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Original Investigation |

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

Andreas Frick, MSc1; Fredrik Åhs, PhD1,2; Jonas Engman, MSc1; My Jonasson, MSc3; Iman Alaie, MSc1; Johannes Björkstrand, MSc1; Örjan Frans, PhD1; Vanda Faria, PhD1,4; Clas Linnman, PhD1,4; Lieuwe Appel, PhD3; Kurt Wahlstedt, MD, PhD1; Mark Lubberink, PhD3; Mats Fredrikson, PhD, DMSc1,2; Tomas Furmark, PhD1
[+] Author Affiliations
1Department of Psychology, Uppsala University, Uppsala, Sweden
2Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
3Department of Nuclear Medicine and Positron Emission Tomography, Uppsala University, Uppsala, Sweden
4Center for Pain and the Brain, Department of Anesthesiology, Perioperative, and Pain Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts
JAMA Psychiatry. 2015;72(8):794-802. doi:10.1001/jamapsychiatry.2015.0125.
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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.

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Figure 1.
Increased Serotonin Synthesis in Social Anxiety Disorder (SAD)

A, The mean serotonin synthesis rate, indexed by influx rate of carbon 11–labeled 5-hydroxytryptophan ([11C]5-HTP Ki) in patients with SAD. B, The mean [11C]5-HTP Ki in healthy control participants. C, Clusters of significantly increased [11C]5-HTP Ki in SAD. Parametric images of serotonin synthesis rate overlaid on a standard magnetic resonance image illustrate an increased rate of serotonin synthesis in the amygdala, brainstem corresponding to the raphe nuclei region, and anterior cingulate cortex. All rows depict sections at Montreal Neurological Institute coordinates −2, 4, 0. The color bar indicates [11C]5-HTP Ki for the 2 top rows (given in minutes−1).

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Figure 2.
Correlations Among Severity of Social Anxiety Symptoms, Serotonin Synthesis Rate, and Serotonin Transporter Availability

A, Significant cluster defining the anatomic extent of the positive relationship between serotonin synthesis rate in the amygdala (Montreal Neurological Institute [MNI] coordinates: 24, 4, −16), indexed by the serotonin synthesis rate of 5-hydroxytryptophan labeled with carbon 11 in the beta position ([11C]5-HTP Ki), and severity of social anxiety symptoms as measured by the Liebowitz Social Anxiety Scale (LSAS) in patients with social anxiety disorder (SAD). The [11C]5-HTP Ki values plotted against the LSAS score for illustrative purposes. The LSAS scores range from 0 to 144, with higher scores indicating greater severity of symptoms. Data points indicate individual values; diagonal line, fit line. B, Significant cluster defining the anatomic location of the negative relationship between serotonin transporter availability in the dorsal anterior cingulate cortex (MNI coordinates −10, 32, 26), indexed by the binding potential of 11C-labeled 3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile ([11C]DASB BPND), and severity of social anxiety symptoms as measured by the LSAS in patients with SAD. The [11C]DASB BPND plotted against the LSAS score for illustrative purposes. AU indicates arbitrary units; data points, individual values; and diagonal line, fit line.

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Figure 3.
Increased Serotonin Transporter Availability in Social Anxiety Disorder (SAD)

A, Mean serotonin transporter availability indexed by the binding potential of carbon 11–labeled 3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile ([11C]DASB BPND) in patients with SAD. B, The [11C]DASB BPND in healthy control participants. C, Clusters of significantly increased [11C]DASB BPND in SAD in the brainstem corresponding to the raphe nuclei region, caudate nucleus, putamen, thalamus, insula cortex, and amygdala. The amygdala is shown at P < .05, uncorrected, for illustrative purposes. Parametric BPND images are overlaid on a standard magnetic resonance image. All rows depict sections at Montreal Neurological Institute coordinates −2, 0, 0. The color bar indicates [11C]DASB BPND for the 2 top rows (given in arbitrary units).

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