Epinephrine-induced panic attacks and hyperventilation

\ PERGAMON

Journal of Psychiatric Research 22 "0888# 62Ð67

Epinephrine!induced panic attacks and hyperventilation G[A[ van Zijdervelda\\ D[J[ Veltmana\ R[ van Dycka\ L[J[P[ van Doornenb a

Department of Psychiatry\ Vrije Universiteit\ PO Box 6946\ 0996 MB Amsterdam\ The Netherlands b Faculteit Sociale Wetenschappen\ Universiteit Utrecht\ Utrecht\ The Netherlands Received 1 October 0886^ received in revised form 29 August 0887^ accepted 18 September 0887

Abstract To assess the e}ects of epinephrine on ventilation in patients with panic disorder and in social phobics\ analyses were performed on pooled data from two previous infusion studies[ Throughout the infusion\ changes in transcutaneous PCO1 "tcPCO1#\ subjective anxiety\ heart rate and blood pressure were recorded continuously[ Twenty!nine patients received epinephrine\ ten patients received placebo[ Thirteen patients "34)# had a panic attack during epinephrine[ The fall in tcPCO1 and the cardiovascular response was greater in panicking patients than patients who did not panic[ Although the fall in tcPCO1 associated with panic was not substantial and did not indicate clinically signi_cant acute hyperventilation\ it appears to be a sensitive index for epinephrine!induced panic[ The fall in tcPCO1 was predicted rather by the frequency of occurrence of anxiety!related somatic symptoms than by the fear of these symptoms[ These _ndings further reduce a role for fear of bodily sensations in epinephrine!induced panic attacks and favor a biological sensitivity to sympathetic stimulation[ Þ 0888 Published by Elsevier Science Ltd[ All rights reserved[

0[ Introduction The hallmark of panic disorder "PD# is acute onset of intense feelings of dread\ apprehension\ or fear with concurrent feelings of impending doom "DSM!IV\ 0883#[ The typical patient reports di.culty in breathing\ tachy! cardia\ dizziness\ and chest pains[ Most of the physical sensations of a panic attack point to massive stimulation of the autonomic nervous system accompanied by hyp! erventilation[ It has long been recognized that adrenal medullary discharge occurs in a variety of stressful or demanding situations[ Many features of spontaneous panic attacks are consistent with b!receptor stimulation suggesting an involvement in the etiology "Norman et al[\ 0889#[ However\ the evidence of increased serum levels of epi! nephrine during panic attacks\ whether induced in the laboratory or naturally occurring\ is inconsistent[ Elev! ated plasma epinephrine has been reported in anxiety disorder patients who panicked during lactate infusion "Appleby et al[\ 0870#\ but other studies showed that chemically!induced panic attacks occurred without such an increase "Liebowitz et al[\ 0874#[ b!blockers are useful in reducing autonomic symptoms in social phobia "Gor! man et al[\ 0874^ Lader\ 0877#\ but they seem not very e}ective in the treatment of panic disorder "Tyrer\ 0878#[

 Corresponding author[ Tel[] ¦20 19 3332114^ fax] ¦20 19 3339086[

Most of the early epinephrine infusion studies showed that epinephrine is e}ective in inducing the peripheral anxiety!like symptoms but does not necessarily evoke the subjective reaction of anxiety "Guttmacher\ 0872^ Breg! gin\ 0853#[ However\ the changes in nomenclature in psy! chiatry and the development of stringent criteria for the diagnosis of anxiety disorders in the last decades make these older studies di.cult to evaluate "Uhde and Tancer\ 0878#[ In contrast to well established {respiratory| pan! icogens "Coplan and Klein\ 0885#\ such as sodium lactate infusions and CO1 inhalation\ epinephrine has not been administered to patients meeting DSM!III!R criteria for panic disorder[ We showed that epinephrine is pan! icogenic in patients with panic disorder and social phobia "Veltman et al[\ 0885a\ 0885b^ van Zijderveld et al[\ 0886#[ Papp et al "0877# found that epinephrine was inadequate in causing panic in patients with social phobia[ Whether epinephrine produces panic remains\ therefore\ con! troversial and the mechanism of a speci_c sensitivity to epinephrine in these patients\ if any\ needs to be clari_ed[ The aim of the present study is to investigate the possible role of hyperventilation in the mechanism of epinephrine! induced panic[ Although hyperventilation has been dis! missed as an important symptom!producing mechanism in panic "Garssen et al[\ 0885^ Hornsveld et al[\ 0885#\ respiratory abnormalities in panic disorder continue to be considered because most panicogens induce respiratory symptoms "Coplan and Klein\ 0885#[ The aim of the present analysis is to examine the role of hyperventilation

9911Ð2845:88:, ! see front matter Þ 0888 Published by Elsevier Science Ltd[ All rights reserved[ PII] S 9 9 1 1 Ð 2 8 4 5 " 8 7 # 9 9 9 4 0 Ð X

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G[A[ van Zijderveld et al[ : Journal of Psychiatric Research 22 "0888# 62Ð67

in patients with panic disorder or social phobia by exam! ining changes in transcutaneous carbon dioxide "tcPCO1# during epinephrine challenge[ The second purpose of our study is to investigate which psychological traits would predict epinephrine!induced changes in tcPCO1[ If trait anxiety or a high fear of bodily sensations in daily life would predict changes in tcPCO1\ this would be con! sistent with cognitive or psychophysiological models of panic[ The cognitive!behavioral approach states that peo! ple prone to panic have the tendency to catastrophically misinterpret benign\ arousal!related bodily sensations "Clark\ 0875^ Ehlers et al[\ 0877^ van den Hout et al[\ 0877#[ To speci_cally assess the role of ventilation in epi! nephrine sensitivity\ we pooled data from two studies on the panicogenic properties of epinephrine in panic disorder patients and in social phobics "Veltman et al[\ 0885a\ 0885b#[ The present report is explorative because the studies from which the data were pooled were not primarily planned for this purpose and not all tcPCO1 levels from subjects participating could be obtained[ Post! hoc comparisons were made among epinephrine panick! ers\ epinephrine nonpanickers and a placebo group[ Step! wise multiple regression was performed to test whether a fear of bodily sensations or the frequency of occurrence in daily life would predict epinephrine!induced changes in tcPCO1[

1[ Method 1[0[ Subjects Data on 31 individual patients were pooled from two recently completed trials studying the panicogenic e}ect of epinephrine[ The criterion of inclusion was if tcPCO1 registrations could be obtained\ the key variable in this analysis[ This resulted in 10 females and 10 males avail! able for analysis[ The two trials included in this pooled analysis were identical with respect to the rate of epi! nephrine infusion and employed a virtually identical design[ Thirty subjects met DSM!III!R criteria for panic disorder with or without agoraphobia and twelve subjects were diagnosed as having social phobia "APA\ 0876#[ Diagnoses were made using the Anxiety Disorder Inter! view Schedule*Revised "DiNardo and Barlow\ 0878^ de Ruiter\ 0878#[ Exclusion criteria were concurrent Axis I disorders\ inability to discontinue psychotropic medi! cation for at least two weeks preceding the study\ or any signi_cant medical condition[ In the comparative study in which all subjects received epinephrine\ patients with panic disorder were compared with social phobics "Velt! man et al[\ 0885b#[ In the placebo!controlled trial\ a group of panic disorder patients were randomized to receive either placebo or epinephrine "Veltman et al[\ 0885a^ van Zijderveld et al[\ 0886#[ Both studies were approved by

the Ethics Committee of the University Hospital of the Vrije Universiteit and informed consent was obtained from participants after the nature of the procedure had been fully explained[ 1[1[ Procedures Before the day of the experiment\ all subjects com! pleted the Body Sensations Questionnaire "BSQ] Cham! bless et al[\ 0873# which measures fear of 06 stress!related somatic symptoms "BSQ!0#\ as well as their frequency of occurrence "BSQ!1#[ Subjects in each study were told they were to receive an infusion with a body compound which might in~uence their emotional state\ either positively or negatively[ In the comparative study all subjects knew they were going to receive an active substance\ but the attending psychiatrist was blind to the subjects| diagnosis "panic disorder or social phobia#[ In the placebo!con! trolled study both subjects and observer were blind to the experimental condition[ An intravenous catheter was inserted into the left ante! cubital vein[ Saline was infused over a 24!min period and baseline measurements were obtained[ Epinephrine was administered at three increasing infusion rates "19\ 39 and 79 ng kg−0 min−0# for 04 min at each dose level\ or saline in the placebo group[ Subjects were unaware of the switch[ Infusion of epinephrine at a dose of 79 ng kg−0 min−0 produces mean plasma concentrations of 599 pg ml−0 "van Faassen et al[\ 0881#\ which is comparable to epinephrine levels reached by humans under stressful circumstances or during strenuous physical exercise "Dimsdale and Moss 0879a\ b#[ The administration of epinephrine was stopped on the subjects| request or if a panic attack occurred[ At the end of each infusion step or at the point of panic\ subjects were asked to rate their anxiety level on a 099!point Subjective Units of Distress Scale "SUD!S#[ A panic attack was diagnosed as such by a psychiatrist and de_ned as a sudden increase in anxiety\ re~ected in an increase of at least 29 points above the lowest score on the 099!point scale\ together with the presence of at least one DSM!III!R cognitive symptom of a panic attack[ In the placebo!controlled study\ this de_nition was extended to include the presence of four "or more# symptoms of the DSM!III!R de_nition of a panic attack\ including at least one psychological symptom "fear of dying\ fear of going crazy\ or fear of losing control#[ 1[2[ Physiolo`ical measurements The validity of the transcutaneous method has been described by Severinghaus et al[ "0867#[ Transcutaneous PCO1 monitoring is frequently used on neonates and adults in the intensive care unit and the operation room "Epstein et al[\ 0874#[ Simultaneous measurement of tcPCO1 using the ambulatory version of the system and

G[A[ van Zijderveld et al[ : Journal of Psychiatric Research 22 "0888# 62Ð67

end!tidal pCO1 showed correlation coe.cients between 9[84 and 0[99[ Values of transcutaneous pO1 and pCO1 pressures are closely related to the arterial blood gas partial pressures "Pilsbury and Hibbert\ 0876^ Garssen et al[\ 0883#[ The equipment for the tcPCO1 measurements was a Microgas monitor "Kontron microgas 6539\ Kontron Instruments#[ It provides reliable\ continuous measure! ments of tcPO1 and tcPCO1 tensions[ A COMBI "PO1:PCO1# sensor "model 70# was heated to a constant temperature of 32[6>C[ To prepare the sensor\ a te~on membrane was positioned on the sensor surface after it had absorbed a small quantity of electrolyte ~uid[ A membrane ring was placed over the sensor and _rmly secured[ Every two weeks the sensor was prepared anew[ The sensor was attached to a cleaned skin area with surgical tape\ on the inside of the lower arm\ just below the elbow[ A small amount of contact gel was applied to provide good thermal contact[ Before each measurement the sensor was calibrated[ This requires the use of two gas mixtures supplied by the Kontron Calibrator 233[ Gas 0 contained 4) CO1 and gas 1 contained 09) CO1[ Approximately 0 h after calibration procedures\ the experimental measurements began[ TcPCO1 values were sampled every 29 s and were fed into the computer for further analysis[ Beat to beat arterial pressure and heart rate were rec! orded non!invasively by the Ohmeda 1299 Finapres "TM# _nger blood pressure monitor "Settels and Wesseling\ 0874#[ The Finapres cu} was a.xed around the second _nger on the same arm as the inserted intravenous cath! eter used for epinephrine infusion and the sensor for tcPCO1 measurements[ 1[3[ Statistical analysis Due to unequal sample sizes in the di}erent groups "epinephrine panickers vs epinephrine nonpanickers vs placebo#\ homogeneity of variances were determined by BartlettÐBox F!tests] if variances in groups were unequal\ the nonparametric KruskalÐWallis test was used[ Change scores from baseline values were computed as the out! come measure for tcPCO1\ subjective distress\ heart rate and blood pressure[ In the placebo group and in the nonpanicking patients this change was de_ned as the di}erence between mean values obtained at the baseline with those at the end of the infusion[ In the panicking subjects the values obtained at the point of panic were considered as end values[ The mean tcPCO1 value obtained in the last 2!min period "averaged over six tcPCO1 values# was considered as an end value[ Post!hoc analysis of di}erences between groups in change!scores were assessed with ANOVA\ followed by pairwise com! parisons when the overall F!value was signi_cant[ In the case of unequal variances of groups\ signi_cant KruskalÐ Wallis tests were followed by two group comparisons

64

using the MannÐWhitney U!test[ Comparisons by chi! square were carried out for categorical measures as panic rate[ Product moment correlations were calculated between anxiety questionnaires and physiological measures\ followed by stepwise multiple regressions[

2[ Results One patient with social phobia panicked during base! line measurements and showed a decrease of 4 mmHg in tcPCO1[ Two patients with panic disorder panicked before any physiological measurement could be obtained[ These three patients were excluded from the analysis[ None of the patients panicked in the placebo group\ but 02 out of 18 "34)# patients panicked during epinephrine[ Thirty nine patients were included in the post!hoc analyses[ Patients who panicked with epinephrine were pooled in one group of panickers comprising both diag! nostic entities\ because the panic rate in patients with panic disorder or social phobia enrolled in these two studies was identical[ Epinephrine panickers were com! pared with patients who did not panic to epinephrine[ The third group comparison group "all panic disorder patients# received placebo[ Table 0 shows the changes from baseline values\ obtained either at the end of the infusion or at the point of panic[ Before infusion the mean tcPCO1 did not di}er between placebo\ epinephrine panickers and epinephrine nonpanickers "24[7 mmHg\ 24[2 mmHg and 24[7 mmHg\ respectively#[ Similarly\ blood pressure\ heart rate and ratings of self!reported anxiety between groups were all equivalent at baseline "all P values × 9[09#[ Multiple comparisons tests showed that the di}erence in tcPCO1 change was signi_cant between groups "x1  03[50\ P ³ 9[9997#[ The decrease in tcPCO1 was larger in epinephrine panickers than in epinephrine non! panickers "P ³ 9[992\ MannÐWhitney U# and in subjects receiving placebo "P ³ 9[9994\ MannÐWhitney U#[ A smaller but signi_cant di}erence was observed between epinephrine nonpanickers and patients receiving placebo "F"0\14#  3[34\ P ³ 9[94#[ The change in heart rate di}ered signi_canty between groups "x1  11[81\ P ³ 9[9994#[ Epinephrine!induced tachycardia was higher in panicking patients compared with epinephrine nonpanicking patients "F"0\16#  09[60\ P ³ 9[992# and placebo "P ³ 9[9994\ MannÐWhitney U#[ The increase in heart rate in the epinephrine nonpanickers di}ered signi_cantly from the fall during placebo "P ³ 9[9992\ MannÐWhitney U#[ The change in diastolic blood pressure "x1  02[20\ P ³ 9[991# and in systolic blood pressure di}ered sig! ni_cantly between groups "F"1\24#  7[93\ P ³ 9[991#[ The decrease in diastolic in epinephrine nonpanicking patients di}ered signi_cantly from the increase observed in epinephrine panicking patients "P ³ 9[992\ MannÐ

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G[A[ van Zijderveld et al[ : Journal of Psychiatric Research 22 "0888# 62Ð67 Table 0 Mean change in cardiorespiratory variables and subjective units of distress "SUD!S# in panic disorder and social phobic patients during epinephrine "n  18# and placebo "n  09# infusions Change from baseline "¦:− S[D[# Epinephrine

tcPCO1 "mmHg# Heart rate "bpm# Diastolic BP "mmHg# Systolic BP "mmHg# SUD!S

Placebo "n  09#

Nonpanickers "n  05#

Panickers "n  02#

9[2 "9[6# −4[0 "3[5# 4[7 "4[2# 4[3 "03[0# −5[4 "09[4#

−9[3 7[8 −4[4 02[9 3[6

−1[67 "1[0# 19[5 "7[2# 6[3 "02[2# 29[0 "06[7# 29[3 "02[3#

Whitney U# and with the increase during placebo "P ³ 9[9997\ MannÐWhitney U#[ The systolic blood pres! sure response was larger in epinephrine panickers com! pared with epinephrine nonpanickers "F"0\16#  7[68\ P ³ 9[996# and patients receiving placebo "F"0\10#  01[78\ P ³ 9[991#[ As was to be expected on the basis of the panic de_! nition\ the change in ratings for Subjective Units of Dis! tress!Scale "SUD!S# di}ered signi_cantly between groups "F"0\27#  03[95\ P ³ 9[9994#\ mainly due to the higher ratings in epinephrine panickers[ Table 0 also shows that a decrease in SUD!S ratings during placebo occurred which di}ered signi_antly "F"0\14#  5[11\ P ³ 9[94# from the increase in SUD!S ratings in the epinephrine nonpanickers[ If all patients who received epinephrine are considered together\ regardless of whether panic occurred\ the fall in tcPCO1 was signi_cantly correlated with the increase in heart rate and in SUD!S ratings[ Reactivity in heart rate\ systolic and diastolic blood pressure correlated sig! ni_cantly with ratings for SUD!S "Table 1#[ It also appears that the frequency of occurrence of stress!related body sensations "BSQ!1# correlates stronger with changes in tcPCO1 than the fear of these symptoms "BSQ!0#[ A series of stepwise multiple regression analyses was performed with the psychological traits BSQ!0\ BSQ!1 and trait anxiety to predict the epinephrine!induced change in tcPCO1[ The analysis showed that 29) of the observed variablity in epinephrine!induced decrease tcPCO1 could be explained by BSQ!1[ Entering fear of somatic sensations "BSQ!0# and trait anxiety had little additional e}ect on the change in R1 and these psycho! logical traits did not meet the criteria for entry as inde! pendent variables in the equation "probability to enter the model was set at a  9[94#[ Thus\ the frequency of occurrence of stress!related bodily symptoms "BSQ!1# appears to be the best predictor of epinephrine!induced changes in tcPCO1[ A panic attack was de_ned according

"9[8# "09[1# "5[7# "02[7# "01[9#

Table 1 Product moment correlations between mean change values "baseline minus endpoint# of transcutaneous carbon dioxide tensions "tcPCO1#\ heart rate "HR#\ diastolic blood pressure "DBP#\ systolic blood pressure "SBP#\ Subjective Units of Distress!Scale "SUD!S#\ fear of bodily sen! sations "BSQ!0# and frequency of occurrence of these sensations "BSQ! 1# in daily life

HR "bpm# DBP "mmHg# SBP "mmHg# SUD!S BSQ!0 BSQ!1

tcPCO1 HR "mmHg# "bpm#

DBP SBP SUD!S "mmHg# "mmHg#

−9[270 −9[19 −9[13 −9[270 −9[310 −9[431

9[300 9[491 9[340 9[280

−9[95 9[280 9[280 9[110 9[260

9[310 9[97 9[11

9[260 9[280

0

p ³ 9[94\ one!tailed^ 1 p ³ 9[994[ All patients received epinephrine "n  18#[

DSM!III!R criteria and as a sudden increase in anxiety\ re~ected in an increase of at least 29 points on baseline SUD!S scores[ Therefore\ the same analysis was run with changes in SUD!S ratings as the dependent variable[ Again\ the BSQ!1 was the best predictor for epinephrine! induced distress\ even though the explained variability was only 05)[

3[ Discussion The available data clearly demonstrate that increased ventilation and tachycardia are consistent biological accompaniments to epinephine!induced panic[ Patients who panicked to epinephrine are characterized by a greater cardiovascular response and a greater fall in tcPCO1 than those who did not panic to epinephrine or received placebo[ The _nding that patients who panicked did not receive the full dose indicates that the decrease in

G[A[ van Zijderveld et al[ : Journal of Psychiatric Research 22 "0888# 62Ð67

tcPCO1 is closely tied to a sensitivity to epinephrine[ The main issue is whether hyperventilation as a mechamism of epinephrine!induced panic is crucial[ The magnitude of tcPCO1 response we found was smaller than or similar to respiratory challenges as CO1 inhalation and lactate infusion "Liebowitz et al[\ 0874^ Gorman et al[\ 0877#[ Using strict criteria indicating clinically signi_cant hyper! ventilation\ i[e[ a de~ection of tcPCO1 × 09 mmHg from baseline levels "Ley\ 0882#\ the fall in tcPCO1 can not be taken as evidence for a substantial role of hyperventila! tion in epinephrine!induced panic[ However\ since the decrease occurred in panickers only\ it appears to be related to panic rather than a speci_c e}ect of epinephrine[ Our data regarding similar panic rates in panic disorder patients and social phobics di}er from lactate studies showing that patients without a history of panic attacks are lactate insensitive "Liebowitz et al[\ 0874#[ Speci_! cally\ unlike other reports "Papp et al[\ 0877# we found that social phobics were susceptible to epinephrine[ Although most of our social phobia patients admitted of having experienced at least one situational panic attack\ the suggestion that panic disorder could have been mis! diagnosed as social phobia can be dismissed "Veltman et al[\ 0885b#[ Alternatively\ the panic we observed in social phobia could be due to a fact that we used a higher maximum infusion rate[ Moreover\ the common _nding of a ventilatory index correlating well with subjective anxiety "Papp et al[\ 0877# may be more relevant to the consequences of anxiety rather than to the cause[ On the other hand\ the beat!to!beat monitoring of the cardio! vascular signals indicated that an overt panic attack was preceded by a sudden rise in heart rate and blood pres! sure\ which in most cases co!occurred with clear signs of breathing irregularities\ followed by a fall in tcPCO1[ It could be argued that tcPCO1 measurements may not be reliable enough to accurately determine the sequence of events[ The slow response time of the transcutaneous electrodes "89 s# prevents the detection of rapid changes in blood gas tensions during hyperventilation "Steurer et al[\ 0886#[ The duration of the observed panic attacks\ however\ were all within the response time of the equip! ment\ suggesting that continuous transcutaneous blood gas monitoring is useful in establishing the presence of hyperventilation[ Another main _nding was the consistency of the psy! chophysiological response pattern] a fall in tcPCO1 was associated with increased reactivity in emotional distress and in cardiovascular reactivity\ irrespective of the occur! rence of panic[ Although {response desynchrony| is the rule rather than the exception in psychophysiologcal literature "Papillo et al[\ 0877#\ the concerted reactivity in our report suggests a more harmonious pattern[ The compatibility in response could in part be inherent to stimulating properties of epinephrine over a wide physio! logical range[ Infused epinephrine evokes potent actions on the heart and on vascular and other smooth muscle

66

and increases general bodily metabolism\ including lac! tate production[ The exact mechanism of ventilatory stimulation is unknown[ Epinephrine a}ects respiration by a strong bronchodilator action "Ho}man and Lefkow! itz\ 0885#[ It has been suggested that epinephrine pen! etrates the blood!brain barrier via the area postrema and stimulates medullary centers involved in the regulation of ventilation "Goldstein\ 0884#[ Thus\ the fall in tcPCO1 during epinephrine may be associated with peripheral action\ but the mechanism that explains the sensitivity of the panicking patients to epinephrine may reside beyond the blood!brain barrier[ Although the di}erence was not signi_cant\ we found that in panickers the frequency of occurrence of stress! related bodily symptoms was a better predictor for induced changes in tcPCO1 and distress than the fear of these symptoms[ Support for cognitive or psy! chophysiological models would require a superior pre! dictive value for fear of bodily sensations[ The _nding that a higher frequency of occurrence of bodily symptoms in everyday life predicts epinephrine!induced symptoms to the same extent or better than the actual fear of these symptoms\ undermines a straightforward psychological explanation[ Biological based theories have to be considered\ although these may involve psychological conditioning factors[ With regard to the proposal of Coplan and Klein "0885# described earlier\ direct evidence is lacking for classi_cation of epinephrine as a {res! piratory| panicogen\ considering that the fall in tcPCO1 was limited in the clinical sense[ Contrary to others "Lie! bowitz et al[\ 0873^ Papp et al[\ 0886#\ who showed that hypocapnia appears to predict the occurrence of panic to CO1 inhalation and to lactate infusion\ we found that patients who went on to panic did not di}er in baseline tcPCO1 levels[ Thus\ epinephrine panic is independent of the pattern of ventilation at baseline[ Taken together\ given the broad range of exaggerated physiological arou! sal elicited by epinephrine it is di.cult to isolate a speci_c biological marker predicting sensitivity to epinephrine[ The exaggerated cardiorespiratory response\ however\ suggests that an autonomic vulnerability may be involved in epinephrine!induced panic[ The interrelations between the magnitude of the tcpCO1 response and the frequent occurrence of bodily sensations associated with panic also raises the posibility that a neurogenic factor is involved[ In conclusion\ we found that tcPCO1 levels dropped following epinephrine infusion with or without panic\ but that the drop was signi_cantly greater in panickers[ The decrease in tcPCO1 can be attributed to hyperventilation as a response to panic\ triggered by increased plasma epinephrine concentrations[ Epinephrine sensitivity did not di}erentiate panic disorder from social phobic pati! ents[ Substantial de~ections in tcPCO1 failed to occur\ arguing against a crucial role for hyperventilation in epi! nephrine panic attacks[ The combination of epinephrine sensitivity with the exaggerated cardiorespiratory

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G[A[ van Zijderveld et al[ : Journal of Psychiatric Research 22 "0888# 62Ð67

response predicted by frequent somatic complaints in daily life\ appears to have a biological basis\ possibly an autonomic vulnerability[

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