Cardiovascular, neuroendocrine, and monoaminergic responses to psychological stressors: Possible differences between remitted panic disorder patients and healthy controls

Cardiovascular, Neuroendocrine, and Monoaminergic Responses to Psychological Stressors: Possible Differences between Remitted Panic Disorder Patients and Healthy Controls Marco Leyton, Claude B61anger, Johanne Martial, Serge Beaulieu, Ellen Corin, John Pecknold, N.M.K. Ng Ying Kin, Michael Meaney, Joseph Thavundayil, Suzanne Larue, and N.P. Vasavan Nair

Both clinical symptomatology and stress research suggest that panic attacks might be partially attributable to exaggerated psychophysiological responses to environmental stressors. In the present study, we aimed to explicitly test this idea by measuring the physiological responses to a mild psychological stressor in both healthy controls (n = 8) and fully remitted, medication-free panic disorder patients (n = 8). One hour before the stressor, former patients, compared to healthy controls, exhibited higher diastolic blood pressure. From a blood sample taken 30 min before the stressor, patients, compared to controls, had lower paroxetine platelet binding site densities. During the stressor, patients, compared to controls, had greater increases in plasma levels of cortisol. These preliminary findings suggest that remitted panic disorder patients might have disturbed physiological responses to mild psychological stressors. These disturbances might be related to the development of future episodes.

Key Words: Panic disorder, stress, cardiovascular, cortisol, paroxetine, serotonin BIOL PSYCHIATRY

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Introduction Anxiety disorder patients in remission are, by definition, free of psychopathology; and yet, compared to the never

From the Douglas Hospital Research Centre, Department of Psychiatry, McGill University, Verdun, Canada. Address reprint requests to Dr. Marco Leyton, Research and Training Building, Department of Psychiatry, McGill University, 1033 Pine Avenue West, Montreal, Quebec, Canada H3A 1A1 Originally presented at The First World Congress on Stress, Bethesda, MD, October 4-7, 1994. Received April 10, 1995; revised August 10, 1995.

© 1996 Society of Biological Psychiatry

before ill, they are at elevated risk for future psychiatric episodes (Barlow 1988). Of interest then, is how remitted patients might differ from healthy controls, and particularly how these differences might be related to the development of future psychopathology. One possibility suggested both by patient symptomatology (Barlow 1988) and by stressful life event studies (Finlay-Jones and Brown 1981) is that remitted patients have disturbed psychophysiological stress responses. In turn, these dysfunctional responses might increase the probability of developing severe anxiety. To our knowledge, however, the physio0006-3223/96/$15.00 SSDI 0006-3223(95)00452-1

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logical responses to psychological stressors in remitted patients have never been reported. In healthy controls, psychological challenges alter cardiovascular (Cacioppo 1994), neuroendocrine (Dienstbier 1989), and monoaminergic activity (Dienstbier 1989; Frankenhaeuser, 1971; Iny et al 1994). It is unclear whether any of these stress responses are disturbed in panic disorder patients. Following 30 min or more of rest, ill panic disorder patients, compared to healthy controls, might have higher plasma levels of cortisol (Goldstein et al 1987; Gurguis et al 1991; Roy-Byrne et al 1986), but other researchers report seeing no differences between the two groups, not only in plasma cortisol (Lesch 1991; Targum 1992), but also in cardiovascular and sympathetic nervous system activity (Asmundson and Stein 1994; MB Stein et al 1992; Weissman et al 1987). In comparison, elevated cardiovascular activity in ill panic disorder patients, compared to healthy controls, has been seen more consistently following either shorter rests (5-20 min) (Yeragani et al 1990a and b), or when waiting for a stressor (Hoehn-Saric et al 1991; Roth et al 1986, 1992; JM Stein et al 1992). Following exposure to various laboratory stressors, ill patients might have greater cardiovascular and lower autonomic nervous system responses (Hoehn-Saric et al 1991), but this has not been seen by most investigators (Asmundson and Stein 1994; Roth et al 1986, 1992; JM Stein et al 1992; Stein and Asmundson 1994). Finally, a single study suggests that remitted panic disorder patients have, compared to controls, higher systolic blood pressure and lower heart rates immediately before moving from a supine to a standing position, but lower systolic pressure once standing (Middleton 1990). The failure to see stressor-induced differences between patients and controls might reflect ceiling effects, the recent use of psychotropic medication (3-21 days previously), inappropriate dependent measures, or, as recently suggested (JM Stein et al 1992; Asmundson and Stein 1994), poorly matched levels of cardiovascular fitness; however, none of these interpretations indicate whether the disturbed stress responses are related to episode onset. The group differences observed during partial rest or anticipation of a stressor might be symptoms of panic disorder rather than causes. To more pointedly investigate variables associated with episode recurrence, we tested fully remitted, medication-free patients. If former patients and healthy controls have different responses to our mild stressors, the difference might reflect a chronic vulnerability to psychological challenges. This vulnerability might be related to the occurrence of subsequent episodes. For the present study, the choice of dependent variables was, by necessity, based largely on findings in ill patients; however, both ill and remitted panic disorder patients might have disturbed cardiovascular stress responses,

Leyton et al

suggesting that they might be suitable experimental measures. Since patients have normal blood pressure when resting but elevated pressure when waiting for a stressor, it was expected that group differences might be apparent on the test but not the medical exam day. Pituitary-adrenal stress responses have not been reported in panic disorder patients but are well documented in healthy controls. Plasma levels of prolactin increase within 5 min of a psychological stressor's presentation (Hudgens et al 1989; Meyerhoff et al 1988), whereas the cortisol response is slower, taking as long as 20 rain (e.g., Kirschbaum et al 1992; Meyerhoff et al 1988). We expected group differences in stress responses at these same points. Ill panic disorder patients might have decreased paroxetine platelet binding site densities (Iny et al 1994; Faludi et al 1994; but for negative findings see Maguire et al 1995; Stein et al 1995), a peripheral index of central serotonin (5-HT) uptake (Habert et al 1985, 1986; Laruelle et al 1988; Mellerup et al 1983). Similar reductions are apparent in healthy controls following 3 weeks of university exams (Iny et al 1994). Thus, paroxetine platelet binding site densities might be a biological index of perceived stress irrespective of present psychopathology. Therefore, if remitted panic disorder patients have exaggerated responses to the stressors in their daily lives, they might also, at baseline, have reduced paroxetine platelet binding. Finally, if group differences in physiological stress responses were found, then they might be related to psychological temperament. To test this possibility, subjects were administered the Tridimensional Personality Questionnaire (TPQ) (Cloninger 1986, 1987). High harm avoidance scores in former panic disorder patients have been reported (Saviotti et al 1991), and were expected in our own patient sample.

Methods Subjects Eight subjects were recruited for the patient sample. Seven of these patients had been treated at Douglas Hospital's outpatient clinics and, with their therapist's approval, were contacted about possible participation in the study. The 8th had never been treated. All patients met DSM-III-R criteria for a past episode of panic disorder with (n = 3) or without (n = 5) agoraphobia. Diagnosis and current state were confirmed during interviews with the Structured Clinical Interview for DSM-III-R (Spitzer 1987) and the 14-item Hamilton Psychiatric Rating Scale for Anxiety (less than or equal to 8) (Hamilton 1959). Financial compensation for lost salary was offered to those patients who took time off work.

Stress Responses in Remitted Panic Patients

All patients were psychotropic medication and symptom free for a minimum of 6 months before testing, and neither they nor their first-degree relatives had had an axis I diagnosis other than panic disorder with or without agoraphobia. Potential subjects were excluded if an axis II disorder was suggested by their file or the clinical interview. Women were not pregnant, lactating, or using steroid contraceptives within 6 months of the test to rule out possible interactions between ovarian hormones and 5-HT (Munaro 1978). Eight healthy control subjects were recruited from the community served by Douglas Hospital. In addition to the above exclusion criteria, control subjects had no personal or first-degree relative history of psychopathology. All control subjects received a small financial remuneration for their participation. The control group was matched with the patient group for age (range 23-52 years), gender (both men and women were tested), height, weight, and years of education (minimum of grade 8). Subjects had no serious organic disorders as determined by clinical judgment from a physical exam (conducted by JT) and laboratory tests. The study was approved by Douglas Hospital's Scientific and Ethics Committee, and was thoroughly described to all subjects, each of whom gave written consent. Demographic and neuroendocrine data were obtained from all subjects. Cardiovascular data were available from 7 patients and 8 controls. Paroxetine binding and TPQ data were available from 7 patients and 7 controls.

Materials Two psychological challenges were employed: five mathematical tests (Mathews et al 1987); and a list of 20 six-letter anagrams, 15 of which were impossible to solve (Harris and Tyron 1983). Subjects worked on each task for 15 min. To increase the perceived importance of the tasks, subjects were told that financial rewards ($50, $40, $30, $20, $10) would be given to the top five performers. The TPQ measures three personality dimensions, novelty seeking, harm avoidance, and reward dependence, each with four subdimensions. It is brief, easy to administer, has moderately high test-retest reliability (r = .70-.79 for the three dimensions) (Cloninger et al 1991), and has been validated with the Eysenck Personality Questionnaire and Tellegen's Multidimensional Personality Questionnaire (Cloninger 1987).

Procedure Potential subjects were initially screened during a 30-min semistructured telephone interview. If eligible subjects were interested, they were then interviewed in more depth

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to determine personal and family histories of psychopathology. One to two weeks later (11.6 _+ 4.0 days), individuals who still met the study's criteria received a medical exam to rule out any serious organic disorder. For 24 hours before the stressor test, all subjects abstained from alcohol and caffeine-containing drinks. On the test day (26.4 + 8.5 days after the medical exam), subjects fasted from 9:00 AM and arrived at 11:30 AM. Upon arrival, heart rate and blood pressure were taken, an intravenous catheter was inserted into a forearm vein, and subjects relaxed for 30 min. A first baseline blood sample (80 mL) was then drawn, followed 30 min later by a second (10 mL). Immediately after taking the second sample, the two 15-min psychological challenges were presented consecutively. Following the beginning of the stressor, serial collections of blood (10 mL) were taken at 5, 10, 20, 30, 45, 60, and 90 min. Once the final blood sample had been taken, subjects were debriefed and completed the TPQ.

Measurement of Physiological Variables Plasma cortisol levels were measured by radioimmunoassay (RIA) with the Kodak Amerlex Cortisol RIA kit (Kodak Clinical Diagnostics Ltd., Amersham, UK). Cortisol is released from transcortin by a chemical blocking agent contained in the kit. Plasma prolactin was also determined using an RIA kit from Kodak Clinical Diagnostics Ltd., Amersham, UK. Paroxetine binding in blood platelets was determined essentially as described by Iny et al (1994). Platelets were prepared from 40 mL of whole blood collected in ethylenediaminetetraacetic acid (EDTA)-coated tubes, and the lysed platelet membrane fractions incubated with 3Hlabeled paroxetine (0.05-10 nmol/L) for 3 hours at 20°C (Segonzac et al 1987). Nonspecific binding was determined in the presence of a 1000-fold excess of citalopram. Cardiovascular activity was measured by a nurse (SL) with a sphygmomanometer. Unfortunately, the nurse was not blind to group designation and this could have introduced bias into the recording of data; however, since she did not know that cardiovascular activity was an experimental variable, the possibility of this bias was at least partially reduced.

Data Analyses Demographic, paroxetine platelet binding, and TPQ variables were analyzed with Student's two-tailed t tests for unpaired samples. Cardiovascular activity variables were analyzed with between and within group × day analyses of variance (ANOVA). Neuroendocrine variables were analyzed with between and within group × time ANOVAs

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Table 1. Demographic Variables Variable Age (years _+ SEM) Education (years + SEM) Height (cm - SEM) Weight (kg --_ SEM) Gender (% female) HAM-A (± SEM) Stressor Task Score (± SEM)

Panic disorder (n = 8)

Controls (n = 8)

p value

37.1 _ 4.4 12.0 ± 1.0 168.2 ± 3.0 70.3 --- 5.5 62.5 1.1 --- 0.5 45.8 ± 9.7

31.5 --- 2.8 12.5 ± 0.9 167.1 ± 3.7 69.6 ± 5.0 62.5 0.25 --_ 0.2 66.5 ± 24.2

.2224 .7192 .8069 .9288 1.000 .1279 .4390

HAM-A = Hamilton Anxiety Scale.

and baseline (mean of the two baseline samples) x group X time analyses of covariance (ANCOVA) followed by Wilks' Lambda. Post hoc analyses were made with Tukey's Honestly Significantly Different test.

Results

Demographic Variables The two groups of subjects were matched, and did not differ significantly, on age [t~15) = 1.277, p > .20], gender IX z' = 0.00, p = 1.000], years of education [t(15) ---- 0.367, p > .70], height [t(15) = 0.249, p > .80], or weight [t(15) = 0.00894, p > .90]. Nor did the two groups give significantly different numbers of correct answers on our tasks [to5 ) = 0.796, p > .40] (Table 1).

Cardiovascular Activity Blood pressure and heart rate were recorded both during the relatively low stress medical exam and before the moderately stressful test session. Overall, there were no significant main effects of day [diastolic pressure: F(1,13), = 0.318, p > .55; systolic pressure: Fo,13 ) = 0.001, p > .95; heart rate: F(L13 ) = 0.095, p > .75]. When the data were collapsed over days, diastolic blood pressure tended to be significantly higher in the patient group [F(1.13) = 4.514, p < .06]. A nearly significant group X day

interaction IF(I,13) = 4.275, p < .06] suggested that the group difference might be greater on one day than the other, a possibility that was supported by simple main effects analyses. Whereas the two groups were not significantly different during the medical exam [F(1,15) = 2.219, p > . 15], patients, compared to controls, had significantly higher diastolic blood pressure 1 hour before the stressor tests [F~1,15) = 6.774, p < .03]. In comparison, systolic pressure in the two groups was not significantly different on either day, and neither group [F(1,13) = 1.448, p > .25] nor group X day effects [F(l:3 ) = 0.886, p > .35] were apparent (Table 2). In an analysis of heart rates on the two days, neither group [F~l,13) = 1.687, p > .20] nor group X day effects [F(1,13) = 2.261, p > .15] were statistically significant; however, simple main effects analyses suggested that the patients had modestly higher heart rates on the test [F(t,lS) = 3.218, p < .10] though not on the medical exam day [F(1,1s) = 0.342, p > .55] (Table 2).

Neuroendocrine Activity The means of the two baseline plasma levels of prolactin were 4.4 _ 0.8 and 5.5 --- 1.2 ng/mL for the patient and control groups, respectively, differences that were not statistically significant (p > .05). For the test as a whole, the two groups did not have significantly different plasma

Table 2. Cardiovascular Activity

Variable Medical exam Systolic pressure (mm ± SEM) Diastolic pressure (mm ± SEM) Heart Rate (beats/60 s - SEM) Test day--60 min before stressor Systolic pressure (mm ± SEM) Diastolic pressure (mm + SEM) Heart rate (beats/60 s -+ SEM) a Statistically significant.

Panic disorder (n = 7)

Controls (n = 8)

p value

120.0 ± 6.8 78.7 - 3.8 72.8 + 3.4

111.5 _+ 6.0 69.2 ± 4.4 70.2 -+ 2.3

.330 .157 .566

121.4 -+ 5.4 81.3 - 4.5 75.0 -- 3.7

110.0 ± 5.5 64.8 ± 5.0 67.0 ± 3.2

.196 .020 a .090

Stress Responses in Remitted Panic Patients

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levels of prolactin [F(1,14) = 0 . 8 4 8 , p > .35], nor was there a significant group x time interaction [F(8,112) = 0.658, p > .70]. There was, however, a significant effect of time [F~8,112) = 3.545, p < .002], reflecting small though consistent decreases in prolactin levels from their high points, 5 and 10 min after the stressor was presented, to their low points, 60 (p < .05) and 90 min (p < .05) after the stressor had begun (not illustrated), A repeated measures ANCOVA, using the baseline levels of prolactin as the covariate, also indicated that there was a significant effect of time [Wilks' Lambda: /'(6,8) = 10.1763, p < .003]; however, this same A N C O V A confirmed that there was no group × time interaction [Wilks' Lambda: F(6,8 ) : 1.0658,p > .45], and that the two groups did not differ significantly at any time point (p > .20). The two groups did not have significantly different baseline levels of cortisol (p > .05). For the test as a whole, there was neither a main effect of group [F(L14 ) = 0.000, p > .95], nor a significant group × time interaction [F~s, I12) = 1.440, p > .15]; however, there was a significant effect of time [Fc8:12) =" 2.079, p < .05], reflecting decreases in cortisol levels from their high point at the first baseline sample to their low points, 10 min after the task had begun (p < .05) and 60 min after it had been completed (p < .05) (Figure la). A repeated measures A N C O V A also indicated that there was a significant effect of time [Wilks' Lambda: F(6,8 ~ = 3.6128, p < .05], but overall neither a main effect of g r o u p [F(I,13) = 1.13, p > .30] nor a group × time interaction [Wilks' Lambda: F(6,8 ) = 1.9040, p > . 15] was apparent. In comparison, a second A N C O V A examining only the 10-, 20- and 30-min poststressor time points--the three time points during which the laboratory stressor would be expected to increase circulating levels of cortisol--obtained a significant effect of group [F(],I3) = 5.24, p < .04]. Moreover, as calculated from either omnibus ANCOVA, simple main effects (Armitage and Berry 1987, p 201) indicated that 20 min after the stressor was presented, the patients had, compared to the controls, modestly higher plasma levels of cortisol [F~I,~3) = 3.670, p < .08]. Thirty minutes after beginning the stressor, the difference was statistically significant [ F ( 1 , 1 3 ) : 5 . 9 8 , p < .03]. Statistically significant group differences were not apparent at any other point (p > .20) (Figure lb).

Paroxetine Platelet Binding Sites Paroxetine platelet binding was characterized with blood samples taken at the first baseline. The two groups did not have significantly different paroxetine platelet binding dissociation c o n s t a n t s It(13) = 0•303, p > .75] (Figure 2a), but, compared to the controls, the patients had signifi-

~ ~ ~

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cantly lower binding site densities [t(13) ---- 2.316, p < .04] (Figure 2b).

Tridimensional Personality Questionnaire As measured by the TPQ, the two groups did not differ significantly on either harm avoidance [t(13) = 0.951, p > .35] or reward dependence [t(~3) = 0•699, p > .45]; however, the remitted panic disorder patients did score significantly higher on novelty seeking [t(13) = 2.95, p < .02], an effect largely attributable to higher scores on the subscale of impulsivity [to3 ) = 2.78, p < .02] (Table 3).

Discussion Since our sample sizes were small, this study's results should be considered preliminary and interpreted with caution; however, our mild psychological stressors slightly increased plasma levels of both prolactin and cortisol in the healthy controls and remitted patients• More importantly, group differences were apparent in cardiovascular, endocrine, paroxetine platelet binding, and TPQ measures. Compared to healthy controls, fully remitted, medication-

358

BIOL PSYCHIATRY 1996;40:353 360

M. L e y t o n et al

0.4

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Panic

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1000 -

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Figure 2. (a) Paroxetine platelet binding dissociation constant (nmol/L + SEM) from plasma sample drawn 30 min before the psychological stressor. (b) Paroxetine platelet binding site density (fmol/mg _+ SEM) from plasma sample drawn 30 min before the psychological stressor. free panic disorder patients displayed modest cardiovascular (diastolic pressure) and adrenocortical (cortisol release) hyperreactivity to the psychological stressors, decreased paroxetine platelet binding site densities, and elevated novelty seeking scores. Exaggerated stress responses might increase susceptibility to future episodes. To our knowledge this is the first report of different physiological responses to psychological stressors in fully recovered psychiatric patients and healthy controls. There is, however, a previous report that, compared to healthy controls, remitted panic disorder patients have higher systolic blood pressure and lower heart rates immediately before moving from a supine to a standing position (Middleton 1990). In comparison, while waiting for psychological stressors, our groups did not have significantly different systolic blood pressure or heart rates, though both tended to be higher in the patients. The difference between our studies might reflect the small sample sizes, or the possibility that different stressors have different effects. The greater physiological stress responses exhibited by the patients are unlikely to be due to greater intellectual difficulty with the task. Not only were the two groups matched on years of education, but their scores on our stressor tasks did not differ significantly. Nor do the group differences appear to be related to gender, age, height, or weight, each of which was, by design, similar in the two samples.

Compared to the control subjects, the remitted patients also displayed a significantly lower paroxetine platelet binding site Bmax at the first baseline. Similarly reduced imipramine and paroxetine platelet binding site densities have been seen in remitted (J. Pecknold, unpublished observations) and acutely ill panic disorder patients (Iny et al 1994; Faludi et al 1994; but see Maguire et al 1995; Stein et al 1995), respectively. Together with our present findings, these observations suggest that decreased paroxetine binding site densities persist beyond the acute illness, possibly reflecting a persistent psychophysiological hyperreactivity to the challenges of daily life. This interpretation is supported by clinical and preclinical research. Decreased paroxetine binding sites are seen on the platelets of both healthy students exposed to 3 weeks of university exams (Iny et al 1994) and posttraumatic stress disorder patients (Arora et al 1993), as well as in the hypothalamus of repeatedly shocked rats (Edwards et al 1992). The physiological significance of altered paroxetine platelet binding remains unclear. Paroxetine binding sites are associated with the 5-HT transporter complex, not only on platelets but also on neurons, and these sites might inhibit 5-HT uptake (Habert et al 1985, 1986; Laruelle et al 1988; Mellerup et al 1983). Thus, a reduction in paroxetine binding sites might lead to increased uptake and decreased synaptic levels of 5-HT. Decreased 5-HT

Table 3. Tridimensional Personality Questionnaire Variable Novelty seeking Exploratory excitability Impulsiveness Extravagance Disorderliness Total

Panic disorder (n = 7) 6.43 ± 0.5 3.71 5.14 5.43 20.71

Harm avoidance Worry and pessimism Fear of uncertainty Shyness with strangers Fatigability Total Reward dependence Sentimentality Persistence Attachment Dependence Total

4.14 5.29 7.29 3.57 20.29

"Statistically significant.

_+ 1.0 -+ 0.5 ± 0.7 + 1.8

Controls (n = 7) 5.43 ± 0.5 0.71 4.00 4.29 14.43

_+ .04 -+ 0.5 ± 0.5 + 1.1

P value .187 .017 a .147 .259 .012"

2.86 _+ 0.4

1.43 _+ 0.9

.162

5.00 _+ 0.5

3.29 _+ 1.1

.182

2.57 ± .06

3.29 ± 0.9

.522

2.86 + 0.6 13.29 ± 1.4

2.00 _+ 0.6 10.0 _+ 3.0

.321 .360

_+ 0.4 ± 0.9 _+ 0.5 _+ 0.4 + 1.4

4.29 5.57 6.71 2.57 19.14

_+ 0.4 -+ 0.5 _+ 1.0 _+ 0.5 + 0.7

.811 .792 .620 .147 .498

Stress R e s p o n s e s in R e m i t t e d Panic Patients

neurotransmission in anxious patients is also suggested by reports of lower plasma levels of 5-HT (Evans et al 1985) and lower cerebrospinal fluid levels of the 5-HT metabolite, 5-hydroxyindoleacetic acid (Banki 1977). If remitted panic disorder patients display constitutional differences in their responses to psychological challenges, then this physiological trait might be associated with temperament. Compared to the controls, our patients displayed elevated novelty seeking, a group difference that might reflect anxiety disorder-related difficulties in impulse control (Linnoila and Virkkunen 1991; McElroy et al 1992). Unexpectedly, however, we did not see elevated harm avoidance scores, as have been reported previously (Saviotti et al 1991). The discrepancy may be due to our small sample size or the co-occurrence of agoraphobia in Saviotti et al's patients (100% vs. our 37.5%). Alternatively, the stressful nature of our experimental protocol might have dissuaded high harm avoidance subjects though not high novelty seekers. Indeed, 71% of contacted former panic disorder patients declined to participate, commonly because they considered the blood sampling to be too frightening.

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The origins of exaggerated stress responses in our patients are unclear--they might reflect inherited predispositions (Torgersen 1987) or physiological sensitization from exposure to previous stressors (Post 1992; Post and Weiss 1988). Post has suggested that repeated exposure to psychological stressors might induce changes that lead to both progressively greater activation of limbic stress mechanisms and increased vulnerability to mood and panic disorders. Alternatively, the disturbed stress responses might reflect long-lasting changes induced by their previous panic attacks. Panic attacks themselves are stressful experiences (e.g., McNally and Lukach 1992).

We thank the nurses of Douglas Hospital's Clinical InvestigationUnit for their excellent clinical assistance. We are particularly grateful to Mr. Dhunraj Ramdoyal and Ms. Mira Thakur for performing the various assays and Ms. Julie Trottier for assisting in the selection of subjects. We also thank Drs. Joseph Rochford and Lawrence Annable and Mr. George Schwartz for helpful suggestions.

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