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Andreas Frick, MSc1Fredrik Åhs, PhD1,2Jonas Engman, MSc1et alMy Jonasson, MSc3Iman Alaie, MSc1Johannes Björkstrand, MSc1Örjan Frans, PhD1Vanda Faria, PhD1,4Clas Linnman, PhD1,4Lieuwe Appel, PhD3Kurt Wahlstedt, MD, PhD1Mark Lubberink, PhD3Mats Fredrikson, PhD, DMSc1,2Tomas Furmark, PhD1 Author Affiliations Article InformationJAMA Psychiatry. 2015;72(8):794-802. doi:10.1001/jamapsychiatry.2015.0125  Abstract

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.


Anxiety disorders are debilitating psychiatric conditions that impose a considerable burden on patients1 and society,2 and social anxiety disorder (SAD) is one of the most common of these conditions.3 The neural underpinnings of excessive social anxiety are not fully characterized, although serotonin (5-hydroxytryptamine) has been suggested to be involved etiologically.4,5

However, only a few studies have used molecular neuroimaging to examine serotonin dysfunction in SAD directly. A single-photon emission tomography study6 found increased serotonin transporter availability in the thalamus, but not in the raphe nuclei, in patients with SAD relative to healthy control individuals. Also, a positron emission tomography (PET) study7 showed that SAD is associated with reduced serotonin 1A receptor binding. Somatodendritic serotonin 1A autoreceptors in the raphe nuclei, which inhibit serotonin synthesis and release,8 and postsynaptic serotonin 1A heteroreceptors, which convey inhibitory signals in the amygdala, anterior cingulate cortex (ACC), and insula cortex, were downregulated.7 In addition, functional neuroimaging studies of SAD9 have demonstrated heightened, fear-induced neural reactivity in the amygdala, which is densely innervated by serotonin,10 with alterations in the hippocampus, ACC, insula cortex, and striatum.9,11 Moreover, the first line of pharmacologic treatment for SAD consists of selective serotonin reuptake inhibitors (SSRIs),1214 which reduce excessive amygdala reactivity, restore initially suppressed ventromedial prefrontal cortex response to emotional challenge,1518 and attenuate resting brain perfusion in the ACC and insula.19 Thus, findings from molecular and functional neuroimaging and treatment studies indicate that serotonergic neurotransmission in the amygdala, raphe nuclei, striatum, thalamus, hippocampus, insula cortex, and ACC may be compromised in SAD.

Given the inhibitory role of serotonin 1A autoreceptors on serotonin synthesis,8 previous findings of decreased autoreceptor binding in SAD7 may indicate increased serotonin formation and enhanced serotonergic activity. On the other hand, because blocking the serotonin reuptake with SSRIs attenuates social anxiety symptoms12,13 and because posttreatment dietary depletion of the serotonin precursor tryptophan reverses the anxiolytic effects of SSRIs,20 the notion that increased serotonin availability is pivotal for anxiety reduction also has support. Indeed, whether anxiety conditions such as SAD are best characterized by serotonin overactivity or underactivity remains a matter of debate.5

Presynaptic serotonin activity, including synthesis and reuptake, are major contributors to serotonin neurotransmission. In vivo measurement of the serotonin synthesis rate can be accomplished by targeting the second enzymatic step of serotonin synthesis using PET and the tracer 5-hydroxytryptophan labeled with carbon 11 ([11C]5-HTP) as the marker.2123 The serotonin transporter, blocked by SSRI treatment,24 is an important regulator of serotonergic neurotransmission that influences responsivity of the neural fear circuitry25 and can be assessed successfully using PET with the tracer 11C-labeled 3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile ([11C]DASB).26

Herein, we used PET imaging with the radioligands [11C]5-HTP and [11C]DASB to evaluate the rate of serotonin synthesis in the brain and serotonin transporter availability, respectively, in patients with SAD and healthy controls. Based on earlier findings of reduced raphe nuclei serotonin 1A autoreceptor density and enhanced serotonin transporter availability in the thalamus,6,7 we could predict that SAD is associated with an increased rate of serotonin synthesis and increased transporter binding, that is, an overactive, presynaptic, serotonergic system. On the other hand, because SSRIs increase serotonin availability27 and reduce SAD symptoms,12 a reduced rate of serotonin synthesis is possible. Furthermore, because attenuated serotonin transporter binding has been reported in other anxiety disorders28,29 (although findings are mixed)30,31 and because genetically modified serotonin transporter knockout mice show increased anxiety levels,32 SAD could also be characterized by reduced transporter availability. Thus, although we predicted abnormalities in presynaptic serotonin functioning in SAD, we did not have a priori hypotheses regarding the direction.



Eighteen patients with SAD (9 men and 9 women; mean [SD] age, 32.6 [8.2] years) and 18 healthy controls (9 men and 9 women; mean [SD] age, 34.7 [9.2] years) underwent [11C]5-HTP PET imaging. Technical problems during PET image acquisition prevented analysis of data from 1 control, leaving 17 with data available for analysis (8 men and 9 women). The groups did not differ by age or sex distribution (P > .63). The [11C]DASB PET images were acquired for another 26 patients with SAD (14 men and 12 women; mean [SD] age, 35.2 [10.7] years) and the same 18 controls. Technical problems prevented analysis of 1 [11C]DASB PET scan from the control group, leaving data from 17 controls available for analysis (9 men and 8 women). Again, these groups did not differ by age or sex distribution (P > .72). The 2 SAD groups did not differ with respect to age, sex distribution, severity of social anxiety, number of individuals with generalized SAD, previous use of psychotropic medication, or number of individuals with current or a history of psychiatric comorbidity (P > .12) (eTable 1 in the Supplement details participant characteristics). Data were acquired from March 12, 2002, through March 5, 2012. The study was approved by the regional ethics committee in Uppsala and the Radiation Safety Committee for [11C]DASB PET and by the ethical review board of the Uppsala University Medical Faculty and the Uppsala University Isotope Committee for [11C]5-HTP PET. All participants gave written informed consent before the start of the study and were reimbursed for participation.

Participants were recruited through newspaper advertising. Main exclusion criteria were any other primary major psychiatric or neurologic disorder, somatic disease, ongoing or discontinued (within 2 months) psychological or psychotropic medication treatment, long-term use of prescribed medication, current drug or alcohol abuse or dependency, previous PET examination, pregnancy, or menopause.

Patients meeting the initial screening criteria for social phobia from the Social Phobia Screening Questionnaire33 and who did not fulfill any exclusion criteria were subsequently administered the Mini-International Neuropsychiatric Interview34 and the Structured Clinical Diagnostic Interview for the DSM-IV35 to ascertain that they fulfilled the DSM-IV-TR criteria for SAD (social phobia).36 All patients had a primary diagnosis of SAD. Severity of social anxiety symptoms was evaluated with the self-reported version of the Liebowitz Social Anxiety Scale (LSAS)37 for the patients who underwent [11C]5-HTP PET imaging and with the clinician-administered version of the LSAS37 for the patients who underwent [11C]DASB PET imaging. Scores on the LSAS range from 0 to 144, with higher scores indicating greater severity of symptoms. The self-reported and clinician-administered versions of the LSAS are highly correlated.37 Finally, a medical examination was performed.

The controls underwent similar assessments. All participants were appraised as healthy, and none of the controls fulfilled criteria for any current psychiatric disorder as assessed with the Mini-International Neuropsychiatric Interview,34 or had any lifetime history of such disorders.

Image Acquisition

The PET images were acquired using a 32-ring high-resolution scanner (ECAT EXACT HR+; Siemens/CTI), which enables the acquisition of 63 contiguous planes of data with a section thickness of 2.46 mm, resulting in a total axial field of view of 155 mm. Participants fasted for 3 hours and refrained from using tobacco, alcohol, and caffeine 12 hours before the PET investigations. A venous catheter for tracer injections was inserted in the arm of the participant. For each PET investigation, participants were positioned in the scanner with their head gently fixated, and a 10-minute transmission scan was performed using 3 retractable germanium 68 rotating line sources.

[11C]5-HTP PET Assessments

For the [11C]5-HTP PET assessments, the tracer [11C]5-HTP21,38 was injected as a rapid bolus (mean [SD], 7.41 [2.68] mCi; to convert to megabecquerels, multiply by 37), whereupon the emission scanning started. Data were acquired in a 3-dimensional mode and consisted of 17 frames (5 × 60 seconds, 3 × 120 seconds, 3 × 180 seconds, 4 × 300 seconds, and 2 × 600 seconds) acquired during 60 minutes. In addition, an oxygen 15–labeled (15O) water PET scan for spatial normalization was obtained with administration of the tracer at approximately 0.27 mCi/kg body weight and acquisition of three 30-second frames. Patients with SAD and controls underwent the same investigations.

[11C]DASB PET Assessments

For the [11C]DASB PET assessments, a similar procedure was used. At the start of the emission scan, participants received the tracer [11C]DASB26 as a rapid bolus intravenous injection (mean [SD], 9.73 [1.22] mCi), and 22 frames of data were acquired in a 3-dimensional mode during 60 minutes (1 × 60 seconds, 4 × 30 seconds, 3 × 60 seconds, 4 × 120 seconds, 2 × 180 seconds, and 8 × 300 seconds).

Image Analysis

Data were analyzed from March 28, 2013, through August 29, 2014. We calculated parametric images using graphic methods with a reference region input, showing an influx rate (Ki, in minutes−1) of [11C]5-HTP, that is, an index of serotonin synthesis rate, and binding potential (BPND)39 of [11C]DASB, that is, an index of serotonin transporter availability, for each voxel. For [11C]5-HTP, a modified reference Patlak method,22,40,41 correcting for binding of [11C]5-HTP in the cerebellum, was used during an interval of 30 to 60 minutes22,23 to estimate Ki. For [11C]DASB, the reference Logan method42 was used during an interval of 30 to 60 minutes, and BPND was estimated as the distribution volume ratio − 1 relative to the cerebellum. The cerebellum was used as the reference region because it is assumed to have no specific binding of [11C]DASB.43

The reference region was defined using the PVElab software,44 an observer-independent approach for automatic generation of volumes of interest. For [11C]5-HTP, a coregistered 15O-water PET scan of each patient was used for volume-of-interest definition44; for [11C]DASB, the volume-of-interest template was applied to a PET image summed for all 22 frames.45

Each individual’s [11C]5-HTP Ki image was coregistered to their 15O-water summation image using affine transformation. The 15O-water summation image was then normalized to the PET template from Statistical Parametric Mapping 8 software (SPM8; Wellcome Department of Cognitive Neurology, University College London []), and the calculated transformation parameters were applied to the [11C]5-HTP Ki image, resulting in [11C]5-HTP Ki images normalized to the Montreal Neurological Institute (MNI) standard space. The MNI-normalized [11C]5-HTP Ki images were subsequently smoothed with a 12-mm isotropic gaussian kernel.

The [11C]DASB BPND images were coregistered to the summation image of all 22 [11C]DASB frames for each participant. The summation images were then normalized to the SPM8 PET template, and the transformation parameters were applied to the BPND images. The resulting MNI-normalized [11C]DASB BPND images were subsequently smoothed with a 12-mm isotropic gaussian kernel.

Statistical Analysis

A priori anatomic regions of interest (ROIs) were chosen based on earlier functional, structural, and neurochemical findings in SAD and areas rich in serotonin synthesis and reuptake (eFigure in the Supplement).6,7,9,4650 The ROIs included the amygdala, raphe nuclei, caudate nucleus, putamen, thalamus, hippocampus, insula cortex, and ACC, defined using the Automated Anatomical Labeling library from the Wake Forest University Pickatlas51 except for the raphe nuclei ROI, which was defined from the PVElab software.44

We entered parametric [11C]5-HTP and [11C]DASB images into separate analyses in SPM8. We examined group differences between patients with SAD and controls using 2-sample t tests. To explore the relationship between severity of social anxiety symptoms and serotonin synthesis or reuptake, parametric [11C]5-HTP and [11C]DASB images were entered into separate regression models with the LSAS total score as the predictor. The statistical threshold for significance was set at P < .05 corrected for familywise error (FWE), using random field theory, including small-volume correction within the ROIs. Behavioral data and participant characteristics were analyzed using publicly available software (R, version 3.1.0; R Foundation for Statistical Computing).

Supplementary Analyses

Because SAD is more prevalent in women than in men52 and because earlier studies have found sex differences in serotonin synthesis53 and serotonin transporter availability54,55 in healthy participants and patients with anxiety disorders,31 we evaluated the effects of sex on serotonin synthesis rate and serotonin transporter availability with the interaction between sex and group (ie, SAD or control). Parametric [11C]5-HTP and [11C]DASB images were entered into separate 2-way, between-subject (sex × group), voxel-wise analyses of variance in SPM8 (eAppendix 1 in the Supplement).


Serotonin Synthesis

Statistical parametric mapping within the a priori ROIs revealed an increased rate of serotonin synthesis in patients with SAD compared with controls in the amygdala, brainstem corresponding to the raphe nuclei region, caudate nucleus, putamen, hippocampus, and dorsal ACC (Figure 1 and Table). No additional significant effect of diagnosis on [11C]5-HTP Ki was found in an exploratory whole-brain analysis. Within the SAD group, social anxiety symptom scores correlated positively with [11C]5-HTP Ki in the right amygdala (MNI coordinates: 24, 4, −16; z = 3.29; cluster size, 1056 mm3P = .001, FWE) (Figure 2).

Serotonin Transporter Availability

Within the predefined ROIs, increased serotonin transporter availability in patients with SAD compared with controls was found in the brainstem corresponding to the raphe nuclei region, caudate nucleus, putamen, thalamus, and insula (Figure 3 and Table) and at a more lenient statistical threshold in the amygdala (right: MNI coordinates: 24, 2, −12; z = 2.61; cluster size, 656 mm3P = .005 uncorrected; left: MNI coordinates: −18, 0, −12; z = 2.04; cluster size, 168 mm3P = .02 uncorrected). A whole-brain exploratory analysis likewise revealed augmented [11C]DASB BPND in patients with SAD compared with controls in the right putamen (MNI coordinates: 26, −12, 12; z = 5.11; cluster size, 2624 mm3P = .003, FWE) and left thalamus (MNI coordinates: −10, −12, 8; z = 4.66; cluster size, 296 mm3P = .02, FWE), with no additional regional differences. Within the SAD group, we found a significant negative correlation between social anxiety symptom severity scores (LSAS) and [11C]DASB BPND in the left dorsal ACC (MNI coordinates: −10, 32, 26; z = 3.44; cluster size, 256 mm3P = .02, FWE) (Figure 2).

Supplementary Analyses

Women had a lower serotonin synthesis rate and higher serotonin transporter availability than men. Also, increased [11C]5-HTP Ki and [11C]DASB BPND were found in patients with SAD compared with controls in men and women during separate analyses, without any significant interactions between sex and group for either tracer (eAppendix 2 and 3 and eTables 2-5 in the Supplement). No significant differences were observed when comparing patients with and without concurrent or previous psychiatric comorbidity or history of psychotropic medication use.


Using PET, we found higher rates of serotonin synthesis and/or transporter availability in patients with SAD than controls in the amygdala, raphe nuclei region, caudate nucleus, putamen, thalamus, hippocampus, insula cortex, and ACC. Although this study is, to our knowledge, the first imaging study of serotonin synthesis in SAD, we replicate and extend previous single-photon emission tomography findings of increased serotonin transporter binding in the thalamus of patients with SAD.6 These findings are consistent with an overactive presynaptic serotonin system in socially anxious individuals, which may be important for the pathogenesis of anxiety.

Notably, within the SAD group, the rate of serotonin synthesis in the dorsal amygdala correlated positively with severity of social anxiety symptoms. Although the spatial resolution of PET imaging is limited, the location of the amygdala cluster is consistent with the central nucleus,56 that is, the major output region of the amygdala, which mediates fear and anxiety.57 Because anxious rat strains are hyperserotonergic58,59 and because results of imaging studies in healthy individuals indicate a positive relationship between extracellular serotonin and reactivity in the amygdala,25,60 our [11C]5-HTP results suggest that increased extracellular serotonin concentration underlies elevated anxiety and amygdala responsivity9,47,61 in SAD. Further supporting this notion, in animals, decreased serotonin concentrations after inhibition of serotonin synthesis with para-chlorophenylalanine are associated with reduced levels of anxiety,62 whereas increased serotonin concentrations after acute SSRI63,64 or fenfluramine65 administration are associated with increased anxiety.4 Moreover, we found an increased serotonin synthesis rate in the dorsal ACC in patients with SAD relative to controls and a negative relationship between the number of serotonin reuptake sites in this region and severity of social anxiety symptoms, consistent with a proposed role for the dorsal ACC in fear expression.66 Collectively, these findings suggest that extracellular serotonin in the amygdala and dorsal ACC is positively related to severity of social anxiety symptoms. Also, a previous study7 reported an association between SAD and reduced levels of inhibitory serotonin 1A heteroreceptors in the amygdala and the ACC, further indicating a link between serotonin and heightened fear circuit reactivity in SAD.9,47

Upregulated presynaptic activity observed in the present study and downregulated postsynaptic serotonin 1A receptors reported previously in SAD7 are consistent with findings of increased serotonin transporter availability30,31 and reduced serotonin 1A binding67,68 in panic disorder and with reports of increased serotonin synthesis in obsessive-compulsive disorder.69 These findings suggest similar serotonergic alterations across these psychiatric disorders. Oler and colleagues70 noted positive correlations among serotonin transporter availability, reactivity, and anxious temperament in the amygdala in rhesus monkeys. In contrast to SAD, major depressive disorder has been associated with a reduced rate of serotonin synthesis38 and serotonin transporter availability,71 although patients with SAD often have comorbid depressive disorder. Furthermore, posttraumatic stress disorder has been associated with decreased serotonin transporter availability in the amygdala.28 This finding suggests a complex relationship between serotonin and mood, anxiety, and stress-related disorders. Although we cannot test causal effects in the present study, we speculate that, because raphe nuclei serotonin 1A autoreceptors exert inhibitory feedback on serotonin synthesis and firing,8 downregulation of inhibitory raphe serotonin 1A autoreceptors previously reported in social anxiety7 and panic disorder67,68 leads to increased serotonin synthesis, and augmented reuptake may be a compensatory mechanism. The serotonin system is under strong internal feedback regulation, and alterations in synthesis, reuptake, or autoreceptor expression would lead to compensatory changes in the other components.72 Furthermore, although serotonin synthesis and reuptake may exert differential effects on extracellular serotonin concentration, they are important contributors to serotonergic firing through replenishment of the releasable pool of serotonin in vesicles.73 Increased synthesis rate and reuptake may consequently suggest a heightened serotonergic firing rate capacity in SAD. Moreover, we cannot exclude that our results are region specific. However, when relaxing the statistical threshold, the trend always pointed to both measures of serotonin function being enhanced in SAD, suggesting that SAD is characterized by a general overactive presynaptic serotonergic system.

Among the study limitations, we could not correlate [11C]5-HTP and [11C]DASB PET measures in a meaningful way because these tracers were collected in different SAD cohorts. This lack of correlation limits the inferences that can be made of the interaction between serotonin synthesis and reuptake. Moreover, some issues regarding the capacity of [11C]5-HTP to measure the serotonin synthesis rate have been raised. For example, since the decarboxylation of 5-HTP to serotonin involves the enzyme amino acid decarboxylase, which is found not only in serotonergic but also in dopaminergic and noradrenergic neurons, the [11C]5-HTP tracer trapping may reflect amino acid decarboxylase activity. However, current evidence indicates that [11C]5-HTP tracer trapping reflects synaptic serotonin synthesis capacity in serotonergic cells,22 and a review concluded that [11C]5-HTP is the most suitable PET tracer for measurement of serotonin synthesis currently available.21


We demonstrate invariably increased serotonin synthesis and transporter availability in patients with SAD relative to healthy controls, which supports an overactive presynaptic serotonin system. Correlations between social anxiety symptoms and serotonergic measures in fear-expressing brain regions further suggest the region-specific anxiogenic effects of serotonin. Our findings are widely consistent with previous imaging reports of anxiety conditions and could provide important insights into the pathogenesis of these impairing disorders.

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Article Information

Submitted for Publication: November 10, 2014; final revision received January 29, 2015; accepted January 30, 2015.

Corresponding Author: Andreas Frick, MSc, Department of Psychology, Uppsala University, PO Box 1225, SE-751 42 Uppsala, Sweden (

Published Online: June 17, 2015. doi:10.1001/jamapsychiatry.2015.0125.

Author Contributions: Drs Fredrikson and Furmark contributed equally to this work. Drs Fredrikson and Furmark had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Lubberink, Fredrikson, Furmark.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Frick, Åhs, Engman, Fredrikson, Furmark.

Critical revision of the manuscript for important intellectual content: Frick, Engman, Jonasson, Alaie, Björkstrand, Frans, Faria, Linnman, Appel, Wahlstedt, Lubberink, Fredrikson, Furmark.

Statistical analysis: Frick, Fredrikson, Furmark.

Obtained funding: Fredrikson, Furmark.

Administrative, technical, or material support: Linnman, Lubberink.

Study supervision: Lubberink, Fredrikson, Furmark.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was supported by the Swedish Research Council, the Swedish Brain Foundation, Riksbankens Jubileumsfond–the Swedish Foundation for Humanities and Social Sciences, and the Swedish Research Council for Health, Working Life, and Welfare. Ligand production of 5-hydroxytryptophan for the patients was supported by GlaxoSmithKline.

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We thank all the study participants and the staff at the Uppsala positron emission tomography center for their assistance in data collection.



Stein  MB, Kean  YM.  Disability and quality of life in social phobia: epidemiologic findings.  Am J Psychiatry. 2000;157(10):1606-1613.PubMedGoogle ScholarCrossref


Whiteford  HA, Degenhardt  L, Rehm  J,  et al.  Global burden of disease attributable to mental and substance use disorders: findings from the Global Burden of Disease Study 2010.  Lancet. 2013;382(9904):1575-1586.PubMedGoogle ScholarCrossref


Kessler  RC, Berglund  P, Demler  O, Jin  R, Merikangas  KR, Walters  EE.  Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication.  Arch Gen Psychiatry. 2005;62(6):593-602.
ArticlePubMedGoogle ScholarCrossref


Griebel  G.  5-Hydroxytryptamine-interacting drugs in animal models of anxiety disorders: more than 30 years of research.  Pharmacol Ther. 1995;65(3):319-395.PubMedGoogle ScholarCrossref


Maron  E, Nutt  D, Shlik  J.  Neuroimaging of serotonin system in anxiety disorders.  Curr Pharm Des. 2012;18(35):5699-5708.PubMedGoogle ScholarCrossref


van der Wee  NJ, van Veen  JF, Stevens  H, van Vliet  IM, van Rijk  PP, Westenberg  HG.  Increased serotonin and dopamine transporter binding in psychotropic medication–naive patients with generalized social anxiety disorder shown by 123I-β-(4-iodophenyl)-tropane SPECT.  J Nucl Med. 2008;49(5):757-763.PubMedGoogle ScholarCrossref


Lanzenberger  RR, Mitterhauser  M, Spindelegger  C,  et al.  Reduced serotonin-1A receptor binding in social anxiety disorder.  Biol Psychiatry. 2007;61(9):1081-1089.PubMedGoogle ScholarCrossref


Boadle-Biber  MC.  Regulation of serotonin synthesis.  Prog Biophys Mol Biol. 1993;60(1):1-15.PubMedGoogle ScholarCrossref


Freitas-Ferrari  MC, Hallak  JEC, Trzesniak  C,  et al.  Neuroimaging in social anxiety disorder: a systematic review of the literature.  Prog Neuropsychopharmacol Biol Psychiatry. 2010;34(4):565-580.PubMedGoogle ScholarCrossref


Asan  E, Steinke  M, Lesch  K-P.  Serotonergic innervation of the amygdala: targets, receptors, and implications for stress and anxiety.  Histochem Cell Biol. 2013;139(6):785-813.PubMedGoogle ScholarCrossref


Sareen  J, Campbell  DW, Leslie  WD,  et al.  Striatal function in generalized social phobia: a functional magnetic resonance imaging study.  Biol Psychiatry. 2007;61(3):396-404.PubMedGoogle ScholarCrossref


Blanco  C, Bragdon  LB, Schneier  FR, Liebowitz  MR.  The evidence-based pharmacotherapy of social anxiety disorder.  Int J Neuropsychopharmacol. 2013;16(1):235-249.PubMedGoogle ScholarCrossref


Ipser  JC, Kariuki  CM, Stein  DJ.  Pharmacotherapy for social anxiety disorder: a systematic review.  Expert Rev Neurother. 2008;8(2):235-257.PubMedGoogle ScholarCrossref


Baldwin  DS, Anderson  IM, Nutt  DJ,  et al.  Evidence-based pharmacological treatment of anxiety disorders, post-traumatic stress disorder and obsessive-compulsive disorder: a revision of the 2005 guidelines from the British Association for Psychopharmacology.  J Psychopharmacol. 2014;28(5):403-439.PubMedGoogle ScholarCrossref


Phan  KL, Coccaro  EF, Angstadt  M,  et al.  Corticolimbic brain reactivity to social signals of threat before and after sertraline treatment in generalized social phobia.  Biol Psychiatry. 2013;73(4):329-336.PubMedGoogle ScholarCrossref


Furmark  T, Tillfors  M, Marteinsdottir  I,  et al.  Common changes in cerebral blood flow in patients with social phobia treated with citalopram or cognitive-behavioral therapy.  Arch Gen Psychiatry. 2002;59(5):425-433.
ArticlePubMedGoogle ScholarCrossref


Furmark  T, Appel  L, Michelgård  A,  et al.  Cerebral blood flow changes after treatment of social phobia with the neurokinin-1 antagonist GR205171, citalopram, or placebo.  Biol Psychiatry. 2005;58(2):132-142.PubMedGoogle ScholarCrossref


Faria  V, Appel  L, Åhs  F,  et al.  Amygdala subregions tied to SSRI and placebo response in patients with social anxiety disorder.  Neuropsychopharmacology. 2012;37(10):2222-2232.PubMedGoogle ScholarCrossref


Warwick  JM, Carey  P, Van der Linden  G,  et al.  A comparison of the effects of citalopram and moclobemide on resting brain perfusion in social anxiety disorder.  Metab Brain Dis. 2006;21(2-3):241-252.PubMedGoogle ScholarCrossref


Argyropoulos  SV, Hood  SD, Adrover  M,  et al.  Tryptophan depletion reverses the therapeutic effect of selective serotonin reuptake inhibitors in social anxiety disorder.  Biol Psychiatry. 2004;56(7):503-509.PubMedGoogle ScholarCrossref


Visser  AKD, van Waarde  A, Willemsen  ATM,  et al.  Measuring serotonin synthesis: from conventional methods to PET tracers and their (pre)clinical implications.  Eur J Nucl Med Mol Imaging. 2011;38(3):576-591.PubMedGoogle ScholarCrossref


Hagberg  GE, Torstenson  R, Marteinsdottir  I, Fredrikson  M, Långström  B, Blomqvist  G.  Kinetic compartment modeling of [11C]-5-hydroxy-L-tryptophan for positron emission tomography assessment of serotonin synthesis in human brain.  J Cereb Blood Flow Metab. 2002;22(11):1352-1366.PubMedGoogle ScholarCrossref


Lundquist  P, Blomquist  G, Hartvig  P,  et al.  Validation studies on the 5-hydroxy-l-[β-11C]-tryptophan/PET method for probing the decarboxylase step in serotonin synthesis.  Synapse. 2006;59(8):521-531.PubMedGoogle ScholarCrossref


Zhong  H, Haddjeri  N, Sánchez  C.  Escitalopram, an antidepressant with an allosteric effect at the serotonin transporter: a review of current understanding of its mechanism of action.  Psychopharmacology (Berl). 2012;219(1):1-13.PubMedGoogle ScholarCrossref


Rhodes  RA, Murthy  NV, Dresner  MA,  et al.  Human 5-HT transporter availability predicts amygdala reactivity in vivo.  J Neurosci. 2007;27(34):9233-9237.PubMedGoogle ScholarCrossref


Houle  S, Ginovart  N, Hussey  D, Meyer  JH, Wilson  AA.  Imaging the serotonin transporter with positron emission tomography: initial human studies with [11C]DAPP and [11C]DASB.  Eur J Nucl Med. 2000;27(11):1719-1722.PubMedGoogle ScholarCrossref


Kim  SW, Park  SY, Hwang  O.  Up-regulation of tryptophan hydroxylase expression and serotonin synthesis by sertraline.  Mol Pharmacol. 2002;61(4):778-785.PubMedGoogle ScholarCrossref


Murrough  JW, Huang  Y, Hu  J,  et al.  Reduced amygdala serotonin transporter binding in posttraumatic stress disorder.  Biol Psychiatry. 2011;70(11):1033-1038.PubMedGoogle ScholarCrossref


Maron  E, Kuikka  JT, Shlik  J, Vasar  V, Vanninen  E, Tiihonen  J.  Reduced brain serotonin transporter binding in patients with panic disorder.  Psychiatry Res. 2004;132(2):173-181.PubMedGoogle ScholarCrossref


Maron  E, Tõru  I, Hirvonen  J,  et al.  Gender differences in brain serotonin transporter availability in panic disorder.  J Psychopharmacol. 2011;25(7):952-959.PubMedGoogle ScholarCrossref


Cannon  DM, Klaver  JM, Klug  SA,  et al.  Gender-specific abnormalities in the serotonin transporter system in panic disorder.  Int J Neuropsychopharmacol. 2013;16(4):733-743.PubMedGoogle ScholarCrossref


Holmes  A, Murphy  DL, Crawley  JN.  Abnormal behavioral phenotypes of serotonin transporter knockout mice: parallels with human anxiety and depression.  Biol Psychiatry. 2003;54(10):953-959.PubMedGoogle ScholarCrossref


Furmark  T, Tillfors  M, Everz  P, Marteinsdottir  I, Gefvert  O, Fredrikson  M.  Social phobia in the general population: prevalence and sociodemographic profile.  Soc Psychiatry Psychiatr Epidemiol. 1999;34(8):416-424.PubMedGoogle ScholarCrossref


Sheehan  DV, Lecrubier  Y, Sheehan  KH,  et al.  The Mini-International Neuropsychiatric Interview (MINI): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10 J Clin Psychiatry. 1998;59(suppl 20):22-33.PubMedGoogle Scholar


First  MB, Gibbon  M, Spitzer  RL, Williams  JBW.  SCID-I: Interview Protocol (Swedish). Stockholm, Sweden: Pilgrim Press; 1998.


American Psychiatric Association.  Diagnostic and Statistical Manual of Mental Disorders.4th ed, text revision. Washington, DC: American Psychiatric Association; 2000.


Fresco  DM, Coles  ME, Heimberg  RG,  et al.  The Liebowitz Social Anxiety Scale: a comparison of the psychometric properties of self-report and clinician-administered formats.  Psychol Med. 2001;31(6):1025-1035.PubMedGoogle Scholar


Agren  H, Reibring  L, Hartvig  P,  et al.  Low brain uptake of L-[11C]5-hydroxytryptophan in major depression: a positron emission tomography study on patients and healthy volunteers.  Acta Psychiatr Scand. 1991;83(6):449-455.PubMedGoogle ScholarCrossref


Innis  RB, Cunningham  VJ, Delforge  J,  et al.  Consensus nomenclature for in vivo imaging of reversibly binding radioligands.  J Cereb Blood Flow Metab. 2007;27(9):1533-1539.PubMedGoogle ScholarCrossref


Patlak  CS, Blasberg  RG, Fenstermacher  JD.  Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data.  J Cereb Blood Flow Metab. 1983;3(1):1-7.PubMedGoogle ScholarCrossref


Bergström  M, Kumlien  E, Lilja  A, Tyrefors  N, Westerberg  G, Långström  B.  Temporal lobe epilepsy visualized with PET with 11C-L-deuterium-deprenyl: analysis of kinetic data.  Acta Neurol Scand. 1998;98(4):224-231.PubMedGoogle ScholarCrossref


Logan  J, Fowler  JS, Volkow  ND, Wang  GJ, Ding  YS, Alexoff  DL.  Distribution volume ratios without blood sampling from graphical analysis of PET data.  J Cereb Blood Flow Metab. 1996;16(5):834-840.PubMedGoogle ScholarCrossref


Meyer  JH.  Imaging the serotonin transporter during major depressive disorder and antidepressant treatment.  J Psychiatry Neurosci. 2007;32(2):86-102.PubMedGoogle Scholar


Svarer  C, Madsen  K, Hasselbalch  SG,  et al.  MR-based automatic delineation of volumes of interest in human brain PET images using probability maps.  Neuroimage. 2005;24(4):969-979.PubMedGoogle ScholarCrossref


Jonasson  M. Automatic definition of volumes of interest using a probability template method (PVElab) without a structural MRI image. In: Poster presented at: 10th International Symposium on Functional Neuroreceptor Mapping of the Living Brain; May 23, 2014; Egmond aan Zee, the Netherlands.


Savli  M, Bauer  A, Mitterhauser  M,  et al.  Normative database of the serotonergic system in healthy subjects using multi-tracer PET.  Neuroimage. 2012;63(1):447-459.PubMedGoogle ScholarCrossref


Shin  LM, Liberzon  I.  The neurocircuitry of fear, stress, and anxiety disorders.  Neuropsychopharmacology. 2010;35(1):169-191.PubMedGoogle ScholarCrossref


Boehme  S, Ritter  V, Tefikow  S,  et al.  Brain activation during anticipatory anxiety in social anxiety disorder.  Soc Cogn Affect Neurosci. 2014;9(9):1413-1418.PubMedGoogle ScholarCrossref


Sripada  C, Angstadt  M, Liberzon  I, McCabe  K, Phan  KL.  Aberrant reward center response to partner reputation during a social exchange game in generalized social phobia.  Depress Anxiety. 2013;30(4):353-361.PubMedGoogle ScholarCrossref


Klumpp  H, Angstadt  M, Phan  KL.  Insula reactivity and connectivity to anterior cingulate cortex when processing threat in generalized social anxiety disorder.  Biol Psychol. 2012;89(1):273-276.PubMedGoogle ScholarCrossref


Maldjian  JA, Laurienti  PJ, Kraft  RA, Burdette  JH.  An automated method for neuroanatomic and cytoarchitectonic atlas–based interrogation of fMRI data sets.  Neuroimage. 2003;19(3):1233-1239.PubMedGoogle ScholarCrossref


Kessler  RC, Petukhova  M, Sampson  NA, Zaslavsky  AM, Wittchen  H-U.  Twelve-month and lifetime prevalence and lifetime morbid risk of anxiety and mood disorders in the United States.  Int J Methods Psychiatr Res. 2012;21(3):169-184.PubMedGoogle ScholarCrossref


Nishizawa  S, Benkelfat  C, Young  SN,  et al.  Differences between males and females in rates of serotonin synthesis in human brain.  Proc Natl Acad Sci U S A. 1997;94(10):5308-5313.PubMedGoogle ScholarCrossref


Jovanovic  H, Lundberg  J, Karlsson  P,  et al.  Sex differences in the serotonin 1A receptor and serotonin transporter binding in the human brain measured by PET.  Neuroimage. 2008;39(3):1408-1419.PubMedGoogle ScholarCrossref


Staley  JK, Krishnan-Sarin  S, Zoghbi  S,  et al.  Sex differences in [123I]β-CIT SPECT measures of dopamine and serotonin transporter availability in healthy smokers and nonsmokers.  Synapse. 2001;41(4):275-284.PubMedGoogle ScholarCrossref


Mai  JK, Assheuer  J, Paxinos  G.  Atlas of the Human Brain. San Diego, CA: Academic Press; 1997.


Kalin  NH, Shelton  SE, Davidson  RJ.  The role of the central nucleus of the amygdala in mediating fear and anxiety in the primate.  J Neurosci. 2004;24(24):5506-5515.PubMedGoogle ScholarCrossref


Hranilovic  D, Cicin-Sain  L, Bordukalo-Niksic  T, Jernej  B.  Rats with constitutionally upregulated/downregulated platelet 5HT transporter: differences in anxiety-related behavior.  Behav Brain Res. 2005;165(2):271-277.PubMedGoogle ScholarCrossref


Bordukalo-Niksic  T, Mokrovic  G, Stefulj  J, Zivin  M, Jernej  B, Cicin-Sain  L.  5HT-1A receptors and anxiety-like behaviours: studies in rats with constitutionally upregulated/downregulated serotonin transporter.  Behav Brain Res. 2010;213(2):238-245.PubMedGoogle ScholarCrossref


Fisher  PM, Meltzer  CC, Ziolko  SK,  et al.  Capacity for 5-HT1A-mediated autoregulation predicts amygdala reactivity.  Nat Neurosci. 2006;9(11):1362-1363.PubMedGoogle ScholarCrossref


Tillfors  M, Furmark  T, Marteinsdottir  I, Fredrikson  M.  Cerebral blood flow during anticipation of public speaking in social phobia: a PET study.  Biol Psychiatry. 2002;52(11):1113-1119.PubMedGoogle ScholarCrossref


Geller  I, Blum  K.  The effects of 5-HTP on para-chlorophenylalanine (p-CPA) attenuation of “conflict” behavior.  Eur J Pharmacol. 1970;9(3):319-324.PubMedGoogle ScholarCrossref


David  DJP, Bourin  M, Jego  G, Przybylski  C, Jolliet  P, Gardier  AM.  Effects of acute treatment with paroxetine, citalopram and venlafaxine in vivo on noradrenaline and serotonin outflow: a microdialysis study in Swiss mice.  Br J Pharmacol. 2003;140(6):1128-1136.PubMedGoogle ScholarCrossref


Drapier  D, Bentué-Ferrer  D, Laviolle  B,  et al.  Effects of acute fluoxetine, paroxetine and desipramine on rats tested on the elevated plus-maze.  Behav Brain Res. 2007;176(2):202-209.PubMedGoogle ScholarCrossref


Arrant  AE, Jemal  H, Kuhn  CM.  Adolescent male rats are less sensitive than adults to the anxiogenic and serotonin-releasing effects of fenfluramine.  Neuropharmacology. 2013;65:213-222.PubMedGoogle ScholarCrossref


Etkin  A, Egner  T, Kalisch  R.  Emotional processing in anterior cingulate and medial prefrontal cortex.  Trends Cogn Sci. 2011;15(2):85-93.PubMedGoogle ScholarCrossref


Nash  JR, Sargent  PA, Rabiner  EA,  et al.  Serotonin 5-HT1A receptor binding in people with panic disorder: positron emission tomography study.  Br J Psychiatry. 2008;193(3):229-234.PubMedGoogle ScholarCrossref


Neumeister  A, Bain  E, Nugent  AC,  et al.  Reduced serotonin type 1A receptor binding in panic disorder.  J Neurosci. 2004;24(3):589-591.PubMedGoogle ScholarCrossref


Berney  A, Leyton  M, Gravel  P,  et al.  Brain regional α-[11C]methyl-L-tryptophan trapping in medication-free patients with obsessive-compulsive disorder.  Arch Gen Psychiatry. 2011;68(7):732-741.
ArticlePubMedGoogle ScholarCrossref


Oler  JA, Fox  AS, Shelton  SE,  et al.  Serotonin transporter availability in the amygdala and bed nucleus of the stria terminalis predicts anxious temperament and brain glucose metabolic activity.  J Neurosci. 2009;29(32):9961-9966.PubMedGoogle ScholarCrossref


Gryglewski  G, Lanzenberger  R, Kranz  GS, Cumming  P.  Meta-analysis of molecular imaging of serotonin transporters in major depression.  J Cereb Blood Flow Metab. 2014;34(7):1096-1103.PubMedGoogle ScholarCrossref


Best  J, Nijhout  HF, Reed  M.  Serotonin synthesis, release and reuptake in terminals: a mathematical model.  Theor Biol Med Model. 2010;7(1):34. doi:10.1186/1742-4682-7-34.PubMedGoogle ScholarCrossref


Borue  X, Condron  B, Venton  BJ.  Both synthesis and reuptake are critical for replenishing the releasable serotonin pool in Drosophila J Neurochem. 2010;113(1):188-199.PubMedGoogle ScholarCrossref