افزایش کورتیزول بزاقی روزانه در زنان مبتلا به اختلال شخصیت مرزی

Abstract Borderline personality disorder (BPD) is characterized by a pervasive pattern of instability in affect regulation, impulse control, interpersonal relationships, and self-image. In previous studies, we have used portable mini-computers to assess the severity of recurrent states of aversive emotional distress and dissociation during ambulatory conditions. Here, we used this approach for the assessment of the hypothalamic–pituitary–adrenal (HPA) axis in patients with BPD. We studied 23 unmedicated female patients with BPD and 24 matched healthy controls. Salivary cortisol was collected from all participants during ambulatory conditions in response to reminders provided by portable mini-computers on 3 consecutive days every 2 h for 14 h after awakening. In addition, cortisol in response to awakening was determined in four 15 min intervals on days 1 and 2. After the last collection of cortisol on the second day, 0.5 mg dexamethasone was administered in order to achieve cortisol suppression on day 3 (low-dose dexamethasone suppression test, DST). Patients with BPD displayed significantly higher salivary cortisol levels than healthy controls as demonstrated by higher total cortisol in response to awakening and higher total daily cortisol levels. There were significantly more non-suppressors of cortisol in the low-dose DST in the patient group when compared to the control group. The ambulatory assessment of saliva cortisol is a suitable approach to study basic parameters of the HPA-axis in patients with BPD. Increased adrenal activity and lowered feedback sensitivity of the HPA-axis may characterise BPD. Further studies have to reveal reasons of heightened adrenal activity in these patients.

1. Introduction Borderline personality disorder (BPD) is characterized by a pervasive pattern of instability in affect regulation, impulse control, interpersonal relationships, and self-image. Clinical hallmarks of the disorder are emotional dysregulation, impulsive aggression, repeated self-injurious behavior and chronic suicidality. In previous investigations, we have carefully assessed key symptoms of the disorder which are most disabling for the patients such as recurrent states of severe and aversive emotional distress (tension) and dissociative experiences and were especially interested in the investigation of diurnal fluctuations of these symptoms. We assessed these fluctuations by the help of portable mini-computers which were given to the patients for three consecutive days and reminded them several times during the day to judge their current degree of aversive tension or dissociation on a Lickert scale between 0 (“no tension/dissociation at all”) and 9 (“most severe tension/dissociation”). Our investigations not only demonstrated that female patients with BPD show significantly higher baseline levels of tension and dissociation, but also suffer from recurrent severe and aversive states of tension and dissociation and that tension and dissociative experiences are highly correlated (Stiglmayr et al., 2001). In the present study, we used this “naturalistic” approach for the first time to assess neurobiological measures in patients with BPD during ambulatory conditions. As a well-established neurobiological marker which has been extensively investigated in the context of emotional stress and psychiatric disorders, we assessed cortisol levels and used the dexamethasone suppression test (DST) to assess feedback sensitivity of the hypothalamic–pituitary–adrenal (HPA) axis (for review, see Holsboer, 2001). The present study had the following aims: (1) to investigate whether this ambulatory assessment is a suitable and reliable study tool to assess HPA-axis functioning in patients with BPD and (2) to assess HPA-axis functioning in patients with BPD as compared to healthy controls. In addition to the application of a completely new method to gather neurobiological data in BPD patients, we tried to overcome some of the problems of previous studies which investigated HPA-axis funtioning in patients with BPD (Baxter et al., 1984; Carroll et al., 1981; Kontaxakis et al., 1998; Krishnan et al., 1984; Soloff et al., 1982; Steiner et al., 1984; Sternbach et al., 1983; for review, see De la Fuente and Mendlewicz, 1996; Koenigsberg et al., 1999; Lahmeyer et al., 1989): (1) we excluded patients with a current major depressive disorder (MDD); (2) we controlled potential confounding variables, which may influence HPA-axis functioning such as smoking, menstrual cycle and physical activity; (3) we measured cortisol in saliva, thus preventing artefacts by stress-induced increases in HPA-axis activity due to invasive blood collection; (4) we carefully synchronised all sampling with the individual pattern of awakening of every participant; and (5), most importantly, we assessed HPA-axis functioning not only by determining cortisol levels at a single time point, but in a detailed analysis of cortisol levels on three consecutive days (for overview, see Kirschbaum and Hellhammer, 1994; Kirschbaum and Hellhammer, 1998).

3. Results 3.1. Basal adrenocortical activity and cortisol response to awakening Salivary cortisol was determined on days 1 and 2 in intervals of 15 min after awakening and seven times in 2 h intervals after awakening during the whole day. As shown in Fig. 2(a) and (b), cortisol levels were higher in patients with BPD than in controls. These differences were not statistically significant at the single time point including the “awakening cortisol” on days 1 and 2 (“cortisol immediately after awakening”, Table 2), which was probably due to the high variability of cortisol levels especially in the patients with BPD. However, calculated AUCs for the “total cortisol response to awakening” and the “total daily cortisol” were significantly higher in patients with BPD than in controls (Table 2). Patients with BPD displayed a significantly higher cortisol response to awakening on day 2 and on days 1 and 2 in combination, whereas the cortisol response to awakening on day 1 showed a trend for higher levels in the patient group. Total daily cortisol was significantly higher on day 1. In an additional repeated measurements model analysis which takes into account the correlation between samples from one patient and which includes time as a covariate, we found identical results as obtained by comparison of AUC values. For example, comparison of diurnal cortisol secretion on day 1 revealed a significant group effect with an estimate for group differences of 3.03 nmol/l (95% CI [0.11–6.0], p<0.05) and a significant time effect with an estimate for time effects of −0.9 nmol/l/2 h (95% CI [from −1.17 to −0.63], p<0.0001). Since results from repeated measurements analysis were identical to the results obtained from AUC analysis, only results from AUC analyses are given in Table 2. Cortisol levels (means±SD) in patients with BPD and healthy controls in the ... Fig. 2. Cortisol levels (means ± SD) in patients with BPD and healthy controls in the course of day 1 (a), day 2 (b), and day 3 after dexamethasone (c). Cortisol was sampled at the indicated time points by use of Salivette devices. Figure options Table 2. Salivary cortisol levels (nmol/l) in patients with BPD and healthy controls (HCs) Time BPD (n=23) HC (n=24) T df p “Cortisol immediately after awakening” (day 3 after DEX) Day 1 20 ± 13 18 ± 6 0.91 45 0.37 Day 2 28 ± 29 18 ± 9 1.48 40 0.15 Day 3 12 ± 16 5 ± 6 2.00 39 0.05 “Total cortisol response to awakening” (AUC) Day 1 113 ± 40 92 ± 35 1.92 45 0.06 Day 2 116 ± 47 91 ± 32 2.06 44 0.04 Days 1 and 2 115 ± 39 91 ± 29 2.36 44 0.02 “Total daily cortisol” (AUC) Day 1 78 ± 39 58 ± 22 2.13 44 0.04 Day 2 82 ± 63 59 ± 18 1.54 40 0.14 “Total daily cortisol after DEX” (AUC) Day 3 54 ± 49 25 ± 17 2.51 39 0.02 Data are given as means ± SD. BPD, borderline personality disorder; AUC, area under the curve; DEX, dexamethasone. Table options 3.2. Feedback sensitivity of the pituitary–adrenal axis The low-dose DST was performed by applying 0.5 mg dexamethasone at 22:30 on day 2. This low dose of dexamethasone was used on the basis of our assumption that patients with BPD would show low cortisol levels and supersuppression to dexamethasone similar to patients with PTSD (Yehuda et al., 1993). As shown in Fig. 3, the oral ingestion of 0.5 mg dexamethasone induced a significant suppression of cortisol levels in both BPD patients and healthy controls (F(1;33)=71; p<0.001). By using the criteria of Heim et al. ( Heim et al., 1998) (see Section 2), significantly more patients with BPD were non-suppressors in the low-dose DST as compared to the healthy controls (14 vs. 4, χ2, p<0.01). Only 1 patient and 4 controls were super-suppressors in the DST. ANCOVA did not reveal a significant dexamethasone × group interaction (F(1;33)=0.07; p=0.8). Baseline differences did not significantly influence suppression in an additional model taking baseline differences in cortisol levels as covariate. Although there was no dexamethasone × group interaction, total daily cortisol on day 3 was significantly higher in the patients with BPD compared to the healthy controls ( Table 2) whereas cortisol immediately after awakening showed a trend for higher levels in patients with BPD. Cortisol levels after dexamethasone on day 3 were higher in the BPD patients at all time points (p<0.05) (see Fig. 2(c)). Effect of 0.5 mg dexamethasone on cortisol levels in 23 patients with BPD and 24 ... Fig. 3. Effect of 0.5 mg dexamethasone on cortisol levels in 23 patients with BPD and 24 healthy controls. Values are expressed as means ± SD for AUCs of “total daily cortisol” on days 2 and 3. ** indicates significant suppression of cortisol secretion in both patients and controls. Differences between patients and controls are given in Table 2. Figure options 3.3. Influence of possible confounding variables To control for confounding variables which might possibly account for the differences in cortisol secretion between patients and controls, we assessed physical activity and smoking preceding the cortisol samplings. In a first analysis, we compared cortisol levels between smokers and non-smokers and found no significant differences in cortisol secretion. In detail, there was no difference between both groups with respect to the adrenocortical reactivity following awakening on day 1 (t(29,742)=−0.848, p=0.403) or on day 2 (t(30,599)=−0.012, p=0.991). Furthermore, no significant difference could be revealed with respect to the basal adrenocortical activity on day 1 (t(34)=−0.087, p⩽0.9) and on day 2 (t(33)=−1.1, p⩽0.3). At 5 time points (10.00 and 14.00 h on day 1; 14.00, 20.00 and 22.00 h on day 2), patients smoked significantly more cigarettes in the 2 h prior to saliva sampling, although the mean of cigarettes smoked did not exceed 2. Integrating smoking as a covariate in the ANCOVA test, however, did not reveal a significant influence of smoking on cortisol secretion. Physical activity as a covariate in the ANCOVA had also no significant effect on cortisol levels.