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Serotonin Synthesis and Reuptake in Social Anxiety Disorder: A Positron Emission Tomography Study.
Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
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2015 (English)In: JAMA psychiatry, ISSN 2168-6238, E-ISSN 2168-622X, Vol. 72, no 8, 794-802 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2015. Vol. 72, no 8, 794-802 p.
National Category
Psychology
Identifiers
URN: urn:nbn:se:uu:diva-259730DOI: 10.1001/jamapsychiatry.2015.0125ISI: 000359200000008PubMedID: 26083190OAI: oai:DiVA.org:uu-259730DiVA: diva2:845240
Funder
Swedish Research CouncilThe Swedish Brain FoundationRiksbankens JubileumsfondForte, Swedish Research Council for Health, Working Life and Welfare
Available from: 2015-08-11 Created: 2015-08-11 Last updated: 2017-12-04Bibliographically approved
In thesis
1. Imaging Anxiety: Neurochemistry in Anxiety Disorders Assessed by Positron Emission Tomography
Open this publication in new window or tab >>Imaging Anxiety: Neurochemistry in Anxiety Disorders Assessed by Positron Emission Tomography
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Anxiety disorders, including social anxiety disorder (SAD) and posttraumatic stress disorder (PTSD) are common and disabling conditions. Largely based on animal and pharmacological studies, both the serotonergic and substance P/neurokinin-1 (SP/NK1) systems have been implicated in their underlying pathology. However, only few neuroimaging studies have directly assessed these neurotransmitter systems in human sufferers of anxiety disorders, and none have addressed possible between-systems relationships.

The overall aim of this thesis was to study possible neurochemical alterations associated with anxiety disorders. To this end, three studies using positron emission tomography (PET) for in-vivo imaging of the brain serotonergic and SP/NK1 systems in patients with SAD and PTSD were conducted. The radiotracers [11C]5-HTP, [11C]DASB, and [11C]GR205171 were used to index serotonin synthesis rate, serotonin transporter (SERT) availability, and NK1 receptor availability respectively.

In Study I, patients with SAD relative to controls exhibited enhanced serotonin synthesis rate and serotonin transporter availability. Serotonin synthesis rate in the amygdala was positively related to social anxiety symptom scores. Study II demonstrated increased NK1 receptor availability in the amygdala in patients with SAD relative to controls. In Study III, patients with PTSD showed elevated NK1 receptor availability in the amygdala as compared to controls. SERT availability in the amygdala was negatively related to PTSD symptom severity, a relationship that was moderated by NK1 receptor levels. The regional overlap between SERT and NK1 receptor expression was altered in patients with PTSD, with reduced overlap linked to more severe symptoms.

Collectively, the findings are consistent with the view that serotonin in the amygdala induces rather than reduces anxiety and links exaggerated anxiety to an overactive presynaptic serotonin system. In addition, the involvement of the SP/NK1 system in stress and anxiety, as suggested by animal studies, was demonstrated in two common human anxiety disorders. Finally, PTSD symptomatology is better accounted for by interactions between the serotonergic and SP/NK1 systems in the amygdala than by each system separately. In conclusion, this thesis supports that both the serotonergic and SP/NK1 systems in and of themselves, but also interactively, may be important contributors to anxiety symptomatology.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. 85 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Social Sciences, ISSN 1652-9030 ; 115
Keyword
Fear, Brain, Serotonin, Neurokinin, Substance P
National Category
Psychology
Research subject
Psychology
Identifiers
urn:nbn:se:uu:diva-261983 (URN)978-91-554-9330-1 (ISBN)
Public defence
2015-10-26, Auditorium Minus, Gustavianum, Akademigatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2015-09-29 Created: 2015-09-07 Last updated: 2015-10-01

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Frick, AndreasÅhs, FredrikEngman, JonasJonasson, MyBjörkstrand, JohannesFrans, ÖrjanFaria, VandaAppel, LieuweLubberink, MarkFredrikson, MatsFurmark, Tomas

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