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High trait anxiety in healthy subjects is associated with low neuroendocrine activity during psychosocial stress
Progress in Neuro-Psychopharmacology & Biological Psychiatry 28 (2004) 1331 – 1336 www.elsevier.com/locate/pnpbp
High trait anxiety in healthy subjects is associated with low neuroendocrine activity during psychosocial stress Daniela Jezovaa,*, Aikaterini Makatsoria, Roman Dunckoa, Fedor Monceka, Martin Jakubekb a
Laboratory of Pharmacological Neuroendocrinology, Institute of Experimental Endocrinology, Slovak Academy of Sciences, Vlarska 3, Bratislava 83306, Slovakia b Department of Psychology, Faculty of Philosophy, Comenius University, Gondova 2, Bratislava 81801, Slovakia Accepted 27 August 2004
Abstract Altered stress responsiveness has been repeatedly related to mood and anxiety disorders. In a traditional view, a reduction of the stress response has been thought favorable. The goal of the present study was to verify the hypothesis that high anxiety is accompanied by enhanced hormone release during stress. Healthy subjects at the upper (anxious, n=15) and lower (non-anxious, n=12) limits of the normal range of a trait anxiety scale (State trait anxiety inventory) were exposed to psychosocial stress procedure based on public speech. Hormone levels, cardiovascular activation and skin conductance were measured. Exposure to psychosocial stress was associated with significant increases of all parameters measured. During the stress procedure, subjects with high trait anxiety exhibited lower levels of hormones of the hypothalamo–pituitary–adrenocortical axis, namely ACTH and cortisol in plasma, as well as cortisol in saliva. Similarly, the stress-induced activation of epinephrine, norepinephrine and prolactin secretion was significantly lower in anxious subjects in comparison with that in nonanxious subjects. Thus, in contrast to the traditional view, high anxiousness was not associated with exaggerated stress response. Our findings suggest that high trait anxiety may be associated with an inability to respond with adequate hormone release to acute stress stimuli. D 2004 Elsevier Inc. All rights reserved. Keywords: Anxiety; Mental stress; Hormones; Skin conductance
1. Introduction In addition to activation of several hormonal systems, stress response includes alterations in the level of anxiety, as well as some loss of cognitive and affective flexibility (Gold and Chrousos, 2002; Tafet and Bernardini, 2003). Stress is considered to play a significant role in the development of mood and anxiety disorders, but the relationship of hormonal and cardiovascular responses during stress in humans to subsequent health consequences is poorly
Abbreviations: ACTH, adrenocorticotropic hormone; ANOVA, analysis of variance; EDTA, ethylenediaminetetraacetic acid; HPA, hypothalamic– pituitary–adrenocortical; IRMA, immunoradiometric assay; RIA, radioimmunoassay; STAI-T, state and trait anxiety inventory-trait. * Corresponding author. Tel.: +421 2 54773800; fax: +421 2 54774247. E-mail address: [email protected] (D. Jezova). 0278-5846/$ - see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2004.08.005
understood. In a traditional view, the hypersecretion of stress hormones, such as cortisol and catecholamines, are thought to be harmful and anxiolytic drugs have been used to attenuate the neuroendocrine response to stressors (Carrasco and Van De Kar, 2003; de Kloet, 2003). In this respect, enhanced hormonal responses during stress would be expected in patients with anxiety disorders. However, investigations performed so far have provided conflicting results. Unchanged (Grunhaus et al., 1983; Levin et al., 1993; Martel et al., 1999; Dorn et al., 2003) or enhanced (Leyton et al., 1996; Gerra et al., 2000; Condren et al., 2002) levels of selected hormones during stressful tasks in patients with general anxiety disorder, social phobia or panic disorder were reported. Moreover, studies performed in depressive patients exposed to stressors indicate reduced rather than enhanced responses to stressors (Grof et al., 1982; Lopez et al., 1987; Kathol et al., 1992; Gotthardt et al., 1995; Young et al., 2000).
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Inconsistent information is available also on the relationship between trait anxiety or other personality variables and stress reactivity in healthy subjects, although the individual variability in stress responses is known to be high (Kirschbaum et al., 1995; Negrao et al., 2000). Zorrilla et al. (1995) have predicted that hardiness and self-esteem as proposed buffers against depressive symptoms would be negatively associated with basal levels of hormones of the hypothalamic–pituitary–adrenocortical (HPA) axis. Unexpectedly, the results of their investigation showed the opposite, namely higher basal levels of cortisol in subjects that had affectively stable personalities including a low trait anxiety level. These authors have introduced a hypothesis that individuals with affectively stable personalities have higher basal cortisol level which result in reduced stress-responsiveness, thereby protecting them from the mood disrupting effects of a stressinduced glucocorticoid increase. The goal of the present study was to verify the hypothesis that high anxiety is accompanied by high stress responses, namely in selected groups of healthy subjects at the upper (anxious) and lower (non-anxious) limits of the normal range of the trait scale in the Spielberger State and Trait Anxiety Inventory (STAI-T). As previous studies were mainly concentrated on hormones of the HPA axis, a broader spectrum of stress hormones, skin conductance and cardiovascular activation during a psychosocial stress were investigated.
Declaration of Helsinki. The protocol was approved by the Ethical Committee of the Slovak Academy of Sciences, Bratislava, Slovakia. 2.2. Study design
2. Methods
Following initial screening and examination, 12 low anxiety and 15 high anxiety subjects participated in the trial. The stress procedure was based on a modified version (Makatsori et al., 2004) of Trier Social Stress Test (Kirschbaum et al., 1993). The tests were performed in the early afternoon. The subjects were asked to abstain from eating at least 3 h prior of the experiment. After the subject was seated and a catheter was inserted into the cubital vein, the subject was asked to complete psychological questionnaires. Half an hour after venipuncture, measurements and blood samples for basal values were taken and the stress procedure was started. The stress test consisted of 15 min of preparation, when the subject was asked to prepare a speech on an emotionally charged topic, followed by the speech for 15 min. During the speech, the subject was standing on a small stand and illuminated by bright light. The performance was recorded by a video camera and observed by a jury of four to five members. Measurements and blood samples for stress and poststress values were taken at the end of the preparation and speech periods, and 15, 30 and 90 min after the speech. Skin conductance was recorded during the three 15min periods (preparation, speech, postspeech). During the time periods after speech, subjects remained in a sitting position completing questionnaires and reading magazines.
2.1. Subjects
2.3. Measurements
Healthy male volunteers in the age of 20–40 years participated in the study. Subjects have been selected according to their score in STAI-T questionnaire and only subjects with high (score N45) or low anxiety (score b39) were included. This selection was based on the distribution of trait anxiety levels in the Slovak population. Their mental and physical health were determined by a psychiatric interview, medical history and vital signs (systolic and diastolic blood pressure, heart rate). Subjects were excluded from the study if they were suffering from any somatic or mental diseases, had family history of psychiatric disorders, had the BMI higher than 28, had control blood pressure higher than 140/90 mm Hg or were taking any medication. The subjects in the two groups were age, height, body weight and BMI matched (Table 1). The subjects gave written informed consent to participate. The study was performed in accordance with the
Measurements of blood pressure and heart rate were performed by an automatic blood pressure measuring device (Dinamap, Criticon). Skin conductance was recorded by a galvanic skin response amplifier connected to a PowerLab 4/20 data recorder (ADInstruments). For all three recording periods, the mean frequency of skin conductance responses higher than 0.05 AS was calculated (Wilken et al., 2000). Blood was collected into two polyethylene tubes using heparin (catecholamines) or EDTA (ACTH, cortisol, prolactin) as anticoagulants. After centrifugation at 4 8C, aliquots of plasma were stored frozen at 20 8C until analyzed. Commercial kits were used for IRMA of ACTH (EuroDiagnostica, The Netherlands) and for RIA of prolactin (CIS bio International, France) and of testosterone (Immunotech, France). Plasma catecholamines were analyzed by the radioenzymatic method (Peuler and Johnson, 1977). Plasma cortisol was analyzed by RIA as described previously (Jezova and Vigas, 1988). Saliva samples were collected in sterile salivettes (Sarstedt, UK), which were capped and frozen at 20 8C until analysis. Salivary cortisol concentrations were measured by RIA as it was described previously (Jezova et al., 2002).
Table 1 Characteristics of subjects Non-anxious Anxious
Age
Weight
Height
BMI
25.6F1.3 27.1F2
78F3.5 76.8F2.7
178.8F1.5 179.7F2.2
24.4F1 23.7F0.6
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Evaluation of nonverbal behavior during speech was based on ethological analysis of selected behavioral patterns (Troisi, 1999). The evaluation was made from the videorecorded speech. 2.4. Statistics Group values are presented as meansFS.E.M. Statistical analysis of psychological parameters was performed by a one-way ANOVA. Cardiovascular and hormonal responses during stress were analyzed by two-way ANOVA with time and group as factors. ANOVA was followed by post hoc Tukey test for pairwise comparisons, when appropriate. The overall level of statistical significance was defined as pb0.05.
3. Results As expected, the anxious and nonanxious groups differed in state ( F=14.5; pb0.001) as well as trait anxiety ( F=32.8; pb0.001). During the stress procedure, both groups showed an increase in state anxiety, which tended to be higher in anxious subjects (Fig. 1). Ethological analysis revealed that during the speech, the most frequent behavioral patterns were the patterns included in the category flight behavior (data not shown). No significant differences between the groups were observed in basal levels of the parameters measured. Stress exposure increased heart rate (time: F=4.8; pb0.001). This increase was significantly enhanced (group: F=7.1; p=0.009) in anxious subjects (Fig. 2). The stress related increase in systolic (time: F=6.9; pb0.001) and diastolic (time: F=5.2; pb0.001) blood pressure was similar in both groups (data not shown). On the other hand, the stressinduced release of epinephrine (time: F=6.3; pb0.001; group: F=6.7; p=0.011) and norepinephrine (time: F=2.3; p=0.045; group: F=5.4; p=0.021) was significantly attenuated in anxious subjects (Fig. 2).
Fig. 2. Changes in heart rate and epinephrine and norepinephrine concentrations in plasma during the stress procedure in non-anxious and anxious groups. Statistical significance as revealed by two-way ANOVA for factors time and group.
Fig. 1. State and trait anxiety levels at the start of the study and changes in state anxiety during the stress procedure. Statistical significance: *pb0.05 as compared to the non/anxious group.
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The stress procedure induced a significant rise in HPA axis activity reflected by ACTH (time: F=3.190; p=0.009) and cortisol concentrations in plasma (time: F=4.1; p=0.002) and cortisol concentrations in saliva (time: F=2.7; p=0.024). In anxious subjects, the levels of ACTH (group: F=11.5; pb0.001) as well as plasma (group: F=7.9; p=0.005) and salivary cortisol (group: F=6.9; p=0.009) were significantly lower in comparison to non-anxious group (Fig. 3). Similarly, anxious subjects had significantly lower concentrations of prolactin in plasma (time: F=5.6; pb0.001; group: F=8.8; p=0.004) during the stress procedure, while plasma testosterone levels remained unchanged.
Fig. 3. Changes in ACTH and corticosterone concentrations in plasma, as well as corticosterone concentrations in saliva during the stress procedure in non-anxious and anxious groups. Statistical significance as revealed by two-way ANOVA for factors time and group.
The increase in frequency of galvanic skin responses tended to be blunted in anxious subjects (data not shown).
4. Discussion The presented results show that subjects with high trait anxiety exhibit decreased rather than increased neuroendocrine activation during a psychosocial stress procedure in comparison with that in individuals with low trait anxiety levels. Higher plasma and salivary cortisol levels in subjects with low trait anxiety as observed in this investigation are consistent with the finding of higher cortisol levels in individuals with high affective stability reported by Zorrilla et al. (1995) but does not support their hypothesis of reduced stress-responsiveness of stable personalities. Actually, the present data indicate an opposite phenomenon, namely reduced responses during psychosocial stress in subjects with high trait anxiety. This applies not only to the hormones of the HPA axis, but also to epinephrine, norepinephrine and prolactin levels, as well as the frequency of galvanic skin responses. These data are opposite to general expectations; however, some supportive data do exist. Cortisol levels were found to be lower in highsymptom subjects compared to those in the low-symptom group during a laboratory session with exposure to stressful films (Vingerhoets et al., 1996). In a recent study in scuba divers, Anegg et al. (2002) have observed that facing a stressful situation subjects with more emotional concern and negative stress coping strategies showed bblunted responsesQ as demonstrated by significantly lower elevations in prolactin levels compared to those in subjects with the very opposite psychological features. These authors did not find any differences in cortisol or catecholamine responses; nevertheless, they conclude that the intensity of physiological responses during stress seems to be higher in stress controllers than in persons with a higher level of anxiety. Consistently, lower electrodermal responses to stressful stimuli were observed in subjects with high trait anxiety (Wilken et al., 2000). So far, the attempts to correlate personality traits were focused mainly on cortisol release. Based on a cluster analysis, Kirschbaum et al. (1995) divided their subjects into low and high cortisol responders, which showed different response kinetics to repeated psychological stress. The psychological profile of high cortisol responders included the occurrence of depressive mood and low self-esteem. More recently, the same group of authors investigated a large sample of subjects with no evidence for a close relationship between personality traits and circadian cortisol rhythm or a single cortisol stress response (Schommer et al., 1999). Others also reported no relationship between trait anxiety and cortisol responses during mental stress (Bohnen et al., 1991). The different results obtained in the present study are likely to be due to
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the fact that the subjects with trait anxiety scores in the middle of the normal range, which represent the majority of the healthy population, were excluded from the investigation. We suggest that individuals with high trait anxiety and affective lability have a different regulation of stress hormone release than those with very low anxiety level. Indeed, our preliminary data on the correlations between psychological characteristics and hormonal responses during psychosocial stress support this suggestion (Duncko et al., unpublished data). It is conceivable that the differences in hormonal responses observed in the present study could be masked if the sample included the majority of subjects with middle range anxiety levels, as it was apparently the case in previous reports. A reduced responsiveness to a stress stimulus may be the result of an inability to respond with an adequate hormone release or of a decreased perception of the stimulus. Concerning the present results, the latter option does not seem to be the case, as the state anxiety following stress exposure was not reduced but tended to be higher in anxious subjects. Accordingly, blood pressure responses during psychosocial stress were similar in both groups of subjects and the rise in the heart rate was enhanced in probands with high trait anxiety. Similar results have been described by others (Koo-Loeb et al., 2000). Recently, Junghanns et al. (2003) reported that an impaired cortisol response to a psychosocial stress test was a predictor of early relapse in abstaining alcohol-dependent males, partly with a comorbid anxiety disorder. We suggest that subjects with high trait anxiety may not be able to produce bnormalQ, adequate neuroendocrine response to certain stress stimuli, which might be associated with a negative outcome. However, we have observed higher hormone levels throughout the whole procedure rather than differences in the magnitude of hormone increases above the basal value. It has recently been shown that repeated antidepressant treatment in healthy men does not inhibit but actually enhances neuroendocrine activation during stress of hypoglycemia (Jezova and Duncko, 2002). Such effects were observed following treatment with antidepressants having an opposite action on brain serotonin, namely tianeptine and citalopram. It is in support of the hypothesis that the clinical effect of antidepressants might be partly due to the adjustment of the stress response, which was reported to be blunted in depressive patients.
5. Conclusion In conclusion, the main finding of the present study was that subjects with high trait anxiety exhibited lower hormone release during psychosocial stress than did subjects with low trait anxiety. It is suggested that high trait anxiety may be associated with an inability to respond with adequate hormone release to acute stress stimuli.
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Acknowledgements We wish to express our thanks for kind help to M. Laniova, A. Zemankova and L. Zilava, as well as to other colleagues for support and consultations. The study was supported by a Centre of Excellence project of European Comission (ICA1-CT-2000-70008) and a grant of VEGA 2/ 2007.
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Negrao, A.B., Deuster, P.A., Gold, P.W., Singh, A., Chrousos, G.P., 2000. Individual reactivity and physiology of the stress response. Biomed. Pharmacother. 54, 122 – 128. Peuler, J.D., Johnson, G.A., 1977. Simultaneous single isotope radioenzymatic assay of plasma norepinephrine, epinephrine and dopamine. Life Sci. 21, 625 – 636. Schommer, N.C., Kudielka, B.M., Hellhammer, D.H., Kirschbaum, C., 1999. No evidence for a close relationship between personality traits and circadian cortisol rhythm or a single cortisol stress response. Psychol. Rep. 84, 840 – 842. Tafet, G.E., Bernardini, R., 2003. Psychoneuroendocrinological links between chronic stress and depression. Prog. Neuro-psychopharmacol. Biol. Psychiatry 27, 893 – 903. Troisi, A., 1999. Ethological research in clinical psychiatry: the study of nonverbal behavior during interviews. Neurosci. Biobehav. Rev. 23, 905 – 913. Vingerhoets, A.J., Ratliff-Crain, J., Jabaaij, L., Tilders, F.J., Moleman, P., Menges, L.J., 1996. Self-reported stressors, symptom complaints and psychobiological functioning: II. Psychoneuroendocrine variables. J. Psychosom. Res. 40, 191 – 203. Wilken, J.A., Smith, B.D., Tola, K., Mann, M., 2000. Trait anxiety and prior exposure to non-stressful stimuli: effects on psychophysiological arousal and anxiety. Int. J. Psychophysiol. 37, 233 – 242. Young, E.A., Lopez, J.F., Murphy-Weinberg, V., Watson, S.J., Akil, H., 2000. Hormonal evidence for altered responsiveness to social stress in major depression. Neuropsychopharmacology 23, 411 – 418. Zorrilla, E.P., DeRubeis, R.J., Redei, E., 1995. High self-esteem, hardiness and affective stability are associated with higher basal pituitary–adrenal hormone levels. Psychoneuroendocrinology 20, 591 – 601.
High trait anxiety in healthy subjects is associated with low neuroendocrine activity during psychosocial stress Daniela Jezovaa,*, Aikaterini Makatsoria, Roman Dunckoa, Fedor Monceka, Martin Jakubekb a
Laboratory of Pharmacological Neuroendocrinology, Institute of Experimental Endocrinology, Slovak Academy of Sciences, Vlarska 3, Bratislava 83306, Slovakia b Department of Psychology, Faculty of Philosophy, Comenius University, Gondova 2, Bratislava 81801, Slovakia Accepted 27 August 2004
Abstract Altered stress responsiveness has been repeatedly related to mood and anxiety disorders. In a traditional view, a reduction of the stress response has been thought favorable. The goal of the present study was to verify the hypothesis that high anxiety is accompanied by enhanced hormone release during stress. Healthy subjects at the upper (anxious, n=15) and lower (non-anxious, n=12) limits of the normal range of a trait anxiety scale (State trait anxiety inventory) were exposed to psychosocial stress procedure based on public speech. Hormone levels, cardiovascular activation and skin conductance were measured. Exposure to psychosocial stress was associated with significant increases of all parameters measured. During the stress procedure, subjects with high trait anxiety exhibited lower levels of hormones of the hypothalamo–pituitary–adrenocortical axis, namely ACTH and cortisol in plasma, as well as cortisol in saliva. Similarly, the stress-induced activation of epinephrine, norepinephrine and prolactin secretion was significantly lower in anxious subjects in comparison with that in nonanxious subjects. Thus, in contrast to the traditional view, high anxiousness was not associated with exaggerated stress response. Our findings suggest that high trait anxiety may be associated with an inability to respond with adequate hormone release to acute stress stimuli. D 2004 Elsevier Inc. All rights reserved. Keywords: Anxiety; Mental stress; Hormones; Skin conductance
1. Introduction In addition to activation of several hormonal systems, stress response includes alterations in the level of anxiety, as well as some loss of cognitive and affective flexibility (Gold and Chrousos, 2002; Tafet and Bernardini, 2003). Stress is considered to play a significant role in the development of mood and anxiety disorders, but the relationship of hormonal and cardiovascular responses during stress in humans to subsequent health consequences is poorly
Abbreviations: ACTH, adrenocorticotropic hormone; ANOVA, analysis of variance; EDTA, ethylenediaminetetraacetic acid; HPA, hypothalamic– pituitary–adrenocortical; IRMA, immunoradiometric assay; RIA, radioimmunoassay; STAI-T, state and trait anxiety inventory-trait. * Corresponding author. Tel.: +421 2 54773800; fax: +421 2 54774247. E-mail address: [email protected] (D. Jezova). 0278-5846/$ - see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2004.08.005
understood. In a traditional view, the hypersecretion of stress hormones, such as cortisol and catecholamines, are thought to be harmful and anxiolytic drugs have been used to attenuate the neuroendocrine response to stressors (Carrasco and Van De Kar, 2003; de Kloet, 2003). In this respect, enhanced hormonal responses during stress would be expected in patients with anxiety disorders. However, investigations performed so far have provided conflicting results. Unchanged (Grunhaus et al., 1983; Levin et al., 1993; Martel et al., 1999; Dorn et al., 2003) or enhanced (Leyton et al., 1996; Gerra et al., 2000; Condren et al., 2002) levels of selected hormones during stressful tasks in patients with general anxiety disorder, social phobia or panic disorder were reported. Moreover, studies performed in depressive patients exposed to stressors indicate reduced rather than enhanced responses to stressors (Grof et al., 1982; Lopez et al., 1987; Kathol et al., 1992; Gotthardt et al., 1995; Young et al., 2000).
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Inconsistent information is available also on the relationship between trait anxiety or other personality variables and stress reactivity in healthy subjects, although the individual variability in stress responses is known to be high (Kirschbaum et al., 1995; Negrao et al., 2000). Zorrilla et al. (1995) have predicted that hardiness and self-esteem as proposed buffers against depressive symptoms would be negatively associated with basal levels of hormones of the hypothalamic–pituitary–adrenocortical (HPA) axis. Unexpectedly, the results of their investigation showed the opposite, namely higher basal levels of cortisol in subjects that had affectively stable personalities including a low trait anxiety level. These authors have introduced a hypothesis that individuals with affectively stable personalities have higher basal cortisol level which result in reduced stress-responsiveness, thereby protecting them from the mood disrupting effects of a stressinduced glucocorticoid increase. The goal of the present study was to verify the hypothesis that high anxiety is accompanied by high stress responses, namely in selected groups of healthy subjects at the upper (anxious) and lower (non-anxious) limits of the normal range of the trait scale in the Spielberger State and Trait Anxiety Inventory (STAI-T). As previous studies were mainly concentrated on hormones of the HPA axis, a broader spectrum of stress hormones, skin conductance and cardiovascular activation during a psychosocial stress were investigated.
Declaration of Helsinki. The protocol was approved by the Ethical Committee of the Slovak Academy of Sciences, Bratislava, Slovakia. 2.2. Study design
2. Methods
Following initial screening and examination, 12 low anxiety and 15 high anxiety subjects participated in the trial. The stress procedure was based on a modified version (Makatsori et al., 2004) of Trier Social Stress Test (Kirschbaum et al., 1993). The tests were performed in the early afternoon. The subjects were asked to abstain from eating at least 3 h prior of the experiment. After the subject was seated and a catheter was inserted into the cubital vein, the subject was asked to complete psychological questionnaires. Half an hour after venipuncture, measurements and blood samples for basal values were taken and the stress procedure was started. The stress test consisted of 15 min of preparation, when the subject was asked to prepare a speech on an emotionally charged topic, followed by the speech for 15 min. During the speech, the subject was standing on a small stand and illuminated by bright light. The performance was recorded by a video camera and observed by a jury of four to five members. Measurements and blood samples for stress and poststress values were taken at the end of the preparation and speech periods, and 15, 30 and 90 min after the speech. Skin conductance was recorded during the three 15min periods (preparation, speech, postspeech). During the time periods after speech, subjects remained in a sitting position completing questionnaires and reading magazines.
2.1. Subjects
2.3. Measurements
Healthy male volunteers in the age of 20–40 years participated in the study. Subjects have been selected according to their score in STAI-T questionnaire and only subjects with high (score N45) or low anxiety (score b39) were included. This selection was based on the distribution of trait anxiety levels in the Slovak population. Their mental and physical health were determined by a psychiatric interview, medical history and vital signs (systolic and diastolic blood pressure, heart rate). Subjects were excluded from the study if they were suffering from any somatic or mental diseases, had family history of psychiatric disorders, had the BMI higher than 28, had control blood pressure higher than 140/90 mm Hg or were taking any medication. The subjects in the two groups were age, height, body weight and BMI matched (Table 1). The subjects gave written informed consent to participate. The study was performed in accordance with the
Measurements of blood pressure and heart rate were performed by an automatic blood pressure measuring device (Dinamap, Criticon). Skin conductance was recorded by a galvanic skin response amplifier connected to a PowerLab 4/20 data recorder (ADInstruments). For all three recording periods, the mean frequency of skin conductance responses higher than 0.05 AS was calculated (Wilken et al., 2000). Blood was collected into two polyethylene tubes using heparin (catecholamines) or EDTA (ACTH, cortisol, prolactin) as anticoagulants. After centrifugation at 4 8C, aliquots of plasma were stored frozen at 20 8C until analyzed. Commercial kits were used for IRMA of ACTH (EuroDiagnostica, The Netherlands) and for RIA of prolactin (CIS bio International, France) and of testosterone (Immunotech, France). Plasma catecholamines were analyzed by the radioenzymatic method (Peuler and Johnson, 1977). Plasma cortisol was analyzed by RIA as described previously (Jezova and Vigas, 1988). Saliva samples were collected in sterile salivettes (Sarstedt, UK), which were capped and frozen at 20 8C until analysis. Salivary cortisol concentrations were measured by RIA as it was described previously (Jezova et al., 2002).
Table 1 Characteristics of subjects Non-anxious Anxious
Age
Weight
Height
BMI
25.6F1.3 27.1F2
78F3.5 76.8F2.7
178.8F1.5 179.7F2.2
24.4F1 23.7F0.6
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Evaluation of nonverbal behavior during speech was based on ethological analysis of selected behavioral patterns (Troisi, 1999). The evaluation was made from the videorecorded speech. 2.4. Statistics Group values are presented as meansFS.E.M. Statistical analysis of psychological parameters was performed by a one-way ANOVA. Cardiovascular and hormonal responses during stress were analyzed by two-way ANOVA with time and group as factors. ANOVA was followed by post hoc Tukey test for pairwise comparisons, when appropriate. The overall level of statistical significance was defined as pb0.05.
3. Results As expected, the anxious and nonanxious groups differed in state ( F=14.5; pb0.001) as well as trait anxiety ( F=32.8; pb0.001). During the stress procedure, both groups showed an increase in state anxiety, which tended to be higher in anxious subjects (Fig. 1). Ethological analysis revealed that during the speech, the most frequent behavioral patterns were the patterns included in the category flight behavior (data not shown). No significant differences between the groups were observed in basal levels of the parameters measured. Stress exposure increased heart rate (time: F=4.8; pb0.001). This increase was significantly enhanced (group: F=7.1; p=0.009) in anxious subjects (Fig. 2). The stress related increase in systolic (time: F=6.9; pb0.001) and diastolic (time: F=5.2; pb0.001) blood pressure was similar in both groups (data not shown). On the other hand, the stressinduced release of epinephrine (time: F=6.3; pb0.001; group: F=6.7; p=0.011) and norepinephrine (time: F=2.3; p=0.045; group: F=5.4; p=0.021) was significantly attenuated in anxious subjects (Fig. 2).
Fig. 2. Changes in heart rate and epinephrine and norepinephrine concentrations in plasma during the stress procedure in non-anxious and anxious groups. Statistical significance as revealed by two-way ANOVA for factors time and group.
Fig. 1. State and trait anxiety levels at the start of the study and changes in state anxiety during the stress procedure. Statistical significance: *pb0.05 as compared to the non/anxious group.
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The stress procedure induced a significant rise in HPA axis activity reflected by ACTH (time: F=3.190; p=0.009) and cortisol concentrations in plasma (time: F=4.1; p=0.002) and cortisol concentrations in saliva (time: F=2.7; p=0.024). In anxious subjects, the levels of ACTH (group: F=11.5; pb0.001) as well as plasma (group: F=7.9; p=0.005) and salivary cortisol (group: F=6.9; p=0.009) were significantly lower in comparison to non-anxious group (Fig. 3). Similarly, anxious subjects had significantly lower concentrations of prolactin in plasma (time: F=5.6; pb0.001; group: F=8.8; p=0.004) during the stress procedure, while plasma testosterone levels remained unchanged.
Fig. 3. Changes in ACTH and corticosterone concentrations in plasma, as well as corticosterone concentrations in saliva during the stress procedure in non-anxious and anxious groups. Statistical significance as revealed by two-way ANOVA for factors time and group.
The increase in frequency of galvanic skin responses tended to be blunted in anxious subjects (data not shown).
4. Discussion The presented results show that subjects with high trait anxiety exhibit decreased rather than increased neuroendocrine activation during a psychosocial stress procedure in comparison with that in individuals with low trait anxiety levels. Higher plasma and salivary cortisol levels in subjects with low trait anxiety as observed in this investigation are consistent with the finding of higher cortisol levels in individuals with high affective stability reported by Zorrilla et al. (1995) but does not support their hypothesis of reduced stress-responsiveness of stable personalities. Actually, the present data indicate an opposite phenomenon, namely reduced responses during psychosocial stress in subjects with high trait anxiety. This applies not only to the hormones of the HPA axis, but also to epinephrine, norepinephrine and prolactin levels, as well as the frequency of galvanic skin responses. These data are opposite to general expectations; however, some supportive data do exist. Cortisol levels were found to be lower in highsymptom subjects compared to those in the low-symptom group during a laboratory session with exposure to stressful films (Vingerhoets et al., 1996). In a recent study in scuba divers, Anegg et al. (2002) have observed that facing a stressful situation subjects with more emotional concern and negative stress coping strategies showed bblunted responsesQ as demonstrated by significantly lower elevations in prolactin levels compared to those in subjects with the very opposite psychological features. These authors did not find any differences in cortisol or catecholamine responses; nevertheless, they conclude that the intensity of physiological responses during stress seems to be higher in stress controllers than in persons with a higher level of anxiety. Consistently, lower electrodermal responses to stressful stimuli were observed in subjects with high trait anxiety (Wilken et al., 2000). So far, the attempts to correlate personality traits were focused mainly on cortisol release. Based on a cluster analysis, Kirschbaum et al. (1995) divided their subjects into low and high cortisol responders, which showed different response kinetics to repeated psychological stress. The psychological profile of high cortisol responders included the occurrence of depressive mood and low self-esteem. More recently, the same group of authors investigated a large sample of subjects with no evidence for a close relationship between personality traits and circadian cortisol rhythm or a single cortisol stress response (Schommer et al., 1999). Others also reported no relationship between trait anxiety and cortisol responses during mental stress (Bohnen et al., 1991). The different results obtained in the present study are likely to be due to
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the fact that the subjects with trait anxiety scores in the middle of the normal range, which represent the majority of the healthy population, were excluded from the investigation. We suggest that individuals with high trait anxiety and affective lability have a different regulation of stress hormone release than those with very low anxiety level. Indeed, our preliminary data on the correlations between psychological characteristics and hormonal responses during psychosocial stress support this suggestion (Duncko et al., unpublished data). It is conceivable that the differences in hormonal responses observed in the present study could be masked if the sample included the majority of subjects with middle range anxiety levels, as it was apparently the case in previous reports. A reduced responsiveness to a stress stimulus may be the result of an inability to respond with an adequate hormone release or of a decreased perception of the stimulus. Concerning the present results, the latter option does not seem to be the case, as the state anxiety following stress exposure was not reduced but tended to be higher in anxious subjects. Accordingly, blood pressure responses during psychosocial stress were similar in both groups of subjects and the rise in the heart rate was enhanced in probands with high trait anxiety. Similar results have been described by others (Koo-Loeb et al., 2000). Recently, Junghanns et al. (2003) reported that an impaired cortisol response to a psychosocial stress test was a predictor of early relapse in abstaining alcohol-dependent males, partly with a comorbid anxiety disorder. We suggest that subjects with high trait anxiety may not be able to produce bnormalQ, adequate neuroendocrine response to certain stress stimuli, which might be associated with a negative outcome. However, we have observed higher hormone levels throughout the whole procedure rather than differences in the magnitude of hormone increases above the basal value. It has recently been shown that repeated antidepressant treatment in healthy men does not inhibit but actually enhances neuroendocrine activation during stress of hypoglycemia (Jezova and Duncko, 2002). Such effects were observed following treatment with antidepressants having an opposite action on brain serotonin, namely tianeptine and citalopram. It is in support of the hypothesis that the clinical effect of antidepressants might be partly due to the adjustment of the stress response, which was reported to be blunted in depressive patients.
5. Conclusion In conclusion, the main finding of the present study was that subjects with high trait anxiety exhibited lower hormone release during psychosocial stress than did subjects with low trait anxiety. It is suggested that high trait anxiety may be associated with an inability to respond with adequate hormone release to acute stress stimuli.
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Acknowledgements We wish to express our thanks for kind help to M. Laniova, A. Zemankova and L. Zilava, as well as to other colleagues for support and consultations. The study was supported by a Centre of Excellence project of European Comission (ICA1-CT-2000-70008) and a grant of VEGA 2/ 2007.
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