Skip to main content Accessibility help
Hostname: page-component-768dbb666b-v9bzm Total loading time: 0.564 Render date: 2023-02-03T17:45:33.385Z Has data issue: true Feature Flags: { "useRatesEcommerce": false } hasContentIssue true

Panic Disorder: The Psychobiology of External Treat and Introceptive Distress

Published online by Cambridge University Press:  07 November 2014


Panic disorder seems to be mediated by the neuronal circuitry and neurochemical systems that have evolved to respond to external threatening stimuli. Distant threats activate prefrontal cortex (involved in complex planning of avoidance strategies), while immediate threats activate midbrain structures (involved in fast reflexive behaviors). Panic disorder may, however, also involve more specific interoceptive mechanisms. For example, the association between respiratory dysfunction and panic disorder has bolstered a false suffocation alarm hypothesis. Genetic and environmental contributors to panic disorder are beginning to be delineated. Effective pharmacotherapy and psychotherapy are able to normalize the relevant psychobiology.

Pearls in Clinical Neuroscience
Copyright © Cambridge University Press 2008

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.)



1.Beyenburg, S, Mitchell, AJ, Schmidt, D, Elger, CE, Reuber, M. Anxiety in patients with epilepsy: systematic review and suggestions for clinical management. Epilepsy Behav. 2005;7:161171.CrossRefGoogle ScholarPubMed
2.Stein, DJ. Cognitive-Affective Neuroscience of Mood and Anxiety Disorders. London, England: Martin Dunitz; 2003.Google Scholar
3.Reiman, EM, Raichle, ME, Robins, E, et al.The application of positron emission tomography to the study of panic disorder. Am J Psychiatry. 1986;143:469477.Google Scholar
4.Vythilingam, M, Anderson, ER, Goddard, A, et al.Temporal lobe volume in panic disorder—a quantitative magnetic resonance imaging study. Psychiatry Res. 2000;99:7582.CrossRefGoogle ScholarPubMed
5.Massana, G, Serra-Grabulosa, JM, Salgado-Pineda, P, et al.Parahippocampal gray matter density in panic disorder: a voxel-based morphometric study. Am J Psychiatry. 2003;160:566568.CrossRefGoogle ScholarPubMed
6.Massana, G, Serra-Grabulosa, JM, Salgado-Pineda, P, et al.Amygdalar atrophy in panic disorder patients detected by volumetric magnetic resonance imaging. Neuroimage. 2003;19:8090.CrossRefGoogle ScholarPubMed
7.Bisaga, A, Katz, JL, Antonini, A, et al.Cerebral glucose metabolism in women with panic disorder. Am J Psychiatry. 1998;155:11781183.CrossRefGoogle ScholarPubMed
8.Lee, YS, Hwang, J, Kim, SJ, et al.Decreased blood flow of temporal regions of the brain in subjects with panic disorder. J Psychiatr Res. 2006;40:528534.CrossRefGoogle ScholarPubMed
9.Sakai, Y, Kumano, H, Nishikawa, M, et al.Cerebral glucose metabolism associated with a fear network in panic disorder. Neuroreport. 2005;16:927931.CrossRefGoogle ScholarPubMed
10.Eren, I, Tükel, R, Polat, A, Karaman, R, Unal, S. Evaluation of regional cerebral blood flow changes in panic disorder with Tc99m-HMPA0 SPECT. Psychiatry Res. 2003;123:135143.CrossRefGoogle ScholarPubMed
11.Uchida, RR, Del Ben, CM, Santos, AC, et al.Decreased left temporal lobe volume of panic patients measured by magnetic resonance imaging. Braz J Med Biol Res. 2003;36:925929.CrossRefGoogle ScholarPubMed
12.Bystritsky, A, Pontillo, D, Powers, M, Sabb, FW, Craske, MG, Bookheimer, SY. Functional MRI changes during panic anticipation and imagery exposure. Neuroreport. 2001;12:39533957.CrossRefGoogle ScholarPubMed
13.Fontaine, R, Breton, G, Déry, R, Fontaine, S, Elie, R. Temporal lobe abnormalities in panic disorder: an MRI study. Biol Psychiatry. 1990;27:304310.CrossRefGoogle Scholar
14.Ontiveros, A, Fontaine, R, Breton, G, Elie, R, Fontaine, S, Déry, R. Correlation of severity of panic disorder and neuroanatomical changes on magnetic resonance imaging. J Neuropsychiatry Clin Neurosci. 1989;1:404408.Google ScholarPubMed
15.De Cristofaro, MT, Sessarego, A, Pupi, A, Biondi, F, Faravelli, C. Brain perfusion abnormalities in drug-naive, lactate-sensitive panic patients: a SPECT study. Biol Psychiatry. 1993;33:505512.CrossRefGoogle ScholarPubMed
16.Nordahl, TE, Semple, WE, Gross, M, et al.Cerebral glucose metabolic differences in patients with panic disorder. Neuropsychopharmacology. 1990;3:261272.Google ScholarPubMed
17.Han, DH, Renshaw, PF, Dager, SR, et al.Altered cingulate white matter connectivity in panic disorder patients. J Psychiatr Res. In press.Google Scholar
18.Pillay, SS, Rogowska, J, Gruber, SA, Simpson, N, Yurgelun-Todd, DA. Recognition of happy facial affect in panic disorder: an fMRI study. J Anxiety Disord. 2007;21:381393.CrossRefGoogle ScholarPubMed
19.Yoo, HK, Kim, MJ, Kim, SJ, et al.Putaminal gray matter volume decrease in panic disorder: an optimized voxel-based morphometry study. Eur J Neurosci. 2005;22:20892094.CrossRefGoogle Scholar
20.Protopopescu, X, Pan, H, Tuescher, O, et al.Increased brainstem volume in panic disorder: a voxel-based morphometric study. Neuroreport. 2006;17:361363.CrossRefGoogle ScholarPubMed
21.Sakai, Y, Kumano, H, Nishikawa, M, et al.Changes in cerebral glucose utilization in patients with panic disorder treated with cognitive-behavioral therapy. Neuroimage. 2006;33:218226.CrossRefGoogle ScholarPubMed
22.Prasko, J, Horacek, J, Zalesky, R, et al.The change of regional brain metabolism (18FDG PET) in panic disorder during the treatment with cognitive behavioral therapy or antidepressants. Neuroendocrinol Lett. 2004;25:340348.Google ScholarPubMed
23.Boshuisen, ML, Reinders, A, Paans, AM, den Boer, JA. Changes in rCBF of panic disorder patients due to effective treatment with sertraline. Neuroimage. 2001;13: S1030S2125.CrossRefGoogle Scholar
24.Carli, V, Sarchiapone, M, Camardese, G, Romano, L, DeRisio, S. Mirtazapine in the treatment of panic disorder. Arch Gen Psychiatry. 2002;59:661662.CrossRefGoogle ScholarPubMed
25.Nordahl, TE, Stein, MB, Benkelfat, C, et al.Regional cerebral metabolic asymmetries replicated in an independent group of patients with panic disorders. Biol Psychiatry. 1998;44:9981006.CrossRefGoogle Scholar
26.Mobbs, D, Petrovic, P, Marchant, JL, et al.When fear is near: threat imminence elicits prefrontal-periaqueductal gray shifts in humans. Science. 2007;317:10791083.CrossRefGoogle ScholarPubMed
27.Neumeister, A, Bain, E, Nugent, AC, et al.Reduced serotonin type 1A receptor binding in panic disorder. J Neurosci. 2004;24:589591.CrossRefGoogle ScholarPubMed
28.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;132:173181.CrossRefGoogle ScholarPubMed
29.Esler, M, Lambert, E, Alvarenga, M, et al.Increased brain serotonin turnover in panic disorder patients in the absence of a panic attack: reduction by a selective serotonin reuptake inhibitor. Stress. 2007;10:295304.CrossRefGoogle ScholarPubMed
30.Maron, E, Shlik, J. Serotonin function in panic disorder: important, but why? Neuropsychopharmacology. 2006;31:111.CrossRefGoogle ScholarPubMed
31.Graeff, FG. Serotonin, the periaqueductal gray and panic. Neurosci Biobehav Rev. 2004;28:239259.CrossRefGoogle ScholarPubMed
32.Ham, BJ, Sung, Y, Kim, N, 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;31:403411.CrossRefGoogle ScholarPubMed
33.Goddard, AW, Mason, GF, Almai A, et al.Reductions in occipital cortex GABA levels in panic disorder detected with 1h-magnetic resonance spectroscopy. Arch Gen Psychiatry. 2001;58:556561.CrossRefGoogle Scholar
34.Cameron, OG, Huang, GC, Nichols, T, et al.Reduced gamma-aminobutyric acid(A)-benzodiazepine binding sites in insular cortex of individuals with panic disorder. Arch Gen Psychiatry. 2007;64:793800.CrossRefGoogle ScholarPubMed
35.Bremner, JD, Innis, RB, White, T, et al.SPECT [I-123]iomazenil measurement of the benzodiazepine receptor in panic disorder. Biol Psychiatry. 2000;47:96106.CrossRefGoogle ScholarPubMed
36.Malizia, AL, Cunningham, VJ, Bell, CJ, Liddle, PF, Jones, T, Nutt, DJ. Decreased brain GABA(A)-benzodiazepine receptor binding in panic disorder: preliminary results from a quantitative PET study. Arch Gen Psychiatry. 1998;55:715720.CrossRefGoogle ScholarPubMed
37.Goddard, AW, Charney, DS. Toward an integrated neurobiology of panic disorder. J Clin Psychiatry. 1997;58(suppl 2):412.Google ScholarPubMed
38.Gorman, JM, Kent, JM, Sullivan, GM, Coplan, JD. Neuroanatomical hypothesis of panic disorder, revised. Am J Psychiatry. 2000;157:493505.CrossRefGoogle ScholarPubMed
39.Papp, LA, Klein, DF, Gorman, JM. Carbon dioxide hypersensitivity, hyperventilation, and panic disorder. Am J Psychiatry. 1993;150:11491157.Google ScholarPubMed
40.Wilhelm, FH, Roth, WT. The somatic symptom paradox in DSM-IV anxiety disorders: suggestions for a clinical focus on psychophysiology. Biol Psychol. 2001;57:105140.CrossRefGoogle ScholarPubMed
41.Garakani, A, Buchsbaum, MS, Newmark, RE, et al.The effect of doxapram on brain imaging in patients with panic disorder. Eur Neuropsychopharmacol. 2007;17:672686.CrossRefGoogle ScholarPubMed
42.Schunck, T, Erb, G, Mathis, A, et al.Functional magnetic resonance imaging characterization of CCK-4-induced panic attack and subsequent anticipatory anxiety. Neuroimage. 2006;31:11971208.CrossRefGoogle ScholarPubMed
43.Boshuisen, ML, Ter Horst, GJ, Paans, AM, Reinders, AA, den Boer, JA. rCBF differences between panic disorder patients and control subjects during anticipatory anxiety and rest. Biol Psychiatry. 2002;52:126135.CrossRefGoogle Scholar
44.Woods, SW, Koster, K, Krystal, JK, et al.Yohimbine alters regional cerebral blood flow in panic disorder. Lancet. 1988;2:678.CrossRefGoogle ScholarPubMed
45.Stewart, RS, Devous, MD Sr, Rush, AJ, Lane, L, Bonte, FJ. Cerebral blood flow changes during sodium-lactate-induced panic attacks. Am J Psychiatry. 1988;145:442449.Google ScholarPubMed
46.Kent, JM, Coplan, JD, Mawlawi, O, et al.Prediction of panic response to a respiratory stimulant by reduced orbitofrontal cerebral blood flow in panic disorder. Am J Psychiatry. 2005;162:13791381.CrossRefGoogle ScholarPubMed
47.Reiman, EM, Raichle, ME, Robins, E, et al.Neuroanatomical correlates of a lactate-induced anxiety attack. Arch Gen Psychiatry. 1989;46:493500.CrossRefGoogle ScholarPubMed
48.Liotti, M, Brannan, S, Egan, G, et al.Brain responses associated with consciousness of breathlessness (air hunger). Proc Natl Acad Sci U S A. 2001;98:20352040.CrossRefGoogle Scholar
49.Corfield, DR, Fink, GR, Ramsay, SC, et al.Activation of limbic structures during C02-stimulated breathing in awake man. Adv Exp Med Biol. 1995;393:331334.CrossRefGoogle ScholarPubMed
50.Evans, KC, Banzett, RB, Adams, L, McKay, L, Frackowiak, RS, Corfield, DR. BOLD fMRI identifies limbic, paralimbic, and cerebellar activation during air hunger. J Neurophysiol. 2002;88:15001511.CrossRefGoogle ScholarPubMed
51.Hettema, JM, Neale, MC, Kendler, KS. A review and meta-analysis of the genetic epidemiology of anxiety disorders. Am J Psychiatry. 2001;158:15681578.CrossRefGoogle ScholarPubMed
52.Gratacòs, M, Sahùn, I, Gallego, X, Amador-Arjona, A, Estivill, X, Dierssen, M. Candidate genes for panic disorder: insight from human and mouse genetic studies. Genes Brain Behav. 2007;6(suppl 1):223.CrossRefGoogle ScholarPubMed
53.Domschke, K, Deckert, J, O'Donovan, MC, Glatt, SJ. Meta-analysis of COMT val158met in panic disorder: ethnic heterogeneity and gender specificity. Am J Med Genet B Neuropsychiatr Genet. 2007;144:667673.CrossRefGoogle Scholar
54.Fyer, AJ, Hamilton, SP, Durner, M, et al.A third-pass genome scan in panic disorder: evidence for multiple susceptibility loci. Biol Psychiatry. 2006;60:388401.CrossRefGoogle ScholarPubMed
55.Klein, DF, Fink, M. Psychiatric reaction patterns to imipramine. Am J Psychiatry. 1962;119:432438.CrossRefGoogle ScholarPubMed
56.Faravelli, C, Webb, T, Ambonetti, A, Fonnesu, F, Sessarego, A. Prevalence of traumatic early life events in 31 agoraphobic patients with panic attacks. Am J Psychiatry. 1985;142:14931494.Google ScholarPubMed
57.Friedman, S, Smith, L, Fogel, D, et al.The incidence and influence of early traumatic life events in patients with panic disorder: a comparison with other psychiatric outpatients. J Anxiety Disord. 2002;16:259272.CrossRefGoogle ScholarPubMed
58.Stein, MB, Walker, JR, Anderson, G, et al.Childhood physical and sexual abuse in patients with anxiety disorders and in a community sample. Am J Psychiatry. 1996;153:275277.Google Scholar
59.Domschke, K, Braun, M, Ohrmann, P, et al.Association of the functional -1019C/G 5-HT1A polymorphism with prefrontal cortex and amygdala activation measured with 3 T fMRI in panic disorder. Int J Neuropsychopharmacol. 2006;9:349355.CrossRefGoogle Scholar
60.Bouton, ME, Mineka, S, Barlow, DH. A modern learning theory perspective on the etiology of panic disorder. Psychol Bev. 2001;108:432.Google ScholarPubMed
61.Panksepp, J. Affective consciousness: core emotional feelings in animals and humans. Conscious Cogn. 2005;14:3080.CrossRefGoogle ScholarPubMed
62.Klein, DF. False suffocation alarms, spontaneous panics, and related conditions: an integrative hypothesis. Arch Gen Psychiatry. 1993;50:306317.CrossRefGoogle Scholar
63.Peiffer, C, Poline, JB, Thivard, L, Aubier, M, Samson, Y. Neural substrates for the perception of acutely induced dyspnea. Am J Respir Crit Care Med. 2001;163:951957.CrossRefGoogle ScholarPubMed
64.Banzett, RB, Mulnier, HE, Murphy, K, Rosen, SD, Wise, RJ, Adams, L. Breathlessness in humans activates insular cortex. Neuroreport. 2000;11:21172120.CrossRefGoogle ScholarPubMed
65.Severson, CA, Wang, W, Pieribone, VA, Dohle, CI, Richerson, GB. Midbrain serotonergic neurons are central pH chemoreceptors. Nat Neurosci. 2003;6:11391140.CrossRefGoogle ScholarPubMed
66.Sinha, SS, Goetz, RR, Klein, DF. Physiological and behavioral effects of naloxone and lactate in normal volunteers with relevance to the pathophysiology of panic disorder. Psychiatry Res. 2007;149:309314.CrossRefGoogle ScholarPubMed
67.Isom, GE, Elshowihy, RM. Interaction of acute and chronic stress with respiration: modification by naloxone. Pharmacol Biochem Behav. 1982;16:599603.CrossRefGoogle ScholarPubMed
68.Bandelow, B, Brunner, E, Broocks, A, Beinroth, D, Hajak, G, Pralle, L, Rüther, E. The use of the Panic and Agoraphobia Scale in a clinical trial. Psychiatry Res. 1998:77:4349.CrossRefGoogle Scholar
69.Muller, JE, Koen, L, Stein, DJ. Anxiety and medical disorders. Curr Psychiatry Rep. 2005;7:245251.CrossRefGoogle ScholarPubMed
70.Baldwin, DS, Anderson, IM, Nutt, DJ, et al.Evidence-based guidelines for the pharmacological treatment of anxiety disorders: recommendations from the British Association for Psychopharmacology. J Psychopharmacol. 2005;19:567596.CrossRefGoogle ScholarPubMed
71.Bandelow, B, Zohar, J, Hollander, E, et al.World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the pharmacological treatment of anxiety, obsessive-compulsive and posttraumatic stress disorders. World J Biol Psychiatry. 2002;3:171199.CrossRefGoogle ScholarPubMed
72.Canadian Psychiatric Association. Clinical practice guidelines. Management of anxiety disorders. Can J Psychiatry. 2006;51(suppl 2):9S91S.Google Scholar
73.Mitte, K. A meta-analysis of the efficacy of psycho- and pharmacotherapy in panic disorder with and without agoraphobia. J Affect Disord. 2005;88:2745.CrossRefGoogle ScholarPubMed
74.Furukawa, TA, Watanabe, N, Churchill, R. Psychotherapy plus antidepressant for panic disorder with or without agoraphobia: systematic review. Br J Psychiatry. 2006;188:305312.CrossRefGoogle ScholarPubMed
75.Kampman, M, Keijsers, GP, Hoogduin, CA, Hendriks, GJ. A randomized, double-blind, placebo-controlled study of the effects of adjunctive paroxetine in panic disorder patients unsuccessfully treated with cognitive-behavioral therapy alone. J Clin Psychiatry. 2002;63:772777.CrossRefGoogle ScholarPubMed
Cited by

Save article to Kindle

To save this article to your Kindle, first ensure is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the or variations. ‘’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Panic Disorder: The Psychobiology of External Treat and Introceptive Distress
Available formats

Save article to Dropbox

To save this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you used this feature, you will be asked to authorise Cambridge Core to connect with your Dropbox account. Find out more about saving content to Dropbox.

Panic Disorder: The Psychobiology of External Treat and Introceptive Distress
Available formats

Save article to Google Drive

To save this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you used this feature, you will be asked to authorise Cambridge Core to connect with your Google Drive account. Find out more about saving content to Google Drive.

Panic Disorder: The Psychobiology of External Treat and Introceptive Distress
Available formats

Reply to: Submit a response

Please enter your response.

Your details

Please enter a valid email address.

Conflicting interests

Do you have any conflicting interests? *