Neurobio­logical Hypotheses in Panic Disorder

Authors: P. Šilhán 1;  MUDr. Martin Hýža 1;  D. Kamarádová 2;  K. Látalová 2;  J. Praško 2
Authors‘ workplace: Oddělení psychiatrické, FN Ostrava 1;  Klinika psychiatrie LF UP a FN Olomouc 2
Published in: Cesk Slov Neurol N 2014; 77/110(3): 314-319
Category: Review Article


Panic disorder is a mental disorder characterized by recurrent panic attacks accompanied by significant somatic and psychological symptoms. Ethiopathogenesis of panic disorder remains unclear although clinical manifestation and proven algorithms of treatment are known. Due to paroxysmal nature of the disorder and its symptoms, functional imaging techniques provide ambiguous results. Leading neurotransmitter theories are based on the proven efficacy of antidepressants treatment. This includes the role of the neurotransmitters involved in modulation of fear circuit (serotonin, norepinephrine, gamma-aminobutyric acid, glutamate, cortikoliberin etc.). From neuroanatomical point of view, the nucleus of amygdala, with a large number of pathways involved in the panic reaction, plays the key role in triggering panic attacks. In contrast, prolonged anxiety is associated with activation of bed nucleus striae terminalis. The entire process is complex and involves interaction of the brainstem and cortical centres, the role of which consists of affective modulation of the limbic system and its regulation by volitional processes.

Key words:
panic disorder – magnetic resonance imaging – positron emission tomography –serotonin – norepinephrine – amygdala –locus coeruleus – prefrontal lobes

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manu­script met the ICMJE “uniform requirements” for biomedical papers.


1. Hirschfeld RM. Panic Disorder: dia­gnosis, epidemiology, and clinical course. J Clin Psychiatry 1996; 57 (Suppl 10): 3– 8.

2. Kukumberg P. Panická porucha: psychoneurologický nexus. Ceska Slov Psychiatr 1994; 90(3): 142– 145.

3. Kukumberg P. Panická porucha –  Neuropsychiatrický profil. Cesk Slov Neurol N 2007; 70/ 103(1): 6– 15.

4. Graeff FG, Del‑ Ben CM. Neurobio­logy of panic disorder: from animal models to brain neuroimaging. Neurosci Biobehav Rev 2008; 32(7): 1326– 1335. doi: 10.1016/ j.neubio­rev.2008.05.017.

5. Sullivan GM, Debiec J, Bush DEA, Lyons DM, Ledoux JE.The Neurobio­logy of fear and anxiety: contributions of animal models to current understanding. In: Charney DS, Nestler EJ. Neurobio­logy of Mental Illness. 3rd ed. New York: Oxford University Press 2009: 603– 626.

6. Grillon C. Models and mechanisms of anxiety: evidence from startle studies. Psychopharmacology (Berl) 2008; 199(3): 421– 437.

7. Sullivan GM, Coplan JD, Kent JM, Gorman JM. The noradrenergic system in pathological anxiety: a focus on panic with relevance to generalized anxiety and phobias. Biol Psychiatry 1999; 46(9): 1205– 1218.

8. Akirav I, Maroun M. The role of the medial prefrontal cortex‑ amygdala circuit in stress effects on the extinction of fear. Neural Plast 2007; 2007: 30873.

9. Milad MR, Rauch SL. The role of the orbitofrontal cortex in anxiety disorders. Ann N Y Acad Sci 2007; 1121: 546– 561.

10. Ressler KJ, Nemeroff CB. Role of serotonergic and noradrenergic systems in the pathophysiology of depression and anxiety disorders. Depress Anxiety 2000; 12 (Suppl 1): 2– 19.

11. Gorman JM, Liebowitz MR, Fyer AJ, Stein J. A neuroanatomical hypothesis for panic disorder. Am J Psychiatry 1989; 146(2): 148– 161.

12. Gorman JM, Kent JM, Sullivan GM, Coplan JD. Neuroanatomical hypothesis of panic disorder, revised. Am J Psychiatry 2000; 157(4): 493– 505.

13. Pitkänen A, Savander V, LeDoux JE. Organization of intra‑ amygdaloid circuitries in the rat: an emerging framework for understanding functions of the amygdala. Trends Neurosci 1997; 20(11): 517– 523.

14. Del‑ Ben CM, Graeff FG. Panic disorder: is the PAG involved? Neural Plast 2009; 2009: 108135. doi: 10.1155/ 2009/ 108135.

15. Mobbs D, Petrovic P, Marchant JL, Hassabis D, Weiskopf N, Seymour B et al. When fear is near: threat imminence elicits prefrontal‑ periaqueductal gray shifts in humans. Science 2007; 317(5841): 1079– 1083.

16. Walker DL, Toufexis DJ, Davis M. Role of the bed nucleus of the stria terminalis versus the amygdala in fear, stress, and anxiety. Eur J Pharmacol 2003; 463(1– 3): 199– 216.

17. Walker DL, Miles LA, Davis M. Selective participation of the bed nucleus of the stria terminalis and CRF in sustained anxiety‑like versus phasic fear‑like responses. Prog Neuropsychopharmacol Biol Psychiatry 2009; 33(8): 1291– 308. doi: 10.1016/ j.pnpbp.2009.06.022.

18. Domschke K, Stevens S, Pfleiderer B, Gerlach AL. Interoceptive sensitivity in anxiety and anxiety disorders: an overview and integration of neurobio­logical findings. Clin Psychol Rev 2010; 30(1): 1– 11. doi: 10.1016/ j.cpr.2009.08.008.

19. Maron E, Shlik J. Serotonin function in panic disorder: important, but why? Neuropsychopharmacology 2006; 31(1): 1– 11.

20. Graeff FG. On serotonin and experimental anxiety. Psychopharmacology (Berl) 2002; 163(3– 4): 467– 476.

21. Nash JR, Sargent PA, Rabiner EA, Hood SD, Argyropoulos SV, Potokar JP et al. Serotonin 5– HT1A receptor binding in people with panic disorder: positron emission tomography study. Br J Psychiatry 2008; 193(3): 229– 234. doi: 10.1192/ bjp.bp.107.041186.

22. Gorman JM, Hirschfeld RM, Ninan PT. New Developments in the Neurobio­logical Basis of Anxiety Disorders. Psychopharmacology Bulletin 2002; 36 (Suppl 2): 49– 67.

23. Vasa RA, Pine DS, Masten CL, Vythilingam M, Collin C, Charney DS et al. Effects of yohimbine and hydrocortisone on panic symptoms, autonomic responses, and attention to threat in healthy adults. Psychopharmacology (Berl) 2009; 204(3): 445– 455. doi: 10.1007/ s00213– 009– 1475– x.

24. Coplan JD, Liebowitz MR, Gorman JM, Fyer AJ, Dillon DJ, Campeas RB et al. Noradrenergic function in panic disorder. Effects of intravenous clonidine pretreatment on lactate induced panic. Biol Psychiatry 1992; 31(2): 135– 146.

25. Sullivan GM, Coplan JD, Kent JM, Gorman JM. The noradrenergic system in pathological anxiety: a focus on panic with relevance to generalized anxiety and phobias. Biol Psychiatry 1999; 46(9): 1205– 1218.

26. Risbrough VB, Stein MB. Role of corticotropin releasing factor in anxiety disorders: a translational research perspective. Horm Behav 2006; 50(4): 550– 561.

27. Butler PD, Weiss JM, Stout JC, Nemeroff CB. Corticotropin‑releasing factor produces fear‑ enhancing and behavioral activating effects following infusion into the locus coeruleus. J Neurosci 1990; 10(1): 176– 183.

28. Shekhar A, Johnson PL, Fitz SD, Nakazato A, Chaki S,Steckler T et al. A selective, non‑peptide CRF receptor 1 antagonist prevents sodium lactate‑induced acute panic‑like responses. Int J Neuropsychopharmacol 2011; 14(3): 355– 365. doi: 10.1017/ S1461145710001355.

29. Shekhar A, Truitt W, Rainnie D, Sajdyk T. Role of stress, corticotrophin releasing factor (CRF) and amygdala plasticity in chronic anxiety. Stress 2005; 8(4): 209– 219.

30. Nordquist RE, Steckler T, Wettstein JG, Mackie C, Spooren W. Metabotropic glutamate receptor modulation, translational methods, and bio­markers: relationships with anxiety. Psychopharmacology (Berl) 2008; 199(3): 389– 402. doi: 10.1007/ s00213– 008– 1096– 9.

31. Zwanzger P, Rupprecht R. Selective GABAergic treatment for panic? Investigations in experimental panic induction and panic disorder. J Psychiatry Neurosci 2005; 30(3): 167– 175.

32. Hasler G, Nugent AC, Carlson PJ, Carson RE, Geraci M, Drevets WC. Altered cerebral gamma‑ aminobutyric acid type A‑ benzodiazepine receptor binding in panic disorder determined by [11C] flumazenil positron emission tomography. Arch Gen Psychiatry 2008; 65(10): 1166– 1175. doi: 10.1001/ archpsyc.65.10.1166.

33. Valença AM, Nardi AE, Nascimento I, Zin WA, Versiani M. Carbon dioxide test as an additional clinical measure of treatment response in panic disorder. Arq Neuropsiquiatr 2002; 60(2– B): 358– 361.

34. Nordquist RE, Steckler T, Wettstein JG, Mackie C, Spooren W. Metabotropic glutamate receptor modulation, translational methods, and bio­markers: relationships with anxiety. Psychopharmacology 2008; 199(3): 389– 402. doi: 10.1007/ s00213- 008- 1096- 9.

35. Nardi AE, Valença AM, Lopes LL, de‑ Melo‑ Neto VL, Freire RC, Veras AB et al. Caffeine and 35% carbon dioxide challenge tests in panic disorder. Hum Psychopharmacol Clin Exp 2007; 22(4): 231– 240.

36. Sardinha A, Freire RC, Zin WA, Nardi AE. Respiratory manifestations of panic disorder: causes, consequences and therapeutic implications. J Bras Pneumol 2009; 35(7): 698– 708.

37. Valença AM, Nardi AE, Nascimento I, Zin WA, Versiani M. Respiratory panic disorder subtype and sensitivity to the carbon dioxide challenge test. Braz J Med Biol Res 2002; 35(7): 783– 788.

38. Freire RC, Nardi AE. Panic disorder and the respiratory system: clinical subtype and challenge tests. Rev Bras Psiquiatr 2012; 34 (Suppl 1): S32– S41.

39. Battaglia M, Ogliari A. Anxiety and panic: from human studies to animal research and back. Neurosci Biobehav Rev 2005; 29(1): 169– 179.

40. Maddock RJ. The lactic acid response to alkalosis in panic disorder: an integrative review. J Neuropsychiatry Clin Neurosci 2001; 13(1): 22– 34.

41. Klein DF. False suffocation alarms, spontaneous panics, and related conditions. An integrative hypothesis. Arch Gen Psychiatry 1993; 50(4): 306– 317.

42. Preter M, Klein DF. Panic, suffocation false alarms, separation anxiety and endogenous opioids. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32(3): 603– 612.

43. Graeff FG, Garcia‑ Leal C, Del‑ Ben CM, Guimarães FS.Does the panic attack activate the hypothalamic‑ pituitary‑adrenal axis? An Acad Bras Cienc 2005; 77(3): 477– 491.

44. Del Casale A, Serata D, Rapinesi C, Kotzalidis GD, Angeletti G, Tatarelli R et al. Structural neuroimaging in patients with panic disorder: findings and limitations of recent studies. Psychiatr Danub 2013; 25(2): 108– 114.

45. Dresler T, Guhn A, Tupak SV, Ehlis AC, Herrmann MJ,Fallgatter AJ et al. Revise the revised? New dimensions of the neuroanatomical hypothesis of panic disorder. J Neural Transm 2013; 120(1): 3– 29. doi: 10.1007/ s00702– 012– 0811– 1.

46. Fischer H, Andersson JL, Furmark T, Fredrikson M.Brain correlates of an unexpected panic attack: a human positron emission tomographic study. Neurosci Lett 1998; 251(2): 137– 140.

47. 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(4): 269– 272.

48. Dresler T, Hahn T, Plichta MM, Ernst LH, Tupak SV, Ehlis AC et al. Neural correlates of spontaneous panic attacks. J Neural Transm 2011; 118(2): 263– 269. doi: 10.1007/ s00702- 010- 0540- 2.

49. Spiegelhalder K, Hornyak M, Kyle SD, Paul D, Blechert J, Seifritz E et al. Cerebral correlates of heart rate variations during a spontaneous panic attack in the fMRI scanner. Neurocase 2009; 15(6): 527– 534. doi: 10.1080/ 13554790903066909.

50. Hosák L, Šilhán P, Hosáková J. Genetika úzkostných poruch. Psychiatr Prax 2013; 14(1): 7– 9.

51. Hettema JM, Prescott CA, Myers JM, Neale MC, Kendler KS. The structure of genetic and environmental risk factors for anxiety disorders in men and women. Arch Gen Psychiatry 2005; 62(2): 182– 189.

52. Maron E, Hettema JM, Shlik J. Advances in molecular genetics of panic disorder. Mol Psychiatry 2010; 15(7): 681– 701. doi: 10.1038/ mp.2009.145.

53. Hosak L. Role of the COMT gene Val158Met polymorphism in mental disorders: a review. European Psychiatry 2007; 22(5): 276– 281.

Paediatric neurology Neurosurgery Neurology

Article was published in

Czech and Slovak Neurology and Neurosurgery

Issue 3

2014 Issue 3

Most read in this issue
Forgotten password

Don‘t have an account?  Create new account

Forgotten password

Enter the email address that you registered with. We will send you instructions on how to set a new password.


Don‘t have an account?  Create new account