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Reduced plasma noradrenaline and abnormal heart rate variability in resting panic disorder patients
BRIEF REPORTS Reduced Plasma Noradrenaline and Abnormal Hem Rate Variability in Resting Panic Disorder Patients Hugh C. Middleton~ Michael Ashby, and Trevor W. Robbins K e y W o r d s : Panic disorder, plasma noradrenaline, heart rate variability, spectral analysis, baroreflex, autonomic function
Introduction
Subjects
Despite numerous ~tudies, the question of abnormal autonomic function in panic disorder (PD) remains unresolved. It has been argued that, where abnormalities of heart rate or blood pressure have been found, these are likely to have been due to situationally induced anxiety (Clark et al 1990; Roth et al 19f2). On the other hand, more recent and sophisticated physiologic~! studies suggest an abnormality of respiratory control (e.g., Papp et al 1993), and investigations of heart rate variability suggest abnormal parasympathetic activity (Yergani et al 1993). Reflex cardiovascular regulation is reflected in nonrandom fluctuations of resting heart rate identifiable by spectral analysis (Appel et al 1989). Such measv_res can now be obtained from an electronically stored ECG recording with minimal disruption to the subject. Heart rate variability in the 0.1 Hz range of the spectrum is believed to reflect modulation of the baroreflex (Wesseling and Settels 1985; Robbe et al 1987), and changes under the influence of cionidine (Grichois et ai i990; Eighozi et ai i99i). We have recently shown that an important feature of this effect is a fall in the dominant frequency in this range (Middleton et al 1994). This report is an analysis of heart rate variability in PD patients with attention to that particular feature. Estimates of circulating plasma noradrenaline are also reported.
Twelve patients ~uffering PD according to DSM-RI-R ~ a (American Psychiatric Association 1987), and 12 age- and sexmatched controls were recruited. All patients repotted being drug free for at least 1 month before the time of testing. Controls were screened at interview to exclude hitherto unrecognized PD. All subjects gave informed written consent, and the investigation was approved by the local research ethics committee.
From the NottinghamUniversityDepartmentof Psychiatry( ~ ) and Cambridge UniversityDepartmentsofClinicalPharmacology(MA).andExperimentalPsychology(TR). Addresst-eprintrequeslsto Dr. H.C.Middle~n,NottinghamUniversityDepartment of psychiatry.A Floor, South Blf,ck. UniversityHospital, Queen's Medical Centre.NottinghamNG72UH;Fax0602790167. ReceivedJanuary12,1994;revisedApri129,1994. © 1994SocietyofBiologicalPsychiatry
Methods Subjects were asked to abstain from alcohol for 24 hours before the test and from tea, coffee, and tobacco on the morning of the test. Subjects were told that the investigation was one of the control of heart rate and blood pressure; they were reassured that their heart rate and blood pressure were going to be checked but ~ nothing threatening would be done to them. All subjects attended at a comparable time (0830-4)900). After instrumentation and acclimatization, during which the Spielberger State Anxiety Inventory (Spielberger et al 1983) was completed, subjects were left alone for 15 minutes. Continuous electrocardiogram (ECG) recording was made during this period; at the end of it, blood pressure was measured by an automated sphygmomanometer (Dinamap) and a 30-ml blood sample was taken. Subjects then stood and remained standing, facing away from the investigator, prohibited from talking and constrained to avoid movement for 10 minutes. Blood pressure was measured at minute intervals and ECG continuously recorded. At the end of this period a further 30-ml blood sample was taken. ECG was sampled at 500 Hz and stored. Subsequently it was analyzed as described elsewhere (Middleton et al 1994) to derive values of the following variables: (R)06-3223/94/$07.00
~48
Brief Reports
BIOLPSYCHIATRY 1994;36:847-849
Table I. Means and Standard Deviations (SDP of Systolic Blood Pressure, Indices of Heart Rate Variability, and Plasma Noradrenaline Levels Among Panic Disorder Patients and Controls Semisupine Patients Systolic BP(mmFIg) Meanheart tale (ms R-R interval) Heart rate variability (ms SD) Spectral I~wer. "resp" range (Hz: x 104) Dominant frequency, "resp" range (Hz) Spectral power, 0.1 Hz range (Hz: x 104) Dominant frequency,0.1 Hz Range (Hz) Plasmanoradrenaline (rig/i)
114.9 837.7 41.8 2.9 0.27 1.6 0,075 247
(12.7) (95.0) (21.4) (I.9) (0.075) (1.0) (0.017) (118)
Standing Controls
115.9 849.1 43.9 3.1 0.25 2.04 0.1023 430
(10.7) (67.7) (2Z2) (2.5) (0.071) (1.3) (0.014)*** (204)*
Patients ! 19.2 654.7 26.8 I.! 0.24 1~6 0.0845 396
(10.2) (106.4) (8.5) (0.7) (0,06) (I,04) (0.018) (196.3)
Comrols 121.1 707.9 46.7 1.3 0,26 3.8 0.0909 681
(9.3) (58.1) (17.5)*** (0.9) (0,05) (2.6)* (0.015) (238.7)**
"SD indicated in parentheses, ***p < .OO5.** p < .Ol, * p < ,O~, unpaired t test. n =12.
1. Mean heart rate during the middle 5 minutes of the 15-minute rest period and the fourth to eighth minutes of the lOminute stand. 2. SD heart rate daring the same periods of measurement. 3. Power in the 0.1 Hz (0.0547-0.156 Hz) and respiratory (Hz) regions of heart rate variability spectra during those same periods. 4. Dominant frequency within each of the above ranges. Plasma catecholamines were assayed by reverse-phase highperformance liquid chromatography with electrochemical detection (HPLC-EC) (Moyer and Jiang 1978; Causon et al 1981), following a modified alumina extraction (Anton and Sayre 1962).
Results Patients" Spielberger scores were significantly higher than those of controls: 50.2 (SD 12.1); 27.1 (SD 3.6),p < .001 unpaired ,test). Semisupine and standing physiological measures revealed sLgnificant group differences in plasma noradrenaline and either heart rate variability or one of its derivatives in both postures (Table).
Di~ussion As patients scored higher on the Spielberger, it is not possible to distinguish between state anxiety and diagnostic status "panic disorder." Nevertheless, there were no group differences in systolic blood pressure or mean heart rate and therefore no evidence of a conventionally defined higher level of arousal among the patients. Previous investigations (Yergani et al 1990, 1993) report reduced overall (SD) heart rate variability. Current findings are consistent with these, although we have not confirmed their find-
ing of reduced overall heart rate variability in the supine posture. Direct comparison of our specwal analysis findings with theirs is not possible because of differing methods of analysis. Normal levels are repotted by most investigations of venous plasma noradreaaline in PD to date (Liebowitz et al 1985; Charney et a11985; Woods et al 1991). There is one report of raised venous plasma noradrenaline (Hesse et al 1984) and one of raised arterialized plasma venous adrenaline (Villacres et al 1987); there is one report of reduced 3-methoxy, 5-hydmxy, phenylglycol (MHPG) (F_dlund et all 1987). Thus, our finding of reduced plasma noradrenaline among PD patients is not that unexpected, and there are reasons to believe that it is consistent with the findings on heart rate variability. The greatest contribution to forearm venous noradrenaline is overflow from sympathetic vasomotor neumnes modulating arteriolar resistance in the course of baroreflex activity (Mathias et al 1975; Kooner et al 1991). As heart rate variability in the 0.1 Hz range of the spectrum has been attributed to the activity of this reflex, abnormal heart rate variability in this region of the spectnun could reflect altered baroreflex activity, consistent with abnormal venous plasma noradrenaline, Thus, the findings revealed by this study can be interpreted as evidence of abnormal baroreflex modulation in PD. Whether or not their similarity with the effects of clonidine means that they ate further evidence of noradrenergic dysregulation in PD will have to await further investigation. The authors wish to thank Professor MJ. Brown, who provided valuable advice upon setting up the catecholamineassays. H.M. acknowledges the assistance of the Wellcome Trust in the form of a generous project grant, and East Anglian Regional Health Authority who purchased much of the equipment used in the study. T.R. acknowledgesthe support of the Wellcome Trust and the MRC.
References American Psychiatric Association (1987): Diagnostic andStatistical M a n u a l o f Mental Disorders, 3rd ed rev. Washington, DC: American Psychiatric Association,
Appel ML, Berger RD, Saul JP, Smith JM, Cohen ILl (1989): Beat to beat variability in cardiovascular variables: noise or music? J
Anton All, Sayre DF (1962): A study of the factors affecting the aluminum oxide-trihydroxyindole procedure for the analysis ofcatecholamines. J P h a r m a c o l E x p Ther 138:360-375.
Causon RC, Carrutbers ME, Rodnight R (1981): Assay of plasma catecholamines by liquid chromatography with electrochemical detection. A n a l y t B i o c h e m 116:223-226.
A m Coil C a r d i o 1 1 4 : 1 1 3 9 - 1 1 4 8 .
Brief Reports
Chamey DS, Heninger GR, Jatlow Pl (1985): Increased anxiogenic effects of caffeine in panic disorders. Arch Gen Psychiatry 42:233-243. Clark DB, Taylor CB, Hayward C, et al (1990): Motor activity and tonic heart rate in panic disorder. Psychiatry Research 32:45-53. Edlund MJ, Swann AC, Davis CM (1987): Plasma MHPG in untreated panic disorder. Biol Psychiatry 22:1491-1495. Elghozi JL, Lande D, Janvier F (1991): Clonidine reduces blood pressure and heart rate oscillations in hypertensive patients. J Cardiovasc Pharmaco117:935-940. Grichois ML, Japundzic N, Head G, Elghozi JL (1990): Clonidine reduces blood pressure and heart rate oscillations in the conscious raL J Cardiovosc Pharmacol 16:449-454. Kooner JS, Birch R, FrankeI HL, Peart WS, Mathias C! (1991): Haemodynamic and neurohormonal effects of clonidine in patients with preganglionic and postgangfionic sympathetic lesions. Evidence of a sympatholytic action. Circulation 84:7583. Liebowitz MR, Gorman JM, Fyer AJ, et al (1985): Lactate provocation in panic attacks. II. Biochemical and physiological findings. Arch Gen Psychiatry 42:709-719. Mathias CJ, Christensen NJ, Corbett JL, Frankel HL, Goodwin T, Peart WS (1975): Plasma catecl~lamines, plasma renin activity and plasma aldostemne in tetraplegic man, horizontal and tilted. Clin Sci 49:291-299. Middleton HC, Coull .IT, Sabakian BJ, Robbins TW (1994): Clonidine-induced changes in the spectral distribution of heart rate variability correlate with performance on a task of sustained mention. J Psychopharmacol 8:1-7. Moyer TP, Jiang NS (1978): Optimised isocratic conditions for analysis of catecholamines by high-performance reversedphase paired-ion chromatography with amperometric detection. J Chromatography 153:365-372.
atOLPSYCmA'rttY |994~6:g4?-.Ss~
849
Hesse RM, Cameron OG, Ctmis C,C, . M ~ DS, Huber-Smith M,I (1984): Ad~nergic function in patients with ~ ~ . Arch Gen Psychiatry 41:771-/76. Papp I.A, Klein DF, German/M (1993): Carbon dioxide hypersensitivity, hyperventil~on and pm~c disorder.Am J P~.~iatry 150:1149--I 157. Robbe HWJ, Mulder LIM, Ruddel H, Lougewilz WA, Veldman JBP, Mulder G (i 987): Assessment of batoreflex by means of spectral analysis. Hypertension 10:.538-543. Roth WT, Margraf 1, Ehlers A, et al (1992): Stress test reactivity in pamc disorder. Arch Gen Psychiatry 49:301-310. Spieiberger CD, Gorsuch RL, Lnshene IL Vogg PR, Jacobs GA ( 1983): Manualfor the State- Trait Anxiety Inventory (Form It). Pao Alto: Consulting Psychologist's Press. Viilacres EC, Hollifieid M, Katon WJ, Wilkinson CW, Veith RC (1987): Sympathetic nervous system activity in panic disorder. Psychiatr Res 21:313-321. Wesseling KH, Settels JJ 1985): Baromodulation explains shortterm blood pressure variabifity. In Orlebeke JF, Mulder G, van Doomen LIP (eds), Psychophysiology of Cardiovascular Control. Models, Methods and Data. New York: Plenum Press, pp 69-97. Woods SW, Chamey DS, Silver JM, Krystal JH, Heninger GR (1991): Behavioural, biochemical and cardiovascular responses to the benzodiazepine receptor antagonist flumazenil in panic disorder. Psychiatr Res 36:115-127. Yergani VK, Balon R, Pohl R, et al (1990): Decreased R-R variance in panic disorder patients. Acta Psychiatr Scand 81:554559. Yergani VIL Pohl R, Berger R, et al (1993): Decreased heart rate variability in panic disorder, A study of power-spectral analysis of heart rate. Psychiatr Res 46:89-103.
Introduction
Subjects
Despite numerous ~tudies, the question of abnormal autonomic function in panic disorder (PD) remains unresolved. It has been argued that, where abnormalities of heart rate or blood pressure have been found, these are likely to have been due to situationally induced anxiety (Clark et al 1990; Roth et al 19f2). On the other hand, more recent and sophisticated physiologic~! studies suggest an abnormality of respiratory control (e.g., Papp et al 1993), and investigations of heart rate variability suggest abnormal parasympathetic activity (Yergani et al 1993). Reflex cardiovascular regulation is reflected in nonrandom fluctuations of resting heart rate identifiable by spectral analysis (Appel et al 1989). Such measv_res can now be obtained from an electronically stored ECG recording with minimal disruption to the subject. Heart rate variability in the 0.1 Hz range of the spectrum is believed to reflect modulation of the baroreflex (Wesseling and Settels 1985; Robbe et al 1987), and changes under the influence of cionidine (Grichois et ai i990; Eighozi et ai i99i). We have recently shown that an important feature of this effect is a fall in the dominant frequency in this range (Middleton et al 1994). This report is an analysis of heart rate variability in PD patients with attention to that particular feature. Estimates of circulating plasma noradrenaline are also reported.
Twelve patients ~uffering PD according to DSM-RI-R ~ a (American Psychiatric Association 1987), and 12 age- and sexmatched controls were recruited. All patients repotted being drug free for at least 1 month before the time of testing. Controls were screened at interview to exclude hitherto unrecognized PD. All subjects gave informed written consent, and the investigation was approved by the local research ethics committee.
From the NottinghamUniversityDepartmentof Psychiatry( ~ ) and Cambridge UniversityDepartmentsofClinicalPharmacology(MA).andExperimentalPsychology(TR). Addresst-eprintrequeslsto Dr. H.C.Middle~n,NottinghamUniversityDepartment of psychiatry.A Floor, South Blf,ck. UniversityHospital, Queen's Medical Centre.NottinghamNG72UH;Fax0602790167. ReceivedJanuary12,1994;revisedApri129,1994. © 1994SocietyofBiologicalPsychiatry
Methods Subjects were asked to abstain from alcohol for 24 hours before the test and from tea, coffee, and tobacco on the morning of the test. Subjects were told that the investigation was one of the control of heart rate and blood pressure; they were reassured that their heart rate and blood pressure were going to be checked but ~ nothing threatening would be done to them. All subjects attended at a comparable time (0830-4)900). After instrumentation and acclimatization, during which the Spielberger State Anxiety Inventory (Spielberger et al 1983) was completed, subjects were left alone for 15 minutes. Continuous electrocardiogram (ECG) recording was made during this period; at the end of it, blood pressure was measured by an automated sphygmomanometer (Dinamap) and a 30-ml blood sample was taken. Subjects then stood and remained standing, facing away from the investigator, prohibited from talking and constrained to avoid movement for 10 minutes. Blood pressure was measured at minute intervals and ECG continuously recorded. At the end of this period a further 30-ml blood sample was taken. ECG was sampled at 500 Hz and stored. Subsequently it was analyzed as described elsewhere (Middleton et al 1994) to derive values of the following variables: (R)06-3223/94/$07.00
~48
Brief Reports
BIOLPSYCHIATRY 1994;36:847-849
Table I. Means and Standard Deviations (SDP of Systolic Blood Pressure, Indices of Heart Rate Variability, and Plasma Noradrenaline Levels Among Panic Disorder Patients and Controls Semisupine Patients Systolic BP(mmFIg) Meanheart tale (ms R-R interval) Heart rate variability (ms SD) Spectral I~wer. "resp" range (Hz: x 104) Dominant frequency, "resp" range (Hz) Spectral power, 0.1 Hz range (Hz: x 104) Dominant frequency,0.1 Hz Range (Hz) Plasmanoradrenaline (rig/i)
114.9 837.7 41.8 2.9 0.27 1.6 0,075 247
(12.7) (95.0) (21.4) (I.9) (0.075) (1.0) (0.017) (118)
Standing Controls
115.9 849.1 43.9 3.1 0.25 2.04 0.1023 430
(10.7) (67.7) (2Z2) (2.5) (0.071) (1.3) (0.014)*** (204)*
Patients ! 19.2 654.7 26.8 I.! 0.24 1~6 0.0845 396
(10.2) (106.4) (8.5) (0.7) (0,06) (I,04) (0.018) (196.3)
Comrols 121.1 707.9 46.7 1.3 0,26 3.8 0.0909 681
(9.3) (58.1) (17.5)*** (0.9) (0,05) (2.6)* (0.015) (238.7)**
"SD indicated in parentheses, ***p < .OO5.** p < .Ol, * p < ,O~, unpaired t test. n =12.
1. Mean heart rate during the middle 5 minutes of the 15-minute rest period and the fourth to eighth minutes of the lOminute stand. 2. SD heart rate daring the same periods of measurement. 3. Power in the 0.1 Hz (0.0547-0.156 Hz) and respiratory (Hz) regions of heart rate variability spectra during those same periods. 4. Dominant frequency within each of the above ranges. Plasma catecholamines were assayed by reverse-phase highperformance liquid chromatography with electrochemical detection (HPLC-EC) (Moyer and Jiang 1978; Causon et al 1981), following a modified alumina extraction (Anton and Sayre 1962).
Results Patients" Spielberger scores were significantly higher than those of controls: 50.2 (SD 12.1); 27.1 (SD 3.6),p < .001 unpaired ,test). Semisupine and standing physiological measures revealed sLgnificant group differences in plasma noradrenaline and either heart rate variability or one of its derivatives in both postures (Table).
Di~ussion As patients scored higher on the Spielberger, it is not possible to distinguish between state anxiety and diagnostic status "panic disorder." Nevertheless, there were no group differences in systolic blood pressure or mean heart rate and therefore no evidence of a conventionally defined higher level of arousal among the patients. Previous investigations (Yergani et al 1990, 1993) report reduced overall (SD) heart rate variability. Current findings are consistent with these, although we have not confirmed their find-
ing of reduced overall heart rate variability in the supine posture. Direct comparison of our specwal analysis findings with theirs is not possible because of differing methods of analysis. Normal levels are repotted by most investigations of venous plasma noradreaaline in PD to date (Liebowitz et al 1985; Charney et a11985; Woods et al 1991). There is one report of raised venous plasma noradrenaline (Hesse et al 1984) and one of raised arterialized plasma venous adrenaline (Villacres et al 1987); there is one report of reduced 3-methoxy, 5-hydmxy, phenylglycol (MHPG) (F_dlund et all 1987). Thus, our finding of reduced plasma noradrenaline among PD patients is not that unexpected, and there are reasons to believe that it is consistent with the findings on heart rate variability. The greatest contribution to forearm venous noradrenaline is overflow from sympathetic vasomotor neumnes modulating arteriolar resistance in the course of baroreflex activity (Mathias et al 1975; Kooner et al 1991). As heart rate variability in the 0.1 Hz range of the spectrum has been attributed to the activity of this reflex, abnormal heart rate variability in this region of the spectnun could reflect altered baroreflex activity, consistent with abnormal venous plasma noradrenaline, Thus, the findings revealed by this study can be interpreted as evidence of abnormal baroreflex modulation in PD. Whether or not their similarity with the effects of clonidine means that they ate further evidence of noradrenergic dysregulation in PD will have to await further investigation. The authors wish to thank Professor MJ. Brown, who provided valuable advice upon setting up the catecholamineassays. H.M. acknowledges the assistance of the Wellcome Trust in the form of a generous project grant, and East Anglian Regional Health Authority who purchased much of the equipment used in the study. T.R. acknowledgesthe support of the Wellcome Trust and the MRC.
References American Psychiatric Association (1987): Diagnostic andStatistical M a n u a l o f Mental Disorders, 3rd ed rev. Washington, DC: American Psychiatric Association,
Appel ML, Berger RD, Saul JP, Smith JM, Cohen ILl (1989): Beat to beat variability in cardiovascular variables: noise or music? J
Anton All, Sayre DF (1962): A study of the factors affecting the aluminum oxide-trihydroxyindole procedure for the analysis ofcatecholamines. J P h a r m a c o l E x p Ther 138:360-375.
Causon RC, Carrutbers ME, Rodnight R (1981): Assay of plasma catecholamines by liquid chromatography with electrochemical detection. A n a l y t B i o c h e m 116:223-226.
A m Coil C a r d i o 1 1 4 : 1 1 3 9 - 1 1 4 8 .
Brief Reports
Chamey DS, Heninger GR, Jatlow Pl (1985): Increased anxiogenic effects of caffeine in panic disorders. Arch Gen Psychiatry 42:233-243. Clark DB, Taylor CB, Hayward C, et al (1990): Motor activity and tonic heart rate in panic disorder. Psychiatry Research 32:45-53. Edlund MJ, Swann AC, Davis CM (1987): Plasma MHPG in untreated panic disorder. Biol Psychiatry 22:1491-1495. Elghozi JL, Lande D, Janvier F (1991): Clonidine reduces blood pressure and heart rate oscillations in hypertensive patients. J Cardiovasc Pharmaco117:935-940. Grichois ML, Japundzic N, Head G, Elghozi JL (1990): Clonidine reduces blood pressure and heart rate oscillations in the conscious raL J Cardiovosc Pharmacol 16:449-454. Kooner JS, Birch R, FrankeI HL, Peart WS, Mathias C! (1991): Haemodynamic and neurohormonal effects of clonidine in patients with preganglionic and postgangfionic sympathetic lesions. Evidence of a sympatholytic action. Circulation 84:7583. Liebowitz MR, Gorman JM, Fyer AJ, et al (1985): Lactate provocation in panic attacks. II. Biochemical and physiological findings. Arch Gen Psychiatry 42:709-719. Mathias CJ, Christensen NJ, Corbett JL, Frankel HL, Goodwin T, Peart WS (1975): Plasma catecl~lamines, plasma renin activity and plasma aldostemne in tetraplegic man, horizontal and tilted. Clin Sci 49:291-299. Middleton HC, Coull .IT, Sabakian BJ, Robbins TW (1994): Clonidine-induced changes in the spectral distribution of heart rate variability correlate with performance on a task of sustained mention. J Psychopharmacol 8:1-7. Moyer TP, Jiang NS (1978): Optimised isocratic conditions for analysis of catecholamines by high-performance reversedphase paired-ion chromatography with amperometric detection. J Chromatography 153:365-372.
atOLPSYCmA'rttY |994~6:g4?-.Ss~
849
Hesse RM, Cameron OG, Ctmis C,C, . M ~ DS, Huber-Smith M,I (1984): Ad~nergic function in patients with ~ ~ . Arch Gen Psychiatry 41:771-/76. Papp I.A, Klein DF, German/M (1993): Carbon dioxide hypersensitivity, hyperventil~on and pm~c disorder.Am J P~.~iatry 150:1149--I 157. Robbe HWJ, Mulder LIM, Ruddel H, Lougewilz WA, Veldman JBP, Mulder G (i 987): Assessment of batoreflex by means of spectral analysis. Hypertension 10:.538-543. Roth WT, Margraf 1, Ehlers A, et al (1992): Stress test reactivity in pamc disorder. Arch Gen Psychiatry 49:301-310. Spieiberger CD, Gorsuch RL, Lnshene IL Vogg PR, Jacobs GA ( 1983): Manualfor the State- Trait Anxiety Inventory (Form It). Pao Alto: Consulting Psychologist's Press. Viilacres EC, Hollifieid M, Katon WJ, Wilkinson CW, Veith RC (1987): Sympathetic nervous system activity in panic disorder. Psychiatr Res 21:313-321. Wesseling KH, Settels JJ 1985): Baromodulation explains shortterm blood pressure variabifity. In Orlebeke JF, Mulder G, van Doomen LIP (eds), Psychophysiology of Cardiovascular Control. Models, Methods and Data. New York: Plenum Press, pp 69-97. Woods SW, Chamey DS, Silver JM, Krystal JH, Heninger GR (1991): Behavioural, biochemical and cardiovascular responses to the benzodiazepine receptor antagonist flumazenil in panic disorder. Psychiatr Res 36:115-127. Yergani VK, Balon R, Pohl R, et al (1990): Decreased R-R variance in panic disorder patients. Acta Psychiatr Scand 81:554559. Yergani VIL Pohl R, Berger R, et al (1993): Decreased heart rate variability in panic disorder, A study of power-spectral analysis of heart rate. Psychiatr Res 46:89-103.