생물정신의학 (Korean Journal of Biological Psychiatry)

  • 제21권4호
  • /
  • Pages.128-140
  • /
  • 2014
  • /
  • 1225-8709(pISSN)
  • /
  • 2005-7571(eISSN)
대한생물정신의학회 (The Korean Society of Biological Psychiatry)
권호 표지

불안 관련 장애의 신경생물학적 이해

Neurobiological Basis of Anxiety Related Disorders

  • 김경민 (차의과학대학교 분당차병원 정신건강의학교실) ;
  • 김민경 (차의과학대학교 분당차병원 정신건강의학교실) ;
  • 이상혁 (차의과학대학교 분당차병원 정신건강의학교실)
  • Kim, Kyung-Min (Department of Psychiatry, CHA Bundang Medical Center, CHA University) ;
  • Kim, Min-Kyoung (Department of Psychiatry, CHA Bundang Medical Center, CHA University) ;
  • Lee, Sang-Hyuk (Department of Psychiatry, CHA Bundang Medical Center, CHA University)
  • 투고 : 2014.08.04
  • 심사 : 2014.10.10
  • 발행 : 2014.11.30
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

Anxiety disorders are characterized by dysregulation of neuroendocrine, neurotransmitter and neuroanatomical functions. Substantial advances in research method offered new insights into the neurobiologic mechanisms in anxiety disorders. Advances in molecular biology have enabled illumination of hormone and neurotransmitters that have important roles in anxiety. The neuroanatomic circuits related to anxiety are also being elucidated by improvements in neuroimaging technology such as structural and functional magnetic resonance imaging. This article reviews the research data in relation to the neurobiology underlying fear and pathologic anxiety and discusses their implications for development of biological treatments for anxiety disorders.

키워드

참고문헌

  1. Charney D, Drevets WC. The neurobiological basis of anxiety disorders. Neuropsychopharmacology: The Fifth Generation of Progress. In: Davis KL, Charney D, Coyle JT, Nemeroff C, editors. Philadelphia: Lippincott Williams & Wilkins;2002.
  2. Schatzberg AF, Nemeroff CB. Textbook of Psychopharmacology. 3rd ed. Washington, DC: The American Psychiatric Publishing; 2004.
  3. Izard CE. Four systems for emotion activation: cognitive and noncognitive processes. Psychol Rev 1993;100:68-90. https://doi.org/10.1037/0033-295X.100.1.68
  4. LeDoux JE. Emotion: clues from the brain. Annu Rev Psychol 1995; 46:209-235. https://doi.org/10.1146/annurev.ps.46.020195.001233
  5. Stratakis CA, Chrousos GP. Neuroendocrinology and pathophysiology of the stress system. Ann N Y Acad Sci 1995;771:1-18. https://doi.org/10.1111/j.1749-6632.1995.tb44666.x
  6. Sorrells SF, Sapolsky RM. An inflammatory review of glucocorticoid actions in the CNS. Brain Behav Immun 2007;21:259-272. https://doi.org/10.1016/j.bbi.2006.11.006
  7. Eggers AE. Redrawing Papez' circuit: a theory about how acute stress becomes chronic and causes disease. Med Hypotheses 2007; 69:852-857. https://doi.org/10.1016/j.mehy.2007.01.074
  8. Gray JA. A theory of anxiety: the role of the limbic system. Encephale 1983;9(4 Suppl 2):161B-166B.
  9. Lilly R, Cummings JL, Benson DF, Frankel M. The human Kluver-Bucy syndrome. Neurology 1983;33:1141-1145. https://doi.org/10.1212/WNL.33.9.1141
  10. Maclean PD. The limbic system (visceral brain) in relation to central gray and reticulum of the brain stem; evidence of interdependence in emotional processes. Psychosom Med 1955;17:355-366. https://doi.org/10.1097/00006842-195509000-00003
  11. Keedwell PA, Andrew C, Williams SC, Brammer MJ, Phillips ML. The neural correlates of anhedonia in major depressive disorder. Biol Psychiatry 2005;58:843-853. https://doi.org/10.1016/j.biopsych.2005.05.019
  12. Drevets WC. Neuroimaging and neuropathological studies of depression: implications for the cognitive-emotional features of mood disorders. Curr Opin Neurobiol 2001;11:240-249. https://doi.org/10.1016/S0959-4388(00)00203-8
  13. Miller EK, Cohen JD. An integrative theory of prefrontal cortex function. Annu Rev Neurosci 2001;24:167-202. https://doi.org/10.1146/annurev.neuro.24.1.167
  14. Vogt BA, Finch DM, Olson CR. Functional heterogeneity in cingulate cortex: the anterior executive and posterior evaluative regions. Cereb Cortex 1992;2:435-443.
  15. Treede RD, Kenshalo DR, Gracely RH, Jones AK. The cortical representation of pain. Pain 1999;79:105-111. https://doi.org/10.1016/S0304-3959(98)00184-5
  16. Kent JM, Mathew SJ, Gorman JM. Molecular targets in the treatment of anxiety. Biol Psychiatry 2002;52:1008-1030. https://doi.org/10.1016/S0006-3223(02)01672-4
  17. Martin EI, Ressler KJ, Binder E, Nemeroff CB. The neurobiology of anxiety disorders: brain imaging, genetics, and psychoneuroendocrinology. Clin Lab Med 2010;30:865-891. https://doi.org/10.1016/j.cll.2010.07.006
  18. LeDoux JE. Emotion circuits in the brain. Annu Rev Neurosci 2000; 23:155-184. https://doi.org/10.1146/annurev.neuro.23.1.155
  19. Zald DH. The human amygdala and the emotional evaluation of sensory stimuli. Brain Res Brain Res Rev 2003;41:88-123. https://doi.org/10.1016/S0165-0173(02)00248-5
  20. Phelps EA, LeDoux JE. Contributions of the amygdala to emotion processing: from animal models to human behavior. Neuron 2005; 48:175-187. https://doi.org/10.1016/j.neuron.2005.09.025
  21. Quirk GJ, Garcia R, Gonzalez-Lima F. Prefrontal mechanisms in extinction of conditioned fear. Biol Psychiatry 2006;60:337-343. https://doi.org/10.1016/j.biopsych.2006.03.010
  22. Bedecs K, Berthold M, Bartfai T. Galanin--10 years with a neuroendocrine peptide. Int J Biochem Cell Biol 1995;27:337-349. https://doi.org/10.1016/1357-2725(95)00008-D
  23. Liu HX, Hokfelt T. The participation of galanin in pain processing at the spinal level. Trends Pharmacol Sci 2002;23:468-474. https://doi.org/10.1016/S0165-6147(02)02074-6
  24. Lang R, Gundlach AL, Kofler B. The galanin peptide family: receptor pharmacology, pleiotropic biological actions, and implications in health and disease. Pharmacol Ther 2007;115:177-207. https://doi.org/10.1016/j.pharmthera.2007.05.009
  25. Gimpl G, Fahrenholz F. The oxytocin receptor system: structure, function, and regulation. Physiol Rev 2001;81:629-683.
  26. Meyer-Lindenberg A. Impact of prosocial neuropeptides on human brain function. Prog Brain Res 2008;170:463-470. https://doi.org/10.1016/S0079-6123(08)00436-6
  27. Egashira N, Tanoue A, Matsuda T, Koushi E, Harada S, Takano Y, et al. Impaired social interaction and reduced anxiety-related behavior in vasopressin V1a receptor knockout mice. Behav Brain Res 2007;178:123-127. https://doi.org/10.1016/j.bbr.2006.12.009
  28. Kendler KS, Gardner CO, Lichtenstein P. A developmental twin study of symptoms of anxiety and depression: evidence for genetic innovation and attenuation. Psychol Med 2008;38:1567-1575. https://doi.org/10.1017/S003329170800384X
  29. Massana G, Serra-Grabulosa JM, Salgado-Pineda P, Gasto C, Junque C, Massana J, et al. Parahippocampal gray matter density in panic disorder: a voxel-based morphometric study. Am J Psychiatry 2003;160:566-568. https://doi.org/10.1176/appi.ajp.160.3.566
  30. Han DH, Renshaw PF, Dager SR, Chung A, Hwang J, Daniels MA, et al. Altered cingulate white matter connectivity in panic disorder patients. J Psychiatr Res 2008;42:399-407. https://doi.org/10.1016/j.jpsychires.2007.03.002
  31. Kim B, Kim JH, Kim MK, Lee KS, Kim Y, Choi TK, et al. Frontal white matter alterations in short-term medicated panic disorder patients without comorbid conditions: a diffusion tensor imaging study. PLoS One 2014;9:e95279. https://doi.org/10.1371/journal.pone.0095279
  32. Kim B, Kim MK, Yoo E, Lee JY, Choe AY, Yook KH, et al. Comparison of panic disorder with and without comorbid major depression by using brain structural magnetic resonance imaging. Prog Neuropsychopharmacol Biol Psychiatry 2013;43:188-196. https://doi.org/10.1016/j.pnpbp.2012.12.022
  33. Pfleiderer B, Zinkirciran S, Arolt V, Heindel W, Deckert J, Domschke K. fMRI amygdala activation during a spontaneous panic attack in a patient with panic disorder. World J Biol Psychiatry 2007; 8:269-272. https://doi.org/10.1080/15622970701216673
  34. Lee YS, Hwang J, Kim SJ, Sung YH, Kim J, Sim ME, et al. Decreased blood flow of temporal regions of the brain in subjects with panic disorder. J Psychiatr Res 2006;40:528-534. https://doi.org/10.1016/j.jpsychires.2005.08.012
  35. Engel K, Bandelow B, Gruber O, Wedekind D. Neuroimaging in anxiety disorders. J Neural Transm 2009;116:703-716. https://doi.org/10.1007/s00702-008-0077-9
  36. Goddard AW, Mason GF, Appel M, Rothman DL, Gueorguieva R, Behar KL, et al. Impaired GABA neuronal response to acute benzodiazepine administration in panic disorder. Am J Psychiatry 2004; 161:2186-2193. https://doi.org/10.1176/appi.ajp.161.12.2186
  37. Ham BJ, Sung Y, Kim N, Kim SJ, Kim JE, Kim DJ, et al. Decreased GABA levels in anterior cingulate and basal ganglia in medicated subjects with panic disorder: a proton magnetic resonance spectroscopy (1H-MRS) study. Prog Neuropsychopharmacol Biol Psychiatry 2007;31:403-411. https://doi.org/10.1016/j.pnpbp.2006.10.011
  38. Helton DR, Tizzano JP, Monn JA, Schoepp DD, Kallman MJ. Anxiolytic and side-effect profile of LY354740: a potent, highly selective, orally active agonist for group II metabotropic glutamate receptors. J Pharmacol Exp Ther 1998;284:651-660.
  39. Cortese BM, Phan KL. The role of glutamate in anxiety and related disorders. CNS Spectr 2005;10:820-830. https://doi.org/10.1017/S1092852900010427
  40. Pull CB, Damsa C. Pharmacotherapy of panic disorder. Neuropsychiatr Dis Treat 2008;4:779-795.
  41. Vaswani M, Linda FK, Ramesh S. Role of selective serotonin reuptake inhibitors in psychiatric disorders: a comprehensive review. Prog Neuropsychopharmacol Biol Psychiatry 2003;27:85-102. https://doi.org/10.1016/S0278-5846(02)00338-X
  42. Schatzberg AF, Nemeroff CB. The American Psychiatric Publishing textbook of psychopharmacology. 3rd ed. Washington, DC: American Psychiatric Pub;2004.
  43. Unschuld PG, Ising M, Erhardt A, Lucae S, Kohli M, Kloiber S, et al. Polymorphisms in the galanin gene are associated with symptom-severity in female patients suffering from panic disorder. J Affect Disord 2008;105:177-184. https://doi.org/10.1016/j.jad.2007.05.006
  44. Hettema JM, Neale MC, Kendler KS. A review and meta-analysis of the genetic epidemiology of anxiety disorders. Am J Psychiatry 2001;158:1568-1578. https://doi.org/10.1176/appi.ajp.158.10.1568
  45. Choe AY, Kim B, Lee KS, Lee JE, Lee JY, Choi TK, et al. Serotonergic genes (5-HTT and HTR1A) and separation life events: gene-byenvironment interaction for panic disorder. Neuropsychobiology 2013;67:192-200. https://doi.org/10.1159/000347084
  46. Smoller JW, Gardner-Schuster E, Covino J. The genetic basis of panic and phobic anxiety disorders. Am J Med Genet C Semin Med Genet 2008;148C:118-126. https://doi.org/10.1002/ajmg.c.30174
  47. Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, et al. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 1996;274: 1527-1531. https://doi.org/10.1126/science.274.5292.1527
  48. Bryant RA, Felmingham K, Kemp A, Das P, Hughes G, Peduto A, et al. Amygdala and ventral anterior cingulate activation predicts treatment response to cognitive behaviour therapy for post-traumatic stress disorder. Psychol Med 2008;38:555-561.
  49. Bryant RA, Felmingham K, Whitford TJ, Kemp A, Hughes G, Peduto A, et al. Rostral anterior cingulate volume predicts treatment response to cognitive-behavioural therapy for posttraumatic stress disorder. J Psychiatry Neurosci 2008;33:142-146.
  50. Morey RA, Petty CM, Cooper DA, Labar KS, McCarthy G. Neural systems for executive and emotional processing are modulated by symptoms of posttraumatic stress disorder in Iraq War veterans. Psychiatry Res 2008;162:59-72. https://doi.org/10.1016/j.pscychresns.2007.07.007
  51. Falconer E, Bryant R, Felmingham KL, Kemp AH, Gordon E, Peduto A, et al. The neural networks of inhibitory control in posttraumatic stress disorder. J Psychiatry Neurosci 2008;33:413-422.
  52. Lyoo IK, Kim JE, Yoon SJ, Hwang J, Bae S, Kim DJ. The neurobiological role of the dorsolateral prefrontal cortex in recovery from trauma. Longitudinal brain imaging study among survivors of the South Korean subway disaster. Arch Gen Psychiatry 2011;68:701-713. https://doi.org/10.1001/archgenpsychiatry.2011.70
  53. Strawn JR, Geracioti TD Jr. Noradrenergic dysfunction and the psychopharmacology of posttraumatic stress disorder. Depress Anxiety 2008;25:260-271. https://doi.org/10.1002/da.20292
  54. Pervanidou P. Biology of post-traumatic stress disorder in childhood and adolescence. J Neuroendocrinol 2008;20:632-638. https://doi.org/10.1111/j.1365-2826.2008.01701.x
  55. Marshall RD, Schneier FR, Fallon BA, Knight CB, Abbate LA, Goetz D, et al. An open trial of paroxetine in patients with noncombat-related, chronic posttraumatic stress disorder. J Clin Psychopharmacol 1998;18:10-18. https://doi.org/10.1097/00004714-199802000-00003
  56. Yehuda R, Brand S, Yang RK. Plasma neuropeptide Y concentrations in combat exposed veterans: relationship to trauma exposure, recovery from PTSD, and coping. Biol Psychiatry 2006;59:660-663. https://doi.org/10.1016/j.biopsych.2005.08.027
  57. Yehuda R, Southwick SM, Nussbaum G, Wahby V, Giller EL Jr, Mason JW. Low urinary cortisol excretion in patients with posttraumatic stress disorder. J Nerv Ment Dis 1990;178:366-369. https://doi.org/10.1097/00005053-199006000-00004
  58. Olff M, Guzelcan Y, de Vries GJ, Assies J, Gersons BP. HPA-and HPT-axis alterations in chronic posttraumatic stress disorder. Psychoneuroendocrinology 2006;31:1220-1230. https://doi.org/10.1016/j.psyneuen.2006.09.003
  59. Bremner JD, Licinio J, Darnell A, Krystal JH, Owens MJ, Southwick SM, et al. Elevated CSF corticotropin-releasing factor concentrations in posttraumatic stress disorder. Am J Psychiatry 1997; 154:624-629. https://doi.org/10.1176/ajp.154.5.624
  60. Baker DG, Ekhator NN, Kasckow JW, Hill KK, Zoumakis E, Dashevsky BA, et al. Plasma and cerebrospinal fluid interleukin-6 concentrations in posttraumatic stress disorder. Neuroimmunomodulation 2001;9:209-217. https://doi.org/10.1159/000049028
  61. Smith MA, Davidson J, Ritchie JC, Kudler H, Lipper S, Chappell P, et al. The corticotropin-releasing hormone test in patients with posttraumatic stress disorder. Biol Psychiatry 1989;26:349-355. https://doi.org/10.1016/0006-3223(89)90050-4
  62. Yehuda R, Halligan SL, Grossman R, Golier JA, Wong C. The cortisol and glucocorticoid receptor response to low dose dexamethasone administration in aging combat veterans and holocaust survivors with and without posttraumatic stress disorder. Biol Psychiatry 2002;52:393-403. https://doi.org/10.1016/S0006-3223(02)01357-4
  63. Raison CL, Miller AH. When not enough is too much: the role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders. Am J Psychiatry 2003;160:1554-1565. https://doi.org/10.1176/appi.ajp.160.9.1554
  64. Segman RH, Shalev AY. Genetics of posttraumatic stress disorder. CNS Spectr 2003;8:693-698. https://doi.org/10.1017/S1092852900008889
  65. Yehuda R, Halligan SL, Bierer LM. Relationship of parental trauma exposure and PTSD to PTSD, depressive and anxiety disorders in offspring. J Psychiatr Res 2001;35:261-270. https://doi.org/10.1016/S0022-3956(01)00032-2
  66. Yehuda R, Halligan SL, Grossman R. Childhood trauma and risk for PTSD: relationship to intergenerational effects of trauma, parental PTSD, and cortisol excretion. Dev Psychopathol 2001;13: 733-753. https://doi.org/10.1017/S0954579401003170
  67. Koenen KC, Lyons MJ, Goldberg J, Simpson J, Williams WM, Toomey R, et al. A high risk twin study of combat-related PTSD comorbidity. Twin Res 2003;6:218-226. https://doi.org/10.1375/136905203765693870
  68. Stein MB, Jang KL, Taylor S, Vernon PA, Livesley WJ. Genetic and environmental influences on trauma exposure and posttraumatic stress disorder symptoms: a twin study. Am J Psychiatry 2002;159: 1675-1681. https://doi.org/10.1176/appi.ajp.159.10.1675
  69. Heils A, Teufel A, Petri S, Stober G, Riederer P, Bengel D, et al. Allelic variation of human serotonin transporter gene expression. J Neurochem 1996;66:2621-2624.
  70. Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 2003;301:386-389. https://doi.org/10.1126/science.1083968
  71. Eley TC, Sugden K, Corsico A, Gregory AM, Sham P, McGuffin P, et al. Gene-environment interaction analysis of serotonin system markers with adolescent depression. Mol Psychiatry 2004;9:908-915. https://doi.org/10.1038/sj.mp.4001546
  72. Kaufman J, Yang BZ, Douglas-Palumberi H, Houshyar S, Lipschitz D, Krystal JH, et al. Social supports and serotonin transporter gene moderate depression in maltreated children. Proc Natl Acad Sci U S A 2004;101:17316-17321. https://doi.org/10.1073/pnas.0404376101
  73. Kendler KS, Kuhn JW, Vittum J, Prescott CA, Riley B. The interaction of stressful life events and a serotonin transporter polymorphism in the prediction of episodes of major depression: a replication. Arch Gen Psychiatry 2005;62:529-535. https://doi.org/10.1001/archpsyc.62.5.529
  74. Gillespie NA, Whitfield JB, Williams B, Heath AC, Martin NG. The relationship between stressful life events, the serotonin transporter (5-HTTLPR) genotype and major depression. Psychol Med 2005;35:101-111. https://doi.org/10.1017/S0033291704002727
  75. Kaufman J, Yang BZ, Douglas-Palumberi H, Grasso D, Lipschitz D, Houshyar S, et al. Brain-derived neurotrophic factor-5-HTTLPR gene interactions and environmental modifiers of depression in children. Biol Psychiatry 2006;59:673-680. https://doi.org/10.1016/j.biopsych.2005.10.026
  76. Grabe HJ, Lange M, Wolff B, Volzke H, Lucht M, Freyberger HJ, et al. Mental and physical distress is modulated by a polymorphism in the 5-HT transporter gene interacting with social stressors and chronic disease burden. Mol Psychiatry. 2005;10:220-224. https://doi.org/10.1038/sj.mp.4001555
  77. Kilpatrick DG, Koenen KC, Ruggiero KJ, Acierno R, Galea S, Resnick HS, et al. The serotonin transporter genotype and social support and moderation of posttraumatic stress disorder and depression in hurricane-exposed adults. Am J Psychiatry 2007;164:1693-1699. https://doi.org/10.1176/appi.ajp.2007.06122007
  78. Stein MB, Goldin PR, Sareen J, Zorrilla LT, Brown GG. Increased amygdala activation to angry and contemptuous faces in generalized social phobia. Arch Gen Psychiatry 2002;59:1027-1034. https://doi.org/10.1001/archpsyc.59.11.1027
  79. Evans KC, Wright CI, Wedig MM, Gold AL, Pollack MH, Rauch SL. A functional MRI study of amygdala responses to angry schematic faces in social anxiety disorder. Depress Anxiety 2008;25: 496-505. https://doi.org/10.1002/da.20347
  80. Norbury R, Mackay CE, Cowen PJ, Goodwin GM, Harmer CJ. Short-term antidepressant treatment and facial processing. Functional magnetic resonance imaging study. Br J Psychiatry 2007; 190:531-532. https://doi.org/10.1192/bjp.bp.106.031393
  81. Lorberbaum JP, Kose S, Johnson MR, Arana GW, Sullivan LK, Hamner MB, et al. Neural correlates of speech anticipatory anxiety in generalized social phobia. Neuroreport 2004;15:2701-2705.
  82. Kilts CD, Kelsey JE, Knight B, Ely TD, Bowman FD, Gross RE, et al. The neural correlates of social anxiety disorder and response to pharmacotherapy. Neuropsychopharmacology 2006;31:2243-2253.
  83. Stein MB, Stein DJ. Social anxiety disorder. Lancet 2008;371:1115-1125. https://doi.org/10.1016/S0140-6736(08)60488-2
  84. Mikkelsen EJ, Detlor J, Cohen DJ. School avoidance and social phobia triggered by haloperidol in patients with Tourette's disorder. Am J Psychiatry 1981;138:1572-1576. https://doi.org/10.1176/ajp.138.12.1572
  85. Stein MB, Heuser IJ, Juncos JL, Uhde TW. Anxiety disorders in patients with Parkinson's disease. Am J Psychiatry 1990;147:217-220. https://doi.org/10.1176/ajp.147.2.217
  86. Liebowitz MR, Schneier F, Campeas R, Hollander E, Hatterer J, Fyer A, et al. Phenelzine vs atenolol in social phobia. A placebo-controlled comparison. Arch Gen Psychiatry 1992;49:290-300. https://doi.org/10.1001/archpsyc.49.4.290
  87. Johnson MR, Lydiard RB, Zealberg JJ, Fossey MD, Ballenger JC. Plasma and CSF HVA levels in panic patients with comorbid social phobia. Biol Psychiatry 1994;36:425-427. https://doi.org/10.1016/0006-3223(94)91217-3
  88. Tiihonen J, Kuikka J, Bergstrom K, Lepola U, Koponen H, Leinonen E. Dopamine reuptake site densities in patients with social phobia. Am J Psychiatry 1997;154:239-242. https://doi.org/10.1176/ajp.154.2.239
  89. Schneier FR, Liebowitz MR, Abi-Dargham A, Zea-Ponce Y, Lin SH, Laruelle M. Low dopamine D(2) receptor binding potential in social phobia. Am J Psychiatry 2000;157:457-459. https://doi.org/10.1176/appi.ajp.157.3.457
  90. Hood SD, Potokar JP, Davies SJ, Hince DA, Morris K, Seddon KM, et al. Dopaminergic challenges in social anxiety disorder: evidence for dopamine D3 desensitisation following successful treatment with serotonergic antidepressants. J Psychopharmacol 2010;24: 709-716. https://doi.org/10.1177/0269881108098144
  91. Condren RM, O'Neill A, Ryan MC, Barrett P, Thakore JH. HPA axis response to a psychological stressor in generalised social phobia. Psychoneuroendocrinology. 2002;27:693-703. https://doi.org/10.1016/S0306-4530(01)00070-1
  92. Roelofs K, van Peer J, Berretty E, Jong Pd, Spinhoven P, Elzinga BM. Hypothalamus-pituitary-adrenal axis hyperresponsiveness is associated with increased social avoidance behavior in social phobia. Biol Psychiatry 2009;65:336-343. https://doi.org/10.1016/j.biopsych.2008.08.022
  93. Martel FL, Hayward C, Lyons DM, Sanborn K, Varady S, Schatzberg AF. Salivary cortisol levels in socially phobic adolescent girls. Depress Anxiety 1999;10:25-27. https://doi.org/10.1002/(SICI)1520-6394(1999)10:1<25::AID-DA4>3.0.CO;2-O
  94. van Veen JF, van Vliet IM, Derijk RH, van Pelt J, Mertens B, Zitman FG. Elevated alpha-amylase but not cortisol in generalized social anxiety disorder. Psychoneuroendocrinology 2008;33:1313-1321. https://doi.org/10.1016/j.psyneuen.2008.07.004
  95. De Bellis MD, Keshavan MS, Shifflett H, Iyengar S, Dahl RE, Axelson DA, et al. Superior temporal gyrus volumes in pediatric generalized anxiety disorder. Biol Psychiatry 2002;51:553-562. https://doi.org/10.1016/S0006-3223(01)01375-0
  96. Monk CS, Nelson EE, McClure EB, Mogg K, Bradley BP, Leibenluft E, et al. Ventrolateral prefrontal cortex activation and attentional bias in response to angry faces in adolescents with generalized anxiety disorder. Am J Psychiatry 2006;163:1091-1097. https://doi.org/10.1176/ajp.2006.163.6.1091
  97. Mathew SJ, Mao X, Coplan JD, Smith EL, Sackeim HA, Gorman JM, et al. orsolateral prefrontal cortical pathology in generalized anxiety disorder: a proton magnetic resonance spectroscopic imaging study. Am J Psychiatry 2004;161:1119-1121. https://doi.org/10.1176/appi.ajp.161.6.1119
  98. Herry C, Ciocchi S, Senn V, Demmou L, Muller C, Luthi A. Switching on and off fear by distinct neuronal circuits. Nature 2008;454:600-606. https://doi.org/10.1038/nature07166
  99. Izumi T, Inoue T, Kato A, Kitaichi Y, Nakagawa S, Koyama T. Changes in amygdala neural activity that occur with the extinction of context-dependent conditioned fear stress. Pharmacol Biochem Behav 2008;90:297-304. https://doi.org/10.1016/j.pbb.2008.02.023
  100. Davis M, Walker DL, Myers KM. Role of the amygdala in fear extinction measured with potentiated startle. Ann N Y Acad Sci 2003; 985:218-232.
  101. Monk CS, Telzer EH, Mogg K, Bradley BP, Mai X, Louro HM, et al. Amygdala and ventrolateral prefrontal cortex activation to masked angry faces in children and adolescents with generalized anxiety disorder. Arch Gen Psychiatry 2008;65:568-576. https://doi.org/10.1001/archpsyc.65.5.568
  102. McClure EB, Adler A, Monk CS, Cameron J, Smith S, Nelson EE, et al. fMRI predictors of treatment outcome in pediatric anxiety disorders. Psychopharmacology (Berl) 2007;191:97-105. https://doi.org/10.1007/s00213-006-0542-9
  103. Whalen PJ, Johnstone T, Somerville LH, Nitschke JB, Polis S, Alexander AL, et al. A functional magnetic resonance imaging predictor of treatment response to venlafaxine in generalized anxiety disorder. Biol Psychiatry 2008;63:858-863. https://doi.org/10.1016/j.biopsych.2007.08.019
  104. Nemeroff CB. The role of GABA in the pathophysiology and treatment of anxiety disorders. Psychopharmacol Bull 2003;37:133-146.
  105. Nutt DJ. Neurobiological mechanisms in generalized anxiety disorder. J Clin Psychiatry 2001;62 Suppl 11:22-27; discussion 28.
  106. Mathew SJ, Amiel JM, Coplan JD, Fitterling HA, Sackeim HA, Gorman JM. Open-label trial of riluzole in generalized anxiety disorder. Am J Psychiatry 2005;162:2379-2381. https://doi.org/10.1176/appi.ajp.162.12.2379
  107. Pittenger C, Coric V, Banasr M, Bloch M, Krystal JH, Sanacora G. Riluzole in the treatment of mood and anxiety disorders. CNS Drugs 2008;22:761-786. https://doi.org/10.2165/00023210-200822090-00004
  108. Maron E, Kuikka JT, Ulst K, Tiihonen J, Vasar V, Shlik J. SPECT imaging of serotonin transporter binding in patients with generalized anxiety disorder. Eur Arch Psychiatry Clin Neurosci 2004;254: 392-396. https://doi.org/10.1007/s00406-004-0520-3
  109. Malison RT, Price LH, Berman R, van Dyck CH, Pelton GH, Carpenter L, et al. Reduced brain serotonin transporter availability in major depression as measured by [123I]-2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane and single photon emission computed tomography. Biol Psychiatry 1998;44:1090-1098. https://doi.org/10.1016/S0006-3223(98)00272-8
  110. Pande AC, Greiner M, Adams JB, Lydiard RB, Pierce MW. Placebo-controlled trial of the CCK-B antagonist, CI-988, in panic disorder. Biol Psychiatry 1999;46:860-862. https://doi.org/10.1016/S0006-3223(99)00090-6
  111. Sajdyk TJ, Shekhar A, Gehlert DR. Interactions between NPY and CRF in the amygdala to regulate emotionality. Neuropeptides 2004; 38:225-234. https://doi.org/10.1016/j.npep.2004.05.006
  112. Ninan PT. Recent perspectives on the diagnosis and treatment of generalized anxiety disorder. Am J Manag Care 2001;7(11 Suppl): S367-S376.
  113. Hettema JM, Prescott CA, Kendler KS. A population-based twin study of generalized anxiety disorder in men and women. J Nerv Ment Dis 2001;189:413-420. https://doi.org/10.1097/00005053-200107000-00001