آلفا آمیلاز بالا اما نه کورتیزول در اختلال اضطراب اجتماعی تعمیم یافته
|کد مقاله||سال انتشار||مقاله انگلیسی||ترجمه فارسی||تعداد کلمات|
|39156||2008||9 صفحه PDF||سفارش دهید||5810 کلمه|
Publisher : Elsevier - Science Direct (الزویر - ساینس دایرکت)
Journal : Psychoneuroendocrinology, Volume 33, Issue 10, November 2008, Pages 1313–1321
Summary Stress-system dysregulation is thought to increase the risk for anxiety disorders. Here we describe both hypothalamic pituitary adrenal (HPA) axis and autonomic nervous system (ANS) activity in basal non-challenging conditions and after 0.5 mg dexamethasone in generalized social anxiety disorder (gSAD) patients. To ensure stress-free sampling we collected saliva and determined cortisol and alpha-amylase (sAA), the latter a relative new marker of autonomic activity. Forty-three untreated gSAD patients without comorbidity were compared with 43 age and gender matched controls in non-stressed conditions on sAA and cortisol after awakening, during the day (including late evening), and after a low dose (0.5 mg) of dexamethasone. Cortisol and sAA were analyzed with mixed models. Additional analyses were done with paired t-tests. Apart from the assessments in the morning, gSAD patients had significantly higher diurnal and post-dexamethasone 1600 h sAA levels. No differences between gSAD and controls in any cortisol measurements were found. In conclusion, in gSAD in basal, non-stimulated conditions and after dexamethasone, we found hyperactivity of the ANS, as measured with sAA, but not of the HPA-axis. This suggests a relative increased activity of the ANS as compared to the HPA-axis, in line with the observed hyperarousal in gSAD.
Introduction Social anxiety disorder (SAD; also known as social phobia) is one of the most common anxiety disorders (Stein, 2006). It is characterised by the fear of scrutiny by others. In specific SAD (sSAD) one or two situations are feared, e.g. speaking in public, while in generalized SAD (gSAD) most social situations are involved (American Psychiatric Association, 2000). The anxiety in gSAD is often accompanied by hyperarousal, such as increased heart rate, trembling, blushing and sweating. These clinical observations suggest an involvement of the stress system (Kloet et al., 2005 and Goldstein, 2003). However, whether the stress system is involved in gSAD is an unresolved question. Moreover, it is unclear under which conditions (basal versus challenge) and which parts of the stress system (autonomic nervous system (ANS) or the hypothalamic pituitary adrenal (HPA) axis are involved. In gSAD, these systems have never been studied in concert, instead previous studies aimed to elucidate the role of these systems separately. The function of the HPA-axis in SAD has been investigated by using cortisol levels as biological marker. In basal conditions no differences were found between gSAD patients and controls with respect to 24-h urine cortisol levels (Potts et al., 1991 and Uhde et al., 1994). Moreover, diurnal saliva cortisol levels of adolescent girls with SAD were comparable with those of healthy controls (Martel et al., 1999). The last study can be criticized since no distinction was made between subtypes of SAD. With some, but not all psychological challenges, HPA-axis dysfunction was reported. In one study gSAD patients had a significantly larger cortisol response to the Trier Social Stress Test than controls (Condren et al., 2002). Another study found a more outspoken dichotomous cortisol response after a stress challenge in gSAD compared to the control group: the cortisol responders in the group of gSAD patients had higher cortisol levels after the stress task than the cortisol responders in the control group, the cortisol non-responders in the gSAD group had lower cortisol levels than the non-responders in the control group (Furlan et al., 2001). However, in the study with adolescent girls mentioned above, Martel et al. (1999) did not find any difference in cortisol responses between SAD and controls after a public speaking challenge. One study on the effects of a pharmacological challenge with dexamethasone in gSAD was published, reporting no differences between gSAD patients and controls in 24-h urine cortisol levels (Uhde et al., 1994). The function of the ANS has been studied in various ways. Stein and colleagues found higher noradrenaline levels in gSAD patients in one study, but could not replicate this finding in another (Stein et al., 1992 and Stein et al., 1994). One study reported on higher baseline heart rate and blood pressure in gSAD patients compared to controls (Bouwer and Stein, 1998), whereas other studies did not (Grossman et al., 2001, Laederach-Hofmann et al., 2002 and Gerlach et al., 2003). A major drawback of autonomic measures, especially plasma (nor)adrenaline obtained by venipuncture, is the stress accompanying the sampling. Furthermore, heart rate and blood pressure are easily influenced by many factors, e.g. posture. Recently, salivary alpha-amylase (sAA) has been proposed to reflect ANS activity (Chatterton et al., 1996 and Granger et al., 2007). In basal conditions in healthy volunteers, sAA activity shows a diurnal profile with a decrease during the first 60 min after awakening and an increase during the rest of the day (Rohleder et al., 2004 and Nater et al., 2007). sAA levels were relatively independent of several possible confounders like gender, body mass index (BMI), activity level, smoking, eating and drinking but significantly associated with chronic stress and stress reactivity in healthy volunteers (Nater et al., 2007). Psychological and physiological challenges were followed by increases in sAA (Gilman et al., 1979, Bosch et al., 1996, Chatterton et al., 1996, Chatterton et al., 1997, Rohleder et al., 2004, Rohleder et al., 2006, Nater et al., 2005, Nater et al., 2006 and Kivlighan and Granger, 2006), although most studies failed to find significant correlations between adrenaline and noradrenaline, peripheral markers of the ANS, and sAA (Rohleder et al., 2004 and Nater et al., 2006) indicating that stress-dependent sAA increases reflect changes of the ANS in general, not catecholamine increases. Furthermore, two pharmacological challenges provided direct evidence that sAA measures ANS activity. Propranolol (a non-selective beta-blocker), combined with a stressful task, resulted in lowering of sAA, showing the sensitivity of sAA to changes in adrenergic activity (Van Stegeren et al., 2006). Similarly, a yohimbine (an alpha-2-receptor antagonist) challenge induced not only increases of peripheral noradrenaline levels but also increases of sAA levels compared to placebo. No correlations were found between adrenaline, noradrenaline and sAA, indicating that sAA reflects central noradrenaline release instead of peripheral noradrenaline secretion (Ehlert et al., 2006). More research on sAA is discussed in the review of Granger et al. (2007). The question remains whether there is a difference in basal autonomic activity in gSAD as compared to controls. Furthermore, we aimed to investigate the ANS and the HPA-axis in concert, since the specific balance between these stress systems, as was shown in experimental animal research, is often overlooked (Goldstein, 2003). Considering sAA as a measure of autonomic activity together with stress-free sampling of saliva stimulated us to use sAA to test basal autonomic activity in gSAD. Here we report the awakening and diurnal rhythm of both cortisol and sAA, in basal conditions. In order to also measure the feedback sensitivity of the HPA-axis, we added a low-dose dexamethasone suppression test with 0.5 mg (Gaab et al., 2002), which is more sensitive to detect differences between different groups than higher dosages. We expected, based on former research, not to find differences in HPA-axis function in gSAD as compared to controls. However, we hypothesized that the ANS, as measured using sAA, would show hyperactivity in gSAD during the day.
نتیجه گیری انگلیسی
. Results 3.1. Subjects Initially 46 patients and 54 controls were screened for this study. Three patients and eleven controls dropped out. For more detailed information on this see the flow chart in Fig. 1. Forty-three patients with gSAD and 43 age (±5 years) and gender matched healthy controls participated in this study. Subject characteristics are given in Table 1. The gSAD group was assessed within 13 months, the control subjects within 2.5 years. Flow chart of recruitment and inclusion process of gSAD patients and ... Figure 1. Flow chart of recruitment and inclusion process of gSAD patients and controls. The numbers of patients and controls that entered the various stages of the recruitment and inclusion process. Figure options Table 1. Characteristics of gSAD patients and controls gSAD patients (n = 43) Healthy controls (n = 43) Characteristics Number of women/men 21/22 21/22 Age women/men (years) 42.1 (±11.8)/41.3 (±13.9) 41.7 (±12.2)/41.4 (±14.5) Age total (years) 41.7 (±12.8) 41.6 (±13.3) Smoking 16.3% (n = 7) 14.0% (n = 6) Number cigarettes/day 8.6 (±6.3) 10.3 (±5.7) Use of alcohol 86.0% (n = 37) 74.4% (n = 32) Number of units alcohol/week 6.6 (±4.2) 5.7 (±3.7) BMI 23.9 (±3.4) 24.4 (±3.9) LSAS score 78.2 (±19.6) 8.6 (±5.6) HRDS score 5.7 (±3.1) 1.3 (±1.5) Trauma 49% (n = 21) 40% (n = 17) Medication Beta-blockers 2% (n = 1) 0% Oxazepam 10 mg (as needed) 2% (n = 1) 2% (n = 1) Nasal glucocorticoids 2% (n = 1) 0% Inhaled glucocorticoids 2% (n = 1) 2% (n = 1) Glucocorticoid crème 0% 5% (n = 2) Oral contraceptives 19% of women (n = 4) 38% of women (n = 8) gSAD = generalized social anxiety disorder; BMI = body mass index; LSAS = Liebowitz Social Anxiety Scale; HRDS = Hamilton rating scale for depression. Table options Of the 43 patients and controls, some data were missing due to insufficient saliva collection. For all missing data, the matching data from the other group were removed from the analyses as well. Insufficient saliva was collected for cortisol measurement of test day II at 900 h in three subjects (n = 40), and of cortisol test day II at 1600 h in one subject (n = 42). Insufficient saliva was collected for sAA measurements of the AUC awakening in one subject (n = 42) and at test day II 900 h in one subject (n = 42). After the test days it appeared that one patient used a beta-blocker for high blood pressure, but did not mention this before. The data of this patient were included in the analyses. 3.2. Salivary cortisol At test day I, we found no differences between gSAD patients and controls on the AUC cortisol after awakening as analysed with mixed models and corrected for the confounders (p = 0.864) (see Fig. 2 and Table 2). In each group we compared cortisol levels at 30 min after awakening with cortisol levels directly at awakening with a paired sample t-test. In both the gSAD and control group no significant differences were found between these time points (mean = −2.62, S.D. = 9.23, p = 0.07; mean = −0.035, S.D. = 5.56, p = 0.967), reflecting the absence of a CAR in both groups (see Fig. 2). Awakening, diurnal and post-dexamethasone salivary cortisol levels (±S.E.M.) in ... Figure 2. Awakening, diurnal and post-dexamethasone salivary cortisol levels (±S.E.M.) in gSAD patients and controls. Awak. = awakening samples, they were taken at the moment of awakening, and after 30 min, 45 min and 1 h after awakening at test day I. The diurnal samples were taken at 1100 h, 1500 h, 1900 h and 2200 h at test day I. Post-dexamethasone salivary cortisol levels: 900 h and 1600 h are the time points at test day II, the day following the ingestion of dexamethasone. Figure options Table 2. Cortisol (log transformed) and sAA (sqrt transformed) data in gSAD patients and controls as analyzed with mixed models (within matched pairs) Mean F p p (bonf. corr.) n gSAD Co Cortisol (nmol/l) Day I AUC awakening 962.2 1060.9 0.030 0.8864 43 AUC diurnal 4993.6 5486.5 0.084 0.773 – 43 Late evening (2200 h) 3.5 4.5 1.687 0.201 – 43 Day II Post-dex. 900 h 4.1 4.5 0.010 0.920 – 40 Post-dex. 1600 h 3.384 3.029 1.307 0.256 – 42 Amylase (U/ml) Day I AUC awakening 9299.145 6959.123 2.612 0.114 – 42 AUC diurnal 225147.69 146808.58 5.413 0.022* 0.044* 43 Day II Post-dex. 900 h 191.776 130.758 3.794 0.059 – 42 Post-dex. 1600 h 327.542 206.047 5.628 0.020* 0.040* 43 sAA = salivary alpha-amylase; gSAD = generalized social anxiety disorder; Co = controls; AUC awakening = the area under the curve of cortisol levels at awakening, 30 min, 45 min and 60 min after awakening; AUC diurnal = the area under the curve of cortisol levels at 1100 h, 1500 h, 1900 h and 2200 h. Late evening cortisol is the cortisol level at 2200 h. Post-dex. are the data following the ingestion of 0.5 mg dexamethasone. These data reflect mixed models analysis of the cortisol and sAA data, corrected for confounders. The cortisol data were log-transformed. For the sAA data a square root transformation was performed. The F- and p-values reflect analyses with the transformed data. p (bonf. corr.) reflects the Bonferroni corrected significant p-values. * Means that the data were statistically significant. For cortisol the confounders that were taken into account were month of measurements, time of awakening, and smoking, for sAA the confounders that were taken into account were use of coffee, smoking, and the body mass index. Table options Mixed models analysis with correction for confounders also showed no differences between both groups in the AUC diurnal cortisol and the cortisol level at 2200 h (p = 0.773; p = 0.201) (see Fig. 2 and Table 2). Compliance was checked in both groups. Dexamethasone was present in the saliva at day II of all subjects, except for three controls and one patient. Since an obvious suppression of their cortisol levels was found, they probably did ingest the dexamethasone. At test day II post-dexamethasone cortisol levels (900 h and 1600 h) did not differentiate between the groups (p = 0.920; p = 0.256) (see Table 2 and Fig. 2). Taken together, we did not observe significant differences in saliva cortisol at any measure of the HPA-axis we used. 3.3. Salivary alpha-amylase In contrast, sAA did show statistically significant differences between patients and controls as analysed with mixed models, after correction for the confounding factors. On test day I in the morning, during the first hour after awakening, we did not find significant differences in the AUC sAA awakening (p = 0.114) (see Fig. 3 and Table 2). However, during the day (from 1100 h to 2200 h), the AUC sAA diurnal was much higher in gSAD patients as compared to controls (p = 0.022). At 1500 h sAA levels were almost twice as high in patients as compared to controls. For details see Fig. 3 and Table 2. Awakening, diurnal and post-dexamethasone salivary alpha-amylase levels ... Figure 3. Awakening, diurnal and post-dexamethasone salivary alpha-amylase levels (±S.E.M.) in gSAD patients and controls. Awak. = awakening samples, they were taken at the moment of awakening, and after 30 min, 45 min and 1 h after awakening at test day I. The diurnal samples were taken at 1100 h, 1500 h, 1900 h and 2200 h at test day I. Post-dexamethasone salivary alpha-amylase levels: 900 h and 1600 h are the time points at test day II, the day following the ingestion of dexamethasone. *Means a statistical difference between patients and controls in sAA levels as analyzed with mixed models (p = 0.009). Figure options On test day II, post-dexamethasone sAA levels were significantly higher in gSAD patients compared to controls at 1600 h (p = 0.02) (see Table 2 and Fig. 3), but not at 900 h (p = 0.059) (see Table 2 and Fig. 3). In Table 2 also the Bonferroni corrected p-values are given.