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by Anna Slabiak, part of the Anxiety Disorder Neurowiki group


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Social anxiety disorder is a mental condition where the individual experiences extreme levels of fear and anxiety arising in relation to social and public situations, potentially impairing normal functionality in their daily life. The origins of the anxiety disorder are caused by multiple factors, affiliated in combination with others, like in the case of genetic and environmental factors. Through the use of neuroimaging studies, researches have been able to examine patients with SAD stimulating the brain through anticipation of speech or faces during functional magnetic resonance imaging. The studies expressed activity in both limbic and prefrontal regions particularly hyperactivity in the amygdala region, which alludes to the fact that patients with social phobia have altered neurological pathways when processing fear response. __[1]__These findings further suggest that SAD patients are more susceptible to a disruption of the serotonergic system, where they may be a carrier of a short allele polymorphism in the serotonin transporter compared to the homozygous long allele found in healthy patients. __[2]__Studies have been conducted with the serotonin transporter knockout and wild type, assessing social interaction among mice. Currently a functional pharmacotherapy being applied, are the SSRI’s: paroxetine, sertraline, fluvoxamine, fluoxetine, and escittalopram in randomized clinical trials examining dosages and efficacy within adult patients who attribute to SAD symptoms, as well challenges in regards to pharmacotherapy. __[3]__










Social Anxiety Disorder Causes

Environmental causes

The familial context poses as a potential risk factor in developing SAD. Familial transmission of SAD can arise on one hand due to the parent’s ability to facilitate children’s social interaction with others and on the other hand, the degree of parental control over them. This establishes a major link between parental rearing and potential risk of offspring anxiety arising.[3] In terms of parental rearing, this can include rejection, overprotection, as well as lack of emotional warmth from the parent towards the child. __[4]__Along with this, it has been reported that offspring are highly susceptible to social anxiety disorder in the case where there is an established history of mental disorders in the family. A study was conducted examining this relationship using “Yale Family Study” and concluded a “linear increase in risk for anxiety in general and social anxiety disorder in particular when the number of affected parents was considered.”__[5]__ Through the conduction of twin studies and animal models the etiology of SAD so far appears to arise to predominantly by environmental factors in comparison to genetic inheritance.

Genetics and heredity

Discovering the genetics of social anxiety disorder, through the first genome-wide linkage scan ever performed, which showed the expression of chromosome 16 risk locus.__[6]__In turn, this lead to detection of the candidate gene d SLC6A2 in this area, also considered to be the norepinephrine transporter protein locus. __[7]__This transporter controls the re-uptake of both norepinephrine and dopamine neurotransmitters, relating to the idea that abnormal dopaminergic systems are plausible cause in relation to social phobia. __[8]__The major neurological pathway under study is the serotonergic system, where patients may be a carrier of a short allele polymorphism in the serotonin transporter compared to the homozygous long allele found in healthy patients, proved to be underlying factor to increasing susceptibility. __[9]__

SLC6A2-gene.png
SLCGA2 gene in genomic location of the chromosome 16

Brain regions

Hyperactivity in the amygdala region

In recent times, there have been neuroimaging studies conducted on SAD patients implicating hyperactivity in the amygdala region of the brain, in reaction to social threat.__[10]__The amygdala being a central regulator in processing and the expression of an individual’s emotions, fittingly associates with this mental disorder, where there is a tendency to fear social situations, even more so disapproval by others.__[11]__Studies performed in obtaining these results commonly are, PET, SPECT and FMRI scans most often comparing healthy patient’s brain activity in relation to people diagnosed with social phobia, expressing “differential activation in the limbic–prefrontal circuit.” __[12]__
amygdala_region.png
A) Hyperactivity in the right amygdala in response to harsh faces B) Scatterplot percent signal change of activation between GSP and HC (Healthy Control)

Comparison of excitability of the amygdala region in response to facial expression in patients with social anxiety disorder versus healthy individuals

To further examine the hyper-activated amygdala in patients with social anxiety disorder, some scientists narrowed their experiments, specifically analyzing the response to emotional expressions: happy, angry and neutral faces. Generally, these experiments are performed using social phobic against healthy subjects presenting them with facial photographifnhum-04-00056-g001.gifc stimuli, while measuring the response through functional magnetic resonance imaging techniques. __[13]__The results expressed greater activity in the right amygdala region corresponding to angry faces, in comparison to happy and neutral expressions in social phobic patients. This is demonstrative of the association of not only the responsiveness of amygdala to aversive faces, but the severity of the symptoms the patient may be enduring. __[14]__Along with this, harsh displays of expressions act as an ideal stimuli, in that they are correspondent to a threatening social signal even a threat that will target the stimulation of the amygdala, and even more so in social phobic individuals. [4]


Serotonergic pathway

Short variation of 5’HTT promoter allele

The serotonergic pathway in social anxiety patients been noted to contain a polymorphism located in the promoter region of the human serotonin transporter (5’HTT) gene. In healthy humans, normally contain the long allele of this gene, as for those with anxiety-related traits they instead, contain the short version 5-HTTLPR. __[15]__Individuals containing one or two short alleles can lead to the disruption in the serotonergic pathway, as a result, decreasing the serotonin reuptake in the synapse by the (5’HTT) transporter. __[16]__The effect on the synapse, causes a reduction in the transcription efficiency of the 5-HTT promoter, decreasing both the tranporters expression and reuptake from the synaptic cleft into the cell. __[17]__This short allele in turn, poses as a risk factor in developing anxiety and other related psychiatric disorders. __[18]__Also, in terms of the neuronal activity in the amygdala, it was shown to increase when the individual had a short allele, unlike when holding the homozygous long allele.__[19]__In respect to symptoms, these patients with the variant have been characterized by higher neuroticism, anxiety and depression than the patients lacking this short allele did not express any related anxiety- traits or symptoms.__[20]__

Animal model

5’HTT promoter allele assessing social interaction

Animal models are effectively employed to further asses’ genetics and to learn the origin of arising anxiety-related behaviours, as well the associated psychiatric disorders. In social anxiety disorder, the underlying genetic cause is a disruption in the 5’HTT gene, which can be translated into a genetic mouse model. To accomplish this, a homozygous knockout mouse is designed by inactivating completely the function of the 5’HTT gene found in humans, through a 5-HTTLPR-like sequence in mice. __[21]__Also for the experiment, taking into consideration modifying a mouse into a heterozygote, pertaining less 5’HTT activity than the knockout mouse and lastly a wild-type mouse, which serves as the healthy control, with normal levels of 5’HTT. __[22]__Specifically, in testing the behaviours in respect to social phobia, all three mouse variants must be assessed in facing social situations, certain behaviours and other encounters, further helping to examine the effects of the disruption in the serotonergic system. Across studies, the SERT-/- mouse model behavior presented itself with negative behavioral outcomes including, higher anxiety and decreased social behavior. __[23]__In assessing the behavior of the mice using various test, such as “nest building, grooming, sticky label, novel object, ethogram, social interaction, tics, wire hanging, balancing, rope climbing, food finding, locomotion and chewing pattern tests”, helped prove and support this theory. __[24]__Particularly shown in the social interaction test, where the differences between the SERT -/- and SERT +/+ were highly distinguishable in that the knockout mouse model had minimal exploration activity, and neither a great deal of hypoactivity, leading to confirm the disabiling effect of anxiety caused by the disruption in the serotonin pathway.
knockout_mouse_model.gif
Horizontal and vertical acitvity of all three phenotypes of mouse models
=[5] [6]

Treatments

SSRI’s

Social Anxiety Disorder first-line of pharmacotherapy comes in the form of SSRI treatment. However, when dealing with mental disorder, diagnosis of the illness is rather difficult in comparison to other diseases, since they are comorbid and symptoms can greatly range. Therefore, additional steps are taken during the process of prescribing these medications, known as an “algorithmic system”. This system is intended as a guideline for clinicians to ensure the most efficient treatment for patients, as well as indicating areas that still need attention and further research. It is designed by eight-sequential steps, beginning with the diagnosis, then treatment and monitoring the treatment effects in long-term. __[25]__Each step addresses major aspects of prescribing medication, while assisting the clinician in decision-making for the optimal treatment for the patient. [26]SSRI is most commonly prescribed medication, based on its consistent efficacy, safety in regards to the patients, tolerability and efficiency in treatment and good outcomes. __[27]__Currently, there are several types of functional SSRI’s, but out of the few there are only two that have been validated as FDA- approved for clinical use and treatment of SAD, and they are paroxetine, and sertraline. __[28]__The duration of the treatment should be maintained from 3-6 months after the patient has responded. __[29]__These periods can vary upon individual cases, and depending if pharmacotherapy is joined with psychotherapy.


Challenges of Treatments

In treating patients with social anxiety disorder, various challenges and limitations continue to arise. Evidently the issue of terminating treatment after a 12-20 week period or even after 5 months, puts the patient at risk of a relapse. __[30]__Studies have suggested that this may be due to the limited period patients are committing in taking the medication, on the other hand it being necessary to combine pharmacotherapy with an additional treatment, such as psychotherapy. Not only is there a chance of relapse, but the onset of the therapeutic effects of the drug may take up to 2-4 weeks to be noticed and help in decreasing anxious-type of behaviour. __[31]__In social anxiety the detection of comorbidity, poses as another factor for treatment resistance to the pharmacotherapy applied. Essentially, there is a lack of a thorough understanding of comorbidity and comorbidity’s influence on particular treatments. __[32]__

External Links:


http://en.wikipedia.org/wiki/Neuroimaging

http://www.genecards.org/cgi-bin/carddisp.pl?gene=SLC6A2

http://www.patient.co.uk/health/Antidepressants-SSRIs.htm

__[1]__Bruhl, A., Rufer, M., Delsignore, A., Kaffenberger, T., Jancke, L., Herwig, U. Neural Correlates of altered general emotion processing in social anxiety disorder. Brain Research. 1378: 72-83 (2010)

__[2]__Furmark, T., Neurobiological Aspects of Social Anxiety Disorder. Israel Journal of Psychiatry and Related Sciences. 46(1): 5-12 (2009)

__[3]__Hedges, DW., Brown, BL., Shwalb, DA., The Efficacy of selective serotonin reuptake inhibitors in adult social anxiety disorder: a meta-analysis of double-blind, placebo-controlled trials. Journal of Psychopharmacolgy. 21: 102-111. (2007)

__[4]__Christina A Brook, Louis A Schmidt. (2008). Social anxiety disorder: A review of environmental risk factors. Neuropsychiatry Disease Treatemnt, 4(1): 123:143
__[5]__K.R. Merikangas, R. Lieb, H.U. wittchen, S. Avenevoli. (2003). Family and high-risk studies of social anxiety disorder. Acta Psychiatrica Scandinavica, 108(417):28-37

__[6]__Gelernter J, Page GP, Stein MB, Woods SW.(2004). Genome-wide linkage scan for loci predisposing to social phobia: evidence for a chromosome 16 risk locus. Am J Psychiatry, 161(1):59-66.
__[7]__Murphy Dennis L.; Fox Meredith A.; Timpano Kiara R. (2008). __How the serotonin story is being rewritten by new gene-based discoveries principally related to SLC6A4, the serotonin transporter gene, which functions to influence all cellular serotonin systems__. Neuropharmacology, 55(6): 932-960
__[8]__Murphy Dennis L.; Fox Meredith A.; Timpano Kiara R. (2008). __How the serotonin story is being rewritten by new gene-based discoveries principally related to SLC6A4, the serotonin transporter gene, which functions to influence all cellular serotonin systems__. Neuropharmacology, 55(6): 932-960
__[9]__ Furmark, T., Tillfors, M., Garpenstrand, H., Marteinsdottie, I., Langstrom, B., Oreland, L., Fredrikson, M., Neuroscience Letters. 362(3): 189-192. 2004
__[10]____K.L. Phan__; __D.A. Fitzgerald__; __P.J. Nathan__; __M.E. Tancer__. (2006). Association between Amygdala Hyperactivity to Harsh Faces and Severity of Social Anxiety in Generalized Social Phobia. Biological Psychiatry, 59 (5): 424-429
__[11]____Stein, MB__ (Stein, MB); __Goldin, PR__ (Goldin, PR); __Sareen, J__ (Sareen, J); __Zorrilla, LTE__ (Zorrilla, LTE); __Brown, GG__. (2002). Increased amygdalaactivationto angry and contemptuous faces in generalized social phobia. Archives of General Psychiatry, 59(11): 1027-1034
__[12]__Veit R; Flor H; Erb M. (2002) __Braincircuitsinvolvedinemotionallearninginantisocialbehavior__ and __socialphobiainhumans__Neuroscience Letters, 328(3):233-236
__[13]____Karleyton C. Evans__; __Christopher I. Wright__; __Michelle M. Wedig__; __Andrea L. Gold__; __Mark H. Pollack__; __Scott L. Rauch__. (2008). A functional MRI study of amygdala responses to angry schematic faces in social anxiety disorder, Depression and Anxiety,25 (6): 496-505
__[14]____K.L. Phan__; __D.A. Fitzgerald__; __P.J. Nathan__; __M.E. Tancer__. (2006). Association between Amygdala Hyperactivity to Harsh Faces and Severity of Social Anxiety in Generalized Social Phobia. Biological Psychiatry, 59 (5): 424-429
__[15]__Christian P. Jacob, M.D.; A. Strobel, Ph.D.; K. Hohenberger, M.D.; T. Ringel, M.D.; L. Gutknecht, Ph.D.; A. Reif, M.D.; B. Brocke, Ph.D.; K.P. Lesch, M.D.(2004). Association Between Allelic Variation of Serotonin Transporter Function and Neuroticism in Anxious Cluster C Personality Disorders. American Journal of Psychiatry, 161(3): 569-572
__[16]__Furmark Tomas; Appel Lieuwe; Henningsson Susanne.(2008) __A Link between Serotonin-Related Gene Polymorphisms, Amygdala Activity, and Placebo-Induced Relief from Social Anxiety__. Journal of Neuroscience, 28(49): 13066-13074
__[17]____Lars Lewejohann__; __Vanessa Kloke__; __Rebecca S. Heiming__; __Friederike Jansen__; __Sylvia Kaiser__; __Angelika Schmitt__; __Klaus Peter Lesch__; __Norbert Sachser__. (2010). Social status and day-to-day behaviour of male serotonin transporter knockout mice. Behavioural Brain Research, 211 (2): 220-228
__[18]__Furmark Tomas; Appel Lieuwe; Henningsson Susanne.(2008) __A Link between Serotonin-Related Gene Polymorphisms, Amygdala Activity, and Placebo-Induced Relief from Social Anxiety__. Journal of Neuroscience, 28(49): 13066-13074
__[19]__Furmark Tomas; Appel Lieuwe; Henningsson Susanne.(2008) __A Link between Serotonin-Related Gene Polymorphisms, Amygdala Activity, and Placebo-Induced Relief from Social Anxiety__. Journal of Neuroscience, 28(49): 13066-13074
__[20]__Jerzy Samochowiec; Anna Hajduk; Agnieszka Samochowiec; Jan Horodnicki; Genowefa Stȩpień; Anna Grzywacz; Jolanta Kucharska-Mazur.(2004) Association studies of MAO-A, COMT, and 5-HTT genes polymorphisms in patients with anxiety disorders of the phobic spectrum. Psychiatry Research, 128 (1): 21-26
__[21]____Lars Lewejohann__; __Vanessa Kloke__; __Rebecca S. Heiming__; __Friederike Jansen__; __Sylvia Kaiser__; __Angelika Schmitt__; __Klaus Peter Lesch__; __Norbert Sachser__. (2010). Social status and day-to-day behaviour of male serotonin transporter knockout mice. Behavioural Brain Research, 211 (2): 220-228
__[22]____Lars Lewejohann__; __Vanessa Kloke__; __Rebecca S. Heiming__; __Friederike Jansen__; __Sylvia Kaiser__; __Angelika Schmitt__; __Klaus Peter Lesch__; __Norbert Sachser__. (2010). Social status and day-to-day behaviour of male serotonin transporter knockout mice. Behavioural Brain Research, 211 (2): 220-228
__[23]____A.V. Kalueff__; __J.D.A. Olivier__; __L.J.P. Nonkes__; __J.R. Homberg__. (2010). Conserved role for the serotonin transporter gene in rat and mouse neurobehavioral endophenotypes. Neuroscience and Biobehavioral Reviews, 34 (3): 373-386
__[24]__. __A.V. Kalueff__; __J.D.A. Olivier__; __L.J.P. Nonkes__; __J.R. Homberg__. (2010). Conserved role for the serotonin transporter gene in rat and mouse neurobehavioral endophenotypes. Neuroscience and Biobehavioral Reviews, 34 (3): 373-386
__[25]__Dan J. Stein & David S. Baldwin & Borwin Bandelow & Carlos Blanco & Leonardo F. Fontenelle & Sing Lee & Hisato Matsunaga & David Osser & Murray B. Stein & Michael van Ameringen.(2010). A 2010 Evidence-Based Algorithm for the Pharmacotherapy of Social Anxiety Disorder. Isr J Psychiatry Relat Sci, 46(1): 53–61
__[26]__ Dan J. Stein & David S. Baldwin & Borwin Bandelow & Carlos Blanco & Leonardo F. Fontenelle & Sing Lee & Hisato Matsunaga & David Osser & Murray B. Stein & Michael van Ameringen.(2010). A 2010 Evidence-Based Algorithm for the Pharmacotherapy of Social Anxiety Disorder. Isr J Psychiatry Relat Sci, 46(1): 53–61

__[27]__Michael Van Ameringem, 2009)
__[28]__Carlos Blanco, Muhammad S. Raza, Franklin R. Schneier and Michael R. Liebowitz. (2003).The evidence-based pharmacological treatment of social anxiety disorder.Department of Psychiatry of Columbia College of Physicians and Surgeons and the New York State Psychiatric Institute,
__[29]__Carlos Blanco, Muhammad S. Raza, Franklin R. Schneier and Michael R. Liebowitz. (2003).The evidence-based pharmacological treatment of social anxiety disorder.Department of Psychiatry of Columbia College of Physicians and Surgeons and the New York State Psychiatric Institute,
__[30]__Carlos Blanco, Muhammad S. Raza, Franklin R. Schneier and Michael R. Liebowitz. (2003).The evidence-based pharmacological treatment of social anxiety disorder. Pharmacotherapy, 12: (16): 2457-2467

__[31]____Jennifer A Reinhold__; __Laura A Mandos__; __Karl Rickels__; __Falk W Lohoff__. (2011). Pharmacological treatment of generalized anxiety disorder. Expert Opinion on Pharmacotherapy, 12: (16): 2457-2467

__[32]____Jennifer A Reinhold__; __Laura A Mandos__; __Karl Rickels__; __Falk W Lohoff__. (2011). Pharmacological treatment of generalized anxiety disorder. Expert Opinion on

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Pharmacotherapy, 12: (16): 2457-2467 | | Social Anxiety Disorder Causes | Brain regions | Serotonergic pathway | Animal model | Treatments
















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    1. Ewbank Michael P.; Fox Elaine; Calder Andrew J. (2010). The interaction between gaze and facial expression in the amygdala and extended amygdala is modulated by anxiety FRONTIERS IN HUMAN NEUROSCIENCE, 4 Volume: 4 (56)
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    1. Christina A. Brook, Louis A. Schmidt. (2008). Social anxiety disorder: A review of environmental risk factors. Neuropsychiatr Dis Treat, 4(1): 123–143
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    2. Kalueff A. V.; Fox M. A.; Gallagher P. S. Hypolocomotion, anxiety and serotonin syndrome-like behavior contribute to the complex phenotype of serotonin transporter knockout mice.Genes Brain and Behavior, 6(4): 389-400
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    1. K.L. Phan; D.A. Fitzgerald; P.J. Nathan; M.E. Tancer. (2006). Association between Amygdala Hyperactivity to Harsh Faces and Severity of Social Anxiety in Generalized Social Phobia. Biological Psychiatry, 59 (5): 424-429