppsala University, Uppsala, Sweden.
authors.forename: Andreas
authors.initials: A
authors.lastname: Frick
authors.affiliation: Department of Psychology, Uppsala University, Uppsala, Sweden2Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Åhs
authors.affiliation: Department of Psychology, Uppsala University, Uppsala, Sweden.
authors.forename: Jonas
authors.initials: J
authors.lastname: Engman
authors.affiliation: Department of Nuclear Medicine and Positron Emission Tomography, Uppsala University, Uppsala, Sweden.
authors.forename: My
authors.initials: M
authors.lastname: Jonasson
authors.affiliation: Department of Psychology, Uppsala University, Uppsala, Sweden.
authors.forename: Iman
authors.initials: I
authors.lastname: Alaie
authors.affiliation: Department of Psychology, Uppsala University, Uppsala, Sweden.
authors.forename: Johannes
authors.initials: J
authors.lastname: Björkstrand
authors.affiliation: Department of Psychology, Uppsala University, Uppsala, Sweden.
authors.forename: Örjan
authors.initials: Ö
authors.lastname: Frans
authors.affiliation: Department of Psychology, Uppsala University, Uppsala, Sweden4Center for Pain and the Brain, Department of Anesthesiology, Perioperative, and Pain Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Vanda
authors.initials: V
authors.lastname: Faria
authors.affiliation: Department of Psychology, Uppsala University, Uppsala, Sweden4Center for Pain and the Brain, Department of Anesthesiology, Perioperative, and Pain Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Clas
authors.initials: C
authors.lastname: Linnman
authors.affiliation: Department of Nuclear Medicine and Positron Emission Tomography, Uppsala University, Uppsala, Sweden.
authors.forename: Lieuwe
authors.initials: L
authors.lastname: Appel
authors.affiliation: Department of Psychology, Uppsala University, Uppsala, Sweden.
authors.forename: Kurt
authors.initials: K
authors.lastname: Wahlstedt
authors.affiliation: Department of Nuclear Medicine and Positron Emission Tomography, Uppsala University, Uppsala, Sweden.
authors.forename: Mark
authors.initials: M
authors.lastname: Lubberink
authors.affiliation: Department of Psychology, Uppsala University, Uppsala, Sweden2Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Mats
authors.initials: M
authors.lastname: Fredrikson
authors.affiliation: Department of Psychology, Uppsala University, Uppsala, Sweden.
authors.forename: Tomas
authors.initials: T
authors.lastname: Furmark
mesh_terms: D006916:5-Hydroxytryptophan; D000328:Adult; D001008:Anxiety Disorders / Q000378:metabolism*; D001596:Benzylamines; D001921:Brain / Q000378:metabolism*; D002250:Carbon Radioisotopes; D016022:Case-Control Studies; D003430:Cross-Sectional Studies; D005260:Female; D059907:Functional Neuroimaging; D006801:Humans; D008297:Male; D010698:Phobic Disorders / Q000378:metabolism*; D049268:Positron-Emission Tomography; D012701:Serotonin / Q000096:biosynthesis / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D012919:Social Behavior; D055815:Young Adult
chemical_list: D001596:Benzylamines; D002250:Carbon Radioisotopes; C420885:N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine; D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin; D006916:5-Hydroxytryptophan