Sympathetic reactivity in agoraphobic patients with and without personality disorders

Journal of Psychosomatic Research 54 (2003) 457 – 463

Sympathetic reactivity in agoraphobic patients with and without personality disorders Øivind Ekeberga,*, Liv Hedleyb, Gunnar Einvikc, Morten Rostrupa, Asle Hoffartb a

Department of Acute Medicine, Ulleval University Hospital, 0407 Oslo, Norway b Research Institute, Modum Bads Nervesanatorium, Vikersund, Norway c Department of Behavioural Sciences in Medicine, University of Oslo, Oslo, Norway Received 4 July 2001; accepted 28 March 2002

Abstract Objective: To compare sympathetic activity in agoraphobic patients with and without personality disorders before and after 11 weeks inpatient treatment. Methods: Agoraphobic patients (n = 38), 84% with panic disorder and 47% with personality disorders underwent cold pressure test (CPT), mental stress test (MST), and a specific anxiety test (SAT). Psychological assessments were done by the Bodily Sensations Questionnaire (BSQ), the Agoraphobic Cognitions Questionnaire (ACQ), Spielberger STAI-1 and -2, and a Stress Test Anxiety (STA) questionnaire. Sympathetic activity was

measured by blood pressure, heart rate, epinephrine, and norepinephrine. Results: The sympathetic activity did not differ significantly between patient groups, and the reactivity to stress was very low. The sympathetic reactivity remained unchanged after treatment, whereas psychiatric symptoms decreased. Correlations between sympathetic activity and psychological distress were not significant. Conclusion: Interpretation of bodily signals seems to be more important than the actual sympathetic activity in agoraphobic patients. D 2003 Elsevier Science Inc. All rights reserved.

Keywords: Agoraphobia; Anxiety; Panic disorder; Personality disorder; Stress test; Sympathetic activity

Introduction For more than a century, the sympathetic nervous system has been linked to the pathogenesis of panic disorder [1,2]. These patients are highly sensitive to bodily sensations that might be subject to catastrophic misinterpretation [3]. This can be illustrated by the finding that among patients referred for first time for outpatient cardiological examination, there were 38% with panic disorder and 16% with coronary heart disease [4]. Increased cardiovascular mortality has been reported in patients with panic disorder as well as in men with phobic anxiety [5 –8]. It has been suggested that the increased mortality may be due to cardiovascular hyperreactivity to stress that may promote future cardiovascular events [9] and essential hypertension [10]. Alderman et al. [11] found that blood pressure reactivity to laboratory stressors might predict myocardial infarction among treated hypertensive subjects.

* Corresponding author. Tel.: +47-22-11-73-00; fax: +47-22-11-73-51. E-mail address: [email protected] (Ø. Ekeberg).

According to the DSM-IV [12], agoraphobia is considered a further development of panic disorder, and therefore a more serious and chronic condition. However, studies on neurobiological factors have almost exclusively focused on panic disorder with or without agoraphobia. This may have followed from the experience that agents like sodium lactate, carbon dioxide, caffeine, isoproterenol, yohimbine, and cholecystokinin may provoke panic attacks. As these agents differ in their specific neurochemical mechanisms and effects, however, a final common pathway has not yet been found [13]. Palmero et al. [14] found that university students with the personality trait Type A behaviour pattern, characterized by time urgency, hostility, and competitive behaviour showed greater activation, reactivity, and slower recovery than those with Type B pattern when in a stressful laboratory situation. Although there might be an association between reactivity and some personality traits, this does not necessarily mean that we would find the same relationship in a clinical sample of patients with personality disorders. Many patients with personality disorders, however, have experienced difficult and stressful life events during life, which may have

0022-3999/03/$ – see front matter D 2003 Elsevier Science Inc. All rights reserved. doi:10.1016/S0022-3999(02)00439-7

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influenced their autonomic nervous system in a different way than patients without personality disorders. The prevalence of personality disorders (mostly cluster C) among panic disordered patients with and without agoraphobia has been reported as ranging from 27% to 58% in psychiatric samples [15,16]. To our knowledge, however, no studies have compared the reactivity in such patients with or without personality disorders. Neither are we aware of studies that have compared reactivity to stress before and after treatment for agoraphobia. We therefore decided to compare reactivity to stress in agoraphobic patients with and without personality disorder. The aims of the present study has been to investigate the following research questions: 1. Are there differences in sympathetic activity at rest in agoraphobic patients with and without personality disorders? 2. Is the sympathetic reactivity to stress different in these two groups? 3. Have the sympathetic responses to stress changed after treatment in the two groups? 4. What is the relationship between sympathetic activity and psychological factors in the two groups?

Methods Included in the study were 38 patients with agoraphobia and 32 (84%) of them also have panic disorder. There were 18 patients with personality disorders and 20 without. The patients had been admitted to an inpatient cognitive treatment program provided in group format. The unit is specialized in treating anxiety disorders. Patients were admitted to an 11-week group cognitive therapy program. The patients were diagnosed before treatment by using the Structural Clinical Interview for DSM-IV Axis I and Axis II disorders [17]. Patients were excluded from the study if there was evidence of long-term substance dependence, psychosis, bipolar disorder, or organic brain syndrome. Eight patients were admitted for each treatment period. They were included in the study consecutively from six admissions. Four patients did not want to participate or were excluded for other reasons. Among the 44 who were eligible, six could not complete the study because of problems with the blood sampling (five did not complete the study mainly because of parasympathetic symptoms that made blood sampling impossible) or withdrawal from treatment. Thus, 38 patients participated, with a mean age of 40.6 years ( ± 8 S.D., range 27 – 62), and 68% were females. The mean age at onset of the disorder was 25.3 years ( ± 7.6 S.D.). The diagnoses were independently checked by a trained rater and psychiatrist, but the patients were not rediagnosed after treatment. The kappa coefficient for panic disorder with agoraphobia was .88, while the kappa for comorbid diagnoses ranged from .70 to 1.00.

Patients using medication (79%) discontinued this on arrival at the hospital. The patients had been without anxiolytics or antidepressants for 1 week before the tests. No patients were hypertensive. Questionnaires The Bodily Sensations Questionnaire (BSQ) [18] was used to measure fear of bodily sensations on a five-point scale (0 – 4). The Agoraphobic Cognitions Questionnaire (ACQ) [18] was used to measure the belief in cognitions associated with agoraphobic behaviour. To measure state and trait anxiety, Spielberger STAI-1 and -2 were used [19]. The patients were asked before and during each stress test what level of anxiety (STA = Stress Test Anxiety) they experienced, on a scale from 0 (no anxiety at all) to 10 (maximum level of anxiety). The figure was written down by the researchers. Stress tests The participants underwent three stress tests. A cold pressure test (CPT) was performed by immersing the hand completely in ice water (0 °C) for 1 min in order to provide a mainly biophysical stressor. A mental stress test (MST) was performed by giving the patients an arithmetic challenge test. They were asked to mentally subtract the number 13 repetitively for 5 min starting with 1079. In order to increase the stress, a metronome making noise at a frequency of 2 Hz was used and the participants were informed of any miscalculation. The number of errors was recorded. A specific anxiety test (SAT) was designed as an individual narrative based on each patient’s memories of a high anxiety situation. The purpose of the SAT was to investigate if anxiety and catastrophic thoughts were elicited by mental imagination; thus, this stressor might be more directly linked to anxiety. One week prior to the administration of the SAT, each patient had given a detailed account of their worst panic attack ever. Based on this, one of the authors (LMH) presented the narrative for the patient and the level of anxiety was recorded. The patient then recorded the level of anxiety on a scale from 0 (no anxiety at all) to 10 (the most anxious I have ever been) and the probability that the catastrophic thoughts would actually happen on a scale from 0 (not at all probable) to 10 (absolute certain that the catastrophe will happen). The tests were performed in random order. After 30 min of rest, about one-third started with the CPT, one-third with the MST, and one-third with the SAT. After each test was completed, the patients rested for at least 15 min before the next test. The patients were supine both during the tests and at rest. The tests were performed after the patients had been hospitalized for 1 week, to ensure that they were all off anxiolytics and antidepressants, and at the beginning of the

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specific treatment program. After 11 weeks, the stress tests were repeated, in the same order as before treatment. The procedures began at 8 a.m. on a Monday immediately before and after treatment. The patients had eaten a regular breakfast and were instructed not to smoke, take alcohol, or coffee later than 24:00 h the evening before the test. Blood pressure, heart rate, and blood samples for analyses of epinephrine and norepinephrine were drawn before, 1 min after test start, and after each test. For MST, the same measures were made after 3– 4 min. As these results were not different from the test after 1 min, these data are not presented. A short Teflon catheter was introduced into the left antecubital vein for blood sampling. The blood was collected in polypropylene syringes and immediately mixed with glutathione and EGTA, placed on ice before it was centrifuged, and the plasmas frozen at 70 °C until the catecholamines could be measured.

Ethics

Assays

Paired t tests gave only 2 out of 18 stress responses that were statistically significant before treatment. There were significantly increased heart rate responses during MST for both groups. After treatment, there were 6 out of 18 significant differences; 5 of these were among the patients without personality disorder: systolic blood pressure and epinephrine during CPT, heart rate, blood pressure, and epinephrine during MST. The only significant response in the other group was heart rate during CPT. Diastolic pressure and norepinephrine measurements gave no more significant responses. Before treatment, the reactivity to stress was generally low in both groups, 4 out of 18 responses even negative, although not statistically significant, adding 3 more when considering diastolic pressure and norepinephrine. There were only significant differences in the level of reactivity between nonpersonality disorder and personality disorder agoraphobic patients on 4 out of 15 variables, MST heart

The plasma catecholamines were measured by a radioenzymatic technique according to Peuler and Johnson [20] as previously reported [21]. On all samples, the assay was performed examiner-blind by the same technician. Statistics The data were analyzed in the SPSS-PC version 9 for windows. Data were analyzed primarily by repeated measurement ANOVAs or by Student’s t tests. For categorical data, chi-square was used. The level of significance was set at P < .05. Corrections for multiple analyses were primarily made by Bonferroni post hoc tests. However, this approach was modified, e.g., if the differences were going in the same direction or were according to previous findings or theories.

The study was approved by the regional ethics committee.

Results The sympathetic activity at rest in agoraphobic patients with and without personality disorder There were no significant differences at rest in agoraphobic patients with and without personality disorder with respect to the levels of heart rate, blood pressure, epinephrine, and norepinephrine either before or after treatment (Tables 1 and 2). Sympathetic reactivity to stress

Table 1 Sympathetic activity for agoraphobic patients with and without personality disorders before treatment (mean ± S.E.) Before stress exposure Test

0

1

0

CPT Heart rate (bpm) Systolic blood pressure (mm Hg) Epinephrine (pg/ml)

65.3 ± 2.8 115.4 ± 6.4 51.4 ± 12.6

69.4 ± 2.6 107.8 ± 3.8 70.1 ± 13.7

1.8 ± 2.2 3.6 ± 2.9 10.1 ± 6.4

MST Heart rate (bpm) Systolic blood pressure (mm Hg) Epinephrine (pg/ml)

65.0 ± 3.1 126.4 ± 5.0 50.8 ± 8.0

67.8 ± 1.8 117.2 ± 4.9 58.4 ± 7.0

SAT Heart rate (bpm) Systolic blood pressure (mm Hg) Epinephrine (pg/ml)

72.6 ± 3.9 120.3 ± 5.5 56.6 ± 6.4

73.3 ± 3.1 120.3 ± 5.9 50.8 ± 8.0

a

P valuesa

Reactivity to stress

0

1

4.2 ± 2.4 2.8 ± 2.7 6.9 ± 7.2

NS NS NS

NS NS NS

9.7 ± 2.2 3.8 ± 3.6 28.4 ± 14.1

4.2 ± 1.1* 5.9 ± 2.5 6.6 ± 6.3*

< .05 NS NS

< .05 NS NS

2.3 ± 3.5 3.9 ± 3.2 2.8 ± 3.2

0.0 ± 2.0 3.7 ± 3.0 3.7 ± 3.0

NS NS NS

NS NS NS

Baseline vs. stress test within groups. * P < .05 for differences between 0 (no personality disorder) and 1 (personality disorder).

1

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Table 2 Sympathetic activity for agoraphobic patients with and without personality disorders after treatment (mean ± S.E.) Before stress exposure

P valuesa

Reactivity to stress

Test

0

1

0

1

0

1

CPT Heart rate (bpm) Systolic blood pressure (mm Hg) Epinephrine (pg/ml)

63.3 ± 2.3 113.9 ± 4.2 66.1 ± 6.1

66.1 ± 2.5 106.9 ± 4.3 53.4 ± 6.5

4.4 ± 2.7 5.4 ± 1.9 9.9 ± 4.0

2.9 ± 1.1 0.0 ± 3.2* 11.7 ± 8.1*

NS < .05 < .05

< .05 NS NS

MST Heart rate (bpm) Systolic blood pressure (mm Hg) Epinephrine (pg/ml)

65.1 ± 2.6 120.0 ± 3.1 61.0 ± 10.0

67.6 ± 3.1 112.2 ± 4.2 55.4 ± 4.9

10.5 ± 2.0 7.2 ± 1.7 16.1 ± 6.7

3.6 ± 2.1 7.4 ± 4.6 23.9 ± 12.5

< .05 < .05 < .05

NS NS NS

SAT Heart rate (bpm) Systolic blood pressure (mm Hg) Epinephrine (pg/ml)

67.3 ± 3.1 122.0 ± 3.5 53.7 ± 7.2

68.6 ± 3.1 110.9 ± 4.8 53.6 ± 3.3

2.8 ± 1.6 2.3 ± 3.1 6.2 ± 6.8

0.1 ± 1.4 3.1 ± 1.8 4.7 ± 6.8

NS NS NS

NS NS NS

a

Baseline vs. stress test within groups. * P < .05 for differences between 0 (no personality disorder) and 1 (personality disorder).

rate, epinephrine, and norepinephrine reactivity was greater among patients without personality disorders, whereas SAT norepinephrine was lower. After treatment, the reactivity was still low (3 out of 18 were negative) (Table 2) and 2 out of 15 of the responses were significantly different between patient groups, CPT systolic blood pressure was higher, and epinephrine lower among the participants without personality disorders than among those with personality disorders. The reactivity did not differ statistically after treatment compared to before, except for a lower reactivity post for CPT epinephrine among patients without personality disorders. Pooling the groups gave two significantly stress responses before treatment (heart rate during CPT and systolic blood pressure during MST), but otherwise no different results regarding either reactivity to stress or effect of treatment. Psychological variables As shown in Table 3, the participants with personality disorder had higher scores in all psychological tests than those without. Comparing the variables pre- and posttreatment, patients with personality disorders improved significantly on ACQ only, whereas those without personality disorder improved both in ACQ and BSQ. There was no

Table 3 Comparisons between psychological variables before and after treatment (mean ± S.E.) Psychological test

Personality disorder

No personality disorder

P values

BSQ before BSQ after ACQ before ACQ after

3.1 ± 0.2 2.9 ± 0.2 47.6 ± 4.1 38.9 ± 4.9a

2.6 ± 0.2 2.2 ± 0.2a 28.5 ± 4.7 19.0 ± 3.3a

.054 .023 .004 .002

P values reflect differences between treatment groups. a Significantly lower posttreatment.

significant improvement in anxiety measured by STAI-1 and -2. Correlations between sympathetic activity and psychological variables At rest Correlation analyses among ACQ, BSQ, STAI-1, and -2 before treatment and levels of heart rate, systolic blood pressure, and epinephrine in the three stress situations at rest showed that 71 out of 72 correlations in the two patient groups were not statistically significant. During stress ACQ and BSQ for patients with personality disorder correlated negatively with most biological variables (13 out of 18), but only systolic blood pressure during SAT (r = .51, P < .05) and heart rate during MST (r = .70, P < .05) were statistically significant. The only significant correlations between BSQ and sympathetic reactivity (during stress before stress) was systolic blood pressure during SAT (r = .52, P < .05), epinephrine during SAT (r = .52, P < .05) and STAI-1 and epinephrine during MST (r = .62, P < .05). There were no significant differences for patients without personality disorder, either in absolute scores or for correlations between psychological variables and sympathetic reactivity. Correlations between STA and sympathetic reactivity The groups did not differ in subjectively reported anxiety either before or during the stress test. They reported significantly more anxiety during stress, the nonpersonality disorder patients increasing from 1.8 ± 0.4 (mean ± S.E.) to 4.6 ± 0.6 during the SAT, while patients with personality disorder increased from 3.2 ± 0.5 to 5.6 ± 0.6.

Ø. Ekeberg et al. / Journal of Psychosomatic Research 54 (2003) 457–463 Table 4 Correlations between differences in STA (anxiety during stress anxiety before stress) and sympathetic reactivity before and after treatment STAdiff

HRdiff

Patients with personality disorders During CPT Before treatment .04 After treatment .05 During MST Before treatment .05 After treatment .10 During SAT Before treatment .41* After treatment .18 Patients without personality disorders During CPT Before treatment .16 After treatment .11 During MST Before treatment .03 After treatment .21 During SAT Before treatment .47* After treatment .26

Sysdiff

Epidiff

.23 .01

.06 .05

.26 .36

.14 .10

.26 .03

.02 .12

.21 .06

.26 .24

.00 .22

.25 .12

.35 .16

.05 .11

STAdiff = STA during stress before stress; HRdiff = heart rate during stress before stress; Sysdiff = systolic blood pressure during stress before stress; Epidiff = epinehrine during stress before stress. * P < .05.

Differences in STA (STA during stress STA before stress) were correlated with sympathetic reactivity for heart rate, systolic blood pressure, and epinephrine (during stress before stress). Only one correlation was statistically significant both for participants with personality disorders and patients without personality disorders (Table 4).

Discussion The present study showed only few and not consistent differences in sympathetic activity at rest in participants with and without personality disorders. The few significant differences in reactivity between patients with or without personality disorders were small, showed no consistent pattern, and were not significant after Bonferroni’s correction. The lack of clinically significant differences between the groups were found at baseline, during and after mental and physical stress, and both before and after treatment for agoraphobia. The sympathetic responses to stress were small, and for most of the assessments, there was no statistically significant increase in sympathetic activity during stress. This may seem surprising, as patients with agoraphobia easily perceive threats and get activated. We have previously found a rather moderate increase in heart rate during flight (83 vs. 74 bpm preflight), systolic blood pressure (125 vs. 114 mm Hg), and epinephrine (0.28 vs. 0.15 nmol/l) for subjects

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with untreated flight phobia, and there were only low correlations between the sympathetic and psychological factors [22]. These subjects generally had less psychiatric problems that the patients with panic disorder and agoraphobia and the real life stress was very demanding. In other studies, both from our laboratory and from others [23.24], including mostly hypertensives or normal, the participants seem to be more reactive to stress than the agoraphobic patients in the present study. Patients admitted to hospital due to chest pain showed different responses to CPT depending on the presence of coronary artery disease (CAD) or not [25]. Patients without CAD showed responses that were in line with our patients. A large proportion of such patients actually suffer from panic disorder [4]. Awareness of harmful events per se may elicit hyperreactivity to stress [26]. Taking into account the great attention to bodily signals among agoraphobic patients, one would assume that they would be more likely to show greater responses in stress situations. We have no data that explain the low reactivity to stress. One suggestion is that agoraphobic patients get easily activated at an early stage of their disorder. Repeated sympathetic activation in situations that are interpreted as threatening might cause down-regulation of receptors, followed by lower responses to stress at a later stage. This might partly explain the lower response in the agoraphobic patients than in those with flight phobia, who most commonly had only one specific phobia. This is in line with Gurguis and Uhde [27] who have suggested that the dysregulation in the noradrenergic system in panic disorder may be akin to animal studies of acute-on-top-of-chronic stress paradigms, whereby chronic stress results in normal or decreased basal norepinephrine turnover and sensitized responses to recurrent stresses. Most of our patients had panic disorder and a possible down-regulation may be even more pronounced in agoraphobia that may be considered a further development of panic disorder. The patients in this study had suffered from agoraphobia for an average of 15 years, which may be sufficient time for down-regulation. Finally, there were no consistent relationships between the psychological factors and the sympathetic responses. In fact, several of the statistically significant correlations were negative. This strengthens the assumption of misinterpretation of bodily signals as crucial to agoraphobia and panic disorder. The patients perceive that some activation takes place, but it seems that the actual level of the bodily activation is of minor importance. This may also explain why patients may improve psychologically without changes in the sympathetic reactivity, given that they interpret the bodily sensations differently. It may also explain why we did not find greater sympathetic responses in participants with personality disorders, although they scored significantly higher on most of the psychological variables than participants without personality disorder. Although the presence of agoraphobia was one of the inclusion criteria, almost all patients had panic disorder.

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Therefore, it is likely that our findings can be generalized to patients with panic disorder as well. Sympathetic reactivity in different patient groups has been compared only to a limited extent. Stein et al. [28] found no differences in plasma norepinephrine or neuropeptide Y under resting conditions or following hand immersion in ice water, and argued that these results are convergent with prior reports of normal sympathetic nerve activity in patients with anxiety disorders. Wilkinson et al. [2] found that whole-body and regional sympathetic nervous activity were not elevated at rest in patients with panic disorder and that responses to laboratory mental stress were almost identical in patient and control groups. It has been pointed out that even though the sympathetic nervous system has been believed to be involved in the pathogenesis of panic disorder, most studies to date have used peripheral venous catecholamine measurements. This may have contributed to conflicting results as the sympathetic nervous system is not globally activated during panic attacks [2]. The reduction in heart rate variability and cardiac vagal tone in panic disorder [29] can be reversed by use of the serotonin reuptake inhibitor paroxetine [30]. Drug treatment may also normalize the lack of normal baroreflex response [30]. Pretreatment abnormalities in hypothalamic – pituitary –adrenal axis function appear to resolve with alprazolam treatment and preliminary observations suggest that pretreatment dysregulation of the hypothalamic – pituitary – adrenal system may predict a more difficult or less satisfactory treatment [31]. Our data may indicate that it will take more than 11 weeks to normalize sympathetic reactivity using psychological intervention. This may indicate that the sympathetic responses may be modified more rapidly by the use of medication than by psychological intervention. In addition to sympathetic responses and misinterpretation of bodily signals, factors like vestibular dysfunction and impaired balance in patients with agoraphobia may play a role. Agoraphobics rely on proprioceptive cues for maintenance of upright balance. Jacob et al. [32] found that agoraphobics had impaired balance when proprioceptive balance information was minimized by sway-referencing the support surface, which may lead to intolerance of situations characterized by unstable support. Simon et al. [33] found that the rates of panic disorder are elevated to 5 –15 times that of the general population among patients presenting for evaluation and treatment of dizziness. This points at explanations other than the sympathetic nervous system in the understanding of agoraphobia. The strengths of the present study are that the patients are rather homogenous, well diagnosed, treated in a specialized psychiatric department, and inpatients and therefore better controlled during the time when they stopped using tranquilizers. The staff at the laboratory at Ulleval hospital who performed the tests and made the analyses of the blood samples is very experienced and has published extensively

on sympathetic activity. Among the limitations is the limited number of patients. In conclusion, our data showed no differences in sympathetic activity between agoraphobic patients with and without personality disorders, either at rest, during stress, or after 11 weeks treatment for agoraphobia. Future studies should focus on the possibility of down-regulation of receptors in studies of agoraphobia, as well as the parasympathetic nervous system, and the relationship between sympathetic and parasympathetic activities.

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