Although the complimentary roles of heart and brain in anxiety have been recognised for centuries, the precise contribution of each and more importantly perhaps their interplay has proved difficult to describe. Recent data from human brain imaging and cardiovascular physiology studies are beginning to delineate the mechanistic pathways of anxiety disorders in general and panic in particular. Evidence for a dysfunction of brain gamma-amino butyric acid-A and serotonin (5HT) systems in both panic and cardiovascular regulation is reviewed along with new evidence for altered sympathetic nervous system activity in the heart and periphery. Testable hypotheses and research ideas are suggested.
Albert, CM, Chae, CU, Rexrode, KM, Cook, NR, Manson, JE, Kawachi, I. ( 2005) Phobic anxiety and risk of coronary heart disease and sudden cardiac death among women. Circulation111: 480-487.
2.
Alvarenga, ME, Richards, JC, Lambert, G., Esler, MD ( 2006) Psychophysiological mechanisms in panic disorder. A correlative analysis of noradrenaline spillover, power spectral analysis of heart rate variability and psychological variables. Psychosom Med68: 8-16.
3.
Argyropoulos, SV, Hood, SD, Adrover, M., Bell, CJ, Rich, AS, Nash, JR, et al. (2004) Tryptophan depletion reverses the therapeutic effect of selective serotonin reuptake inhibitors in social anxiety disorder . Biol Psychiatry56: 503-509.
4.
Bailey, JE, Argyropoulos, SV, Lightman, SL, Nutt, DJ ( 2003) Does the brain noradrenaline network mediate the effects of the CO2 challenge? J Psychopharmacol17: 252-259.
5.
Bailey, JE, Papadopoulos, A., Seddon, K., Nutt, DJ (2009) A comparison of the effects of a subtype selective and non-selective benzodiazepine receptor agonist in two CO2 models of experimental human anxiety . J Psychopharmacol23: 117-122.
6.
Baldwin, DS, Anderson, IM, Nutt, DJ, Bandelow, B., Bond, A., Davidson, JR, et al. (2005) Evidence-based guidelines for the pharmacological treatment of anxiety disorders: recommendations from the British Association for Psychopharmacology. J Psychopharmacol19: 567-596.
7.
Bell, C., Forshall, S., Adrover, M., Nash, J., Hood, S., Argyropoulos, S., et al. (2002) Does 5-HT restrain panic? A tryptophan depletion study in panic disorder patients recovered on paroxetine. J Psychopharmacol16: 5-14.
8.
Bremner, JD, Innis, RB, Southwick, SM, Staib, L., Zoghbi, S., Charney, DS ( 2000) Decreased benzodiazepine receptor binding in prefrontal cortex in combat-related posttraumatic stress disorder. Am J Psychiatry157: 1120-1126.
9.
Cameron, OG, Huang, GC, Nichols, T., Koeppe, RA, Minoshima, S., Rose, D., et al. (2007) Reduced gamma-aminobutyric acid(A)-benzodiazepine binding sites in insular cortex of individuals with panic disorder. Arch Gen Psychiatry64: 793-800.
10.
Cannon, WB ( 1927) The James-Lange theory of emotions: act-ideal examination and an alternative theory. Am J Psychol39: 106-124.
11.
Charney, DS, Heninger, GR ( 1986) Abnormal regulation of noradrenergic function in panic disorders. Effects of clonidine in healthy subjects and patients with agoraphobia and panic disorder. Arch Gen Psychiatry43: 1042-1054.
12.
Coplan, JD, Papp, LA, Pine, D., Martinez, J., Cooper, T., Rosenblum, LA, et al. (1997) Clinical improvement with fluoxetine therapy and noradrenergic function in patients with panic disorder. Arch Gen Psychiatry54: 643-648.
13.
Corchs, F., et al. in press.
14.
Critchley, HD, Taggart, P., Sutton, PM, Holdright, DR, Batchvarov, V., Hnatkova, K., et al. (2005) Mental stress and sudden cardiac death: asymmetric midbrain activity as a linking mechanism. Brain128 (Pt 1): 75-85.
15.
Cross National Collaborative Panic Study (CNCPS) ( 1992) Drug treatment of panic disorder, comparative efficacy of Alprazolam, Imipramine and Placebo. Br J Psychiatry160: 191-202.
16.
Davies, SJ, Jackson, PR, Lewis, G., Hood, SD, Nutt, DJ, Potokar, JP ( 2008) Is the association of hypertension and panic disorder explained by clustering of autonomic panic symptoms in hypertensive patients ? J Affect Disord111: 344-350.
17.
Davies, SJ, Lowry, CA, Nutt, DJ ( 2007) Panic and hypertension - brothers in arms through 5HT . J Psychopharmacol21: 561-566.
18.
Davies, SJC, Ghahramani, P., Jackson, PR, Noble, TW, Hardy, PG, Hippisley-Cox, J., et al. (1999) Association of panic disorder and panic attacks with hypertension. Am J Med107: 310-316.
19.
Davies, SJC, Hood, SD, Argyropoulos, SV, Morris, K., Bell, C., Witchel, HJ, et al. (2006) Depleting Serotonin enhances both cardiovascular and psychological stress reactivity in recovered patients with anxiety disorders . J Clin Psychopharm26: 414-418.
20.
Esler, M., Eikelis, N., Schlaich, M., Lambert, G., Alvarenga, M., Dawood, T., et al. (2008) Chronic mental stress is a cause of essential hypertension: presence of biological markers of stress. Clin Exp Pharmacol Physiol35: 498-502.
21.
Esler, M., Lambert, E., Alvarenga, M., Socratous, F., Richards, J., Barton, D., et al. (2007) Increased brain serotonin turnover in panic disorder patients in the absence of a panic attack. Reduction by a selective serotonin reuptake inhibitor. Stress10: 295-304.
22.
Flaa, A., Eide, IK, Kjeldsen, SE, Rostrup, M. ( 2008) Sympathoadrenal stress reactivity is a predictor of future blood pressure: an 18-year follow-up study. Hypertension52: 336-341.
23.
Geuze, E., van Berckel, BN, Lammertsma, AA, Boellaard, R., de Kloet, CS, Vermetten, E., et al. (2008) Reduced GABAA benzodiazepine receptor binding in veterans with post-traumatic stress disorder. Mol Psychiatry13: 74-83.
24.
Gianaros, PJ, Jennings, JR, Sheu, LK, Derbyshire, SW, Matthews, KA ( 2007) Heightened functional neural activation to psychological stress covaries with exaggerated blood pressure reactivity. Hypertension49: 134-140.
25.
Gray, MA, Harrison, NA, Wiens, S., Critchley, HD ( 2007) Modulation of emotional appraisal by false physiological feedback during fMRI. PLoS ONE2: e546.
26.
Green, AR ( 2006) Neuropharmacology of 5-hydroxytryptamine. Br J Pharmacol147 (Suppl. 1): S145-S152.
27.
Hasler, G., Nugent, AC, Carlson, PJ, Carson, RE, Geraci, M., Drevets, WC ( 2008) Altered cerebral gamma-aminobutyric acid type A-benzodiazepine receptor binding in panic disorder determined by [11C]flumazenil positron emission tomography. Arch Gen Psychiatry65: 1166-1175.
28.
James, W. ( 1884) What is an emotion? Mind9: 188-205.
29.
James, W. ( 1890) Principles of Psychology. New York : Dove, pp. 450.
30.
Kalueff, A., Nutt, DJ ( 1996) Role of GABA in memory and anxiety. Depress Anxiety4: 100-110.
31.
Kawachi, I., Colditz, GA, Aschiero, A., Rimm, EB, Giovannucci, E., Stampfer, MJ, et al. (1994) Prospective study of phobic anxiety and risk of coronary heart disease in men. Circulation89: 1992- 1997.
32.
Lambert, E., Dawood, T., Schlaich, M., Straznicky, N., Esler, M., Lambert, G. ( 2008) Single-unit sympathetic discharge pattern in pathological conditions associated with elevated cardiovascular risk. Clin Exp Pharmacol Physiol35: 503-507.
33.
Lambert, E., Hotchkin, E., Alvarenga, M., Pier, C., Richards, J., Barton, D., et al. (2006) Single-unit analysis of sympathetic nervous discharges in patients with panic disorder. J Physiol570 (Pt 3): 637-643.
34.
Lanzenberger, RR, Mitterhauser, M., Spindelegger, C., Wadsak, W., Klein, N., Mien, LK, et al. (2007) Reduced serotonin-1A receptor binding in social anxiety disorder. Biol Psychiatry61: 1081-1089.
35.
Malizia, AL ( 2003) Brain imaging and anxiety disorders. In: Nutt, DJ, Ballenger, JC, (eds), Anxiety Disorders. Oxford : Blackwell Science, pp. 201-228.
36.
Malizia, AL, Cunningham, VJ, Bell, CJ, Liddle, PF, Jones, T., Nutt, DJ ( 1998) Decreased brain GABA(A)-benzodiazepine receptor binding in panic disorder: preliminary results from a quantitative PET study . Arch Gen Psychiatry55: 715-720.
37.
Mansour, VM, Wilkinson, DJC, Jennings, GL, Schwarz, RG, Thompson, JM, Esler, MD ( 1998) Panic disorder: coronary spasm as a basis for cardiac risk? Med J Aust168: 390-392.
38.
Nalivaiko, E., Mastorci, F., Sgoifo, A (2009) 8-OH-DPAT prevents cardiac arrhythmias and attenuates tachycardia during social stress in rats. Physiol Behav96: 320-327.
39.
Nash, JR, Sargent, PA, Rabiner, EA, Hood, SD, Argyropoulos, SV, Potokar, JP, et al. (2008) Serotonin 5-HT1A receptor binding in people with panic disorder: positron emission tomography study. Br J Psychiatry193: 229-234.
40.
Neumeister, A., Bain, E., Nugent, AC, Carson, RE, Bonne, O., Luckenbaugh, DA, et al. (2004) Reduced serotonin type 1A binding in panic disorder. J Neurosci24: 589-591.
41.
Nutt, DJ ( 1986) Increased central alpha 2-adrenoceptor sensitivity in panic disorder. Psychopharmacology ( Berl ) 90: 268-269.
42.
Nutt, DJ ( 1989) Altered central alpha 2-adrenoceptor sensitivity in panic disorder. Arch Gen Psychiatry46: 165-169.
43.
Nutt, DJ, Glue, P. ( 1991) Imipramine in panic disorder (2): effects on alpha2-adrenoceptor function. J Psychopharmacol5: 135-141.
44.
Nutt, D., Lawson, C. ( 1992) Panic attacks. A neurochemical overview of models and mechanisms. Br J Psychiatry160: 165-178.
45.
Nutt, DJ, Malizia, AL ( 2001) New insights into the role of the GABA(A)-benzodiazepine receptor in psychiatric disorder. Br J Psychiatry179: 390-396.
46.
Phillips, SJ, Richens, A., Shand, DG ( 1973) Adrenergic control of tendon jerk reflexes in man . Br J Pharmacol47: 595-605.
47.
Polyák, J. ( 2001) How should we manage cardiovascular panic disorder accompanied by hypertension?J Hypertens19 (Suppl. 2): S64 (abstract).
48.
Rosen, SD, Paulesu, E., Wise, RJ, Camici, PG ( 2002) Central neural contribution to the perception of chest pain in cardiac syndrome X. Heart87: 513-519.
49.
Roy-Byrne, PP, Lewis, N., Villacres, E., Diem, H., Greenblatt, DJ, Shader, RI, et al. (1989) Preliminary evidence of benzodiazepine subsensitivity in panic disorder. Biol Psychiatry26: 744-748.
50.
Roy-Byrne, PP, Lewis, N., Villacres, E., Greenblatt, DJ, Shader, RI, Veith, RC ( 1988) Suppression of norepinephrine appearance rate in plasma by diazepam in humans. Life Sci43: 1615-1623.
51.
Steptoe, A., Willemsen, G. ( 2004) The influence of low job control on ambulatory blood pressure and perceived stress over the working day in men and women from the Whitehall II cohort. J Hypertens22: 915-920.
52.
Tiihonen, J., Kuikka, J., Rasanen, P., Lepola, U., Koponen, H., Liuska, A., et al. (1997) Cerebral benzodiazepine receptor binding and distribution in generalized anxiety disorder: a fractal analysis. Mol Psychiatry2: 463-471.
53.
Tyacke, RJ, Robinson, ES, Lalies, MD, Hume, SP, Hudson, AL, Nutt, DJ ( 2005) Estimation of endogenous noradrenaline release in rat brain in vivo using [(3)H]RX 821002. Synapse55: 126-132.
54.
Weissman, MM, Markowitz, JS, Ouellette, R., Greenwald, S., Kahn, JP ( 1990) Panic disorder and cardiovascular/cerebrovascular problems: results from a community survey. Am J Psychiatry147: 1504-1508.
