title: Reduced serotonin synthesis and regional cerebral blood flow after anxiolytic treatment of social anxiety disorder.
abstract: Social anxiety disorder (SAD) is associated with increased fear-related neural activity in the amygdala and we recently found enhanced serotonin synthesis rate in the same region. Anxiolytic agents like selective serotonin re-uptake inhibitors (SSRIs) and neurokinin-1 receptor (NK1R) antagonists reduce amygdala activity and may attenuate serotonin formation according to animal studies. Here, we examined the effects of SSRI pharmacotherapy, NK1R antagonism, and placebo on serotonin synthesis rate in relation to neural activity, measured as regional cerebral blood flow (rCBF), and symptom improvement in SAD. Eighteen SAD patients were randomized to receive daily double-blind treatment for six weeks either with the SSRI citalopram (n=6; 40mg), the NK1R antagonist GR205171 (n=6; 5mg; 4 weeks following 2 weeks of placebo), or placebo (n=6). Serotonin synthesis rate at rest and rCBF during stressful public speaking were assessed, before and after treatment, using positron emission tomography with the tracers [11C]5-hydroxytryptophan and [15O]water respectively. The Liebowitz Social Anxiety Scale (LSAS-SR) indexed symptom severity. All groups exhibited attenuated amygdala serotonin synthesis rate after treatment, which was associated with reduced amygdala rCBF during public speaking and accompanied by symptom improvement. These results are consistent with the notion that serotonin in the amygdala exerts an anxiogenic influence and, conversely, that anxiolysis is achieved through decreased serotonin formation in the amygdala.
authors.affiliation: Department of Psychology, Uppsala University, Uppsala, Sweden. Electronic address: andreas.frick@psyk.uu.se.
authors.forename: Andreas
authors.initials: A
authors.lastname: Frick
authors.affiliation: Department of Psychology, Uppsala University, Uppsala, Sweden; Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Åhs
authors.affiliation: Section of Nuclear Medicine and PET, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Lieuwe
authors.initials: L
authors.lastname: Appel
authors.affiliation: Section of Nuclear Medicine and PET, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: My
authors.initials: M
authors.lastname: Jonasson
authors.affiliation: Department of Psychology, Uppsala University, Uppsala, Sweden.
authors.forename: Kurt
authors.initials: K
authors.lastname: Wahlstedt
authors.affiliation: GlaxoSmithKline, Verona, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Bani
authors.affiliation: GlaxoSmithKline, Verona, Italy.
authors.forename: Emilio
authors.initials: E
authors.lastname: Merlo Pich
authors.affiliation: GlaxoSmithKline, Verona, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Bettica
authors.affiliation: Department of Chemistry, Uppsala University, Uppsala, Sweden.
authors.forename: Bengt
authors.initials: B
authors.lastname: Långström
authors.affiliation: Section of Nuclear Medicine and PET, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Mark
authors.initials: M
authors.lastname: Lubberink
authors.affiliation: Department of Psychology, Uppsala University, Uppsala, Sweden; Department 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: D000328:Adult; D000679:Amygdala / Q000187:drug effects; D014151:Anti-Anxiety Agents / Q000627:therapeutic use*; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D015283:Citalopram / Q000627:therapeutic use; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007700:Kinetics; D008297:Male; D064729:Neurokinin-1 Receptor Antagonists / Q000494:pharmacology; D000072861:Phobia, Social / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism*; D010880:Piperidines / Q000627:therapeutic use; D049268:Positron-Emission Tomography; D011569:Psychiatric Status Rating Scales; D012701:Serotonin / Q000096:biosynthesis*; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use; D012931:Social Environment; D013315:Stress, Psychological / Q000503:physiopathology / Q000523:psychology; D013777:Tetrazoles / Q000627:therapeutic use
chemical_list: D014151:Anti-Anxiety Agents; D015283:Citalopram; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; D013777:Tetrazoles; C103207:vofopitant
keywords: 5-HT; NK1; Positron emission tomography; SSRI; Social phobia