Herz und Hirn - Die Auswirkungen psychischer Erkrankungen und ihrer Therapie auf die Herzfrequenzvariabilität

Zusammenfassung

Psychische Erkrankungen gehen mit Störungen des autonomen Nervensystems einher, die möglicherweise mitverantwortlich für das erhöhte Mortalitätsrisiko dieser Erkrankungen sind. Die Bestimmung der Herzfrequenzvariabilität (heart rate variability = HRV) ist eine einfach durchzuführende Untersuchung, die Aussagen über den Einfluss des zentralen Nervensystems auf die Herzaktion zulässt. Zur Charakterisierung der HRV wurde eine Vielzahl an Kennwerten mit zum Teil erheblich differierender physiologischer Bedeutung definiert. Die gebräuchlichsten Kennwerte werden in der vorliegenden Arbeit dargestellt. Patienten mit einer Major Depression weisen eine eingeschränkte HRV auf, die entsprechend der Mehrzahl der vorliegenden Untersuchungen auf eine verminderte parasympathische Aktivität zurückgeführt wird. Einige Autoren vermuten auch eine erhöhte sympathoadrenerge Aktivität. Das Ausmaß der HRV-Verminderung korreliert mit dem Schweregrad der Depression. Patienten mit einer koronaren Herzerkrankung, die zugleich depressiv erkrankt sind, haben ein deutlich erhöhtes Mortalitätsrisiko im Vergleich zu nicht depressiv erkrankten Herzpatienten. Dieses erhöhte Risiko kann durch eine antidepressive Therapie mit einem Serotonin-Wiederaufnahmehemmer nicht gemindert werden. Eine Verminderung der HRV ist auch bei Patienten mit einer Panikstörung gefunden worden. Angeführt werden sowohl eine erhöhte sympathische Kontrolle der HRV als auch ein reduzierter vagaler Tonus. Bei schizophrenen Patienten wurde in Langzeit-EKG-Aufzeichnungen eine verminderte HRV gefunden, während Kurzzeitaufzeichnungen keine Veränderungen der HRV im Vergleich zu Kontrollpersonen ergaben. Patienten mit einer Alzheimer-Demenz weisen eine reduzierte HRV auf, welche konsistent in einer reduzierten Low Frequency-Komponente zu finden ist. Die Therapie mit Cholinesterase-Inhibitoren führt zu einer zusätzlichen Verminderung der HRV und damit möglicherweise zu einem erhöhten Risiko für Herzrhythmusstörungen. Die konsequente Analyse der HRV im (Langzeit)-EKG kann zur Aufklärung der mit psychischen Erkrankungen assoziierten autonomen Dysregulation führen und so zur Therapieoptimierung beitragen.

Abstract

Psychiatric disorders are associated with autonomic dysregulations. There is evidence that these dysregulations are partly responsible for the increased mortality in patients with psychiatric disorders. The determination of the heart rate variability (HRV) is a method easily applicable and allows the assessment of the autonomic control of the heart rate regulation. A multitude of HRV parameters with different physiological meanings have been introduced, the most widely used parameters are presented and characterized in this paper. Many studies have shown a reduced HRV in patients with major depression. Most studies found a reduced parasympathetic activity. However some authors discuss an elevated sympathetic activity. The magnitude of HRV reduction correlates to the severity of the depression. In patients with coronary diseases, major depression is an independent risk factor of mortality. Antidepressive therapy with serotonine reuptake inhibitors has failed to improve the prognosis of this patients. Patients with panic disorders also have a reduced HRV due to an elevated sympathetic control and reduced vagal control. In schizophrenic patients a reduced HRV was found in long term electrocardiogram recordings, whereas short term recordings did not show a reduced HRV. Patients with Alzheimer's disease also have a reduced HRV, which is limited to the low frequency component. Therapy with cholinesterase inhibitors further influences HRV by reducing the high frequency component and might increase the risk for arrhythmias. HRV analysis and integration in the assessment and monitoring of psychiatric patients before and during therapy elucidate the role of autonomic disturbances in such diseases and may help to optimize treatment.

Literatur

• 1 Frasure-Smith N Lesperance. Depression and other psychological risks following myocardial infarction.  Arch Gen Psychiatry. 2003;  60 627-636
• 2 Ruo B, Rumsfeld J S, Hlatky M A, Liu H, Browner W S, Whooley M A. Depressive symptoms and health-related quality of life: the Heart and Soul Study.  JAMA. 2003;  290 215-221
• 3 Lecrubier Y. The burden of depression and anxiety in general medicine.  J Clin Psychiatry. 2001;  62 (Suppl 8) 4-9; discussion 10 - 1 : 4 - 9
• 4 Katon W. Clinical and health services relationships between major depression, depressive symptoms, and general medical illness.  Biol Psychiatry. 2003;  54 216-226
• 5 Glassman A H, Bigger Jr J T. Antipsychotic Drugs: Prolonged QTc Interval, Torsade de Pointes, and Sudden Death.  Am J Psychiatry. 2001;  158 1774-1782
• 6 Muck-Jorgensen P, Mors O, Mortensen P B, Ewald H. The schizophrenic patient in the somatic hospital.  Acta Psychiatr Scand Suppl. 2000;  102 96-99
• 7 Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Heart rate variability: standards of measurement, physiological interpretation and clinical use.   Circulation. 1996;  93 1043-1065
• 8 Guo Z L, Li P, Longhurst J C. Central pathways in the pons and midbrain involved in cardiac sympathoexcitatory reflexes in cats.  Neuroscience. 2002;  113 435-447
• 9 Verberne A J, Owens N C. Cortical modulation of the cardiovascular system.  Prog Neurobiol. 1998;  54 149-168
• 10 Ramage A G. Central cardiovascular regulation and 5-hydroxytryptamine receptors.  Brain Res Bull. 2001;  56 425-439
• 11 Hilz M J, Stemper B, Neundorfer B. [Physiology and methods for studying the baroreceptor reflex].  Fortschr Neurol Psychiatr. 2000;  68 37-47
• 12 Malpas S C. Neural influences on cardiovascular variability: possibilities and pitfalls.  Am J Physiol Heart Circ Physiol. 2002;  282 H6-20
• 13 Barthel P, Schneider R, Bauer A, Ulm K, Schmitt C, Schomig A, Schmidt G. Risk stratification after acute myocardial infarction by heart rate turbulence.  Circulation. 2003;  108 1221-1226
• 14 Schmidt G, Malik M, Barthel P, Schneider R, Ulm K, Rolnitzky L, Camm A J, Bigger Jr J T, Schomig A. Heart-rate turbulence after ventricular premature beats as a predictor of mortality after acute myocardial infarction.  Lancet. 1999;  353 1390-1396
• 15 Kleiger R E, Miller J P, Bigger Jr J T, Moss A J. Decreased heart rate variability and its association with increased mortality after acute myocardial infarction.  Am J Cardiol. 1987;  59 256-262
• 16 Szabo B M, van Veldhuisen D J, van der Veer V, Brouwer J, de Graeff P A, Crijns H J. Prognostic value of heart rate variability in chronic congestive heart failure secondary to idiopathic or ischemic dilated cardiomyopathy.  Am J Cardiol. 1997;  79 978-980
• 17 Nolan J, Batin P D, Andrews R, Lindsay S J, Brooksby P, Mullen M, Baig W, Flapan A D, Cowley A, Prescott R J, Neilson J M, Fox K A. Prospective study of heart rate variability and mortality in chronic heart failure: results of the United Kingdom heart failure evaluation and assessment of risk trial (UK-heart).  Circulation. 1998;  98 1510-1516
• 18 Whitsel E A, Raghunathan T E, Pearce R M, Lin D, Rautaharju P M, Lemaitre R, Siscovick D S. RR interval variation, the QT interval index and risk of primary cardiac arrest among patients without clinically recognized heart disease.  Eur Heart J. 2001;  22 165-173
• 19 Malik M. Heart rate variability.  Curr Opin Cardiol. 1998;  13 36-44
• 20 Li M, Zheng C, Sato T, Kawada T, Sugimachi M, Sunagawa K. Vagal nerve stimulation markedly improves long-term survival after chronic heart failure in rats.  Circulation. 2004;  109 120-124
• 21 Ravenswaaij-Arts C M, Kollee L A, Hopman J C, Stoelinga G B, Geijn H P van. Heart rate variability.  Ann Intern Med. 1993;  118 436-447
• 22 Tygesen H, Wettervik C, Claes G, Drott C, Emanuelsson H, Solem J, Lomsky M, Radberg G, Wennerblom B. Long-term effect of endoscopic transthoracic sympathicotomy on heart rate variability and QT dispersion in severe angina pectoris.  Int J Cardiol. 1999;  70 283-292
• 23 Ewing D J, Neilson J M, Shapiro C M, Stewart J A, Reid W. Twenty four hour heart rate variability: effects of posture, sleep, and time of day in healthy controls and comparison with bedside tests of autonomic function in diabetic patients.  Br Heart J. 1991;  65 239-244
• 24 Maddens M, Lipsitz L A, Wei J Y, Pluchino F C, Mark R. Impaired heart rate responses to cough and deep breathing in elderly patients with unexplained syncope.  Am J Cardiol. 1987;  60 1368-1372
• 25 O'Brien I A, O'Hare P, Corrall R J. Heart rate variability in healthy subjects: effect of age and the derivation of normal ranges for tests of autonomic function.  Br Heart J. 1986;  55 348-354
• 26 Malliani A, Pagani M, Lombardi F, Cerutti S. Cardiovascular neural regulation explored in the frequency domain.  Circulation. 1991;  84 482-492
• 27 Pagani M, Lombardi F, Guzzetti S, Rimoldi O, Furlan R, Pizzinelli P, Sandrone G, Malfatto G, Dell'Orto S, Piccaluga E. Power spectral analysis of heart rate and arterial pressure variabilities as a marker of sympatho-vagal interaction in man and conscious dog.  Circ Res. 1986;  59 178-193
• 28 Cacioppo J T, Berntson G G, Binkley P F, Quigley K S, Uchino B N, Fieldstone A. Autonomic cardiac control. II. Noninvasive indices and basal response as revealed by autonomic blockades.  Psychophysiology. 1994;  31 586-598
• 29 Lazzeri C, La Villa G, Mannelli M, Janni L, Franchi F. Effects of acute clonidine administration on power spectral analysis of heart rate variability in healthy humans.  J Auton Pharmacol. 1998;  18 307-312
• 30 Brown T E, Beightol L A, Koh J, Eckberg D L. Important influence of respiration on human R-R interval power spectra is largely ignored.  J Appl Physiol. 1993;  75 2310-2317
• 31 Kobayashi H, Ishibashi K, Noguchi H. Heart rate variability; an index for monitoring and analyzing human autonomic activities.  Appl Human Sci. 1999;  18 53-59
• 32 Bacon S L, Watkins L L, Babyak M, Sherwood A, Hayano J, Hinderliter A L, Waugh R, Blumenthal J A. Effects of daily stress on autonomic cardiac control in patients with coronary artery disease.  Am J Cardiol. 2004;  93 1292-1294
• 33 Ghuran A, Reid F, La Rovere M T, Schmidt G, Bigger Jr J T, Camm A J, Schwartz P J, Malik M. Heart rate turbulence-based predictors of fatal and nonfatal cardiac arrest (The Autonomic Tone and Reflexes After Myocardial Infarction substudy).  Am J Cardiol. 2002;  89 184-190
• 34 Huikuri H V, Kessler K M, Terracall E, Castellanos A, Linnaluoto M K, Myerburg R J. Reproducibility and circadian rhythm of heart rate variability in healthy subjects.  Am J Cardiol. 1990;  65 391-393
• 35 Kleiger R E, Bigger Jr J T, Bosner M S, Chung M K, Cook J R, Rolnitzky L M, Steinman R, Fleiss J L. Stability over time of variables measuring heart rate variability in normal subjects.  Am J Cardiol. 1991;  68 626-630
• 36 Kowalewski M A, Urban M. Short- and long-term reproducibility of autonomic measures in supine and standing positions.  Clin Sci (Lond). 2004;  106 61-66
• 37 Marks B L, Lightfoot J T. Reproducibility of resting heart rate variability with short sampling periods.  Can J Appl Physiol. 1999;  24 337-348
• 38 Kautzner J, Camm A J. Clinical relevance of heart rate variability.  Clin Cardiol. 1997;  20 162-168
• 39 Smirne S, Ferini S L, Zucconi M, Pinto P, Franceschi M. Cardiac autonomic dysfunction during sleep in some neurological diseases.  Neurophysiol Clin. 1990;  20 131-136
• 40 Ferrari A U, Radaelli A, Centola M. Invited review: aging and the cardiovascular system.  J Appl Physiol. 2003;  95 2591-2597
• 41 Umetani K, Singer D H, McCraty R, Atkinson M. Twenty-four hour time domain heart rate variability and heart rate: relations to age and gender over nine decades.  J Am Coll Cardiol. 1998;  31 593-601
• 42 Agelink M W, Baumann B, Sanner D, Kavuk I, Mueck-Weymann M. [Comorbidity between cardiovascular disease and affective illness].  Dtsch Med Wochenschr. 2004;  129 697-700
• 43 Keyes C L. The nexus of cardiovascular disease and depression revisited: the complete mental health perspective and the moderating role of age and gender.  Aging Ment Health. 2004;  8 266-274
• 44 Carney R M, Freedland K E, Miller G E, Jaffe A S. Depression as a risk factor for cardiac mortality and morbidity: a review of potential mechanisms.  J Psychosom Res. 2002;  53 897-902
• 45 Hance M, Carney R M, Freedland K E, Skala J. Depression in patients with coronary heart disease. A 12-month follow-up.  Gen Hosp Psychiatry. 1996;  18 61-65
• 46 Carney R M, Freedland K E, Rich M W, Smith L J, Jaffe A S. Ventricular tachycardia and psychiatric depression in patients with coronary artery disease.  Am J Med. 1993;  95 23-28
• 47 Januzzi Jr J L, Stern T A, Pasternak R C, DeSanctis R W. The influence of anxiety and depression on outcomes of patients with coronary artery disease.  Arch Intern Med. 2000;  160 1913-1921
• 48 Zellweger M J, Osterwalder R H, Langewitz W, Pfisterer M E. Coronary artery disease and depression.  Eur Heart J. 2004;  25 3-9
• 49 Penninx B W, Beekman A T, Honig A, Deeg D J, Schoevers R A, Eijk J T van, Tilburg W van. Depression and cardiac mortality: results from a community-based longitudinal study.  Arch Gen Psychiatry. 2001;  58 221-227
• 50 Barefoot J C, Helms M J, Mark D B, Blumenthal J A, Califf R M, Haney T L, O'Connor C M, Siegler I C, Williams R B. Depression and long-term mortality risk in patients with coronary artery disease.  Am J Cardiol. 1996;  78 613-617
• 51 Carney R M, Blumenthal J A, Stein P K, Watkins L, Catellier D, Berkman L F, Czajkowski S M, O'Connor C, Stone P H, Freedland K E. Depression, heart rate variability, and acute myocardial infarction.  Circulation. 2001;  104 2024-2028
• 52 Frasure-Smith N, Lesperance F, Talajic M. Depression following myocardial infarction. Impact on 6-month survival.  JAMA. 1993;  270 1819-1825
• 53 Frasure-Smith N, Lesperance F, Talajic M. Depression and 18-month prognosis after myocardial infarction.  Circulation. 1995;  91 999-1005
• 54 Molgaard H, Sorensen K E, Bjerregaard P. Attenuated 24-h heart rate variability in apparently healthy subjects, subsequently suffering sudden cardiac death.  Clin Auton Res. 1991;  1 233-237
• 55 Anda R, Williamson D, Jones D, Macera C, Eaker E, Glassman A, Marks J. Depressed affect, hopelessness, and the risk of ischemic heart disease in a cohort of U.S. adults.  Epidemiology. 1993;  4 285-294
• 56 Deuschle M, Lederbogen F. [Depression and cardiovascular disease: pathogenetic factors of the stress concept].  Fortschr Neurol Psychiatr. 2002;  70 268-275
• 57 Yeragani V K. Major depression and long-term heart period variability.  Depress Anxiety. 2000;  12 51-52
• 58 Yeragani V K, Pesce V, Jayaraman A, Roose S. Major depression with ischemic heart disease: effects of paroxetine and nortriptyline on long-term heart rate variability measures.  Biol Psychiatry. 2002;  52 418-429
• 59 Glassman A H, Bigger Jr J T. Cardiovascular effects of therapeutic doses of tricyclic antidepressants. A review.  Arch Gen Psychiatry. 1981;  38 815-820
• 60 Walsh B T, Greenhill L L, Giardina E G, Bigger J T, Waslick B D, Sloan R P, Bilich K, Wolk S, Bagiella E. Effects of desipramine on autonomic input to the heart.  J Am Acad Child Adolesc Psychiatry. 1999;  38 1186-1192
• 61 Roose S P, Glassman A H, Attia E, Woodring S, Giardina E G, Bigger Jr J T. Cardiovascular effects of fluoxetine in depressed patients with heart disease.  Am J Psychiatry. 1998;  155 660-665
• 62 Sauer W H, Berlin J A, Kimmel S E. Selective serotonin reuptake inhibitors and myocardial infarction.  Circulation. 2001;  104 1894-1898
• 63 Glassman A H, O'Connor C M, Califf R M, Swedberg K, Schwartz P, Bigger Jr J T, Krishnan K RR, Zyl L T van, Swenson J R, Finkel M S, Landau C, Shapiro P A, Pepine C J, Mardekian J, Harrison W M. for the Sertraline Antidepressant Heart Attack Randomized Trial Group . Sertraline Treatment of Major Depression in Patients With Acute MI or Unstable Angina.  JAMA. 2002;  288 701-709
• 64 Pacher P, Ungvari Z, Nanasi P P, Furst S, Kecskemeti V. Speculations on difference between tricyclic and selective serotonin reuptake inhibitor antidepressants on their cardiac effects. Is there any?.  Curr Med Chem. 1999;  6 469-480
• 65 Pacher P, Ungvari Z. Use of selective serotonin reuptake inhibitors and myocardial infarction.  Circulation. 2002;  105 e84
• 66 Carney R M, Freedland K E, Stein P K, Skala J A, Hoffman P, Jaffe A S. Change in heart rate and heart rate variability during treatment for depression in patients with coronary heart disease.  Psychosom Med. 2000;  62 639-647
• 67 Writing Committee for the ENRICHD Investigators . Effects of Treating Depression and Low Perceived Social Support on Clinical Events After Myocardial Infarction: The Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) Randomized Trial.  JAMA. 2003;  289 3106-3116
• 68 Rees K, Bennett P, West R, Davey S G, Ebrahim S. Psychological interventions for coronary heart disease.  Cochrane Database Syst Rev. 2004;  2 CD002902
• 69 Dalack G W, Roose S P. Perspectives on the relationship between cardiovascular disease and affective disorder.  J Clin Psychiatry. 1990;  51 Suppl 4-9
• 70 Balogh S, Fitzpatrick D F, Hendricks S E, Paige S R. Increases in heart rate variability with successful treatment in patients with major depressive disorder.  Psychopharmacol Bull. 1993;  29 201-206
• 71 Rechlin T, Weis M, Spitzer A, Kaschka W P. Are affective disorders associated with alterations of heart rate variability?.  J Affect Disord. 1994;  32 271-275
• 72 Guinjoan S M, Bernabo J L, Cardinali D P. Cardiovascular tests of autonomic function and sympathetic skin responses in patients with major depression.  J Neurol Neurosurg Psychiatry. 1995;  59 299-302
• 73 Tulen J H, Bruijn J A, de Man K J, van der Velden E, Pepplinkhuizen L, Man in 't Veld A J. Anxiety and autonomic regulation in major depressive disorder: an exploratory study.  J Affect Disord. 1996;  40 61-71
• 74 Agelink M W, Boz C, Ullrich H, Andrich J. Relationship between major depression and heart rate variability. Clinical consequences and implications for antidepressive treatment.  Psychiatry Res. 2002;  113 139-149
• 75 Yeragani V K, Rao K A, Smitha M R, Pohl R B, Balon R, Srinivasan K. Diminished chaos of heart rate time series in patients with major depression.  Biol Psychiatry. 2002;  51 733-744
• 76 Moser M, Lehofer M, Hoehn-Saric R, McLeod D R, Hildebrandt G, Steinbrenner B, Voica M, Liebmann P, Zapotoczky H G. Increased heart rate in depressed subjects in spite of unchanged autonomic balance?.  J Affect Disord. 1998;  48 115-124
• 77 Agelink M W, Majewski T, Wurthmann C, Postert T, Linka T, Rotterdam S, Klieser E. Autonomic neurocardiac function in patients with major depression and effects of antidepressive treatment with nefazodone.  J Affect Disord. 2001;  62 187-198
• 78 Thayer J F, Smith M, Rossy L A, Sollers J J, Friedman B H. Heart period variability and depressive symptoms: gender differences.  Biol Psychiatry. 1998;  44 304-306
• 79 Hughes J W, Stoney C M. Depressed mood is related to high-frequency heart rate variability during stressors.  Psychosom Med. 2000;  62 796-803
• 80 Musselman D L, Evans D L, Nemeroff C B. The relationship of depression to cardiovascular disease: epidemiology, biology, and treatment.  Arch Gen Psychiatry. 1998;  55 580-592
• 81 Barefoot J C, Brummett B H, Helms M J, Mark D B, Siegler I C, Williams R B. Depressive symptoms and survival of patients with coronary artery disease.  Psychosom Med. 2000;  62 790-795
• 82 Rechlin T. Decreased parameters of heart rate variation in amitriptyline treated patients: lower parameters in melancholic depression than in neurotic depression - a biological marker?.  Biol Psychiatry. 1994;  36 705-707
• 83 Stein P K, Carney R M, Freedland K E, Skala J A, Jaffe A S, Kleiger R E, Rottman J N. Severe depression is associated with markedly reduced heart rate variability in patients with stable coronary heart disease.  J Psychosom Res. 2000;  48 493-500
• 84 Krittayaphong R, Cascio W E, Light K C, Sheffield D, Golden R N, Finkel J B, Glekas G, Koch G G, Sheps D S. Heart rate variability in patients with coronary artery disease: differences in patients with higher and lower depression scores.  Psychosom Med. 1997;  59 231-235
• 85 Rechlin T, Weis M, Kaschka W P. Is diurnal variation of mood associated with parasympathetic activity?.  J Affect Disord. 1995;  34 249-255
• 86 Cohen H W, Gibson G, Alderman M H. Excess risk of myocardial infarction in patients treated with antidepressant medications: association with use of tricyclic agents.  Am J Med. 2000;  108 2-8
• 87 Kristensen E, Jakobsen J, Bartels U, Vestergaard P. Cholinergic dysfunction of heart, pupil, salivary glands, and urinary bladder in healthy volunteers during long-term treatment with clomipramine.  Psychopharmacology (Berl). 1989;  98 398-402
• 88 Jakobsen J, Hauksson P, Vestergaard P. Heart rate variation in patients treated with antidepressants.  An index of anticholinergic effects? Psychopharmacology (Berl). 1984;  84 544-548
• 89 Rechlin T, Weis M, Claus D. Heart rate variability in depressed patients and differential effects of paroxetine and amitriptyline on cardiovascular autonomic functions.  Pharmacopsychiatry. 1994;  27 124-128
• 90 Tulen J H, Bruijn J A, de Man K J, Pepplinkhuizen L, Meiracker A H van den, Man in 't Veld A J. Cardiovascular variability in major depressive disorder and effects of imipramine or mirtazapine (Org 3770).  J Clin Psychopharmacol. 1996;  16 135-145
• 91 Lederbogen F, Gernoth C, Weber B, Colla M, Kniest A, Heuser I, Deuschle M. Antidepressive treatment with amitriptyline and paroxetine: comparable effects on heart rate variability.  J Clin Psychopharmacol. 2001;  21 238-239
• 92 Volkers A C, Tulen J H, Broek W W van den, Bruyn J A, Passchier J, Pepplinkhuizen L. Effects of imipramine, fluvoxamine and depressive mood on autonomic cardiac functioning in major depressive disorder.  Pharmacopsychiatry. 2004;  37 18-25
• 93 Rechlin T. The effect of amitriptyline, doxepin, fluvoxamine, and paroxetine treatment on heart rate variability.  J Clin Psychopharmacol. 1994;  14 392-395
• 94 Shores M M, Pascualy M, Lewis N L, Flatness D, Veith R C. Short-term sertraline treatment suppresses sympathetic nervous system activity in healthy human subjects.  Psychoneuroendocrinology. 2001;  26 433-439
• 95 Pohl R, Balon R, Jayaraman A, Doll R G, Yeragani V. Effect of fluoxetine, pemoline and placebo on heart period and QT variability in normal humans.  Journal of Psychosomatic Research. 2003;  55 247-251
• 96 Agelink M W, Ullrich H, Baumann B, Strum S, Majewski T. Effects of reboxetine, a selective norepinephrine reuptake inhibitor, on sympathetic and parasympathetic outflow to the heart: preliminary data.  Psychopharmacology (Berl). 2002;  163 151-156
• 97 Khaykin Y, Dorian P, Baker B, Shapiro C, Sandor P, Mironov D, Irvine J, Newman D. Autonomic correlates of antidepressant treatment using heart-rate variability analysis .  Can J Psychiatry. 1998;  43 183-186
• 98 Rechlin T, Weis M, Schneider K, Zimmermann U, Kaschka W P. Does bright-light therapy influence autonomic heart-rate parameters?.  J Affect Disord. 1995;  34 131-137
• 99 Rechlin T, Hegmann H, Weis M, Stemmler M, Claus D, Kaschka W P. Prediction of response to total sleep deprivation by autonomic heart rate parameters?.  Biol Psychiatry. 1995;  37 280-282
• 100 Agelink M W, Sanner D, Eich H, Pach J, Bertling R, Lemmer W, Klieser E, Lehmann E. [Does acupuncture influence the cardiac autonomic nervous system in patients with minor depression or anxiety disorders?].  Fortschr Neurol Psychiatr. 2003;  71 141-149
• 101 Schultz S K, Anderson E A, van de Borne P. Heart rate variability before and after treatment with electroconvulsive therapy.  J Affect Disord. 1997;  44 13-20
• 102 Agelink M W, Malessa R, Kamcili E, Zeit T, Lemmer W, Bertling R, Klieser E. Cardiovascular autonomic reactivity in schizophrenics under neuroleptic treatment: A potential predictor of short-term outcome?.  Neuropsychobiology. 1998;  38 19-24
• 103 Roose S P, Glassman A H, Dalack G W. Depression, heart disease, and tricyclic antidepressants.  J Clin Psychiatry. 1989;  50 Suppl 12-6; discussion 17.: 12 - 16
• 104 Nahshoni E, Aizenberg D, Sigler M, Zalsman G, Strasberg B, Imbar S, Weizman A. Heart rate variability in elderly patients before and after electroconvulsive therapy.  Am J Geriatr Psychiatry. 2001;  9 255-260
• 105 Karpyak V M, Rasmussen K G, Hammill S C, Mrazek D A. Changes in heart rate variability in response to treatment with electroconvulsive therapy.  J ECT. 2004;  20 81-88
• 106 Barlow D H. In: Anxiety and its Disorders. New York: Guilford 1988
• 107 Kawachi I, Sparrow D, Vokonas P S, Weiss S T. Symptoms of anxiety and risk of coronary heart disease. The Normative Aging Study.  Circulation. 1994;  90 2225-2229
• 108 Weissman M M, Markowitz J S, Ouellette R, Greenwald S, Kahn J P. Panic disorder and cardiovascular/cerebrovascular problems: results from a community survey.  Am J Psychiatry. 1990;  147 1504-1508
• 109 Haines A, Cooper J, Meade T W. Psychological characteristics and fatal ischaemic heart disease.  Heart. 2001;  85 385-389
• 110 Thomas S A, Friedmann E, Wimbush F, Schron E. Psychological factors and survival in the cardiac arrhythmia suppression trial (CAST): a reexamination.  Am J Crit Care. 1997;  6 116-126
• 111 Fleet R, Lavoie K, Beitman B D. Is panic disorder associated with coronary artery disease? A critical review of the literature.  J Psychosom Res. 2000;  48 347-356
• 112 Friedman B H, Thayer J F, Borkovec T D, Tyrrell R A, Johnson B H, Columbo R. Autonomic characteristics of nonclinical panic and blood phobia.  Biol Psychiatry. 1993;  34 298-310
• 113 Klein E, Cnaani E, Harel T, Braun S, Ben Haim S A. Altered heart rate variability in panic disorder patients.  Biol Psychiatry. 1995;  37 18-24
• 114 Friedman B H, Thayer J F. Anxiety and autonomic flexibility: a cardiovascular approach.  Biol Psychol. 1998;  49 303-323
• 115 Cohen H, Benjamin J, Geva A B, Matar M A, Kaplan Z, Kotler M. Autonomic dysregulation in panic disorder and in post-traumatic stress disorder: application of power spectrum analysis of heart rate variability at rest and in response to recollection of trauma or panic attacks.  Psychiatry Res. 2000;  96 1-13
• 116 Rechlin T. [The significance of heart rate analysis in psychiatric questions].  Fortschr Neurol Psychiatr. 1995;  63 106-120
• 117 Friedman B H, Thayer J F. Autonomic balance revisited: panic anxiety and heart rate variability.  J Psychosom Res. 1998;  44 133-151
• 118 Yeragani V K, Srinivasan K, Balon R, Ramesh C, Berchou R. Lactate sensitivity and cardiac cholinergic function in panic disorder.  Am J Psychiatry. 1994;  151 1226-1228
• 119 Asmundson G J, Stein M B. Vagal attenuation in panic disorder: an assessment of parasympathetic nervous system function and subjective reactivity to respiratory manipulations.  Psychosom Med. 1994;  56 187-193
• 120 Seier F E, Kellner M, Yassouridis A, Heese R, Strian F, Wiedemann K. Autonomic reactivity and hormonal secretion in lactate-induced panic attacks.  Am J Physiol. 1997;  272 H2630-H2638
• 121 Slaap B R, Nielen M M, Boshuisen M L, Roon A M van, Boer J A den. Five-minute recordings of heart rate variability in obsessive-compulsive disorder, panic disorder and healthy volunteers.  J Affect Disord. 2004;  78 141-148
• 122 Ito T, Inoue Y, Sugihara T, Yamada H, Katayama S, Kawahara R. Autonomic function in the early stage of panic disorder: power spectral analysis of heart rate variability.  Psychiatry Clin Neurosci. 1999;  53 667-672
• 123 Yeragani V K, Tancer M, Uhde T. Heart rate and QT interval variability: abnormal α-2 adrenergic function in patients with panic disorder.  Psychiatry Res. 2003;  121 185-196
• 124 McCraty R, Atkinson M, Tomasino D, Stuppy W P. Analysis of twenty-four hour heart rate variability in patients with panic disorder.  Biol Psychol. 2001;  56 131-150
• 125 Yeragani V K, Sobolewski E, Igel G, Johnson C, Jampala V C, Kay J, Hillman N, Yeragani S, Vempati S. Decreased heart-period variability in patients with panic disorder: a study of Holter ECG records.  Psychiatry Res. 1998;  20; 78 89-99
• 126 Srinivasan K, Ashok M V, Vaz M, Yeragani V K. Decreased chaos of heart rate time series in children of patients with panic disorder.  Depress Anxiety. 2002;  15 159-167
• 127 Kawachi I, Sparrow D, Vokonas P S, Weiss S T. Decreased heart rate variability in men with phobic anxiety (data from the Normative Aging Study).  Am J Cardiol. 1995;  75 882-885
• 128 Kawachi I, Colditz G A, Ascherio A, Rimm E B, Giovannucci E, Stampfer M J, Willett W C. Prospective study of phobic anxiety and risk of coronary heart disease in men.  Circulation. 1994;  89 1992-1997
• 129 Haines A P, Imeson J D, Meade T W. Phobic anxiety and ischaemic heart disease.  Br Med J (Clin Res Ed). 1987;  295 297-299
• 130 Thayer J F, Friedman B H, Borkovec T D. Autonomic characteristics of generalized anxiety disorder and worry.  Biol Psychiatry. 1996;  39 255-266
• 131 Coplan J D, Papp L A, Pine D, Martinez J, Cooper T, Rosenblum L A, Klein D F, Gorman J M. Clinical improvement with fluoxetine therapy and noradrenergic function in patients with panic disorder.  Arch Gen Psychiatry. 1997;  54 643-648
• 132 Middleton H C. Cardiovascular dystonia in recovered panic patients.  J Affect Disord. 1990;  19 229-236
• 133 Middleton H C, Ashby M. Clinical recovery from panic disorder is associated with evidence of changes in cardiovascular regulation.  Acta Psychiatr Scand. 1995;  91 108-113
• 134 Tucker P, Adamson P, Miranda Jr R, Scarborough A, Williams D, Groff J, McLean H. Paroxetine increases heart rate variability in panic disorder.  J Clin Psychopharmacol. 1997;  17 370-376
• 135 Baker B, Khaykin Y, Devins G, Dorian P, Shapiro C, Newman D. Correlates of therapeutic response in panic disorder presenting with palpitations: heart rate variability, sleep, and placebo effect.  Can J Psychiatry. 2003;  48 381-387
• 136 Slaap B R, Boshuisen M L, Roon A M van, Boer J A den. Heart rate variability as predictor of nonresponse to mirtazapine in panic disorder: a preliminary study.  Int Clin Psychopharmacol. 2002;  17 69-74
• 137 Volz H P, Mackert A. [Cardiovascular irregularities in schizophrenia-more than an epiphenomenon?].  Nervenarzt. 1991;  62 298-302
• 138 Volz H P, Mackert A, Diefenbacher A, Friedrich A, Gaebel W, Muller H, Stock G, Moller H J. Orthostatic challenge during neuroleptic test dose: a possible predictor of short-term outcome.  Neuropsychobiology. 1994;  30 94-100
• 139 Dawson M E, Nuechterlein K H, Schell A M, Gitlin M, Ventura J. Autonomic abnormalities in schizophrenia. State or trait indicators?.  Arch Gen Psychiatry. 1994;  51 813-824
• 140 Nielsen B M, Mehlsen J, Behnke K. Altered balance in the autonomic nervous system in schizophrenic patients.  Clin Physiol. 1988;  8 193-199
• 141 Olbrich R, Kirsch P, Pfeiffer H, Mussgay L. Patterns of recovery of autonomic dysfunctions and neurocognitive deficits in schizophrenics after acute psychotic episodes.  J Abnorm Psychol. 2001;  110 142-150
• 142 Rechlin T, Claus D, Weis M. Heart rate variability in schizophrenic patients and changes of autonomic heart rate parameters during treatment with clozapine.  Biol Psychiatry. 1994;  35 888-892
• 143 Valkonen-Korhonen M, Tarvainen M P, Ranta-Aho P, Karjalainen P A, Partanen J, Karhu J, Lehtonen J. Heart rate variability in acute psychosis.  Psychophysiology. 2003;  40 716-726
• 144 Malaspina D, Bruder G, Dalack G W, Storer S, Kammen M van, Amador X, Glassman A, Gorman J. Diminished cardiac vagal tone in schizophrenia: associations to brain laterality and age of onset.  Biol Psychiatry. 1997;  41 612-617
• 145 Kosky N. A possible association between high normal and high dose olanzapine and prolongation of the PR interval.  J Psychopharmacol. 2002;  16 181-182
• 146 Hennessy S, Bilker W B, Knauss J S, Margolis D J, Kimmel S E, Reynolds R F, Glasser D B, Morrison M F, Strom B L. Cardiac arrest and ventricular arrhythmia in patients taking antipsychotic drugs: cohort study using administrative data.  BMJ. 2002;  325 1070-1074
• 147 Appleby L, Thomas S, Ferrier N, Lewis G, Shaw J, Amos T. Sudden unexplained death in psychiatric in-patients.  Br J Psychiatry. 2000;  176 405-406
• 148 Ruschena D, Mullen P E, Burgess P, Cordner S M, Barry-Walsh J, Drummer O, Palmer S, Browne C, Wallace C. Sudden death in psychiatric patients .  Br J Psychiatry. 1998;  172 : 331 - 6. 331-336
• 149 Curkendall S M, Mo J, Glasser D B, Rose S M, Jones J K. Cardiovascular disease in patients with schizophrenia in Saskatchewan, Canada.  J Clin Psychiatry. 2004;  65 715-720
• 150 Chute D, Grove C, Rajasekhara B, Smialek J E. Schizophrenia and sudden death: a medical examiner case study.  Am J Forensic Med Pathol. 1999;  20 131-135
• 151 Ray W A, Meredith S, Thapa P B, Meador K G, Hall K, Murray K T. Antipsychotics and the risk of sudden cardiac death.  Arch Gen Psychiatry. 2001;  58 1161-1167
• 152 Silke B, Campbell C, King D J. The potential cardiotoxicity of antipsychotic drugs as assessed by heart rate variability.  J Psychopharmacol. 2002;  16 355-360
• 153 Zahn T P, Pickar D. Autonomic effects of clozapine in schizophrenia: comparison with placebo and fluphenazine.  Biol Psychiatry. 1993;  34 3-12
• 154 Agelink M W, Majewski T, Wurthmann C, Lukas K, Ullrich H, Linka T, Klieser E. Effects of newer atypical antipsychotics on autonomic neurocardiac function: a comparison between amisulpride, olanzapine, sertindole, and clozapine.  J Clin Psychopharmacol. 2001;  21 8-13
• 155 Cohen H, Loewenthal U, Matar M, Kotler M. Association of autonomic dysfunction and clozapine. Heart rate variability and risk for sudden death in patients with schizophrenia on long-term psychotropic medication.  Br J Psychiatry. 2001;  179 167-171
• 156 Glassman A H. Clinical management of cardiovascular risks during treatment with psychotropic drugs.  J Clin Psychiatry. 2002;  63 Suppl 9 12-17
• 157 Toichi M, Kubota Y, Murai T, Kamio Y, Sakihama M, Toriuchi T, Inakuma T, Sengoku A, Miyoshi K. The influence of psychotic states on the autonomic nervous system in schizophrenia.  Int J Psychophysiol. 1999;  31 147-154
• 158 Kim J H, Yi S H, Yoo C S, Yang S A, Yoon S C, Lee K Y, Ahn Y M, Kang U G, Kim Y S. Heart rate dynamics and their relationship to psychotic symptom severity in clozapine-treated schizophrenic subjects.  Prog Neuropsychopharmacol Biol Psychiatry. 2004;  28 371-378
• 159 Rechlin T, Beck G, Weis M, Kaschka W P. Correlation between plasma clozapine concentration and heart rate variability in schizophrenic patients.  Psychopharmacology (Berl). 1998;  135 338-341
• 160 Eschweiler G W, Bartels M, Langle G, Wild B, Gaertner I, Nickola M. Heart-rate variability (HRV) in the ECG trace of routine EEGs: fast monitoring for the anticholinergic effects of clozapine and olanzapine?.  Pharmacopsychiatry. 2002;  35 96-100
• 161 Ballard C G, Shaw F, Lowery K, McKeith I, Kenny R. The Prevalence, Assessment and Associations of Falls in Dementia with Lewy Bodies and Alzheimer's Disease.  Dementia and Geriatric Cognitive Disorders. 1999;  10 97-103
• 162 Horimoto Y, Matsumoto M, Akatsu H, Ikari H, Kojima K, Yamamoto T, Otsuka Y, Ojika K, Ueda R, Kosaka K. Autonomic dysfunctions in dementia with Lewy bodies.  J Neurol. 2003;  250 530-533
• 163 Tinetti M E, Speechley M, Ginter S F. Risk factors for falls among elderly persons living in the community.  N Engl J Med. 1988;  319 1701-1707
• 164 Dijk P T van, Meulenberg O G, Sande H J van de, Habbema J D. Falls in dementia patients.  Gerontologist. 1993;  33 200-204
• 165 Davies A J, Kenny R A. Falls presenting to the accident and emergency department: types of presentation and risk factor profile.  Age Ageing. 1996;  25 362-366
• 166 McIntosh S J, Lawson J, Kenny R A. Clinical characteristics of vasodepressor, cardioinhibitory, and mixed carotid sinus syndrome in the elderly.  Am J Med. 1993;  95 203-208
• 167 Richardson D A, Bexton R S, Shaw F E, Kenny R A. Prevalence of cardioinhibitory carotid sinus hypersensitivity in patients 50 years or over presenting to the accident and emergency department with „unexplained” or „recurrent” falls.  Pacing Clin Electrophysiol. 1997;  20 820-823
• 168 Calvo-Romero J M, Ramos-Salado J L. [Symptomatic sinus bradycardia associated with donepezil].  Rev Neurol. 1999;  28 1070-1072
• 169 Kenny R A, Kalaria R, Ballard C. Neurocardiovascular instability in cognitive impairment and dementia.  Ann N Y Acad Sci. 2002;  977 183-195
• 170 Morganroth J, Graham S, Hartman R, Anand R. Electrocardiographic effects of rivastigmine.  J Clin Pharmacol. 2002;  42 558-568
• 171 Dunn N R, Pearce G L, Shakir S A. Adverse effects associated with the use of donepezil in general practice in England.  J Psychopharmacol. 2000;  14 406-408
• 172 Pratt R D, Perdomo C A, Surick I W, Ieni J R. Donepezil: tolerability and safety in Alzheimer's disease.  Int J Clin Pract. 2002;  56 710-717
• 173 Cummings J L, Cyrus P A, Bieber F, Mas J, Orazem J, Gulanski B. Metrifonate treatment of the cognitive deficits of Alzheimer's disease. Metrifonate Study Group.  Neurology. 1998;  50 1214-1221
• 174 Szili-Torok T, Kalman J, Paprika D, Dibo G, Rozsa Z, Rudas L. Depressed baroreflex sensitivity in patients with Alzheimer's and Parkinson's disease.  Neurobiol Aging. 2001;  22 435-438
• 175 Aharon-Peretz J, Harel T, Revach M, Ben Haim S A. Increased sympathetic and decreased parasympathetic cardiac innervation in patients with Alzheimer's disease.  Arch Neurol. 1992;  49 919-922
• 176 Algotsson A, Viitanen M, Winblad B, Solders G. Autonomic dysfunction in Alzheimer's disease.  Acta Neurol Scand. 1995;  91 14-18
• 177 Giubilei F, Strano S, Imbimbo B P, Tisei P, Calcagnini G, Lino S, Frontoni M, Santini M, Fieschi C. Cardiac autonomic dysfunction in patients with Alzheimer disease: possible pathogenetic mechanisms.  Alzheimer Dis Assoc Disord. 1998;  12 356-361
• 178 Idiaquez J, Sandoval E. High prevalence of neurovascular instability in neurodegenerative dementias.  Neurology. 1999;  53 1610
• 179 Murakami S, Yamanaka T, Kubo Y, Wada T, Yano S, Nishimura Y, Shinagawa M, Matsubayashi K, Otsuka K, Ohkawa S, Kawata H. [Heart rate variability analysis and neurobehavioral function in community-dwelling older people aged 75 or older].  Nippon Ronen Igakkai Zasshi. 2002;  39 520-526
• 180 McLaren A T, Allen J, Murray A, Ballard C G, Kenny R A. Cardiovascular effects of donepezil in patients with dementia.  Dement Geriatr Cogn Disord. 2003;  15 183-188
• 181 Masuda Y, Kawamura A. Acetylcholinesterase inhibitor (donepezil hydrochloride) reduces heart rate variability.  J Cardiovasc Pharmacol. 2003;  41 Suppl 1 S67-S71
• 182 Stampfer H G. The relationship between psychiatric illness and the circadian pattern of heart rate.  Aust N Z J Psychiatry. 1998;  32 187-198
• 183 Bigger Jr J T, Fleiss J L, Steinman R C, Rolnitzky L M, Schneider W J, Stein P K. RR Variability in Healthy, Middle-Aged Persons Compared With Patients With Chronic Coronary Heart Disease or Recent Acute Myocardial Infarction.  Circulation. 1995;  91 1936-1943
• 184 Serrador J M, Finlayson H C, Hughson R L. Physical activity is a major contributor to the ultra low frequency components of heart rate variability.  Heart. 1999;  82 e9
• 185 Yeragani V K, Pohl R, Balon R, Ramesh C, Glitz D, Jung I, Sherwood P. Heart rate variability in patients with major depression.  Psychiatry Res. 1991;  37 35-46
• 186 Rechlin T, Claus D, Weis M. Heart rate analysis in 24 patients treated with 150 mg amitriptyline per day.  Psychopharmacology (Berl). 1994;  116 110-114