Hostname: page-component-cd9895bd7-7cvxr Total loading time: 0 Render date: 2024-12-25T19:19:06.745Z Has data issue: false hasContentIssue false

Neurobiological correlates of social anxiety disorder: an update

Published online by Cambridge University Press:  26 February 2014

Donatella Marazziti*
Affiliation:
Dipartimento di Medicina Clinica e Sperimentale, Section of Psychiatry, University of Pisa, Pisa, Italy
Marianna Abelli
Affiliation:
Dipartimento di Medicina Clinica e Sperimentale, Section of Psychiatry, University of Pisa, Pisa, Italy
Stefano Baroni
Affiliation:
Dipartimento di Medicina Clinica e Sperimentale, Section of Psychiatry, University of Pisa, Pisa, Italy
Barbara Carpita
Affiliation:
Dipartimento di Medicina Clinica e Sperimentale, Section of Psychiatry, University of Pisa, Pisa, Italy
Carla E. Ramacciotti
Affiliation:
Dipartimento di Medicina Clinica e Sperimentale, Section of Psychiatry, University of Pisa, Pisa, Italy
Liliana Dell'Osso
Affiliation:
Dipartimento di Medicina Clinica e Sperimentale, Section of Psychiatry, University of Pisa, Pisa, Italy
*
*Address for correspondence: Donatella Marazziti, MD, Dipartimento di Medicina Clinica e Sperimentale Section of Psychiatry, University of Pisa, Via Roma 67, Pisa 56100, Italy. (Email: dmarazzi@psico.med.unipi.it)

Abstract

Social anxiety disorder (SAD) is a condition characterized by pervasiveness and impairment in social functioning, with a prevalence in the general population between 1.9% and 12.1%. The most consistent findings on its neurobiological underpinnings involve a wide range of neurotransmitters (serotonin, norepinephrine, glutamate, and GABA) and neuropeptides (oxytocin), but no comprehensive hypothesis is yet available. In particular, oxytocin is becoming increasingly established as a “prosocial neuropeptide” and, as such, is a major focus of current research, with a great range of therapeutic applications including SAD treatment. Specifically, the amygdala plays a pivotal role in conditioning and processing of fear, and exaggerated amygdala responses in SAD patients have been observed during various social-emotional stimuli. In addition to the amygdala, other brain areas of interest in SAD-related circuitry are represented by the medial prefrontal cortex, dorsal raphe, striatum, locus coeruleus, prefrontal cortex, insular cortex, and anterior cingulate cortex. The aim of this review is to provide an update on neurobiological correlates of SAD, with a special focus on neurotransmitters and brain areas possibly involved, and suggestions for future research that could lead to more specific therapeutic interventions.

Type
Review Article
Copyright
Copyright © Cambridge University Press 2014 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

1. Janet, P. Les obsessions et la psychasthenie. Paris: Alcan; 1903.Google Scholar
2. Liebowitz, MR, Gorman, JM, Fyer, AJ, etal. Social phobia: review of a neglected anxiety disorder. Arch Gen Psychiatry. 1985; 42(7): 729736.CrossRefGoogle ScholarPubMed
3. Marks, IM, Gelder, MG. Different ages of onset in varieties of phobia. Am J Psychiatry. 1966; 123(2): 218221.Google Scholar
4. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 3rd ed. Washington, DC: American Psychiatric Association; 1980.Google Scholar
5. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 3rd ed., rev. Washington, DC: American Psychiatric Association; 1987.Google Scholar
6. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, DC: American Psychiatric Association; 1994.Google Scholar
7. Furmark, T. Social phobia: from epidemiology to brain function. In: Comprehensive Summaries of Uppsala Dissertations from the Faculty of Social Sciences. Uppsala, Sweden: Acta Universitatis Upsaliensis; 2000.Google Scholar
8. Liebowitz, MR, Heimberg, RG, Fresco, DM, etal. Social phobia or social anxiety disorder: what's in name? Arch Gen Psychiatry. 2000; 57(2): 191192.Google Scholar
9. Stein, MB, Gorman, JM. Unmasking social anxiety disorder. J Psychiatry Neurosci. 2001; 26(3): 185189.Google Scholar
10. Van Roy, B, Kristense, H, Groholt, B, etal. Prevalence and characteristics of significant social anxiety in children aged 8–13 years: a Norwegian cross-sectional population study. Soc Psychiatry Psychiatr Epidemiol. 2009; 44(5): 407415.CrossRefGoogle Scholar
11. Pietrini, F, Lelli, L, Lo Sauro, C, etal. Epidemiologia della fobia sociale. Rivista di Psichiatria. 2009; 44(4): 203213.Google Scholar
12. Dell'Osso, L, Rucci, P, Cassano, GB, etal. Measuring social anxiety and obsessive-compulsive spectra: comparison of interviews and self-report instruments. Compr Psychiatry. 2002; 43(2): 8187.Google Scholar
13. Dell'Osso, L, Rucci, P, Ducci, F, etal. Social anxiety spectrum. Eur Arch Psychiatry Clin Neurosci. 2003; 253(6): 286291.CrossRefGoogle ScholarPubMed
14. Stein, DJ. Social anxiety disorder in the West and in the East. Ann Clin Psychiatry. 2009; 21(2): 109117.Google Scholar
15. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th ed., text rev. Washington, DC: American Psychiatric Association; 2000.Google Scholar
16. Bogels, SM, Alden, L, Beidel, DC, etal. Social anxiety disorder: question and answers for the DSM-V. Depress Anxiety. 2010; 27(2): 168189.Google Scholar
17. El-Gabalawy, R, Cox, B, Mackenzie, C, etal. Assessing the validity of social anxiety disorder subtypes using a nationally representative sample. J Anxiety Disord. 2010; 24(2): 244249.Google Scholar
18. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th ed. Arlington, VA: American Psychiatric Publishing; 2013.Google Scholar
19. Kerns, CE, Comer, JS, Pincus, DB, etal. Evaluation of the proposed social anxiety disorder specific change for DSM-5 in a treatment-seeking sample of anxious youth. Depress Anxiety. 2013; 30(8): 709715.Google Scholar
20. Assunção, MC, Costa, DL, de Mathis, MA, etal. Social phobia in obsessive-compulsive disorder: prevalence and correlates. J Affect Disord. 2012; 143(1–3): 138147.Google Scholar
21. Rodriguez, BF, Bruce, SE, Pagano, ME, etal. Relationships among psychosocial functioning, diagnostic comorbidity, and the recurrence of generalized anxiety disorder, panic disorder, and major depression. J Anxiety Disord. 2005; 19(7): 752766.Google Scholar
22. Talati, A, Ponniah, K, Strug, LJ, etal. Stress, anxiety, and post-traumatic stress disorder, panic disorder, social anxiety disorder and a possible medical syndrome previously linked to Chromosome 13. Biol Psychiatry. 2008; 63(6): 594601.Google Scholar
23. Fang, A, Hofmann, SH. Relationship between social anxiety disorder and body dysmorphic disorder. Clin Psychol Rev. 2010; 30(8): 10401048.CrossRefGoogle ScholarPubMed
24. Pini, S, Cassano, GB, Simonini, E, etal. Prevalence of anxiety disorders comorbidity in bipolar depression, unipolar depression and dysthymia. J Affect Disord. 1997; 42(2–3): 145153.Google Scholar
25. Pini, S, Maser, JD, Dell'Osso, L. Social anxiety disorder comorbidity in patients with bipolar disorder: a clinical replication. J Anxiety Disord. 2006; 20(8): 11481157.CrossRefGoogle ScholarPubMed
26. Behrendt, S, Beesdo-Baum, K, Zimmermann, P, etal. The role of mental disorders in the risk and speed of transition to alcohol use disorders among community youth. Psychol Med. 2011; 41(5): 10731085.Google Scholar
27. Blier, P, de Montigny, C. Serotonin and drug-induced therapeutic responses in major depression, obsessive-compulsive and panic disorders. Neuropsychopharmacology. 1999; 21(2 Suppl): 91S98S.Google Scholar
28. Lanzenberger, RR, Mitterhauser, M, Spindelegger, C, etal. Reduced serotonin-1A receptor binding in social anxiety disorder. Biol Psychiatry. 2007; 61(9): 10811089.Google Scholar
29. Akimova, E, Lanzenberger, R, Kasper, S. The serotonin-1A receptor in anxiety disorders. Biol Psychiatry. 2009; 66(7): 627635.Google Scholar
30. Van Veen, JF, van Vliet, IM, de Rijk, RH, etal. Tryptophan depletion affects the autonomic stress response in generalized social anxiety disorder. Psychoneuroendocrinology. 2009; 34(10): 15901594.CrossRefGoogle ScholarPubMed
31. Holmes, A, Yang, RJ, Lesch, KP, etal. Mice lacking the serotonin transporter exhibit 5-HT(1A) receptor-mediated abnormalities in tests for anxiety-like behavior. Neuropsychopharmacology. 2003; 28(12): 20772088.Google Scholar
32. Ansorge, MS, Zhou, M, Lira, A, etal. Early-life blockade of the 5-HT transporter alters emotional behavior in adult mice. Science. 2004; 306(5697): 879881.CrossRefGoogle ScholarPubMed
33. Lohmueller, KE, Pearce, CL, Pike, M, etal. Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat Genet. 2003; 33(2): 177182.CrossRefGoogle ScholarPubMed
34. Caspi, A, Sugden, K, Moffitt, TE, etal. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science. 2003; 301(5631): 386389.Google Scholar
35. Heils, A, Teufel, A, Petri, S, etal. Allelic variation of human serotonin transporter gene expression. J Neurochem. 1996; 66(6): 26212624.Google Scholar
36. Lesch, KP, Bengel, D, Heils, A, etal. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science. 1996; 274(5292): 15271531.Google Scholar
37. Borsini, F, Podhorna, J, Marazziti, D. Do animal models of anxiety predict anxiolytic-like effects of antidepressants? Psychopharmacology (Berl). 2002; 163(2): 121141.Google Scholar
38. Furmark, T, Tillfors, M, Garpenstrand, H, etal. Serotonin transporter polymorphism related to amygdala excitability and symptom severity in patients with social phobia. Neurosci Lett. 2004; 362(3): 189192.Google Scholar
39. Hariri, AR, Mattay, VS, Tessitore, A, etal. Serotonin transporter genetic variation and the response of the human amygdala. Science. 2002; 297(5580): 400403.Google Scholar
40. Davis, M, Whalen, PJ. The amygdala: vigilance and emotion. Mol Psychiatry. 2001; 6(1): 1334.Google Scholar
41. Harley, CW. A role for norepinephrine in arousal, emotion and learning? Limbic modulation by norepinephrine and the Kety hypothesis. Prog Neuropsychopharmacol Biol Psychiatry. 1987; 11(4): 419448.Google Scholar
42. Ressler, KJ, Nemeroff, CB. Role of norepinephrine in the pathophysiology and treatment of mood disorders. Biol Psychiatry. 1999; 46(9): 12191233.Google Scholar
43. Tanaka, M, Yoshida, M, Emoto, H, etal. Noradrenaline systems in the hypothalamus, amygdala and locus coeruleus are involved in the provocation of anxiety: basic studies. Eur J Pharmacol. 2000; 405(1–3): 397406.Google Scholar
44. Stein, MB, Heuser, IJ, Juncos, JL, etal. Anxiety disorders in patients with Parkinson's disease. Am J Psychiatry. 1990; 147(2): 217220.Google Scholar
45. Rosen, JB, Hamerman, E, Sitcoske, M, etal. Hyperexcitability and exaggerated fear-potentiated startle produced by partial amygdala kindling. Behav Neurosci. 1996; 110(1): 4350.Google Scholar
46. Heimberg, RG, Hope, DA, Dodge, CS, etal. DSM-III-R subtypes of social phobia: Comparison of generalized social phobics and public speaking phobics. J Nerv Ment Dis. 1990; 178(3): 172179.Google Scholar
47. Potts, NL, Davidson, JR, Krishnan, KR, etal. Levels of urinary free cortisol in social phobia. J Clin Psychiatry. 1991; 52: Suppl:4142.Google ScholarPubMed
48. Potts, NL, Book, S, Davidson, JR. The neurobiology of social phobia. Int Clin Psychopharmacol. 1996; 11(Suppl 3): 4348.Google Scholar
49. Girault, JA, Greengard, P. The neurobiology of dopamine signaling. Arch Neurol. 2004; 61(5): 641644.Google Scholar
50. Sareen, J, Campbell, DW, Leslie, WD, etal. Striatal function in generalized social phobia: a functional magnetic resonance imaging study. Biol Psychiatry. 2007; 61(3): 396404.Google Scholar
51. Tiihonen, J, Kuikka, J, Bergstrom, K, etal. Dopamine reuptake site densities in patients with social phobia. Am J Psychiatry. 1997; 154(2): 239242.Google Scholar
52. Schneier, FR, Liebowitz, MR, Abi-Dargham, A, etal. Low dopamine D2 receptor binding potential in social phobia. Am J Psychiatry. 2000; 157(3): 457459.Google Scholar
53. Ohman, A. Face the beast and fear the face: animal and social fears as prototypes for evolutionary analyses of emotion. Psychophysiology. 1986; 23(2): 123145.Google Scholar
54. Grant, KA, Shively, CA, Nader, MA, etal. Effect of social status on striatal DA D2 receptor binding characteristics in cynomolgus monkeys assessed with positron emission tomography. Synapse. 1998; 29(1): 8083.Google Scholar
55. Schneier, FR, Abi-Dargham, A, Martinez, D, etal. Dopamine transporters, D2 receptors, and dopamine release in generalized social anxiety disorder. Depress Anxiety. 2009; 26(5): 411418.Google Scholar
56. Cervenka, S, Hedman, E, Ikoma, Y, etal. Changes in dopamine D2-receptor binding are associated to symptom reduction after psychotherapy in social anxiety disorder. Transl Psychiatry. 2012; 2(5): e120.Google Scholar
57. Blair, K, Geraci, M, Devido, J, etal. Neural response to self- and other referential praise and criticism in generalized social phobia. Arch Gen Psychiatry. 2008; 65(10): 11761184.Google Scholar
58. Sotres-Bayon, F, Cain, CK, LeDoux, JE. Brain mechanisms of fear extinction: historical perspectives on the contribution of prefrontal cortex. Biol Psychiatry. 2006; 60(4): 329336.Google Scholar
59. Milad, MR, Quirk, GJ. Neurons in medial prefrontal cortex signal memory for fear extinction. Nature. 2002; 420(6911): 7074.Google Scholar
60. Marazziti, D, Catena Dell'osso, M. The role of oxytocin in neuropsychiatric disorders. Curr Med Chem. 2008; 15(7): 698704.Google Scholar
61. Guastella, AJ, Einfeld, SL, Gray, KM, etal. Intranasal oxytocin improves emotion recognition for youth with autism spectrum disorders. Biol Psychiatry. 2010; 67(7): 692694.Google Scholar
62. Hollander, E, Bartz, J, Chaplin, W, etal. Oxytocin increases retention in social cognition in autism. Biol Psychiatry. 2007; 61(4): 498503.Google Scholar
63. Bakermans-Kranenburg, MJ, van I Jzendoorn, MH. Sniffing around oxytocin: review and meta-analyses of trials in healthy and clinical groups with implications for pharmacotherapy. Transl Psychiatry. 2013; 3: 258267.Google Scholar
64. Domes, G, Heinrichs, M, Kumbier, E, etal. Effects of intranasal oxytocin on the neural basis of face processing in autism spectrum disorder. Biol Psychiatry. 2013; 74(3): 164171.Google Scholar
65. Hall, SS, Lightbody, AA, McCarthy, BE, etal. Effects of intranasal oxytocin on social anxiety in males with fragile X syndrome. Psychoneuroendocrinology. 2012; 37(4): 509518.Google Scholar
66. Eisenstein, M. Treatments: in the waiting room. Nature. 2012; 491(7422): S14S16.CrossRefGoogle ScholarPubMed
67. Stevens, FL, Wiesman, O, Feldman, R, etal. Oxytocin and behavior: evidence for effects in the brain. J Neuropsychiatry Clin Neurosci. 2013; 25(2): 96102.Google Scholar
68. Bartz, JA, Zaki, J, Bolger, N, etal. Oxytocin selectively improves empathic accuracy. Psychol Sci. 2010; 21(10): 14261428.Google Scholar
69. Meyer-Lindenberg, A, Domes, G, Kirsch, P, etal. Oxytocin and vasopressin in the human brain: social neuropeptides for translational medicine. Nat Rev Neurosci. 2011; 12(9): 524538.Google Scholar
70. Heim, C, Owens, MJ, Plotsky, PM, etal. Persistent changes in corticotropin-releasing factor systems due to early life stress: relationship to the pathophysiology of major depression and post-traumatic stress disorder. Psychopharmacol Bull. 1997; 33(2): 185192.Google Scholar
71. Mirescu, C, Peters, JD, Gould, E. Early life experience alters response of adult neurogenesis to stress. Nat Neurosci. 2004; 7(8): 841846.Google Scholar
72. Carter, CS. Developmental consequences of oxytocin. Physiol Behav. 2003; 79(3): 383397.Google Scholar
73. Wismer Fries, AB, Ziegler, TE, Kurian, JR, Jacoris, S, Pollak, SD. Early experience in humans is associated with changes in neuropeptides critical for regulating social behavior. Proc Natl Acad Sci U S A. 2005; 102(47): 1723717240.Google Scholar
74. Heim, C, Young, LJ, Newport, DJ, etal. Lower CSF oxytocin concentrations in women with a history of childhood abuse. Mol Psychiatry. 2009; 14(10): 954958.Google Scholar
75. Meinlschmidt, G, Heim, C. Sensitivity to intranasal oxytocin in adult men with early parental separation. Biol Psychiatry. 2007; 61(9): 11091111.Google Scholar
76. Ditzen, B, Schaer, M, Gabriel, B, etal. Intranasal oxytocin increases positive communication and reduces cortisol levels during couple conflict. Biol Psychiatry. 2009; 65(9): 728731.Google Scholar
77. Kirsch, P, Esslinger, C, Chen, Q, etal. Oxytocin modulates neural circuitry for social cognition and fear in humans. J Neurosci. 2005; 25(49): 1148911493.Google Scholar
78. Kosfeld, M, Heinrichs, M, Zak, PJ, etal. Oxytocin increases trust in humans. Nature. 2005; 435(7042): 673676.CrossRefGoogle ScholarPubMed
79. Prather, MD, Lavenex, P, Mauldin-Jourdain, ML, etal. Increased social fear and decreased fear of objects in monkeys with neonatal amygdala lesions. Neuroscience. 2001; 106(4): 653658.Google Scholar
80. Meyer-Lindenberg, A, Hariri, AR, Munoz, KE, etal. Neural correlates of genetically abnormal social cognition in Williams syndrome. Nat Neurosci. 2005; 8(8): 991993.Google Scholar
81. Marazziti, D, Dell'Osso, B, Baroni, S, etal. Relationship between oxytocin and anxiety of romantic attachment. Clin Pract Epidemiol Ment Health. 2006; 2: 2836.Google Scholar
82. Carter, CS. Oxytocin and sexual behavior. Neurosci Biobehav Rev. 1992; 16(2): 131144.Google Scholar
83. Uvnås-Moberg, K. Oxytocin linked antistress effects—the relaxation and growth response. Acta Physiol Scand Suppl. 1997; 640: 3842.Google Scholar
84. Insel, TR, Young, LJ. The neurobiology of attachment. Nat Rev Neurosci. 2001; 2(2): 129136.Google Scholar
85. Heinrichs, M, Baumgartner, T, Kirschbaum, C, etal. Social support and oxytocin interact to suppress cortisol and subjective responses to psychosocial stress. Biol Psychiatry. 2003; 54(12): 13891398.Google Scholar
86. Jezova, D, Skultetyova, I, Tokarev, DI, etal. Vasopressin and oxytocin in stress. Ann N Y Acad Sci. 1995; 771: 192203.Google Scholar
87. McCarthy, MM, McDonald, CH, Brooks, PJ, etal. An anxiolytic action of oxytocin is enhanced by estrogen in the mouse. Physiol Behav. 1996; 60(5): 12091215.Google Scholar
88. Marazziti, D, Bani, A, Casamassima, F, etal. Oxytocin: an old hormone for new avenues. Clinical Neuropsychiatry. 2006; 3(5): 302321.Google Scholar
89. Hoge, EA, Pollack, MH, Kaufman, RE, Zak, PJ, Simon, NM. Oxytocin levels in social anxiety disorder. CNS Neurosci Ther. 2008; 14(3): 165170.Google Scholar
90. Papadopoulos, V, Baraldi, M, Guilarte, TR, etal. Translocator protein (18kDa): new nomenclature for the peripheral type benzodiazepine receptor based on its structure and molecular function. Trends Pharmacol Sci. 2006; 27(8): 402409.Google Scholar
91. Drugan, RC, Basile, AS, Crawley, JN, etal. Inescapable shock reduces [3H]Ro 5-4864 binding to “peripheral-type” benzodiazepine receptors in the rat. Pharmacol Biochem Behav. 1986; 24(6): 16731677.Google Scholar
92. Weizman, R, Laor, N, Karp, L, etal. Alteration of platelet benzodiazepine receptors by stress of war. Am J Psychiatry. 1994; 151(5): 766767.Google Scholar
93. Marazziti, D, Rotondo, A, Martini, C, etal. Changes in peripheral benzodiazepine receptors in patients with panic disorder and obsessive-compulsive disorder. Neuropsychobiology. 1994; 29(1): 811.Google Scholar
94. Gavish, M, Laor, N, Bidder, M, etal. Altered platelet peripheral-type benzodiazepine receptor in posttraumatic stress disorder. Neuropsychopharmacology. 1996; 14(3): 181186.Google Scholar
95. Ferrarese, C, Appollonio, I, Frigo, M, etal. Decreased density of benzodiazepine receptors in lymphocytes of anxious patients: reversal after chronic diazepam treatment. Acta Psychiatr Scand. 1990; 82(2): 169173.Google Scholar
96. Rocca, P, Ferrero, P, Gualerzi, A, etal. Peripheral-type benzodiazepine receptors in anxiety disorders. Acta Psychiatr Scand. 1991; 84(6): 537544.Google Scholar
97. Weizman, R, Tanne, Z, Granek, M, etal. Peripheral benzodiazepine binding sites on platelet membranes are increased during diazepam treatment of anxious patients. Eur J Pharmacol. 1987; 138(2): 289292.Google Scholar
98. Johnson, MR, Marazziti, D, Brawman-Mintzer, O, etal. Abnormal peripheral benzodiazepine receptor density associated with generalized social phobia. Biol Psychiatry. 1998; 43(4): 306309.Google Scholar
99. Heydari, B, Le Melledo, JM. Low pregnenolone sulphate plasma concentrations in patients with generalized social phobia. Psychol Med. 2002; 32(5): 929933.Google Scholar
100. Harmer, CJ. Have no fear: the neural basis of anxiolytic drug action in generalized social phobia. Biol Psychiatry. 2013; 73(4): 300301.Google Scholar
101. Schüle, C, Nothdurfter, C, Rupprecht, R. The role of allopregnanolone in depression and anxiety. Prog Neurobiol. In press. DOI: 10.1016/j.pneurobio.2013.09.003.Google Scholar
102. Carta, MG, Bhat, KM, Preti, A. GABAergic neuroactive steroids: a new frontier in bipolar disorders? Behav Brain Funct. 2011, 19; 8(1): 6168.Google Scholar
103. Cannistraro, PA, Rauch, SL. Neural circuitry of anxiety: evidence from structural and functional neuroimaging studies. Psychopharmacol Bull. 2003; 37(4): 825.Google Scholar
104. Adolphs, R. Neural systems for recognizing emotion. Curr Opin Neurobiol. 2002; 12(2): 169177.Google Scholar
105. Tillfors, M, Furmark, T, Marteinsdottir, I, etal. Cerebral blood flow during anticipation of public speaking in social phobia: a PET study. Biol Psychiatry. 2002; 52(11): 11131119.Google Scholar
106. Lorberbaum, JP, Kose, S, Johnson, MR, etal. Neural correlates of speech anticipatory anxiety in generalized social phobia. Neuroreport. 2004; 15(18): 27012705.Google Scholar
107. Yoon, KL, Fitzgerald, DA, Angstadt, M, etal. Amygdala reactivity to emotional faces at high and low intensity in generalized social phobia: a 4-Tesla functional MRI study. Psychiatry Res. 2007; 154(1): 9398.Google Scholar
108. Stein, JL, Wiedholz, LM, Bassett, DS, etal. A validated network of effective amygdala connectivity. Neuroimage. 2007; 36(3): 736745.Google Scholar
109. Stein, MB, Goldin, PR, Sareen, J, etal. Increased amygdala activation to angry and contemptuous faces in generalized social phobia. Arch Gen Psychiatry. 2002; 59(11): 10271034.Google Scholar
110. Cooney, RE, Atlas, LY, Joormann, J, etal. Amygdala activation in the processing of neutral faces in social anxiety disorder: is neutral really neutral? Psychiatry Res. 2006; 148(1): 5559.Google Scholar
111. Frazer, A, Hensler, J. Serotonin. In: Siegal G, Agranoff B, Albers R, etal., eds. Basic Neurochemistry, 5th ed. New York: Raven Press Ltd.; 1994: 283308.Google Scholar
112. Hajós, M, Richards, CD, Székely, AD, Sharp, T. An electrophysiological and neuroanatomical study of the medial prefrontal cortical projection to the midbrain raphe nuclei in the rat. Neuroscience. 1998; 87(1): 95108.Google Scholar
113. Aston-Jones, G, Akaoka, H, Charlety, P, etal. Serotonin selectively attenuates glutamate-evoked activation of noradrenergic locus coeruleus neurons. J Neurosci. 1991; 11(3): 760769.Google Scholar
114. Gorman, JM, Kent, JM, Sullivan, GM, etal. Neuroanatomical hypothesis of panic disorder, revised. Am J Psychiatry. 2000; 157(4): 493505.Google Scholar
115. Chalmers, DT, Lovenberg, TW, De Souza, EB. Localization of novel corticotropin-releasing factor receptor (CRF2) mRNA expression to specific subcortical nuclei in rat brain: comparison with CRF1 receptor mRNA expression. J Neurosci. 1995; 15(10): 63406350.Google Scholar
116. Price, ML, Lucki, I. Regulation of serotonin release in the lateral septum and striatum by corticotropin-releasing factor. J Neurosci. 2001; 21(8): 28332841.Google Scholar
117. Marcin, MS, Nemeroff, CB. The neurobiology of social anxiety disorder: the relevance of fear and anxiety. Acta Psychiatr Scand Suppl. 2003; 108(417): 5164.Google Scholar
118. Graeff, FG, Guimaraes, FS, De Andrade, TG, etal. Role of 5-HT in stress, anxiety, and depression. Pharmacol Biochem Behav. 1996; 54(1): 129141.Google Scholar
119. Robbins, TW, Everitt, BJ. Central norepinephrine neurons and behavior. In: Bloom FE, Kupfer DJ, eds. Psychopharmacology: The Fourth Generation of Progress. New York: Raven Press; 1995: 363372.Google Scholar
120. Valentino, RJ, Foote, SL, Page, ME. The locus coeruleus as a site for integrating corticotropin-releasing factor and noradrenergic mediation of stress responses. Ann N Y Acad Sci. 1993; 697(1): 173188.Google Scholar
121. Fitzgerald, KD, Liu, Y, Stern, ER, etal. Reduced error-related activation of dorsolateral prefrontal cortex across pediatric anxiety disorders. J Am Acad Child Adolesc Psychiatry. 2013; 52(11): 11831191.Google Scholar
122. Moscovitch, DA, Santesso, DL, Miskovic, V, etal. Frontal EEG asymmetry and symptom response to cognitive behavioral therapy inpatients with social anxiety disorder. Biol Psychol. 2011; 87(3): 379385.Google Scholar
123. Amir, N, Klumpp, H, Elias, J, etal. Increased activation of the anterior cingulate cortex during processing of disgust faces in individuals with social phobia. Biol Psychiatry. 2005; 57(9): 975981.Google Scholar
124. Quadflieg, S, Mohr, A, Mentzel, HJ, Miltner, WH, Straube, T. Modulation of the neural network involved in the processing of anger prosody: the role of task-relevance and social phobia. Biol Psychol. 2008; 78(2): 129137.Google Scholar
125. Van Ameringen, M, Mancini, C, Szechtman, H, etal. A PET provocation study of generalized social phobia. Psychiatry Res. 2004; 132(1): 1318.CrossRefGoogle ScholarPubMed
126. Evans, KC, Simon, NM, Dougherty, DD, etal. A PET study of tiagabine treatment implicates ventral medial prefrontal cortex in generalized social anxiety disorder. Neuropsychopharmacology. 2009; 34(2): 390398.Google Scholar
127. Phan, KL, Fitzgerald, DA, Cortese, BM, etal. Anterior cingulate neurochemistry in social anxiety disorder: 1H-MRS at 4 Tesla. Neuroreport. 2005; 16(2): 183186.Google Scholar
128. Kilts, CD, Kelsey, JE, Knight, B, etal. The neural correlates of social anxiety disorder and response to pharmacotherapy. Neuropsychopharmacology. 2006; 31(10): 22432253.Google Scholar
129. Campbell, DW, Sareen, J, Paulus, MP, etal. Time-varying amygdala response to emotional faces in generalized social phobia. Biol Psychiatry. 2007; 62(5): 455463.Google Scholar
130. Blanco, C, Bragdon, LB, Schneier, FR, etal. The evidence-based pharmacotherapy of social anxiety disorder. Int J Neuropsychopharmacol. 2013; 16(1): 235249.CrossRefGoogle ScholarPubMed
131. Schneier, FR. Pharmacotherapy of social anxiety disorder. Expert Opin Pharmacother. 2011; 12(4): 615625.Google Scholar