Blunted salivary and plasma cortisol response in patients with panic disorder under psychosocial stress

INTPSY-10585; No of Pages 5 International Journal of Psychophysiology xxx (2013) xxx–xxx

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Katja Petrowski a,⁎, Gloria-Beatrice Wintermann a, Marco Schaarschmidt a, Stefan R. Bornstein a, Clemens Kirschbaum b a b

Dept. of Psychotherapy and Psychosomatic Medicine, University Hospital Carl Gustav Carus Dresden, Technische Universität Dresden, Fetscherstr. 74, 01307 Dresden, Germany Department of Psychology, Technische Universität Dresden, Germany

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Background: Panic disorder (PD) has been associated with an altered activity of the hypothalamic–pituitary– adrenal–cortical (HPA) axis. Recent findings from a patient sample with PD with secondary depression on psychotropic medication using salivary cortisol as outcome measure suggest a non-responsiveness of the HPA-axis under acute psychosocial stress. Salivary cortisol does not necessarily reflect the total plasma cortisol due to interfering variables. Whether the present findings can be replicated on a patient sample with pure PD using both salivary cortisol and total plasma cortisol as outcome variables remains to be elucidated. Methods: For this study, the Trier Social Stress Test (TSST) was implemented to assess the HPA-axis reactivity indicated by the plasma adreno-corticotropin-hormone (ACTH), plasma cortisol, and salivary cortisol release. The sample included 32 patients diagnosed with PD in a Structured Clinical Interview (SCID). Twelve male and fifteen female patients [mean age = 32.87 years, SD = 11.23] were matched with 32 healthy controls by age and gender. Results: The plasma ACTH, total plasma cortisol and salivary cortisol release increased significantly in both groups due to the psychosocial stress test. The patients with PD showed a decreased plasma and salivary cortisol response as compared to the healthy controls. Plasma cortisol and salivary cortisol were highly correlated in both groups. Conclusion: These findings provide strong evidence for a hypo-responsiveness of the HPA-axis as measured in both blood and saliva. Salivary and total plasma cortisol showed a strong concordance of results. Thus, future investigations could consider salivary cortisol as reliable marker of the HPA-axis under psychosocial stress. © 2013 Published by Elsevier B.V.

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Article history: Received 15 November 2012 Received in revised form 29 December 2012 Accepted 2 January 2013 Available online xxxx

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Keywords: Panic disorder Trier Social Stress Test TSST Hypothalamic–pituitary–adrenal–cortical (HPA)-axis Plasma cortisol Plasma ACTH Salivary cortisol

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Blunted salivary and plasma cortisol response in patients with panic disorder under psychosocial stress

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1. Introduction

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Panic disorder (PD) is a common disorder with a large number of hospital admissions (Roy-Byrne et al., 2000), significant economic costs for society (Greenberg et al., 1999), and increased mortality (Albert et al., 2005; Smoller et al., 2007). Since the empirical results are not conclusive, the exact pathophysiological mechanism underlying PD is of major interest (van Duinen et al., 2007; Revest et al., 2009). Considerable research efforts have associated PD with an abnormal functioning of the hypothalamic–pituitary–adrenal–cortical (HPA)

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Abbreviations: AUCg, area under the curve ground; ACTH, adreno-corticotropinhormone; ANCOVA, analysis of covariance; ANOVA, analysis of variance; CRH, corticotropin-releasing hormone; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders; HPA-axis, hypothalamic–pituitary–adrenal–cortical-axis; PAS, Panic and Agoraphobia-Scale; PD, Panic disorder; SCID, Structured Clinical Interview for DSM-IV; SPSS, Statistical Package for Social Sciences; STAI, State-Trait-Anxiety-Inventory; TSST, Trier Social Stress Test; VAS, Visual analog scale. ⁎ Corresponding author. Tel.: +49 351 4583634; fax: +49 351 2636268. E-mail address: [email protected] (K. Petrowski).

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system (Heuser et al., 1994; Schreiber et al., 1996; Erhardt et al., 2006; Petrowski et al., 2010, 2012). Abelson et al. (2007) demonstrated that PD is characterized by an enhanced sensitivity of HPA-axis to novel, threatening and uncontrollable situations (Abelson et al., 2007). One way to induce novelty, threat and uncontrollability under standardized laboratory conditions is the implementation of a psychosocial stress test: the Trier Social Stress Test (TSST; Kirschbaum et al., 1993). Using the TSST patients with PD showed an abnormal non-responsiveness of the HPA-axis with a reduced salivary cortisol response (Petrowski et al., 2010) which is in contrast to the previously published results with different psychological stressors (Leyton et al., 1996; Hoehn et al., 1997; Garcia-Leal et al., 2005). Therefore, the non-responsiveness after the TSST remains to be elucidated further as the patients included were under antidepressant drugs or had psychiatric comorbidities such as major depression. Moreover, only salivary cortisol was used as measurement method (Petrowski et al., 2010). Recent findings showed that absolute levels of cortisol in the saliva are significantly lower than in the blood due to differences in the availability of the corticosteroid binding globulines (CBG) in the blood (Kirschbaum and Hellhammer, 2007; Levine et al., 2007; Henley and Lightman, 2011). Even though the

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Please cite this article as: Petrowski, K., et al., Blunted salivary and plasma cortisol response in patients with panic disorder under psychosocial stress, International Journal of Psychophysiology (2013), http://dx.doi.org/10.1016/j.ijpsycho.2013.01.002

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2. Materials and methods

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2.1. Study participants

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Patients with panic disorder were recruited from May 2008 to November 2011 at the anxiety outpatient unit of the University Hospital of the Technische Universität Dresden, Germany. All patients that fit the inclusion criteria were consecutively included and tested as part of the diagnostic procedure. The Structured Clinical Interview (SCID, Spitzer et al., 1990; Wittchen et al., 1990) of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) was used to diagnose the current primary diagnosis of panic disorder with or without agoraphobia (APA, 2004), respectively. Diagnostic exclusion criteria were: any other mental disorder according to the SCID, personality disorder and any acute and/or chronic medical illness (e.g. endocrinological, cardiological, chronically-inflammable diseases) as assessed by a physical examination and routine laboratory tests. In order to avoid a significant selection bias in the recruitment of patients, habitual cigarette smoking and the use of oral contraceptives were accepted. Patients with panic disorder under psychotropic drug treatment were not included as it may have evoked an influence on the HPA-axis. Patients with panic disorder were matched in age and gender with healthy control subjects. A total of 39 patients were approached. In all, n = 7 patients had to be excluded due to the following reasons: more than one missing value in the plasma cortisol sampling, a panic attack during testing or familiarity with the TSST. The sample for the analyses consisted of n = 32 patients with a primary diagnosis of PD. The mean age at the onset of panic disorder was 28.45 (SD = 10.39) years of age, and the mean duration of the panic disorder was 4.52 (SD = 6.44) years. According to the Panic and Agoraphobia-Scale (PAS) (Bandelow, 1997) seven patients showed a borderline severity of panic and agoraphobic symptoms, four patients showed a mild and n = 16 patients a moderate severity, five patients with PD showed a severe psychopathology on the Panic and Agoraphobia-Scale, respectively. Furthermore, n = 15 of the patients had shown a first manifestation of the symptomatology during the previous 1.5 years. The healthy controls (n=32) had been recruited through newspaper advertisements and were matched to the patient sample by age and gender. Both, healthy controls and patients were rewarded with 50 € expense allowance for their participation. The characteristics of the patients and the matched controls are provided in Table 1. Significant differences between the patients with PD and the healthy controls could

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The participants were scheduled individually for the TSST at 1400 h in order to minimize the circadian variations in the cortisol levels. The participants were asked to refrain from eating, drinking, and smoking for at least two hours before testing as well as during the two-and-a-half-hour testing session. The subjects were fitted a belt for continuous wireless transmission of heart rate signals (Polar S810, Polar, Finland) and rested in a comfortable, supine position with light reading permitted. Postural changes from sitting to standing and repeated sitting were necessary only for accomplishing the TSST and are not accompanied by major changes of ACTH or cortisol (Mlynarik et al., 2007). A venous catheter was placed at 1415 h to later collect eight consecutive blood samples each for analyzing ACTH and cortisol concentration, respectively. After an accommodation time of 45 min to control the influence of previously experienced stress on the baseline cortisol, two blood samples (− 15 min, − 1 min) were taken before the study participant was exposed to the TSST. After the completion of the TSST, six more blood samples (+1 min, +10 min, +20 min, +30 min, +45 min, +60 min) were collected at regular intervals. In total, eight plasma cortisol, eight plasma ACTH, and eight salivary cortisol samples were collected. All blood samples were taken in a supine body position. The psychosocial stress protocol mainly consists of a social-evaluative situation including a five-minute mock job interview and a subsequent five-minute mental arithmetic task in front of a two-person-panel. A detailed description and evaluation of the TSST was published by Kudielka and colleagues (Kudielka et al., 2007). Healthy controls and patients were tested in the same setting with identical procedures.

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2.3. ACTH and cortisol analysis

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be shown for the severity of the panic disorder on the PAS and the Trait-Anxiety (Table 1). All study participants provided written informed consent. The study protocol was approved by the local Ethics Committee of the Medical Faculty of the Technical University of Dresden, Germany (No. #EK7012006).

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salivary cortisol significantly correlates with total plasma cortisol under baseline condition in patients with PD (Wedekind et al., 2000) data considering both salivary and plasma cortisol under acute psychosocial stress in patients with PD are still lacking. Studies in healthy controls, showed that high trait anxiety is associated with a reduced salivary and plasma cortisol response under psychosocial stress (Jezova et al., 2004; Beaton et al., 2006). The lower plasma cortisol response was associated with exaggerated perception of stress (Duncko et al., 2006) and a higher emotional arousal after the TSST (Het et al., 2012). Therefore, the lacking salivary cortisol response following the TSST in patients with PD needs to be replicated based on total plasma cortisol in a sample of patients without secondary depression and without the use of psychotropic drugs (Petrowski et al., 2010). Based on the results on healthy individuals (Kirschbaum and Hellhammer, 2007; Levine et al., 2007; Henley and Lightman, 2011), we expect a highly significant correlation between salivary cortisol and total plasma cortisol in both healthy controls and patients with PD under acute psychosocial stress. Based on the results on anxious healthy individuals, we expect a blunted plasma cortisol response with a higher perception of stress and higher emotional arousal under the TSST.

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Analysis of plasma ACTH and cortisol was realized as already 175 described by Petrowski et al. (2012). 50 μl of saliva supernatant 176 of low viscosity was removed for the cortisol analysis using a 177

Table 1 t1:1 Characteristics of patients (N = 32) and controls (N = 32). Displayed are the means and t1:2 standard deviations (SD). t1:3

Total, N Females, n Males, n Age (years) Cycle week BMI (kg/m2) Smokers, n (%) Cigarettes/day Contraceptive pill, n (%) Total triglyceride, mmol/l PAS STAI-Trait

Patients with PD (PD)

Controls (C)

32 20 12 32.87 (11.23) 2.90 (.90) 22.66 (3.27) 16 (50.0) 3.59 (4.29) 9 (45) 1.18 (.73) 19.59 (11.10) 46.59 (9.40)

32 20 12 31.17 (11.12) 2.93 (.48) 23.22 (2.54) 9 (45.0) 1.84 (3.93) 9 (45) 1.26 (.71) 1.18 (3.33) 36.44 (8.22)

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.000 .370 121.000 .578 3.216 .032 .000 .196 80.705 21.177

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1.000a .545 .822 (U) .450 .123a .860 .624a .659 b.001⁎⁎⁎ b.001⁎⁎⁎

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U = Mann–Whitney U-test; STAI = State-Trait-Anxiety-Inventory (Spielberger, 1970; t1:17 Q3 Laux et al., 1981); PAS = Panic and Agoraphobia-Scale (Bandelow, 1997). t1:18 a Chi-square test. t1:19 ⁎⁎⁎ p ≤.001. t1:20

Please cite this article as: Petrowski, K., et al., Blunted salivary and plasma cortisol response in patients with panic disorder under psychosocial stress, International Journal of Psychophysiology (2013), http://dx.doi.org/10.1016/j.ijpsycho.2013.01.002

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The psychopathological burden and the severity of the panicagoraphobia symptoms were measured by two instruments: (1) the Panic and Agoraphobia-Scale (PAS; Bandelow, 1997) consisting of 13 items rated on a five-point rating-scale (range: 0–52) to assess the symptom severity for phobic anxiety. (2) To evaluate the extent of anxiety induced by the acute psychosocial stress protocol, the state version of the State-Trait-Anxiety-Inventory (STAI, Spielberger, 1970; Laux et al., 1981) was applied before and after the TSST. The STAI consists of two 20-item scales for measuring the intensity of anxiety as an emotional state and individual differences in anxiety proneness as a personality trait on a four-point scale. Anxiety as a personality trait was measured before the TSST during resting. Additionally we used a visual analog scale (VAS) as a straight line ranging from 0 (not at all) to 100 (very much) to assess the extent of perceived stressfulness of the stress task.

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(1) For the comparison of the baseline values (− 15 min) for plasma ACTH, plasma cortisol, salivary cortisol and heart rate, univariate analyses of covariance (ANCOVA) were performed. (2) Furthermore, to estimate the reactivity of the HPA-axis due to the TSST, a 2 × 8 [group (patients vs. controls) by time (− 15, − 1, 1, 10, 20, 30, 45, 60)] analysis of variance (ANOVA) for repeated measures was performed to assess the possible main effects of time and group, and the interaction effect time x group for plasma ACTH, plasma cortisol, salivary cortisol and heart rate response. The degree of freedom was adjusted with the Greenhouse–Geisser approach, taking sphericity into account. To evaluate any differences between the same time-points between groups, multivariate ANOVAs were applied. P-values were Bonferroni-corrected. (3) A response to the TSST was defined as an increase in plasma cortisol of 27.6 nmol/l (Schommer et al., 2003). According to the salivary cortisol, a response to the TSST was defined as an increase of 2.5 nmol/l over the baseline (Van Cauter and Refetoff, 1985). Differences in the amount of responders were tested for by chi-square test. (4) Parameters of the HPA-axis (plasma ACTH, plasma cortisol, salivary cortisol) were calculated as areas under the response curve with respect to ground (AUCg, Pruessner et al., 2003) and Pearson's correlations were performed separately for patients with PD and healthy controls, respectively. (5) Differences in the subjective anxiety level (state anxiety) before and after psychosocial stress exposure were analyzed with ANOVAs for repeated measures. Differences in the perceived stressfulness (VAS) of the TSST were analyzed by Mann–Whitney U-test. Pearson's partial correlations were carried out to specify the interrelationship between the cortisol and the ACTH response pattern and the psychopathology. The main effects of the smoking status and the use of contraceptive pills were taken into account as covariates in ANCOVAs. For salivary cortisol and plasma ACTH, log-transformed values were used as the prerequisite of normal distribution was violated. Data analyses were performed using SPSS v. 19 (SPSS Inc., Chicago, IL, USA).

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For the heart rate mean heart rate responses were available for a pre-stress period of three minute duration, the speech task (3 min), the mental arithmetic (3 min) and a post-stress period of three minute duration. Heart rate values within a period were averaged to generate means.

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(1) There were no significant differences in the baseline value (− 15 min) for either plasma ACTH or plasma cortisol and salivary cortisol between patients with PD and the healthy controls [plasma ACTH: F(1,56)=.436, p=.512); plasma cortisol: F(1,56) = .054, p = .818; salivary cortisol: F(1,56) = .122, p = .728]. The baseline values were not influenced by either the use of contraceptive pill or the smoking status (all p > .05). (2) The TSST led to a highly significant increase in plasma ACTH in both groups (main effect of time: F(7,434) = 60.841, p b .001). Also, there was a significant interaction effect time × group for plasma ACTH (F(7,434) = 3.284, p = .023). However, the main effect of group did not reach statistical significance (F(1,62) = .955, p = .332) (Fig. 1, left). For plasma cortisol, both groups showed a highly significant increase due to the TSST (F(7,434) = 38.779, p b .001). Also, there was a significant interaction effect time × group (F(7,434) = 3.511, p = .039) and a significant main group effect (F(1,62) = 4.643, p = .035). Patients with PD showed a significantly lower plasma cortisol increase under the TSST than healthy controls. (Fig. 1, right). Both groups showed a highly significant increase in salivary cortisol due to the TSST (F(1,434) = 28.120, p b .001). Also, there was a significant interaction effect time × group (F(7,434)= 3.959, p = .026). The main effect of group showed a tendency towards statistical significance (F(1,62) = 3.206, p = .078). Patients with PD showed a significantly lower salivary cortisol increase due to the TSST than healthy controls (Fig. 1, right). Neither the use of contraceptive pill nor the smoking status had an impact on plasma ACTH, plasma cortisol or salivary cortisol response (p > .05). Heart rate responses did not differ between PD patients and controls (group: F(1,46) = 1.121, p = .295; group × time: F(3,138) = 2.006, p = .148). Significant heart rate increases were observed in both groups (time: F(3,138) = 89.525, p b .001). (3) For plasma cortisol, there was a significant difference in the responder rate to the TSST between patients and healthy controls (χ 2 = 7.346, df = 2, p = .025). 37.5% of the patients with PD vs. 65.6% of the healthy controls showed a plasma cortisol response of 27.6 nmol/l according to Schommer et al. (2003). 21.9% of the patients with PD vs. 3.1% in healthy controls showed no response. 40.6% in patients with PD vs. 31.3% in healthy controls even showed a decline in plasma cortisol. (4) Baseline levels for salivary and plasma cortisol were correlated. Both in patients with PD and in healthy controls the correlations were highly significant (patients with PD: r = .879, p b .001; healthy controls: r = .720, p b .001). For AUCg both groups showed highly significant Pearson's correlations between plasma and salivary cortisol (patients with PD: r = .823, p b .001; healthy controls: r = .827, p b .001). (5) The TSST led to a significant increase in state anxiety in both groups (main effect of time: F(1,58) = 12.930, p = .001). There was only a tendency towards a significant interaction time x group (F(1,58) = 3.368, p = .072). However, it could be shown that patients with PD showed significantly higher state anxiety values than healthy controls both before and after psychosocial stress exposure (main effect of group: F(1,58) = 10.692, p = .002) [state anxiety before/after the TSST, healthy controls vs. patients: 36.32 (12.48) vs. 41.94 (10.74)/39.11 (10.31) vs. 50.53 (13.25)]. Both groups did not significantly differ according to perceived stressfulness of the task on the VAS (U = 468.000, p = .554).

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commercially available immunoassay with chemical luminescence detection as described previously in detail by Dressendörfer et al. (1992).

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Please cite this article as: Petrowski, K., et al., Blunted salivary and plasma cortisol response in patients with panic disorder under psychosocial stress, International Journal of Psychophysiology (2013), http://dx.doi.org/10.1016/j.ijpsycho.2013.01.002

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This is the second report of a cortisol hypo-response to psychosocial stress in patients with panic disorder. The present results clearly suggest normal increase in heart rate under acute psychosocial stress and an attenuated reactivity of the HPA-axis which can be explained by neither the use of psychotropic medication nor by comorbid depression. This finding is in line with the first study which showed salivary cortisol non-responsiveness to the same stressor (Petrowski et al., 2010) and ruled out influencing variables with an impact on the availability of CBG (Kirschbaum et al., 1999; Kumsta et al., 2007). The fact that the present finding suggests a blunted cortisol response rather than a non-responsiveness as has been found in our former study (Petrowski et al., 2010) could be explained by differences in the sample composition. In the present study patients were younger and thus had a shorter duration of psychopathology. Nevertheless, the question remains, where the attenuated reactivity of the HPA-axis in patients with PD comes from. Jezova et al. (2004) argue that a reduced reactivity of the HPA-axis might be associated with an inability to elicit an adequate hormone release possibly accompanied by an enhanced perception of the stress stimulus (Junghanns et al., 2003; Jezova et al., 2004). Besides, this response pattern is assumed to be the result of an adaptation of the adrenocortical system due to prolonged and repeated stress exposure (Heim et al., 2000; Fries et al., 2005; Beaton et al., 2006). Most patients studied for acute endocrine responses to panic attacks (naturally or in the lab) had experienced dozens of attacks before. Hence, it is tempting to speculate that the cortisol hypo-response to acute psychosocial stress simply reflects successful habituation to repeated stimulation from complex emotional events. However, the possible moodbuffering effect of cortisol (Het et al., 2012) could be replicated since the attenuated stress response under psychosocial stress is accompanied by increased stress perception of the task. Consistent with McEwen's pattern of “repeated hits” in his allostatic load model we postulate that these patients develop a hypo-responsiveness over time. An insufficient ability to adjust to the repeated stress exposure to the same stressor is considered one of the conditions that leads to the allostatic load (McEwen, 1998). In the long run, a decrease of the HPA-axis reactivity might occur as a

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compensatory strategy. This might result from either a down-regulation of the pituitary receptors for the corticotropin-releasing hormone (CRH) (Heim et al., 2000) or a diminished adrenocortical sensitivity to ACTH (Wüst et al., 2005). As in the present study the patients with PD showed an attenuated reactivity of the HPA-axis on both the central and the peripheral level, an overall down-regulation of the CRH-receptors may be assumed. This mechanism seems to be specific under acute psychosocial stress stimulation only as there is no difference between patients and healthy controls in neither baseline ACTH nor baseline cortisol levels. One limitation of the present study is the control for other possible interfering variables such as the intake of caffeine (Lovallo et al., 2006) and alcohol (Lovallo et al., 2000). In the present study, these variables were only ensured by asking the subjects about their drinking habits. Furthermore, the subjects were asked to refrain from alcohol and caffeine consumption at least two hours before the test was to take place. Due to the subjective nature of the information, the effect of social desirability cannot be excluded and the reliability of data can thus be refined. Therefore, future studies should additionally prove these variables through blood analyses. Furthermore, future studies should account for markers of the sympathetic nervous system such as heart rate variability and (nor-) epinephrines and their metabolites under acute psychosocial stress (Gurguis and Uhde, 1990; Kalk et al., 2011). Moreover, pro-inflammatory cytokines under psychosocial stress in patients with PD should be addressed as a suppressed HPA-axis reactivity can result in an enhanced pro-inflammatory response (Heim et al., 2000; Wolf et al., 2009). Furthermore, future studies should focus on the impact of an attenuated cortisol secretion under psychosocial stress on the effects of psychotherapy. Recent findings indicate that a clear activation of the HPA-axis during exposure therapy might be necessary for a positive therapy outcome (Siegmund et al., 2011). Siegmund et al. (2011) showed that patients lacking a cortisol response during an exposure to fearful situations elicited the least benefit from psychotherapy. These findings might emphasize the importance of cortisol for extinction-based learning and the interference with retrieval of aversive memories (Siegmund et al., 2011; de Quervain et al., 2011). Besides, physiological habituation seems to be important for psychotherapy outcome, and a low cortisol response has been associated with a weak habituation to repeated stress exposure (Wüst et al., 2005). To conclude, the present findings show a clear but attenuated reactivity of the HPA-axis in patients with PD under a potent psychosocial stress protocol. Salivary and blood cortisol, both markers of the HPA-axis, are highly correlated with each other. The present findings

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There were no significant correlations between ACTH and cortisol values (AUCg/baseline) with neither the subscales of the PAS, nor the age of onset of the PD and the duration of PD (all p > .05).

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Fig. 1. Plasma ACTH response (pmol/l) (left), salivary and plasma cortisol response (right: a) plasma cortisol, b) salivary cortisol) to psychosocial stress (TSST) in patients with panic disorder and healthy matched controls. Displayed are the mean values and the standard errors of the mean (SEM); **PD × C, p ≤ .01; t-test, Bonferroni-corrected for multiple comparisons.

Please cite this article as: Petrowski, K., et al., Blunted salivary and plasma cortisol response in patients with panic disorder under psychosocial stress, International Journal of Psychophysiology (2013), http://dx.doi.org/10.1016/j.ijpsycho.2013.01.002

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The authors declare that, except for the income received from their primary employer, no financial support or compensation has been received from any individual or corporate entity over the past three years for research or professional services and that there are no personal financial holdings that could be perceived as constituting a potential conflict of interest.

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confirm the bio-marker salivary cortisol as a valid, non-invasive measuring method, which reliably and effectively depicts an activation of the HPA-axis under psychosocial stress induction.

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Please cite this article as: Petrowski, K., et al., Blunted salivary and plasma cortisol response in patients with panic disorder under psychosocial stress, International Journal of Psychophysiology (2013), http://dx.doi.org/10.1016/j.ijpsycho.2013.01.002

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