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Effects of the cortisol stress response on the psychotherapy outcome of panic disorder patients
Accepted Manuscript Title: Effects of the cortisol stress response on the psychotherapy outcome of panic disorder patients Author: Susann Wichmann Clemens Kirschbaum Thomas Lorenz Katj Petrowski PII: DOI: Reference:
S0306-4530(16)30812-5 http://dx.doi.org/doi:10.1016/j.psyneuen.2016.11.030 PNEC 3469
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18-10-2016 23-11-2016 23-11-2016
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Effects of the cortisol stress response on the psychotherapy outcome of panic disorder patients
Wichmann, Susanna*, Kirschbaum, Clemensa, Lorenz, Thomasb, & Petrowski, Katjab
a
Department of Psychology, Institute of Biological Psychology, Technische Universität Dresden
b
Department of Psychotherapy and Psychosomatic Medicine, University Hospital Carl Gustav
Carus Dresden, Technische Universität Dresden
* Corresponding author: Susann Wichmann Technische Universität Dresden Department of Psychology Zellescher Weg 19 01062 Dresden, Germany Phone: 0049 351 46 39002, Fax: 0049 351 46 337274 Email: [email protected]
Abstract: 386 words Text: 4833 words Tables: 2 Figures: 3
Highlights Relationship between cortisol stress response and psychotherapy outcome in panic disorder patients. Standardized manual-based cognitive behavioural therapy implemented. Cortisol stress response is inversely associated with agoraphobic avoidance after psychotherapy. Subjective level of fear is positively associated with fear of bodily sensations after psychotherapy. Potential impact of comorbid depression on the cortisol stress response in panic disorder patients.
Summary Background: A proportion of patients with panic disorder (PD) fail to show a remission after psychotherapy. Biological correlates of psychotherapy non-response have rarely been described in the literature. The aim of the present study was to research the relationship between the cortisol stress response and the psychotherapy outcome in PD patients. Methods: Twenty-eight PD patients (20 females, mean age ± SD: 35.71 ± 13.18) seeking psychological treatment for PD and n = 32 age- and sex-matched healthy control participants (21 females, aged 34.66 ± 12.07) participated in this study. The patients underwent five weeks of cognitive behavioural therapy (CBT). Within the first two weeks of the CBT, both study groups were confronted with the Trier Social Stress Test (TSST). Blood sampling for cortisol and adrenocorticotropic hormone (ACTH) evaluation as well as fear-rating (Visual Analogue Scale; Primary Appraisal and Secondary Appraisal Questionnaire, PASA) accompanied the TSST. The global severity of PD (Panic & Agoraphobia Scale; PAS), agoraphobic cognitions (Agoraphobic Cognitions Questionnaire; ACQ), fear of bodily sensations (Bodily Sensations Questionnaire; BSQ), agoraphobic avoidance (Mobility Inventory; MI), and depressiveness (Beck Depression Inventory; BDI) were assessed before and after the CBT (except the BDI). Results: The statistical analysis revealed significant main effects of time for cortisol and the ACTH concentration in response to the TSST, independently of the study group. 42.9 % of the PD patients and 65.6 % of the healthy control participants showed a cortisol stress response to the TSST ≥ 55.2 nmol/l (descriptive finding). The data showed a significant inverse association of the TSST cortisol stress response with the MI total score when accompanied. Further, a significant association of the PASA subjective level of fear and the BSQ as well as a trend for an association of the PASA with the ACQ were observed.
Conclusion: Consistent with prior research, we could replicate findings of decreased cortisol concentrations in the PD patients in comparison to the healthy control participants. Furthermore, our findings agree with previous data showing an association of the attenuated cortisol stress response with the psychotherapy non-response. In the present sample, those patients with the lowest cortisol concentrations showed the least improvement in agoraphobic avoidance after psychotherapy. The patients with the highest level of fear showed the most improvement in fear of bodily sensations. Study limitations as well as implications for future studies will be discussed.
Keywords: panic disorder; TSST; cortisol; ACTH.
Introduction Panic disorder (PD) is a serious mental disorder associated with high levels of disability and impairment in the quality of life, next to depressive disorders (Wittchen & Jacobi, 2005). The most recent 12-month-prevalence of PD, with and without agoraphobia, in the German adult population was 2.0 % (Jacobi et al., 2014). Patients with PD experience acute, stressful panic attacks as well as chronic stress due to being concerned about future panic attacks and their implications to health as well as changes in behaviour related to the panic attacks. The hypothalamic-pituitary-adrenal (HPA)-axis is the body’s major endocrine stress system controlling responses to various stressors. In clinical psychological research, the activity of the HPA-axis has been investigated extensively in reference to the pathophysiology of panic attacks. The hypothalamus directs the secretion of the adrenocorticotropic hormone (ACTH) from the anterior pituitary which, in turn, stimulates the secretion of cortisol from the adrenal cortex. Under resting conditions, the ACTH and cortisol secretion follow a circadian rhythm as a function of light exposure to stress (Jung et al., 2010), caffeine (Lovallo, Farag, Vincent, Thomas, & Wilson, 2006), intense aerobic exercise (Fuqua & Rogol, 2013), and disrupted sleep (Leproult, 1997), among others. During acute stress, the diurnal hormone secretion is disrupted, which increased release of both cortisol and ACTH in healthy individuals (Tsigos & Chrousos, 2002). In individuals with stress-related mental disorders, this mechanism seems impaired. Thus, ACTH and cortisol release during non-stressful basal and stressful conditions provide an index for the normative (or disrupted) stress-regulating function of the HPA-axis. Contradictory evidence has been reported on the cortisol levels of PD. Basal cortisol concentrations represent the resting activity of the HPA-axis and have been reported as “normative” with no difference from healthy individuals (Abelson & Curtis, 1996; Holsboer, Von Bardeleben, Buller, Heuser, & Steiger, 1986; Uhde, Joffe, Jimerson, & Post, 1988). However,
contradictory to this normative pattern, elevations (Goldstein, 1987; Wedekind, Bandelow, Broocks, Hajak, & Rüther, 2000) as well as reductions (Stones, Groome, Perry, Hucklebridge, & Evans, 1999) in basal cortisol concentrations have been reported as well. Findings on the cortisol stress response are also mixed. The cortisol stress response provides an indicator for the acute HPA-axis reaction to laboratory-induced stressors. Overall, previous research suggests a hyporesponsiveness of the HPA-axis in patients diagnosed with PD. Different panic-related stimuli were used in the activation of the HPA-axis which, in fact, triggered panic but failed to result in cortisol secretion (lactate-induced panic: (Hollander et al., 1989; Levin et al., 1987; Peskind et al., 1998; Seier et al., 1997); CO2-induced panic: (van Duinen, Schruers, Jaegers, Maes, & Griez, 2004; Sinha et al., 1999)). These results correlate with our findings of a cortisol non-response pattern to the Trier Social Stress Test (TSST; Kirschbaum, Pirke, and Hellhammer (1993))in patients with PD (Petrowski, Herold, Joraschky, Wittchen, & Kirschbaum, 2010). The TSST reliably induces subjective stress with concomitant cortisol release showing 2- to 4-fold elevations above baseline levels in healthy individuals (Kirschbaum et al., 1993). In patients diagnosed with PD, the cortisol response was absent (Petrowski et al., 2010). Further, patients with PD were found to show decreased plasma and cortisol stress response in response to the TSST as compared to healthy control participants, independent of comorbid depression and psychoactive medication (Petrowski, Wintermann, Schaarschmidt, Bornstein, & Kirschbaum, 2013). Occasionally, however, increased cortisol stress responses to laboratory-induced panic (CO2: (Woods, Charney, Goodman, & Heninger, 1988); yohimbine: (Charney, Woods, Goodman, & Heninger, 1987); respiratory stimulant: (Abelson, Khan, Liberzon, & Young, 2007)), and spontaneously occurring unprovoked panic attacks (Bandelow, Wedekind, Pauls, Broocks, & Rï, 2000) have previously been reported in the literature.
Until now, it is unknown whether stress (non-)responsiveness is related to the psychotherapy outcome. A proportion of PD patients fail to show a symptom reduction or a remission following psychotherapy (Kampman, Keijsers, & Hendriks, 2002; Keller et al., 1994), which is the first choice treatment for PD (Bandelow, Hau, & Beutel, 2014). Different variables have been associated with the psychotherapy outcome, among them agoraphobic avoidance (Andersson, Carlbring, & Grimlund, 2008) and catastrophic agoraphobic cognition (Keijsers, Hoogduin, & Schaap, 1994) as negative predictors, especially for agoraphobic patients (Keller et al., 1994; Steketee & Shapiro, 1995), anxiety and depression comorbidity with no impediment to the therapy success (Allen et al., 2010; Brown, Antony, & Barlow, 1995; Kampman, Keijsers, Hoogduin, & Hendriks, 2008), as well as the comorbid cluster C personality disorder and initial motivation for therapy, again with no influence on the therapy outcome (Kampman et al., 2008; Keijsers et al., 1994). Overall, recent research efforts failed to identify consistent therapy outcome predictors of a psychological or disorder-related kind. To date, there is a lack of studies focusing on the biological correlates of the psychotherapy outcome. One study group reported an association of poor actual and perceived health with the failure to meet recovery criteria after psychotherapy (Schmidt & Telch, 1997). Similarly, in a previous study, psychotherapy nonresponse was associated with decreased cortisol levels upon provocation (Siegmund et al., 2011). Siegmund et al. (2011) found a dissociative pattern in the hormonal stress response and the subjective level of fear during an in-vivo exposure to feared situations: despite experiencing fear, the hormonal stress response did not significantly increase during exposure. And further, patients with the lowest cortisol stress response showed the least improvement from psychotherapy. The aim of the present study was to research the relationship between the cortisol stress response to the TSST and the psychotherapy outcome in patients diagnosed with PD, with or without agoraphobia. We hypothesized that the cortisol stress response is predictive of symptom
recovery. Specifically, we predicted that the TSST non-response is associated with a higher panic symptom severity and psychotherapy non-response.
Methods Study participants The data were collected from June 2008 to October 2012. The patients were recruited from the University Hospital of the Technische Universität Dresden, Germany, before the start of cognitive behavioural psychotherapy. In addition, the healthy control participants were recruited via newspaper advertisements and matched to the patient sample by age and sex. General inclusion criteria were being 18 to 65 years of age and fluency in the German language. Exclusion criteria included a history of substance (ab)use, psychotic or bipolar disorder, posttraumatic stress disorder, eating disorder, as well as familiarity with the TSST (Kirschbaum et al., 1993), pregnancy as well as any severe physical illness (e. g. cancer, a metabolic or autoimmune disorder) within the previous two years. The Structured Clinical Interview (SCID; (Spitzer, First, Gibbon, & Williams, 1990; Wittchen et al., 1990) for DSM-IV-TR diagnosis of mental disorders on axis I and II (American Psychiatric Association, 2000) was conducted by trained clinical interviewers and the diagnoses confirmed by an experienced psychotherapist (KP). Patients with a current primary diagnosis of PD, with or without agoraphobia, were included in the study. Inclusion in the healthy control group was established using the DIA-X stem questions (Wittchen, 2007) which confirm that the participants did not have a history of mental disorders. Thirty patients with PD and 32 healthy control participants were screened with respect to the defined inclusion and exclusion criteria. Two patients were excluded due to a 12-monthdiagnosis of post-traumatic stress disorder and alcohol abuse disorder, resulting in a sample of n = 28 patients with a primary diagnosis of PD and n = 32 age- and sex-matched healthy control
participants. According to the Panic & Agoraphobia Scale (Bandelow, 1995), n = 5 PD patients showed borderline panic and agoraphobic symptoms, n = 7 a mild, n = 11 a moderate and n = 5 a severe psychopathology. Two patients were on antidepressant medication (selective serotonin reuptake inhibitor: Citalopram, Paroxetine). All the other patients were free of antidepressant or anxiolytic medication. Comorbid mental disorders were major depression (single episode: n = 6; recurrent episode: n = 4) and specific phobia (n = 4). A brief description of sociodemographic and clinical characteristics of the included study participants is provided in Table 1. All the study participants gave written informed consent. The study procedure was approved by the local Ethics Committee of the Medical Faculty of the Technische Universität Dresden, Germany (No# EK46032008).
Cognitive behavioural therapy and clinical measures Cognitive behavioural therapy (CBT) for the patients (not the healthy control participants) was administered in individual and group sessions within five weeks of semi-residential care. The therapy was standardized based on the manual by Lang, Helbig-Lang, Westphal, Gloster, and Wittchen (2011). The CBT encompassed: group psycho-education referring to anxiety and PD; explanation of the treatment rationale; exposure therapy involving interoceptive exposure, therapist-accompanied and self-managed confrontation with feared situations as well as cognitive therapy to reduce anxiety-maintaining beliefs. Except for psycho-education, all the other interventions were administered in individual sessions. All the therapists were experienced in cognitive behavioural techniques and regularly supervised by the senior author (KP). Information on sociodemographic variables (sex, age, body mass index, smoking status) as well as any acute or chronic medical illnesses and medication intake were assessed in a routine medical examination and laboratory test prior to the CBT. A questionnaire battery was used to
measure severity of PD: (1) The Panic & Agoraphobia Scale (PAS; Bandelow (1995)) was obtained to evaluate the global severity of illness including five subscales (panic attacks, agoraphobia, anticipatory anxiety, disability, and concerns about health). Hereby, the respondent is asked to answer the 13 items on a 4-point Likert scale. (2) The Agoraphobic Cognitions Questionnaire (ACQ; Chambless, Caputo, Bright, and Gallagher (1984)) is a self-report survey measuring fearful panic beliefs and catastrophic cognitions about panic. The respondent is asked to answer the items on a 5-point scale anchored from 0 (“thought never occurs”) to 4 (“thought always occurs”). The items are then averaged. (3) The Bodily Sensations Questionnaire (BSQ; Chambless et al. (1984)) assesses fear of bodily sensations that often occur during panic attacks with 17 items to be answered on a 5–point Likert scale ranging from 0 (“not frightened”) to 4 (“extremely frightened”). The items are then averaged. (4) Agoraphobic avoidance was assessed using the Mobility Inventory (MI; Chambless, Caputo, Jasin, Gracely, and Williams (1985)). Twice, the respondent indicates for 26 situations avoidance behaviour on a 5-point scale with response anchors ranging from 0 (“never”) to 4 (“always”), once when confronted with the situation by him-/herself and once when accompanied by another person. The items are averaged separately for both. To account for comorbid depression, the Beck Depression Inventory II (Beck, Steer, & Brown, 1996; Hautzinger, Keller, & Kühner, 2006) was administered to evaluate severity of depressiveness. This self-report rating inventory is composed of 21 groups of items matching the DSM-IV-TR major depression criteria. Each item group consists of a list of four statements arranged in increasing intensity. The respondent is asked to choose the most appropriate alternative that best describes the way he or she felt during the past two weeks including the present day. The German language questionnaires were handed out to the participants at the beginning of the study and at post-therapy (except for the BDI).
Trier Social Stress Test (TSST) and cortisol collection All study participants performed the standardized protocol for the TSST (Kirschbaum et al., 1993) within the first two weeks of the CBT. The TSST reliably induces acute moderate psychosocial stress under laboratory conditions (review: Foley and Kirschbaum (2010)). In brief, participants are confronted with a mock job interview (5 min) and a mental arithmetic task (5 min) to be performed in front of a selection committee. The Primary Appraisal Secondary Appraisal Questionnaire (PASA; Gaab (2009)) was used prior to the TSST and a Visual Analogue Scale was used following the TSST to assess the subjective level of distress. Blood samples were collected via a venous catheter 75 min and 1 min prior to the TSST as well as 1 min, 10 min, 20 min, 30 min, 45 min, and 60 min after the TSST and stored at 4°C. For the determination of plasma ACTH concentrations, blood was collected into tubes containing a mixture of trasylol and EDTA (Sarstedt, Nümbrecht, Germany). For the determination of plasma cortisol concentrations, blood was collected in serum gel monovette (Sarstedt, Nümbrecht, Germany) and immediately centrifuged at 4°C and 3000 rpm for 10 min. Then, plasma was stored at -80°C and at -20°C before being assayed for ACTH and cortisol. Plasma cortisol concentrations were determined using a commercially available radioimmunoassay kit with the Solid Phase Antigen Linked Technique (SPALT) with the LIAISON-Analyzer® (DiaSorin, S.p.A., Italy). Plasma ACTH was analysed using an immunoradiometric assay (Immulite, 2500 ACTH, Germany). To account for circadian rhythm of cortisol secretion, the TSST was performed in the afternoon not earlier than 2 pm. Female participants underwent the TSST in the luteal phase in order to account for the influence of the menstrual cycle.
Statistical analyses Group comparisons with respect to sociodemographic and clinical variables (pre-therapy) were evaluated using univariate analyses of variance (ANOVA) for continuous variables and Chisquare test (χ2) for dichotomous variables. ANOVA for repeated measures were conducted to test for differences over time in the continuous clinical outcome measures of the ACQ, BSQ, MI, and PAS. Blood ACTH and cortisol data were subject to log transformation to reduce the skewness parameter. Group differences in the cortisol stress response (cortisol, ACTH) were assessed using a 2 (group: PD patients, healthy control participants) x 8 (time: 75 min and 1 min prior to the TSST, 1 min, 10 min, 20 min, 30 min, 45 min, and 60 min after the TSST) ANCOVA for repeated measures with baseline hormonal values (-75 min, -1 min) as covariate and with Greenhouse-Geisser corrections. For ACTH analysis, data from one PD patient and from one healthy control participant were excluded due to outlying values of more than three standard deviations above the mean. Pearson’s correlations were conducted to quantify the associations between mean cortisol concentrations and the psychotherapy outcome as well as between the subjective level of distress and the psychotherapy outcome. The cortisol stress response to the TSST was defined as an increase of at least 55.2 nmol/l compared to baseline (Kirschbaum, Wüst, & Strasburger, 1992; Weitzman et al., 1971; Wuest et al., 2000). The response to the psychotherapy was defined as 50% symptom reduction from pre- to post-therapy. All statistical analyses were performed using SPSS for Windows, version 22 (IBM, Chicago, Illinois). The figures were created by Sigma Plot 11.0 for Windows (Systat Software Inc., Erkrath, Germany). For descriptive purposes, the data in the figures are presented in original units.
Results Clinical measures The groups were well matched on sociodemographic variables (p’s ≥ .109) as shown in Table 1. There were no significant differences in age, sex, body mass index, or smoking status. As expected, the study groups differed significantly with regard to the panic-specific questionnaires with the PD patients showing higher scores in agoraphobic cognitions (p’s ≤ .05), concerns about body sensations (p ≤ .05), avoidance behaviour (p’s ≤ .001), and the global PAS symptom score (p’s ≤ .001). Further, the study groups were found to differ significantly in reported depressive symptoms (p ≤ .001), with the post-hoc analysis revealing higher BDI scores in PD patients with comorbid depression as compared to the PD patients without comorbid depression (p ≤ .01) and compared to the healthy control participants (p ≤ .001).
[insert Table 1 about here]
TSST cortisol profile Twelve PD patients (42.9 %) and n = 21 (65.6 %) healthy control participants showed a cortisol stress response to the TSST according to the defined response criterion. This difference did not reach statistical significance (χ² = 3.128, df = 1, p = .118). Figure 1 demonstrates the hormonal stress response to the TSST. Plasma cortisol levels (F1.500;83.990 = 12.006, p ≤ .001, ηp2 = 0.177) as well as plasma ACTH levels (F1.939;102.761 = 3.543, p ≤ .05, ηp2 = 0.063) were found to increase in response to the TSST. Repeated measures ANCOVA, with baseline cortisol concentrations (-75 min, -1 min) added as covariates, revealed neither a main effect of group (F1;56 = 0.650, p = .424, ηp2 = 0.011) nor a time x group interaction effect (F1.500;83.990 = 0.728, p = .449, ηp2 = 0.013). There were no baseline cortisol differences (-75 min: F1;59 = 0.780, p = .381) nor any baseline
ACTH differences (-75 min: F1;58 = 2.637, p = .110; -1 min: F1;56 = 2.445, p = .124) between the groups, except for baseline cortisol 1 min prior to the TSST (F1;59 = 5.278, p = .025) with lower baseline cortisol concentrations in PD patients. Repeated measures ANCOVA, with baseline ACTH concentrations (-75 min, -1 min) added as covariates, revealed neither a main effect of group (F1;53 = 0.014, p = .905, ηp2 = 0.000) nor a time x group interaction effect (F1.939;102.761 = 0.633, p = .528, ηp2 = 0.012). Groups did not differ significantly in their subjective distress ratings before (PASA: p = .117) and after (VAS: p = .578) the TSST. Descriptively, PD patients who displayed a TSST non-response scored higher in the panic-specific questionnaires at post-therapy (ACQ, BSQ, MI, PAS). These differences did not reach statistical significance (p’s ≥ .106).
[insert Figure 1 about here]
Psychotherapy outcome All the named panic-specific outcome measures significantly decreased from pre- to post-therapy (p’s ≤ .001; see Table 2). With regards to the PAS accounting for all the panic-specific complaints (agoraphobic cognitions, fear of bodily sensations and agoraphobic avoidance behaviour), nine PD patients (32.1 %) were classified as psychotherapy responders according to the defined criterion of at least 50 % symptom reduction from pre- to post-therapy. On a descriptive level, psychotherapy non-responders showed lower mean stress hormone concentrations during the TSST as compared with psychotherapy responders (ACTH: nonresponders: 3.12 (mean) ± 2.00 (SD), responders 4.56 ± 4.00; cortisol: non-responders 190.67 ± 93.86, responders 232.00 ± 129.54). Group differences did not reach statistical significance (p’s ≥ .211).
[insert Table 2 about here]
Pearson’s correlation analyses revealed significant inverse associations between the mean cortisol concentration and the post-therapy MI total score when accompanied (r = - .396, p ≤ .05) as well as a trend for an inverse association for post-therapy MI total score when by themselves (r = .345, p = .072). Patients with the highest stress hormone concentration after the TSST showed the most improvement by psychotherapy in the agoraphobic avoidance behaviour (see Figure 2). No significant correlations were observed between mean cortisol concentration and ACQ, BSQ or PAS (p’s ≥ .273) as well as between mean ACTH concentrations and the mentioned post-therapy outcome measures (p’s ≥ .276).
[insert Figure 2 about here]
Further, Pearson’s correlation analyses revealed significant associations between the PASA stress index and the BSQ (r = .438, p ≤ .05) as well as a trend toward an association with ACQ loss of control (r = .402, p = .051) and ACQ total score (r = .387, p = .062). Patients with high subjective distress showed the most improvement by psychotherapy in catastrophic agoraphobic cognitions and fear of bodily sensations. No significant associations were observed for the VAS stress index and the psychotherapy outcome measures (p’s ≥ .183).
Data with comorbid depression taken into account Due to the known influence of depressive disorders on the HPA axis functioning (Burke, Davis, Otte, & Mohr, 2005), the TSST cortisol profile was analysed additionally with the BDI symptom score as covariate. The mean BDI score in the patient group was 11.93 ± 9.40.
Reported main and interaction effects were basically the same. The main effect of time could be found both for cortisol (F1.568;86.267 = 10.861, p ≤ .001, ηp2 = 0.165) and ACTH (F2.003;102.158 = 6.052, p ≤ .01, ηp2 = 0.106). ANCOVA revealed significant interaction effect of time x BDI score, both for cortisol (F1.568;86.267 = 6.193, p ≤ .01, ηp2 = 0.101) and ACTH (F2.003;102.158 = 3.079, p ≤ .05, ηp2 = 0.057). The time x group interaction effect for cortisol (F1.568;86.267 = 0.720, p = .458, ηp2 = 0.013) and ACTH (F2.003;102.158 = 0.940, p = .394, ηp2 = 0.018) as well as the main effect of group for cortisol (F1;55 = 0.684, p = .412, ηp2 = 0.012) and ACTH (F1;51 = 0.677, p = .414, ηp2 = 0.013) did not reach significance. Additionally, ANCOVA was conducted with separated PD patient groups based on comorbid depression. For cortisol there was a significant main effect of time (F1.498;82.363 = 11.591, p ≤ .001, ηp2 = 0.174). Neither a significant time x group interaction effect (F2.995;82.363 = 0.611, p = .610, ηp2 = 0.022) nor a main effect of group (F2;55 = 0.499, p = .610, ηp2 = 0.018) were found. Descriptively, PD patients without comorbid depression showed the least mean plasma cortisol concentrations (see Figure 3). For ACTH, ANCOVA revealed a significant main effect of time (F1.930;100.374 = 3.460, p ≤ .05, ηp2 = 0.062), no significant main effect of group (F2;52 = 0.014, p = .986, ηp2 = 0.001) and no significant interaction effect (F3.861;100.374 = 0.419, p = .788, ηp2 = 0.016). Further, significant differences in the BDI score were observed with post-hoc comparisons revealing higher depressiveness in the PD patients with comorbid depression (16.60 (mean) ± 10.47 (SD)) as compared to the PD patients without comorbid depression (9.33 ± 7.90) and healthy control participants (3.50 ± 3.34) (p’s ≤ .05).
[insert Figure 3 about here]
Further, partial correlations were conducted to analyse relationships between psychotherapy outcome measures and mean stress hormone concentrations controlling for depressiveness. A trend toward a positive association between the mean cortisol concentration and the post-therapy MI total score when accompanied (p = .073) was observed. With respect to the other psychotherapy outcome measures, associations with the mean cortisol concentration did not reach significance (p’s ≥ .129). No significant associations were observed with mean ACTH concentrations (p’s ≥ .348).
Discussion
The present study was aimed at analysing the relationship between the cortisol stress response to the TSST and the psychotherapy outcome in patients diagnosed with PD, with or without agoraphobia. We predicted that the TSST non-response would be associated with higher panic symptom severity after the CBT and with psychotherapy non-response. The data showed a significant inverse relationship between the cortisol stress response to the TSST and agoraphobic avoidance behaviour: patients with the lowest cortisol concentration showed the least improvement after psychotherapy in agoraphobic avoidance. Overall, for patients diagnosed with PD, previous research suggested a hyporesponsiveness of the HPA-axis in response to different stressors (van Duinen et al., 2004; Hollander et al., 1989; Levin et al., 1987; Peskind et al., 1998; Petrowski et al., 2010; Petrowski et al., 2013; Seier et al., 1997; Sinha et al., 1999). Our findings agreed partly with the previous studies showing that the hypo-response-pattern was not so clearly pronounced in our sample. The TSST response rates were lower in the patient group: 42.9 % of the PD patients and 65.6 % of the healthy control participants showed a hormonal stress response to the TSST. A non-response
pattern was seen in 57.1 % of the PD patients, thus agreeing with our earlier findings of an absent TSST cortisol response (Petrowski et al., 2010). Descriptively, but not significantly, the PD patients of the present sample displayed lower hormone concentrations after the TSST as compared to the healthy control participants. When the patient group was separated into two groups based on comorbid depression, this difference became more pronounced, with PD patients without comorbid depression showing a marked blunted cortisol response, thus combining well with our previous findings of a decreased cortisol stress response in the TSST in patients with PD (Petrowski et al., 2010; Petrowski et al., 2013). In a previous sample, we already observed that only those PD patients with comorbid depression tended to show a small, but not statistically significant, elevation of cortisol concentration (Petrowski et al., 2010). Since this is a descriptive finding without significant group differences, findings agree also with those studies that reported “normative” cortisol patterns as compared to healthy individuals (Abelson & Curtis, 1996; Holsboer et al., 1986; Uhde et al., 1988). However, the findings in the present sample conflict with previous studies that reported a hyper-responsiveness in PD patients as compared to healthy individuals (Abelson et al., 2007; Bandelow et al., 2000; Charney et al., 1987; Woods et al., 1988). The correlation analyses revealed associations between the cortisol stress response and an improvement in agoraphobic avoidance behaviour. Concurrently, the TSST non-responders within the PD patient group scored higher in agoraphobic avoidance and the other panicsymptom questionnaires at post-therapy. Thus, our findings partially replicate and extend the study results by Siegmund et al. (2011) who demonstrated a dissociative pattern between the hormonal stress response and the subjective level of fear during in-vivo exposure, with an absent hormonal stress response but a high level of fear. While we could not replicate such a dissociative pattern in our sample, the results of the correlational analyses suggest that the patients with the
lowest cortisol levels following psychosocial stress showed the least improvement by psychotherapy as previously reported by Siegmund et al. (2011). Furthermore, our findings combine well with established recommendations for cognitive behavioural treatment for PD patients. Guidelines recommend a high level of fear and psychophysiological arousal during exposure treatment as measured, for instance, with the stress hormone concentration (Lang et al., 2011). In the present sample, higher cortisol concentrations were related to an improvement in agoraphobic avoidance, and high subjective distress was related to an improvement in fear of bodily sensations as well as (descriptively) with an improvement in agoraphobic cognitions. Together, these results emphasise the importance of a “normative” neuroendocrine adaptation to stress. Patients who failed to show a remission after psychotherapy had a less distinctive hormonal stress response than patients who showed improvement following psychotherapy. However, an interpretive challenge for these study results might be that the TSST as a psychosocial stressor did not resemble a panic-specific stressor for which it is essential to adapt for PD patients, e.g. fear of a physical or mental catastrophe. However, the TSST is a standardized laboratory stress induction instrument that reliably induces subjective stress with (in healthy individuals) concomitant cortisol release (Foley & Kirschbaum, 2010; Kirschbaum et al., 1993). Limitations of this study include the psychiatric comorbidity. Ten patients with PD (35.7 %) showed a comorbid depressive disorder. Statistical analyses were repeated with the BDI symptom score included as covariate. As specified in the result section, the findings basically remained the same. Furthermore, a meta-analysis by Allen et al. (2010) showed that comorbid depression is not related to a differential improvement of PD severity. A second limitation is the relatively small sample size, making it harder to detect significant associations. Besides, PD patients underwent the TSST within the first two weeks of CBT. Until then, the patients were
merely confronted with psycho-education and the therapy rationale. TSST stress induction at the end of the psychotherapy may have produced different cortisol profiles. A further limitation is the lack of a follow-up assessment to explore the stability of the observed findings. Implications for future studies are the replication of the current findings with the inclusion of a follow-up assessment and using larger sample sizes. PD has a chronic course with some probability of relapses (American Psychiatric Association, 2000). Possibly, the psychotherapy outcome and the increased relapse risk may be predicted from pre-therapy cortisol stress profiles. Further research ought to analyse whether the cortisol stress response and its relationship to the psychotherapy outcome is associated with the duration of the illness as could be shown for the stress response to hormonal stressors (Petrowski, Wintermann, Kirschbaum, & Bornstein, 2012). Further, future studies ought to analyse the influence of psychotherapy experience. More chronic PD patients with psychotherapy experience might profit less from additional psychotherapy as compared to psychotherapy-naïve patients. Additionally, it would be interesting to compare the findings directly with other patient groups. Similar results on the association between the hormonal stress profiles and the psychotherapy outcome have been obtained for post-traumatic stress disorder (PTSD). Patients with PTSD also display HPA-axis dysregulations during basal conditions and upon stress provocation. Elevated (Lemieux & Coe, 1995; Lindley, Carlson, & Benoit, 2004; Pitman & Orr, 1990) as well as attenuated basal cortisol concentrations (De Kloet et al., 2006; Gill, Vythilingam, & Page, 2008; Olff, Güzelcan, de Vries, Assies, & Gersons, 2006; Rohleder, Joksimovic, Wolf, & Kirschbaum, 2004; Steudte et al., 2013; Wessa, Rohleder, Kirschbaum, & Flor, 2006; Yehuda et al., 1990) were reported. Results concerning the cortisol stress response upon provocation in PTSD are also mixed (no difference to healthy control individuals: (Bremner et al., 2003; Elzinga, Spinhoven, Berretty, de Jong, & Roelofs, 2010; Liberzon, Abelson, Flagel, Raz, & Young, 1999); hyper-responsiveness: (Elzinga, Schmahl, Vermetten, van Dyck, &
Bremner, 2003); hypo-responsiveness: (MacMillan et al., 2009; Pierrehumbert et al., 2009; Roelofs et al., 2009). In PTSD patients, psychotherapy non-response was associated with decreased urinary cortisol levels (Yehuda et al., 2009) and decreased blood cortisol levels (Olff, de Vries, Güzelcan, Assies, & Gersons, 2007). In conclusion, to our knowledge this is one of few published studies focusing on the biological correlates of psychotherapy success. We hope these findings will stimulate future research in the prediction of the psychotherapy outcome for PD patients. Author Notes Conflict of interest. All authors declare that they have no conflicts of interest.
Ethical approval. All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent. Informed consent was obtained from all individual participants included in the study.
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Figure 1. Mean (± SE) blood plasma cortisol (left) and ACTH (right) concentrations of panic disorder (PD) patients and healthy control participants.
Figure 2. Scatterplot showing the relationship between mean cortisol concentration during the TSST and symptom severity post-therapy. * p ≤ .05.
Figure 3. Mean (± SE) blood plasma cortisol (left) and ACTH (right) concentrations of panic disorder (PD) patients with/without comorbid depression and healthy control participants.
Table 1 Characteristics of the total sample. Mean (SD) are listed except where noted
Panic patients
disorder Healthy subjects
control F/χ2
p
Sociodemographics Age (years) Females, n (%) † Body mass index Smoking † Oral contraceptive use †
35.71 (13.18) 20 (71.4) 23.10 (3.08) 13 (46.4) 7 (35.0)
34.66 (12.07) 21 (65.6) 22.92 (2.35) 10 (31.3) 7 (33.3)
1.574 0.232 0.732 1.455 0.013
.109 .782 .755 .291 1.00
Clinical measures PAS total score [0-52] ACQ loss of control [0-4] ACQ physical concerns [0-4] ACQ total score [0-4] BSQ total score [0-4] MI alone [0-4] MI accompanied [0-4] BDI [0-63]
19.00 (10.73) 1.00 (0.70) 1.40 (0.69) 1.20 (0.56) 1.88 (0.78) 1.06 (0.80) 1.67 (1.07) 11.93 (9.40)
1.55 (3.40) 0.58 (0.69) 0.23 (0.56) 0.41 (0.59) 0.82 (0.53) 0.17 (0.27) 0.08 (0.19) 3.41 (3.34)
73.949 1.867 9.137 4.404 2.277 6.132 18.056 23.013
.000*** .048* .000*** .000*** .024* .000*** .000*** .000***
-1.10 (2.73)
2.54
.117
61.11 (26.24)
1.103
.578
Subjective level of distress PASA stress index [-3.75 – 0.03 (2.41) 3.75]a VAS mean 53.98 (14.74) Therapy-Responderb PAS (%) ACQ total score (%) BSQ total score (%) MI alone (%) MI accompanied (%)
9 (32.1) 16 (57.1) 8 (28.6) 19 (67.9) 17 (60.7)
Note. PAS = Panic & Agoraphobia Scale; ACQ = Agoraphobic Cognitions Questionnaire; BSQ = Body Sensations Questionnaire; MI = Mobility Inventory; BDI = Beck Depression Inventory; PASA = Primary Appraisal Secondary Appraisal scale; VAS = Visual Analogue Scale. † Chi-square test. a Panic disorder patients: n = 24; Healthy control subjects, n = 30. b Response to psychotherapy was defined as 50% symptom reduction at post-therapy compared to symptom assessment before therapy, separate for the named questionnaires. * p ≤ .05; *** p ≤ .001.
Table 2 Clinical measures before and after psychotherapy for panic disorder patients Clinical measure PAS total score ACQ loss of control ACQ physical concerns ACQ total score BSQ total score MI alone MI accompanieda
Before therapy Mean (SD) 19.00 (10.73) 1.00 (0.70) 1.40 (0.69) 1.20 (0.56) 1.88 (0.78) 1.06 (0.80) 1.67 (1.07)
After therapy Mean (SD) 13.11 (8.40) 0.49 (0.38) 0.63 (0.48) 0.56 (0.40) 1.17 (0.64) 0.44 (0.47) 0.78 (0.69)
Statistics F1;27 15.714 18.931 44.217 49.795 34.928 32.004 24.887
p .000*** .000*** .000*** .000*** .000*** .000*** .000***
ηp2 .368 .412 .621 .648 .564 .542 .489
Note. PAS = Panic & Agoraphobia Scale; ACQ = Agoraphobic Cognitions Questionnaire; BSQ = Body Sensations Questionnaire; MI = Mobility Inventory. a n = 27. *** p ≤ .001.
S0306-4530(16)30812-5 http://dx.doi.org/doi:10.1016/j.psyneuen.2016.11.030 PNEC 3469
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Effects of the cortisol stress response on the psychotherapy outcome of panic disorder patients
Wichmann, Susanna*, Kirschbaum, Clemensa, Lorenz, Thomasb, & Petrowski, Katjab
a
Department of Psychology, Institute of Biological Psychology, Technische Universität Dresden
b
Department of Psychotherapy and Psychosomatic Medicine, University Hospital Carl Gustav
Carus Dresden, Technische Universität Dresden
* Corresponding author: Susann Wichmann Technische Universität Dresden Department of Psychology Zellescher Weg 19 01062 Dresden, Germany Phone: 0049 351 46 39002, Fax: 0049 351 46 337274 Email: [email protected]
Abstract: 386 words Text: 4833 words Tables: 2 Figures: 3
Highlights Relationship between cortisol stress response and psychotherapy outcome in panic disorder patients. Standardized manual-based cognitive behavioural therapy implemented. Cortisol stress response is inversely associated with agoraphobic avoidance after psychotherapy. Subjective level of fear is positively associated with fear of bodily sensations after psychotherapy. Potential impact of comorbid depression on the cortisol stress response in panic disorder patients.
Summary Background: A proportion of patients with panic disorder (PD) fail to show a remission after psychotherapy. Biological correlates of psychotherapy non-response have rarely been described in the literature. The aim of the present study was to research the relationship between the cortisol stress response and the psychotherapy outcome in PD patients. Methods: Twenty-eight PD patients (20 females, mean age ± SD: 35.71 ± 13.18) seeking psychological treatment for PD and n = 32 age- and sex-matched healthy control participants (21 females, aged 34.66 ± 12.07) participated in this study. The patients underwent five weeks of cognitive behavioural therapy (CBT). Within the first two weeks of the CBT, both study groups were confronted with the Trier Social Stress Test (TSST). Blood sampling for cortisol and adrenocorticotropic hormone (ACTH) evaluation as well as fear-rating (Visual Analogue Scale; Primary Appraisal and Secondary Appraisal Questionnaire, PASA) accompanied the TSST. The global severity of PD (Panic & Agoraphobia Scale; PAS), agoraphobic cognitions (Agoraphobic Cognitions Questionnaire; ACQ), fear of bodily sensations (Bodily Sensations Questionnaire; BSQ), agoraphobic avoidance (Mobility Inventory; MI), and depressiveness (Beck Depression Inventory; BDI) were assessed before and after the CBT (except the BDI). Results: The statistical analysis revealed significant main effects of time for cortisol and the ACTH concentration in response to the TSST, independently of the study group. 42.9 % of the PD patients and 65.6 % of the healthy control participants showed a cortisol stress response to the TSST ≥ 55.2 nmol/l (descriptive finding). The data showed a significant inverse association of the TSST cortisol stress response with the MI total score when accompanied. Further, a significant association of the PASA subjective level of fear and the BSQ as well as a trend for an association of the PASA with the ACQ were observed.
Conclusion: Consistent with prior research, we could replicate findings of decreased cortisol concentrations in the PD patients in comparison to the healthy control participants. Furthermore, our findings agree with previous data showing an association of the attenuated cortisol stress response with the psychotherapy non-response. In the present sample, those patients with the lowest cortisol concentrations showed the least improvement in agoraphobic avoidance after psychotherapy. The patients with the highest level of fear showed the most improvement in fear of bodily sensations. Study limitations as well as implications for future studies will be discussed.
Keywords: panic disorder; TSST; cortisol; ACTH.
Introduction Panic disorder (PD) is a serious mental disorder associated with high levels of disability and impairment in the quality of life, next to depressive disorders (Wittchen & Jacobi, 2005). The most recent 12-month-prevalence of PD, with and without agoraphobia, in the German adult population was 2.0 % (Jacobi et al., 2014). Patients with PD experience acute, stressful panic attacks as well as chronic stress due to being concerned about future panic attacks and their implications to health as well as changes in behaviour related to the panic attacks. The hypothalamic-pituitary-adrenal (HPA)-axis is the body’s major endocrine stress system controlling responses to various stressors. In clinical psychological research, the activity of the HPA-axis has been investigated extensively in reference to the pathophysiology of panic attacks. The hypothalamus directs the secretion of the adrenocorticotropic hormone (ACTH) from the anterior pituitary which, in turn, stimulates the secretion of cortisol from the adrenal cortex. Under resting conditions, the ACTH and cortisol secretion follow a circadian rhythm as a function of light exposure to stress (Jung et al., 2010), caffeine (Lovallo, Farag, Vincent, Thomas, & Wilson, 2006), intense aerobic exercise (Fuqua & Rogol, 2013), and disrupted sleep (Leproult, 1997), among others. During acute stress, the diurnal hormone secretion is disrupted, which increased release of both cortisol and ACTH in healthy individuals (Tsigos & Chrousos, 2002). In individuals with stress-related mental disorders, this mechanism seems impaired. Thus, ACTH and cortisol release during non-stressful basal and stressful conditions provide an index for the normative (or disrupted) stress-regulating function of the HPA-axis. Contradictory evidence has been reported on the cortisol levels of PD. Basal cortisol concentrations represent the resting activity of the HPA-axis and have been reported as “normative” with no difference from healthy individuals (Abelson & Curtis, 1996; Holsboer, Von Bardeleben, Buller, Heuser, & Steiger, 1986; Uhde, Joffe, Jimerson, & Post, 1988). However,
contradictory to this normative pattern, elevations (Goldstein, 1987; Wedekind, Bandelow, Broocks, Hajak, & Rüther, 2000) as well as reductions (Stones, Groome, Perry, Hucklebridge, & Evans, 1999) in basal cortisol concentrations have been reported as well. Findings on the cortisol stress response are also mixed. The cortisol stress response provides an indicator for the acute HPA-axis reaction to laboratory-induced stressors. Overall, previous research suggests a hyporesponsiveness of the HPA-axis in patients diagnosed with PD. Different panic-related stimuli were used in the activation of the HPA-axis which, in fact, triggered panic but failed to result in cortisol secretion (lactate-induced panic: (Hollander et al., 1989; Levin et al., 1987; Peskind et al., 1998; Seier et al., 1997); CO2-induced panic: (van Duinen, Schruers, Jaegers, Maes, & Griez, 2004; Sinha et al., 1999)). These results correlate with our findings of a cortisol non-response pattern to the Trier Social Stress Test (TSST; Kirschbaum, Pirke, and Hellhammer (1993))in patients with PD (Petrowski, Herold, Joraschky, Wittchen, & Kirschbaum, 2010). The TSST reliably induces subjective stress with concomitant cortisol release showing 2- to 4-fold elevations above baseline levels in healthy individuals (Kirschbaum et al., 1993). In patients diagnosed with PD, the cortisol response was absent (Petrowski et al., 2010). Further, patients with PD were found to show decreased plasma and cortisol stress response in response to the TSST as compared to healthy control participants, independent of comorbid depression and psychoactive medication (Petrowski, Wintermann, Schaarschmidt, Bornstein, & Kirschbaum, 2013). Occasionally, however, increased cortisol stress responses to laboratory-induced panic (CO2: (Woods, Charney, Goodman, & Heninger, 1988); yohimbine: (Charney, Woods, Goodman, & Heninger, 1987); respiratory stimulant: (Abelson, Khan, Liberzon, & Young, 2007)), and spontaneously occurring unprovoked panic attacks (Bandelow, Wedekind, Pauls, Broocks, & Rï, 2000) have previously been reported in the literature.
Until now, it is unknown whether stress (non-)responsiveness is related to the psychotherapy outcome. A proportion of PD patients fail to show a symptom reduction or a remission following psychotherapy (Kampman, Keijsers, & Hendriks, 2002; Keller et al., 1994), which is the first choice treatment for PD (Bandelow, Hau, & Beutel, 2014). Different variables have been associated with the psychotherapy outcome, among them agoraphobic avoidance (Andersson, Carlbring, & Grimlund, 2008) and catastrophic agoraphobic cognition (Keijsers, Hoogduin, & Schaap, 1994) as negative predictors, especially for agoraphobic patients (Keller et al., 1994; Steketee & Shapiro, 1995), anxiety and depression comorbidity with no impediment to the therapy success (Allen et al., 2010; Brown, Antony, & Barlow, 1995; Kampman, Keijsers, Hoogduin, & Hendriks, 2008), as well as the comorbid cluster C personality disorder and initial motivation for therapy, again with no influence on the therapy outcome (Kampman et al., 2008; Keijsers et al., 1994). Overall, recent research efforts failed to identify consistent therapy outcome predictors of a psychological or disorder-related kind. To date, there is a lack of studies focusing on the biological correlates of the psychotherapy outcome. One study group reported an association of poor actual and perceived health with the failure to meet recovery criteria after psychotherapy (Schmidt & Telch, 1997). Similarly, in a previous study, psychotherapy nonresponse was associated with decreased cortisol levels upon provocation (Siegmund et al., 2011). Siegmund et al. (2011) found a dissociative pattern in the hormonal stress response and the subjective level of fear during an in-vivo exposure to feared situations: despite experiencing fear, the hormonal stress response did not significantly increase during exposure. And further, patients with the lowest cortisol stress response showed the least improvement from psychotherapy. The aim of the present study was to research the relationship between the cortisol stress response to the TSST and the psychotherapy outcome in patients diagnosed with PD, with or without agoraphobia. We hypothesized that the cortisol stress response is predictive of symptom
recovery. Specifically, we predicted that the TSST non-response is associated with a higher panic symptom severity and psychotherapy non-response.
Methods Study participants The data were collected from June 2008 to October 2012. The patients were recruited from the University Hospital of the Technische Universität Dresden, Germany, before the start of cognitive behavioural psychotherapy. In addition, the healthy control participants were recruited via newspaper advertisements and matched to the patient sample by age and sex. General inclusion criteria were being 18 to 65 years of age and fluency in the German language. Exclusion criteria included a history of substance (ab)use, psychotic or bipolar disorder, posttraumatic stress disorder, eating disorder, as well as familiarity with the TSST (Kirschbaum et al., 1993), pregnancy as well as any severe physical illness (e. g. cancer, a metabolic or autoimmune disorder) within the previous two years. The Structured Clinical Interview (SCID; (Spitzer, First, Gibbon, & Williams, 1990; Wittchen et al., 1990) for DSM-IV-TR diagnosis of mental disorders on axis I and II (American Psychiatric Association, 2000) was conducted by trained clinical interviewers and the diagnoses confirmed by an experienced psychotherapist (KP). Patients with a current primary diagnosis of PD, with or without agoraphobia, were included in the study. Inclusion in the healthy control group was established using the DIA-X stem questions (Wittchen, 2007) which confirm that the participants did not have a history of mental disorders. Thirty patients with PD and 32 healthy control participants were screened with respect to the defined inclusion and exclusion criteria. Two patients were excluded due to a 12-monthdiagnosis of post-traumatic stress disorder and alcohol abuse disorder, resulting in a sample of n = 28 patients with a primary diagnosis of PD and n = 32 age- and sex-matched healthy control
participants. According to the Panic & Agoraphobia Scale (Bandelow, 1995), n = 5 PD patients showed borderline panic and agoraphobic symptoms, n = 7 a mild, n = 11 a moderate and n = 5 a severe psychopathology. Two patients were on antidepressant medication (selective serotonin reuptake inhibitor: Citalopram, Paroxetine). All the other patients were free of antidepressant or anxiolytic medication. Comorbid mental disorders were major depression (single episode: n = 6; recurrent episode: n = 4) and specific phobia (n = 4). A brief description of sociodemographic and clinical characteristics of the included study participants is provided in Table 1. All the study participants gave written informed consent. The study procedure was approved by the local Ethics Committee of the Medical Faculty of the Technische Universität Dresden, Germany (No# EK46032008).
Cognitive behavioural therapy and clinical measures Cognitive behavioural therapy (CBT) for the patients (not the healthy control participants) was administered in individual and group sessions within five weeks of semi-residential care. The therapy was standardized based on the manual by Lang, Helbig-Lang, Westphal, Gloster, and Wittchen (2011). The CBT encompassed: group psycho-education referring to anxiety and PD; explanation of the treatment rationale; exposure therapy involving interoceptive exposure, therapist-accompanied and self-managed confrontation with feared situations as well as cognitive therapy to reduce anxiety-maintaining beliefs. Except for psycho-education, all the other interventions were administered in individual sessions. All the therapists were experienced in cognitive behavioural techniques and regularly supervised by the senior author (KP). Information on sociodemographic variables (sex, age, body mass index, smoking status) as well as any acute or chronic medical illnesses and medication intake were assessed in a routine medical examination and laboratory test prior to the CBT. A questionnaire battery was used to
measure severity of PD: (1) The Panic & Agoraphobia Scale (PAS; Bandelow (1995)) was obtained to evaluate the global severity of illness including five subscales (panic attacks, agoraphobia, anticipatory anxiety, disability, and concerns about health). Hereby, the respondent is asked to answer the 13 items on a 4-point Likert scale. (2) The Agoraphobic Cognitions Questionnaire (ACQ; Chambless, Caputo, Bright, and Gallagher (1984)) is a self-report survey measuring fearful panic beliefs and catastrophic cognitions about panic. The respondent is asked to answer the items on a 5-point scale anchored from 0 (“thought never occurs”) to 4 (“thought always occurs”). The items are then averaged. (3) The Bodily Sensations Questionnaire (BSQ; Chambless et al. (1984)) assesses fear of bodily sensations that often occur during panic attacks with 17 items to be answered on a 5–point Likert scale ranging from 0 (“not frightened”) to 4 (“extremely frightened”). The items are then averaged. (4) Agoraphobic avoidance was assessed using the Mobility Inventory (MI; Chambless, Caputo, Jasin, Gracely, and Williams (1985)). Twice, the respondent indicates for 26 situations avoidance behaviour on a 5-point scale with response anchors ranging from 0 (“never”) to 4 (“always”), once when confronted with the situation by him-/herself and once when accompanied by another person. The items are averaged separately for both. To account for comorbid depression, the Beck Depression Inventory II (Beck, Steer, & Brown, 1996; Hautzinger, Keller, & Kühner, 2006) was administered to evaluate severity of depressiveness. This self-report rating inventory is composed of 21 groups of items matching the DSM-IV-TR major depression criteria. Each item group consists of a list of four statements arranged in increasing intensity. The respondent is asked to choose the most appropriate alternative that best describes the way he or she felt during the past two weeks including the present day. The German language questionnaires were handed out to the participants at the beginning of the study and at post-therapy (except for the BDI).
Trier Social Stress Test (TSST) and cortisol collection All study participants performed the standardized protocol for the TSST (Kirschbaum et al., 1993) within the first two weeks of the CBT. The TSST reliably induces acute moderate psychosocial stress under laboratory conditions (review: Foley and Kirschbaum (2010)). In brief, participants are confronted with a mock job interview (5 min) and a mental arithmetic task (5 min) to be performed in front of a selection committee. The Primary Appraisal Secondary Appraisal Questionnaire (PASA; Gaab (2009)) was used prior to the TSST and a Visual Analogue Scale was used following the TSST to assess the subjective level of distress. Blood samples were collected via a venous catheter 75 min and 1 min prior to the TSST as well as 1 min, 10 min, 20 min, 30 min, 45 min, and 60 min after the TSST and stored at 4°C. For the determination of plasma ACTH concentrations, blood was collected into tubes containing a mixture of trasylol and EDTA (Sarstedt, Nümbrecht, Germany). For the determination of plasma cortisol concentrations, blood was collected in serum gel monovette (Sarstedt, Nümbrecht, Germany) and immediately centrifuged at 4°C and 3000 rpm for 10 min. Then, plasma was stored at -80°C and at -20°C before being assayed for ACTH and cortisol. Plasma cortisol concentrations were determined using a commercially available radioimmunoassay kit with the Solid Phase Antigen Linked Technique (SPALT) with the LIAISON-Analyzer® (DiaSorin, S.p.A., Italy). Plasma ACTH was analysed using an immunoradiometric assay (Immulite, 2500 ACTH, Germany). To account for circadian rhythm of cortisol secretion, the TSST was performed in the afternoon not earlier than 2 pm. Female participants underwent the TSST in the luteal phase in order to account for the influence of the menstrual cycle.
Statistical analyses Group comparisons with respect to sociodemographic and clinical variables (pre-therapy) were evaluated using univariate analyses of variance (ANOVA) for continuous variables and Chisquare test (χ2) for dichotomous variables. ANOVA for repeated measures were conducted to test for differences over time in the continuous clinical outcome measures of the ACQ, BSQ, MI, and PAS. Blood ACTH and cortisol data were subject to log transformation to reduce the skewness parameter. Group differences in the cortisol stress response (cortisol, ACTH) were assessed using a 2 (group: PD patients, healthy control participants) x 8 (time: 75 min and 1 min prior to the TSST, 1 min, 10 min, 20 min, 30 min, 45 min, and 60 min after the TSST) ANCOVA for repeated measures with baseline hormonal values (-75 min, -1 min) as covariate and with Greenhouse-Geisser corrections. For ACTH analysis, data from one PD patient and from one healthy control participant were excluded due to outlying values of more than three standard deviations above the mean. Pearson’s correlations were conducted to quantify the associations between mean cortisol concentrations and the psychotherapy outcome as well as between the subjective level of distress and the psychotherapy outcome. The cortisol stress response to the TSST was defined as an increase of at least 55.2 nmol/l compared to baseline (Kirschbaum, Wüst, & Strasburger, 1992; Weitzman et al., 1971; Wuest et al., 2000). The response to the psychotherapy was defined as 50% symptom reduction from pre- to post-therapy. All statistical analyses were performed using SPSS for Windows, version 22 (IBM, Chicago, Illinois). The figures were created by Sigma Plot 11.0 for Windows (Systat Software Inc., Erkrath, Germany). For descriptive purposes, the data in the figures are presented in original units.
Results Clinical measures The groups were well matched on sociodemographic variables (p’s ≥ .109) as shown in Table 1. There were no significant differences in age, sex, body mass index, or smoking status. As expected, the study groups differed significantly with regard to the panic-specific questionnaires with the PD patients showing higher scores in agoraphobic cognitions (p’s ≤ .05), concerns about body sensations (p ≤ .05), avoidance behaviour (p’s ≤ .001), and the global PAS symptom score (p’s ≤ .001). Further, the study groups were found to differ significantly in reported depressive symptoms (p ≤ .001), with the post-hoc analysis revealing higher BDI scores in PD patients with comorbid depression as compared to the PD patients without comorbid depression (p ≤ .01) and compared to the healthy control participants (p ≤ .001).
[insert Table 1 about here]
TSST cortisol profile Twelve PD patients (42.9 %) and n = 21 (65.6 %) healthy control participants showed a cortisol stress response to the TSST according to the defined response criterion. This difference did not reach statistical significance (χ² = 3.128, df = 1, p = .118). Figure 1 demonstrates the hormonal stress response to the TSST. Plasma cortisol levels (F1.500;83.990 = 12.006, p ≤ .001, ηp2 = 0.177) as well as plasma ACTH levels (F1.939;102.761 = 3.543, p ≤ .05, ηp2 = 0.063) were found to increase in response to the TSST. Repeated measures ANCOVA, with baseline cortisol concentrations (-75 min, -1 min) added as covariates, revealed neither a main effect of group (F1;56 = 0.650, p = .424, ηp2 = 0.011) nor a time x group interaction effect (F1.500;83.990 = 0.728, p = .449, ηp2 = 0.013). There were no baseline cortisol differences (-75 min: F1;59 = 0.780, p = .381) nor any baseline
ACTH differences (-75 min: F1;58 = 2.637, p = .110; -1 min: F1;56 = 2.445, p = .124) between the groups, except for baseline cortisol 1 min prior to the TSST (F1;59 = 5.278, p = .025) with lower baseline cortisol concentrations in PD patients. Repeated measures ANCOVA, with baseline ACTH concentrations (-75 min, -1 min) added as covariates, revealed neither a main effect of group (F1;53 = 0.014, p = .905, ηp2 = 0.000) nor a time x group interaction effect (F1.939;102.761 = 0.633, p = .528, ηp2 = 0.012). Groups did not differ significantly in their subjective distress ratings before (PASA: p = .117) and after (VAS: p = .578) the TSST. Descriptively, PD patients who displayed a TSST non-response scored higher in the panic-specific questionnaires at post-therapy (ACQ, BSQ, MI, PAS). These differences did not reach statistical significance (p’s ≥ .106).
[insert Figure 1 about here]
Psychotherapy outcome All the named panic-specific outcome measures significantly decreased from pre- to post-therapy (p’s ≤ .001; see Table 2). With regards to the PAS accounting for all the panic-specific complaints (agoraphobic cognitions, fear of bodily sensations and agoraphobic avoidance behaviour), nine PD patients (32.1 %) were classified as psychotherapy responders according to the defined criterion of at least 50 % symptom reduction from pre- to post-therapy. On a descriptive level, psychotherapy non-responders showed lower mean stress hormone concentrations during the TSST as compared with psychotherapy responders (ACTH: nonresponders: 3.12 (mean) ± 2.00 (SD), responders 4.56 ± 4.00; cortisol: non-responders 190.67 ± 93.86, responders 232.00 ± 129.54). Group differences did not reach statistical significance (p’s ≥ .211).
[insert Table 2 about here]
Pearson’s correlation analyses revealed significant inverse associations between the mean cortisol concentration and the post-therapy MI total score when accompanied (r = - .396, p ≤ .05) as well as a trend for an inverse association for post-therapy MI total score when by themselves (r = .345, p = .072). Patients with the highest stress hormone concentration after the TSST showed the most improvement by psychotherapy in the agoraphobic avoidance behaviour (see Figure 2). No significant correlations were observed between mean cortisol concentration and ACQ, BSQ or PAS (p’s ≥ .273) as well as between mean ACTH concentrations and the mentioned post-therapy outcome measures (p’s ≥ .276).
[insert Figure 2 about here]
Further, Pearson’s correlation analyses revealed significant associations between the PASA stress index and the BSQ (r = .438, p ≤ .05) as well as a trend toward an association with ACQ loss of control (r = .402, p = .051) and ACQ total score (r = .387, p = .062). Patients with high subjective distress showed the most improvement by psychotherapy in catastrophic agoraphobic cognitions and fear of bodily sensations. No significant associations were observed for the VAS stress index and the psychotherapy outcome measures (p’s ≥ .183).
Data with comorbid depression taken into account Due to the known influence of depressive disorders on the HPA axis functioning (Burke, Davis, Otte, & Mohr, 2005), the TSST cortisol profile was analysed additionally with the BDI symptom score as covariate. The mean BDI score in the patient group was 11.93 ± 9.40.
Reported main and interaction effects were basically the same. The main effect of time could be found both for cortisol (F1.568;86.267 = 10.861, p ≤ .001, ηp2 = 0.165) and ACTH (F2.003;102.158 = 6.052, p ≤ .01, ηp2 = 0.106). ANCOVA revealed significant interaction effect of time x BDI score, both for cortisol (F1.568;86.267 = 6.193, p ≤ .01, ηp2 = 0.101) and ACTH (F2.003;102.158 = 3.079, p ≤ .05, ηp2 = 0.057). The time x group interaction effect for cortisol (F1.568;86.267 = 0.720, p = .458, ηp2 = 0.013) and ACTH (F2.003;102.158 = 0.940, p = .394, ηp2 = 0.018) as well as the main effect of group for cortisol (F1;55 = 0.684, p = .412, ηp2 = 0.012) and ACTH (F1;51 = 0.677, p = .414, ηp2 = 0.013) did not reach significance. Additionally, ANCOVA was conducted with separated PD patient groups based on comorbid depression. For cortisol there was a significant main effect of time (F1.498;82.363 = 11.591, p ≤ .001, ηp2 = 0.174). Neither a significant time x group interaction effect (F2.995;82.363 = 0.611, p = .610, ηp2 = 0.022) nor a main effect of group (F2;55 = 0.499, p = .610, ηp2 = 0.018) were found. Descriptively, PD patients without comorbid depression showed the least mean plasma cortisol concentrations (see Figure 3). For ACTH, ANCOVA revealed a significant main effect of time (F1.930;100.374 = 3.460, p ≤ .05, ηp2 = 0.062), no significant main effect of group (F2;52 = 0.014, p = .986, ηp2 = 0.001) and no significant interaction effect (F3.861;100.374 = 0.419, p = .788, ηp2 = 0.016). Further, significant differences in the BDI score were observed with post-hoc comparisons revealing higher depressiveness in the PD patients with comorbid depression (16.60 (mean) ± 10.47 (SD)) as compared to the PD patients without comorbid depression (9.33 ± 7.90) and healthy control participants (3.50 ± 3.34) (p’s ≤ .05).
[insert Figure 3 about here]
Further, partial correlations were conducted to analyse relationships between psychotherapy outcome measures and mean stress hormone concentrations controlling for depressiveness. A trend toward a positive association between the mean cortisol concentration and the post-therapy MI total score when accompanied (p = .073) was observed. With respect to the other psychotherapy outcome measures, associations with the mean cortisol concentration did not reach significance (p’s ≥ .129). No significant associations were observed with mean ACTH concentrations (p’s ≥ .348).
Discussion
The present study was aimed at analysing the relationship between the cortisol stress response to the TSST and the psychotherapy outcome in patients diagnosed with PD, with or without agoraphobia. We predicted that the TSST non-response would be associated with higher panic symptom severity after the CBT and with psychotherapy non-response. The data showed a significant inverse relationship between the cortisol stress response to the TSST and agoraphobic avoidance behaviour: patients with the lowest cortisol concentration showed the least improvement after psychotherapy in agoraphobic avoidance. Overall, for patients diagnosed with PD, previous research suggested a hyporesponsiveness of the HPA-axis in response to different stressors (van Duinen et al., 2004; Hollander et al., 1989; Levin et al., 1987; Peskind et al., 1998; Petrowski et al., 2010; Petrowski et al., 2013; Seier et al., 1997; Sinha et al., 1999). Our findings agreed partly with the previous studies showing that the hypo-response-pattern was not so clearly pronounced in our sample. The TSST response rates were lower in the patient group: 42.9 % of the PD patients and 65.6 % of the healthy control participants showed a hormonal stress response to the TSST. A non-response
pattern was seen in 57.1 % of the PD patients, thus agreeing with our earlier findings of an absent TSST cortisol response (Petrowski et al., 2010). Descriptively, but not significantly, the PD patients of the present sample displayed lower hormone concentrations after the TSST as compared to the healthy control participants. When the patient group was separated into two groups based on comorbid depression, this difference became more pronounced, with PD patients without comorbid depression showing a marked blunted cortisol response, thus combining well with our previous findings of a decreased cortisol stress response in the TSST in patients with PD (Petrowski et al., 2010; Petrowski et al., 2013). In a previous sample, we already observed that only those PD patients with comorbid depression tended to show a small, but not statistically significant, elevation of cortisol concentration (Petrowski et al., 2010). Since this is a descriptive finding without significant group differences, findings agree also with those studies that reported “normative” cortisol patterns as compared to healthy individuals (Abelson & Curtis, 1996; Holsboer et al., 1986; Uhde et al., 1988). However, the findings in the present sample conflict with previous studies that reported a hyper-responsiveness in PD patients as compared to healthy individuals (Abelson et al., 2007; Bandelow et al., 2000; Charney et al., 1987; Woods et al., 1988). The correlation analyses revealed associations between the cortisol stress response and an improvement in agoraphobic avoidance behaviour. Concurrently, the TSST non-responders within the PD patient group scored higher in agoraphobic avoidance and the other panicsymptom questionnaires at post-therapy. Thus, our findings partially replicate and extend the study results by Siegmund et al. (2011) who demonstrated a dissociative pattern between the hormonal stress response and the subjective level of fear during in-vivo exposure, with an absent hormonal stress response but a high level of fear. While we could not replicate such a dissociative pattern in our sample, the results of the correlational analyses suggest that the patients with the
lowest cortisol levels following psychosocial stress showed the least improvement by psychotherapy as previously reported by Siegmund et al. (2011). Furthermore, our findings combine well with established recommendations for cognitive behavioural treatment for PD patients. Guidelines recommend a high level of fear and psychophysiological arousal during exposure treatment as measured, for instance, with the stress hormone concentration (Lang et al., 2011). In the present sample, higher cortisol concentrations were related to an improvement in agoraphobic avoidance, and high subjective distress was related to an improvement in fear of bodily sensations as well as (descriptively) with an improvement in agoraphobic cognitions. Together, these results emphasise the importance of a “normative” neuroendocrine adaptation to stress. Patients who failed to show a remission after psychotherapy had a less distinctive hormonal stress response than patients who showed improvement following psychotherapy. However, an interpretive challenge for these study results might be that the TSST as a psychosocial stressor did not resemble a panic-specific stressor for which it is essential to adapt for PD patients, e.g. fear of a physical or mental catastrophe. However, the TSST is a standardized laboratory stress induction instrument that reliably induces subjective stress with (in healthy individuals) concomitant cortisol release (Foley & Kirschbaum, 2010; Kirschbaum et al., 1993). Limitations of this study include the psychiatric comorbidity. Ten patients with PD (35.7 %) showed a comorbid depressive disorder. Statistical analyses were repeated with the BDI symptom score included as covariate. As specified in the result section, the findings basically remained the same. Furthermore, a meta-analysis by Allen et al. (2010) showed that comorbid depression is not related to a differential improvement of PD severity. A second limitation is the relatively small sample size, making it harder to detect significant associations. Besides, PD patients underwent the TSST within the first two weeks of CBT. Until then, the patients were
merely confronted with psycho-education and the therapy rationale. TSST stress induction at the end of the psychotherapy may have produced different cortisol profiles. A further limitation is the lack of a follow-up assessment to explore the stability of the observed findings. Implications for future studies are the replication of the current findings with the inclusion of a follow-up assessment and using larger sample sizes. PD has a chronic course with some probability of relapses (American Psychiatric Association, 2000). Possibly, the psychotherapy outcome and the increased relapse risk may be predicted from pre-therapy cortisol stress profiles. Further research ought to analyse whether the cortisol stress response and its relationship to the psychotherapy outcome is associated with the duration of the illness as could be shown for the stress response to hormonal stressors (Petrowski, Wintermann, Kirschbaum, & Bornstein, 2012). Further, future studies ought to analyse the influence of psychotherapy experience. More chronic PD patients with psychotherapy experience might profit less from additional psychotherapy as compared to psychotherapy-naïve patients. Additionally, it would be interesting to compare the findings directly with other patient groups. Similar results on the association between the hormonal stress profiles and the psychotherapy outcome have been obtained for post-traumatic stress disorder (PTSD). Patients with PTSD also display HPA-axis dysregulations during basal conditions and upon stress provocation. Elevated (Lemieux & Coe, 1995; Lindley, Carlson, & Benoit, 2004; Pitman & Orr, 1990) as well as attenuated basal cortisol concentrations (De Kloet et al., 2006; Gill, Vythilingam, & Page, 2008; Olff, Güzelcan, de Vries, Assies, & Gersons, 2006; Rohleder, Joksimovic, Wolf, & Kirschbaum, 2004; Steudte et al., 2013; Wessa, Rohleder, Kirschbaum, & Flor, 2006; Yehuda et al., 1990) were reported. Results concerning the cortisol stress response upon provocation in PTSD are also mixed (no difference to healthy control individuals: (Bremner et al., 2003; Elzinga, Spinhoven, Berretty, de Jong, & Roelofs, 2010; Liberzon, Abelson, Flagel, Raz, & Young, 1999); hyper-responsiveness: (Elzinga, Schmahl, Vermetten, van Dyck, &
Bremner, 2003); hypo-responsiveness: (MacMillan et al., 2009; Pierrehumbert et al., 2009; Roelofs et al., 2009). In PTSD patients, psychotherapy non-response was associated with decreased urinary cortisol levels (Yehuda et al., 2009) and decreased blood cortisol levels (Olff, de Vries, Güzelcan, Assies, & Gersons, 2007). In conclusion, to our knowledge this is one of few published studies focusing on the biological correlates of psychotherapy success. We hope these findings will stimulate future research in the prediction of the psychotherapy outcome for PD patients. Author Notes Conflict of interest. All authors declare that they have no conflicts of interest.
Ethical approval. All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent. Informed consent was obtained from all individual participants included in the study.
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Figure 1. Mean (± SE) blood plasma cortisol (left) and ACTH (right) concentrations of panic disorder (PD) patients and healthy control participants.
Figure 2. Scatterplot showing the relationship between mean cortisol concentration during the TSST and symptom severity post-therapy. * p ≤ .05.
Figure 3. Mean (± SE) blood plasma cortisol (left) and ACTH (right) concentrations of panic disorder (PD) patients with/without comorbid depression and healthy control participants.
Table 1 Characteristics of the total sample. Mean (SD) are listed except where noted
Panic patients
disorder Healthy subjects
control F/χ2
p
Sociodemographics Age (years) Females, n (%) † Body mass index Smoking † Oral contraceptive use †
35.71 (13.18) 20 (71.4) 23.10 (3.08) 13 (46.4) 7 (35.0)
34.66 (12.07) 21 (65.6) 22.92 (2.35) 10 (31.3) 7 (33.3)
1.574 0.232 0.732 1.455 0.013
.109 .782 .755 .291 1.00
Clinical measures PAS total score [0-52] ACQ loss of control [0-4] ACQ physical concerns [0-4] ACQ total score [0-4] BSQ total score [0-4] MI alone [0-4] MI accompanied [0-4] BDI [0-63]
19.00 (10.73) 1.00 (0.70) 1.40 (0.69) 1.20 (0.56) 1.88 (0.78) 1.06 (0.80) 1.67 (1.07) 11.93 (9.40)
1.55 (3.40) 0.58 (0.69) 0.23 (0.56) 0.41 (0.59) 0.82 (0.53) 0.17 (0.27) 0.08 (0.19) 3.41 (3.34)
73.949 1.867 9.137 4.404 2.277 6.132 18.056 23.013
.000*** .048* .000*** .000*** .024* .000*** .000*** .000***
-1.10 (2.73)
2.54
.117
61.11 (26.24)
1.103
.578
Subjective level of distress PASA stress index [-3.75 – 0.03 (2.41) 3.75]a VAS mean 53.98 (14.74) Therapy-Responderb PAS (%) ACQ total score (%) BSQ total score (%) MI alone (%) MI accompanied (%)
9 (32.1) 16 (57.1) 8 (28.6) 19 (67.9) 17 (60.7)
Note. PAS = Panic & Agoraphobia Scale; ACQ = Agoraphobic Cognitions Questionnaire; BSQ = Body Sensations Questionnaire; MI = Mobility Inventory; BDI = Beck Depression Inventory; PASA = Primary Appraisal Secondary Appraisal scale; VAS = Visual Analogue Scale. † Chi-square test. a Panic disorder patients: n = 24; Healthy control subjects, n = 30. b Response to psychotherapy was defined as 50% symptom reduction at post-therapy compared to symptom assessment before therapy, separate for the named questionnaires. * p ≤ .05; *** p ≤ .001.
Table 2 Clinical measures before and after psychotherapy for panic disorder patients Clinical measure PAS total score ACQ loss of control ACQ physical concerns ACQ total score BSQ total score MI alone MI accompanieda
Before therapy Mean (SD) 19.00 (10.73) 1.00 (0.70) 1.40 (0.69) 1.20 (0.56) 1.88 (0.78) 1.06 (0.80) 1.67 (1.07)
After therapy Mean (SD) 13.11 (8.40) 0.49 (0.38) 0.63 (0.48) 0.56 (0.40) 1.17 (0.64) 0.44 (0.47) 0.78 (0.69)
Statistics F1;27 15.714 18.931 44.217 49.795 34.928 32.004 24.887
p .000*** .000*** .000*** .000*** .000*** .000*** .000***
ηp2 .368 .412 .621 .648 .564 .542 .489
Note. PAS = Panic & Agoraphobia Scale; ACQ = Agoraphobic Cognitions Questionnaire; BSQ = Body Sensations Questionnaire; MI = Mobility Inventory. a n = 27. *** p ≤ .001.