Psychiatry Research 149 (2007) 177 – 184 www.elsevier.com/locate/psychres A preliminary study of cortisol and norepinephrine reactivity to psychosocial stress in borderline personality disorder with high and low dissociation Daphne Simeon ⁎, Margaret Knutelska, Lisa Smith, Bryann R. Baker, Eric Hollander Department of Psychiatry, Mount Sinai School of Medicine, Psychiatry Box #1230, One Gustave L. Levy Place, New York, NY 10029, United States Received 13 December 2004; received in revised form 4 October 2005; accepted 23 November 2005 Abstract The goal of the current study was to investigate subjective and neurohormonal reactivity to acute psychosocial stress in borderline personality disorder (BPD) as a function of dissociative symptoms. Five BPD subjects with high dissociation, 8 BPD subjects with low dissociation, and 11 healthy control subjects were compared in basal urinary cortisol and norepinephrine, as well as in plasma cortisol and norepinephrine reactivity to the Trier Social Stress Test (TSST). Subjective stress rating and emotional response to the TSST were also measured. The three groups differed significantly in cortisol stress reactivity, with the highdissociation BPD group demonstrating the most robust response. The three groups did not significantly differ in norepinephrine stress reactivity. In the combined BPD sample, dissociation severity tended to be inversely correlated with basal urinary norepinephrine, was positively correlated with norepinephrine stress reactivity. Childhood trauma was inversely correlated with basal urinary cortisol. In conclusion, despite its small sample size this pilot study suggests that dissociative symptomatology may be a marker of heightened biological vulnerability to stress in BPD, and merits further study. © 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Trier Social Stress test; Stress; HPA axis; Autonomic system; Trauma; Dissociative Experiences Scale; Neurochemistry; Neurohormones 1. Introduction Dissociative symptoms are a prominent feature in a subgroup of borderline personality disorder (BPD) individuals, and comprise one of the nine current diagnostic criteria for the disorder (“transient, stressrelated paranoid ideation or severe dissociative symptoms”). It has been suggested that the addition of this criterion was the most significant revision of the BPD diagnosis instituted by the DSM-IV, and the criterion ⁎ Corresponding author. Tel.: +1 212 241 7477; fax: +1 212 427 6929. E-mail address: daphne.simeon@mssm.edu (D. Simeon). carries excellent specificity for the disorder (Skodol et al., 2002). In one study of a large sample of 290 BPD patients, 32% had low, 42% moderate, and 26% high levels of dissociation (Zanarini et al., 2000a). Dissociation severity was predicted by inconsistent caretaking, sexual abuse by a caretaker, childhood witnessing of sexual violence and adult rape (Zanarini et al., 2000b). Simeon et al. (2003b) found that dissociation in a BPD sample was specifically related to emotional neglect rather than total childhood trauma, as well as to fearful attachment style. Goodman et al. (2001) on the other hand reported that pathological dissociation in BPD was unrelated to childhood trauma, but was possibly related to genetic factors. 0165-1781/$ - see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.psychres.2005.11.014 178 D. Simeon et al. / Psychiatry Research 149 (2007) 177–184 One compelling reason for greater attention to dissociative symptoms in BPD is the strong association between dissociation and high-risk BPD behaviors such as self-mutilation (Brodsky et al., 1995; Zlotnick et al., 1999); greater depressive, anxious, posttraumatic, behavioral dyscontrol and alcohol abuse symptomatology (Shearer, 1994; Brodsky et al., 1995; Wildgoose et al., 2000); and greater overall utilization of psychiatric services (Brodsky et al., 1995). Specifically, Zlotnick et al. (1999) showed that a higher level of dissociation was associated with self-injuring behavior, even when controlling for borderline personality disorder diagnosis and for childhood abuse. In a study by Brodsky et al. (1995), self-injury, childhood trauma, depression, and psychiatric treatment were all significant predictors of dissociation when all other variables were controlled for. It remains unknown whether a dissociative symptom domain can be reliably defined in BPD, with associated neurobiological features, particularly perturbations in stress-related neurohormones such as the HPA axis and the noradrenergic system which are widely implicated in stress-related psychopathology. Indeed, a hallmark feature of BPD that has been relatively ignored in clinical research is BPD patients' pronounced stress intolerance. It has been argued that the proneness to regression may be a hallmark feature of the condition, and possibly should comprise a diagnostic criterion (Skodol et al., 2002); such regression typically occurs under conditions of diminished structure and constancy and increasing stress. In a naturalistic study that investigated the correlates of stress in BPD, participants were monitored over a 24-h period in order to examine self-reported states associated with the experience of “aversive tension,” i.e. feeling overwhelmingly stressed unlinked to a specific clearly identifiable affect (Stiglmayr et al., 2001); substantial inter-individual differences were found in the duration and intensity of subjectively perceived tension, and this tension correlated strongly with dissociative symptoms. To our knowledge, there are no studies that have examined HPA axis or noradrenergic functioning in BPD in relation to dissociative symptoms. Other BPD symptom domains, e.g. impulsive aggression and affective instability, have been much better characterized to date, phenomelogically, neurobiologically, and in terms of treatment response (Best et al., 2002; Koenigsberg et al., 2002; Hollander et al., 2003). The HPA axis has been the subject of some investigation in BPD. Several studies have examined dexamethasone suppression in BPD and have fairly consistently shown that the DST is neither particularly sensitive to the diagnosis nor helpful in differentiating BPD from other affective spectrum disorders (Lahmeyer et al., 1988; Korzekwa et al., 1991; De la Fuente and Mendlewicz, 1996). In personality-disordered subjects, cortisol hypersuppression in response to dexamethasone has been found to be associated with comorbid PTSD rather than with trauma exposure or with the BPD diagnosis per se (Grossman et al., 2003). In a more naturalistic design, Lieb et al. (2004) conducted sequential ambulatory salivary cortisol monitoring over a 3-day period and reported significantly higher ambient cortisol levels in BPD compared to healthy controls. Another study examined cortisol reactivity to traumatic and abandonment scripts, and found that BPD patients had enhanced cortisol reactivity compared to PTSD and control subjects (Elzinga et al., 2002). Unlike BPD, the HPA axis has been minimally investigated in dissociative disorders; Simeon et al. (2001) reported elevated basal cortisol and dexamethasone suppression resistance in depersonalization disorder compared to healthy controls. Norepinephrine also plays a central role in regulating the organism's response to stress, via its effects on arousal, selective attention, vigilance, and the encoding of emotional memory. It has been proposed that childhood trauma may contribute to BPD patients' hyperreactivity to stress and interpersonal hypersensitivity, and that these heightened responses may be in part mediated by trauma-related noradrenergic dysregulation (Figueroa and Silk, 1997). Indeed, unmedicated patients with BPD were reported to have significantly decreased platelet alpha 2-adrenergic receptor binding sites (Southwick et al., 1990). Another study of personality-disordered subjects showed that plasma MHPG, the major metabolite of NE, was inversely correlated with lifetime history of aggression (Coccaro et al., 2003). These two conflicting studies are suggestive of heightened versus blunted noradrenergic tone, respectively, in BPD, and to our knowledge there are no other studies examining the noradrenergic system in BPD and its responsivity to stress. With respect to dissociative symptoms and the noradrenergic system, the few pertinent studies in the literature are suggestive of autonomic blunting. After rape, women scoring high in dissociation showed diminished heart rate and galvanic skin responses (Griffin et al., 1997). Sierra et al. (2002) found that, compared to anxiety disorder and healthy control subjects, individuals with depersonalization exhibited reduced magnitude and increased latency of skin conductance response to unpleasant compared to neutral stimuli suggestive of autonomic hyporesponsivity. Delahanty et al. (2003) reported that in motor vehicle D. Simeon et al. / Psychiatry Research 149 (2007) 177–184 accident victims, peritraumatic dissociation was negatively associated with norepinephrine and epinephrine in a 15-h urine sample collected in the emergency room. Simeon et al. (2003a) found a strong inverse relationship between dissociation severity and resting 24-h urine norepinephrine in depersonalization disorder. To our knowledge, there have been no studies in BPD investigating the neurobiological response to a standardized psychosocial stress paradigm in general, or with respect to dissociative symptoms in particular. Therefore, the goal of this pilot study was to investigate stress hormone levels at baseline and in response to acute psychosocial stress in two BPD samples, with and without prominent dissociative symptoms. 2. Methods Thirteen BPD and eleven healthy control (HC) subjects completed the study. The study was approved by the institution's review board, and all subjects gave written informed consent prior to participation. BPD participants were outpatients recruited from the community via newspaper advertisements. All subjects were medically healthy and free of all medications for at least 5 weeks, including oral contraceptives. In order to minimize the impact of comorbidity on biological findings, BPD subjects were excluded if they had current substance use disorder (assessed by structured interview and urine toxicology), current mania, current major depression, current PTSD, current eating disorder, and lifetime psychotic disorder or mental retardation. Healthy controls were free of lifetime Axis I and Axis II disorders. BPD diagnosis was initially assessed by psychiatric interview, and then independently confirmed by a psychologist who administered the SID-P (Pfohl et al., 1997), also assessing other personality disorders. Axis I disorders were assessed by the SCID-P (First et al., 1995). All subjects were administered the Dissociative Experiences Scale DES (Carlson and Putnam, 1993). High-dissociating subjects were defined as those with DES scores >25, while low-dissociating subjects were defined as those with DES scores <25. Childhood trauma was measured with the Childhood Trauma Questionnaire-short version (Bernstein et al., 2006). Subjects were administered a highly shortened version of the POMS scale (modification of Shacham, 1983, abbreviated POMS Scale), just prior to the TSST test (POMS-Anticipation) and immediately after its conclusion (POMS-Completion). The POMS scale consisted of 7 “negative mood” items rated on a 5-point scale (0—not at all to 4—extremely), applied to “how you are feeling at this moment,” with 6 items representing the standard 179 factors of the POMS and one additional item representing dissociation (“fatigued/worn out, tense/anxious, resentful/ angry, sad/discouraged, forgetful/confused, embarrassed/ ashamed, detached/spaced”). Subjects were also asked to complete a Stress Rating of the TSST right after its completion, inquiring “how stressful” the TSST was for them on a 7-point Likert scale (1—“hardly any stress” to 7—“worse stress ever”). Subjects were admitted to the Mount Sinai General Clinical Research Center at 8:00 am of Day 1 and were discharged on noon of Day 2. Admission was not timed with respect to menstrual cycle for menstruating females. By 9:00 am of Day 1 an IV catheter was inserted, allowing for urine and blood sampling exempt from the stress-inducing effects of later needle sticks. Subjects were tested under strictly controlled conditions, including minimal activity, meals at specified times (8:00 am, noon, 6:00 pm prior to respective blood drawings), and sleep from 11:00 pm to 7:30 am of the next day. The 24-h urine collection for cortisol and norepinephrine commenced at 10:00 am of Day 1 and was completed at 10:00 am of Day 2. The Trier Social Stress Test (TSST) (Kirschbaum et al., 1993) was conducted at 10:30 am of Day 2. The TSST is a standardized psychosocial stressor that has been reliably shown to induce mild to moderate stress in healthy subjects, inducing measurable subjective, cognitive and biological reactivity. It is a public performance test conducted in front of a group, and consisted of a 5-min preparation phase and a 10-min presentation phase (5 min of a job interview speech and 5 min of out-loud mental arithmetic). Blood samples for cortisol and norepinephrine determination were drawn at 8:00am, 10:30 am (beginning of TSST), 10:45 am (end of TSST preparation phase), 11:00 am (end of TSST presentation phase) and 11:30 am (one-half hour after termination of the stressor). Analyses of variance were used to compare descriptive variables and urinary hormones between groups. Repeated measures analyses of variance over the five time points were used to compare the three groups in plasma cortisol and norepinephrine. In addition, for cortisol and norepinephrine reactivity to stress, “peak stress reactivity” was defined as the difference between the 11:00 am minus the 10:30 am plasma levels. All between-group stress hormone comparisons were covaried for age, given the significant age difference between groups (see Section 3). Gender was not entered as a covariate, since groups did not differ significantly in gender, and gender was not associated with differences in cortisol or norepinephrine reactivity (see Results). Within the BPD and the HC groups, relationships between symptom ratings, trauma history, and stress 180 D. Simeon et al. / Psychiatry Research 149 (2007) 177–184 Table 1 Comparison of the high-dissociation BPD group, low-dissociation BPD group, and HC group a Variable High-dissociation BPD (N = 5) Low-dissociation BPD (N = 8) HC (N = 11) F P DES CTQ POMS-Anticipation POMS-Completion Subjective stress rating Urinary cortisol (μg/day) Cortisol peak reactivity (μg/dl) Urinary norepinephrine (μg/day) Norepinephrine peak reactivity (μg/dl) 46.4 ± 10.6 67.0 ± 26.9 8.4 ± 4.0 11.0 ± 3.4 4.8 ± 1.1 46.1 ± 19.9 9.0 ± 2.3 20.2 ± 6.7 187.2 ± 54.6 15.8 ± 8.0 45.6 ± 11.6 4.9 ± 3.4 8.4 ± 5.1 5.0 ± 0.8 58.4 ± 22.5 4.05 ± 5.3 33.4 ± 12.6 28.3 ± 110.5 3.0 ± 2.3 35.3 ± 13.0 2.7 ± 1.7 3.56 ± 1.6 4.1 ± 0.8 59.7 ± 25.5 5.0 ± 5.0 21.4 ± 7.8 85.0 ± 154.8 71.57 6.25 6.79 9.52 2.84 0.59 4.12 0.95 2.35 <0.001 0.008 0.005 0.001 0.08 0.56 0.03 0.40 0.12 a Stress hormone comparisons are covaried for age. hormones were examined using Pearson's correlation coefficients. All statistical analyses were two-tailed with a 0.05 level of significance. tion and trauma scores were not significantly related to the subjective stress rating of the TSST (r = 0.06, df = 11, P = 0.85 and r = − 0.31, df = 11, P = 0.30 respectively). 3. Results 3.1. Demographics and phenomenology The 5 female and 6 male HC subjects had a mean age of 27.1 ± 6.2 years, with very low DES dissociation scores (3.0 ± 2.3). The 13 BPD subjects, 6 females and 7 males, had a mean age of 39.2 ± 10.6 years, with a wide range of dissociation scores (30.4 ± 19.7, range 8.9– 62.5). The low-dissociation BPD group consisted of 8 subjects (2 females and 6 males), with a mean age of 43.4 ± 11.7 years and a mean DES score of 15.8 ± 8.0. The high-dissociation BPD group consisted of 5 subjects (4 females and 1 male), with a mean age of 32. 6 ± 3.4 years and a mean DES score of 46.4 ± 10.6. The three groups differed significantly in age (F = 9.41, df = 2, P = 0.001) but not gender (χ2 = 3.75, df = 2, P = 0.15). The two BPD subgroups tended to differ in age (t = 1.98, df = 11, P = 0.07) and did not differ significantly in gender (Fischer's exact P = 0.10). Current Axis I comorbidity for the BPD group was as follows: dysthymia—1, social phobia—3, OCD—1, GAD—2, binge eating—4, somatoform disorder—1, hypochondriasis—1, body dysmorphic disorder—1. On Axis II, all but 3 BPD participants had additional personality disorder diagnoses (mean PD/subject 2.8 ± 1.2, ranging from 1 to 3). Table 1 presents the descriptive comparisons between the three groups. Within the combined BPD sample (high and low dissociation), dissociation tended to be positively correlated with childhood trauma (r = 0.50, df = 11, P = 0 .08) and with POMS-anticipation score (r = 0.52, df = 11, P = 0.07), but less so with POMSCompletion score (r = 0.43, df = 11, P = 0.14). Dissocia- Fig. 1. Cortisol reactivity (A) and norepinephrine reactivity (B) to acute psychosocial stress in the high-dissociation BPD group (N = 5), low-dissociation BPD group (N = 8), and HC group (N = 11). 181 D. Simeon et al. / Psychiatry Research 149 (2007) 177–184 3.2. Between-group stress hormone comparisons 3.2.1. Cortisol There was no difference between the three groups in 24-h basal urinary cortisol (Table 1). The intraclass correlation coefficient of the five plasma cortisol levels for the entire study sample was 0.88, demonstrating high intra-individual consistency in the measurement of plasma cortisol. Comparison of plasma cortisol levels over the five time points revealed a significant “group × time” interaction effect (Fig. 1A) (F = 2.69, df = 8, 80, P = 0.016), as well as a significant “age × time” interaction effect (F = 4.04, df = 4, 80, P = 0.007). Similarly, the three groups differed significantly in cortisol peak stress reactivity, with the high-dissociation BPD group manifesting approximately double the surge in plasma cortisol from the start to the finish of the TSST compared to the other two groups (Table 1). Importantly, the heightened cortisol stress reactivity in the highdissociation BPD group could not be attributed to the impact of outliers, as all five subjects in the highdissociation BPD group had cortisol surges under stress that were greater than the mean of the HC group (range 5.7–11.3 μg/dl). There was no gender difference in cortisol peak stress reactivity (females 6.2 ± 5.0 μg/dl, males 4.9 ± 4.9 μg/dl, t = 0.66, df = 22, P = 0.52). Of note, the combined BPD sample (high and low dissociation) did not differ from the control group in either basal or stress-induced cortisol levels. 3.2.2. Norepinephrine There was no difference between the three groups in 24-h basal urinary norepinephrine (Table 1). The intraclass correlation coefficient of the five plasma norepinephrine levels for the entire study sample was 0.82, demonstrating high intra-individual consistency in the measurement of plasma norepinephrine. Betweengroup comparison of plasma norepinephrine levels over the five time points did not reveal a significant “group × time” interaction effect (Fig. 1B) (F = 1.44, df = 8, 80, P = 0.19). Similarly, the three groups did not differ significantly in norepinephrine peak stress reactivity (Table 1). There was no gender difference in norepinephrine peak stress reactivity (females 121.3 ± 112.8 μg/dl, males 58.7 ± 148.4 μg/dl, t = 1.15, df = 22, P = 0.26). Of note, the combined BPD sample (high and low dissociation) did not differ from the control group in either basal or stress-induced norepinephrine levels. 3.3. Within-group relationships between stress hormones and descriptive variables In the BPD group, there was a trend significant correlation between cortisol and norepinephrine reactivity to psychosocial stress (r = 0.51, df = 11, P = 0.07), while the two were not associated in the HC group (r = − 0.05, df = 9, P = 0.89). Table 2 summarizes the correlations between stress hormones and dissociation severity, trauma history, subjective stress rating, and emotional state before and after stress, for the BPD and the HC samples. Dissociation and childhood trauma were associated with both ambient and reactive stress hormone levels in the BPD group. There was a trend significant negative association between basal urinary norepinephrine and dissociation, and a significant negative association between basal urinary cortisol and childhood trauma. There was also a trend significant positive association between dissociation and cortisol Table 2 Pearson's correlations between stress hormone response to the TSST and descriptive variables in the BPD group (N = 13) and the HC group (N = 11) Basal urinary cortisol Cortisol peak stress reactivity Basal urinary norepinephrine r P r P r P r P 0.29 0.19 0.09 0.80 N/A POMS post-stress N/A 0.06 0.21 0.28 0.38 0.15 0.39 0.50 0.002 0.83 0.25 − 0.52 0.04 0.06 0.27 N/A POMS pre-stress 0.52 0.41 0.32 0.31 − 0.42 − 0.29 0.21 0.82 − 0.07 0.38 0.06 0.90 0.85 0.45 Subjective stress rating − 0.32 − 0.43 − 0.69 0.009 N/A 0.56 −0.26 0.10 0.36 −0.15 0.22 0.37 −0.10 0.47 0.55 0.048 0.23 0.75 0.31 0.62 0.53 0.21 0.77 0.11 0.08 Dissociation (DES) Childhood trauma (CTQ) The top line in each cell represents correlations for the BPD group. The bottom line in each cell represents correlations for the HC group. N/A = not applicable. N/A N/A Norepinephrine peak stress reactivity 182 D. Simeon et al. / Psychiatry Research 149 (2007) 177–184 stress reactivity, and a significant positive association between dissociation and norepinephrine stress reactivity. 4. Conclusions This pilot study of stress hormone response to psychosocial stress in BPD suggests that prominent dissociative symptoms in BPD may be associated with greater HPA axis and noradrenergic reactivity to stress, as well as with lower ambient noradrenergic tone. Dissociation in the BPD group also tended to be associated with greater childhood trauma, and with greater emotional distress surrounding stress regardless of cognitive appraisal of the stressor. The study then suggests that the dissociative domain of BPD may be a neglected but important area to investigate, and may be associated with greater trauma, more negative affect in the context of stressful experiences, and heightened biological reactivity to stress. Thus, dissociation in BPD may constitute a valuable marker of ongoing stress vulnerability with important implications for intervention. The basal stress hormone findings of this study are consistent with other reports in the literature. The association between dissociative symptoms and lower basal urinary norepinephrine in the BPD group is consistent with the only two other studies in the literature, to our knowledge, that have examined the relationship between dissociation and norepinephrine, in car accident victims in the acute aftermath of the trauma (Delahanty et al., 2003) and in depersonalization disorder subjects (Simeon et al., 2003a). Both studies found a significant inverse relationship between basal urinary norepinephrine and dissociation severity, supporting the notion of autonomic blunting as a biological marker of dissociative states. The association between childhood trauma and lower urinary cortisol in the BPD group is reminiscent of reports of lower basal cortisol in the PTSD literature. Although our study excluded individuals with PTSD, it has more recently been suggested that low cortisol may not be associated with the PTSD diagnosis per se, but may predate and be a risk factor for PTSD, marking greater HPA axis vulnerability to traumatic events, possibly in relation to early life trauma (Yehuda et al., 2000; King et al., 2001; Young et al., 2004). The stress reactivity hormone findings of this study are in accord with other recent studies showing that psychopathology linked to early life stress, as well as trauma history in and of itself, are associated with greater biological responsivity to stress. Heim et al. (2000) reported that major depression with a history of childhood sexual abuse was associated with a more robust HPA axis response to the TSST in adult women. Rinne et al. (2002) reported hyperresponsiveness of the HPA axis in response to combined dexamethasone/CRH challenge in BPD patients with childhood abuse; sustained abuse history rather than current diagnoses of BPD, major depression, or PTSD accounted for this finding. Adult women with abuse-related PTSD have been reported to have greater cortisol reactivity to trauma scripts during anticipation, exposure and recovery compared to controls (Elzinga et al., 2003). The small sample of the current study did not permit a systematic statistical dissection of the contribution of dissociative symptomatology, trauma history, and comorbid diagnoses with respect to stress reactivity. Still, the correlational findings in the BPD group suggest that dissociation rather than trauma history was driving the heightened stress reactivity. The presence of comorbid anxiety disorders, especially social phobia and GAD, could be confounding interpretation of the TSST findings; social phobia was present in two participants from the high-dissociation BPD group and one participant from the low-dissociation BPD group, while both participants with GAD were in the low-dissociation group. However, when the 4 BPD participants with either of these anxiety disorders were compared to the 9 BPD individuals without comorbid anxiety disorder, there were no differences between the two subgroups in cortisol stress reactivity (F = 0.002, df = 1, 10, P = 0.97) or norepinephrine stress reactivity (F = 1.68, df = 1, 10, P = 0.22). Strengths of this pilot study include its thorough diagnostic procedures; exclusion of BPD participants with major depression or PTSD; use of well-validated scales and stress-induction methodology; and highly controlled conditions during biological measurements. The effect sizes found in this pilot study were quite robust, overall in the “large” range, although not always statistically significant due to the limited power of the small sample. Major limitations of the study include the small sample size, as well as the absence of other measures of comorbid BPD pathology such as affective instability and impulsivity. It is conceivable that these BPD domains, as well as uncontrolled for Axis I comorbidity, may have covaried with dissociation severity and may be in part driving the biological findings. Therefore, it is not possible to definitively state whether the study's findings are indicative of greater dissociative psychopathology in particular, or greater BPD severity in general. A larger study is needed to address these issues, controlling for overall BPD D. Simeon et al. / Psychiatry Research 149 (2007) 177–184 disorder severity, quantifying multiple symptom domains, and having the power to examine the impact of comorbid psychiatric disorders. Acknowledgements This study was supported in part by NIH 5 MO1 RR0071 to the Mount Sinai GCRC. References Bernstein, D.P., Stein, J.A., Newcomb, M.D., Waker, E., Pogge, D., Ahluvalia, T., Stokes, J., Handelsman, L., Medrano, M., Desmond, D., Zule, W., 2003. Development and validation of a brief screening version of the Childhood Trauma Questionnaire. Child Abuse and Neglect 27, 169–190. Best, M., Williams, J.M., Coccaro, E.F., 2002. Evidence for a dysfunctional prefrontal circuit in patients with an impulsive aggressive disorder. Proceedings of National Academy of Sciences USA 99, 8448–8453. Brodsky, B.S., Cloitre, M., Dulit, R.A., 1995. Relationship of dissociation to self-mutilation and childhood abuse in borderline personality disorder. American Journal of Psychiatry 152, 1788–1792. Carlson, E., Putnam, F.W., 1993. An update on the Dissociative Experiences Scale. Dissociation 6, 16–27. Coccaro, E.F., Lee, R., McCloskey, M., 2003. Norepinephrine function in personality disorder: plasma free MHPG correlates inversely with life history of aggression. CNS Spectrums 8, 731–736. De la Fuente, J.M., Mendlewicz, J., 1996. TRH stimulation and dexamethasone suppression in borderline personality disorder. Biological Psychiatry 40, 412–418. Delahanty, D.L., Royer, D.K., Raimonde, A.J., Spoonster, Eileen, 2003. Peritraumatic dissociation is inversely related to catecholamine levels in initial urine samples of motor vehicle accident victims. Journal of Trauma and Dissociation 4, 65–79. Elzinga, B.M., Schmahl, C.G., Bremner, J.D., 2002. Cortisol reactivity to traumatic scripts in borderline personality disorder and PTSD. Presented at the 5th ISSPD European Congress on Personality Disorders, Munich. Elzinga, B.M., Schmahl, C.G.T., Vermetten, E., van Dyck, R., Bremner, D.J., 2003. Higher cortisol levels following exposure to traumatic reminders in abuse-related PTSD. Neuropsychopharmacology 28, 1656–1665. Figueroa, E., Silk, K.R., 1997. Biological implications of childhood sexual abuse in borderline personality disorder. Journal of Personality Disorders 11, 71–92. First, M.B., Spitzer, RL., Gibbon, M., Williams, J.B.W., 1995. Structured Clinical Interview for DSM-IVAxis I Disorders, Patient Version (SCID-P). New York State Psychiatric Institute, Biometrics Research, New York, NY. Goodman, M., New, A., Mitropoulou, V., Koenigsberg, H., Weiss, D., Siever, L., 2001 May. Pathological dissociation in borderline personality disorder: the role of childhood trauma and serotonergic genes. Society of Biological Psychiatry Annual Meeting, New Orleans, LA. Abstract #248. Griffin, M.G., Resick, P.A., Mechanic, M.B., 1997. Objective assessment of peritraumatic dissociation: psychophysiological indicators. American Journal of Psychiatry 154, 1081–1088. Grossman, R., Yehuda, R., New, A., Schmeidler, J., Silverman, J., Mitropoulou, V., StaMaria, N., Golier, J., Siever, L., 2003. 183 Dexamethasone suppression test findings in subjects with personality disorders: associations with posttraumatic stress disorder and major depression. American Journal of Psychiatry 160, 1291–1297. Heim, C., Newport, D.J., Heit, S., Graham, Y.P., Wilcox, M., Bonsall, R., Miller, A.H., Nemeroff, C.B., 2000. Pituitary-adrenal and autonomic responses to stress in women after sexual and physical abuse in childhood. Journal of the American Medical Association 284, 592–597. Hollander, E., Tracy, K.A., Swann, A.C., Coccaro, E.F., McElroy, S.L., Wozniak, P., Sommerville, K.W., Nemeroff, C.B., 2003. Divalproex in the treatment of impulsive aggression: efficacy in cluster B personality disorders. Neuropsychopharmacology 28, 1186–1197. King, J.A., Mandansky, D., Fletcher, K.E., Brewer, J., 2001. Early sexual abuse and low cortisol. Psychiatry Clinical Neuroscience 55, 71-71. Kirschbaum, C., Pirke, K.M., Hellhammer, D.H., 1993. The Trier Social Stress Test: A tool for investigating psychobiological stress responses in a laboratory setting. Neuropsychoendocrinology 28, 76–81. Koenigsberg, H.W., Harvey, P.D., Mitropoulou, V., Schmeidler, J., New, A.S., Goodman, M., Silverman, J.M., Serby, M., Schopick, F., Siever, L.J., 2002. Characterizing affective instability in borderline personality disorder. American Journal of Psychiatry 159, 784–788. Korzekwa, M., Steiner, M., Links, P., Eppel, A., 1991. The dexamethasone suppression test in borderlines: is it useful? Canadian Journal of Psychiatry 36, 26–28. Lahmeyer, H.W., Val, E., Gaviria, F.M., Prasad, R.B., Pandey, G.N., Rodgers, P., Weiler, M.A., Altman, E.G., 1988. EEG sleep, lithium transport, dexamethasone suppression, and monoamine oxidase activity in borderline personality disorder. Psychiatry Research 25, 19–30. Lieb, K., Rexhausen, J.E., Kahl, K.G., Schweiger, U., Philipsen, A., Hellhammer, D.H., Bohus, M., 2004. Increased diurnal salivary cortisol in women with borderline personality disorder. Journal of Psychiatric Research 38, 559–565. Pfohl, B., Blum, N., Zimmerman, M., 1997. Structured Interview for DSM-IV Personality. American Psychiatric Press, Inc., Washington, DC. Rinne, T., de Kloet, E.R., Wouters, L., Goekoop, J.G., DeRijk, R.H., van den Brink, W., 2002. Hyperresponsiveness of hypothalamicpituitary-adrenal axis to combined dexamethasone/corticotrophinreleasing hormone challenge in female borderline personality disorder subjects with a history of sustained childhood abuse. Biological Psychiatry 52, 1102–1112. Shacham, S., 1983. A shortened version of the profile of mood states. Journal of Personality Assessment 47, 305–306. Shearer, S.L., 1994. Dissociative phenomena in women with borderline personality disorder. American Journal of Psychiatry 151, 1324–1328. Sierra, M., Senior, C., Dalton, J., McDonough, M., Bond, A., Phillips, M.L., O'Dwyer, A.M., David, A.S., 2002. Autonomic response in depersonalization disorder. Archives of General Psychiatry 59, 833–838. Simeon, D., Guralnik, O., Knutelska, M., Hollander, R., Schmeidler, J., 2001. Hypothalamic-pituitary-adrenal axis dysregulation in depersonalization disorder. Neuropsychopharmacology 25, 793–795. Simeon, D., Guralnik, O., Knutelska, M., Yehuda, R., Schmeidler, J., 2003a. Basal norepinephrine in depersonalization disorder. Psychiatry Research 121, 93–97. 184 D. Simeon et al. / Psychiatry Research 149 (2007) 177–184 Simeon, D., Nelson, D., Elias, R., Greenberg, J., Hollander, E., 2003b. Relationship of personality to dissociation and childhood trauma in borderline personality disorder. CNS Spectrums 8, 755–762. Skodol, A.E., Gunderson, J.G., Pfohl, B., Widiger, T.A., Livesley, W.J., Siever, L.J., 2002. The borderline diagnosis I: psychopathology, comorbidity, and personality structure. Biological Psychiatry 51, 936–950. Southwick, S.M., Yehuda, R., Giller, E.L., Perry, B.D., 1990. Altered platelet alpha2 adrenergic receptor binding sites in borderline personality disorder. American Journal of Psychiatry 147, 1014–1017. Stiglmayr, C.E., Shapiro, D.A., Stieglitz, R.D., Limberger, M.F., Bohus, M., 2001. Experience of aversive tension and dissociation in female patients with borderline personality disorder—a controlled study. Journal of Psychiatric Research 35, 111–118. Wildgoose, A., Waller, G., Clarke, S., Reid, A., 2000. Psychiatric symptomatology in borderline and other personality disorders: dissociation and fragmentation as mediators. Journal of Nervous and Mental Disease 188, 757–763. Yehuda, R., Bierer, L.M., Schmeidler, J., Aferiat, D.H., Breslau, I., Dolan, S., 2000. Low cortisol and risk for PTSD in adult offspring of holocaust survivors. American Journal of Psychiatry 157, 1252–1259. Young, E.A., Tolman, R., Witkowski, K., Kaplan, G., 2004. Salivary cortisol and posttraumatic stress disorders in a low-income community sample of women. Biological Psychiatry 55, 621–626. Zanarini, M.C., Ruser, T., Frankenburg, F.R., Hennen, J., 2000a. The dissociative experiences of borderline patients. Comprehensive Psychiatry 41, 223–227. Zanarini, M.C., Ruser, T.F., Frankenburg, F.R., Hennen, J., Gunderson, J.G., 2000b. Risk factors associated with the dissociative experiences of borderline patients. Journal of Nervous Mental Disorders 188, 26–30. Zlotnick, C., Mattia, J.I., Zimmerman, M., 1999. Clinical correlates of self-mutilation in a sample of general psychiatric patients. Journal of Nervous Mental Disorders 187, 296–301.