Mineralocorticoid Receptor Function in Patients With Posttraumatic

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Roche, Grenzach-Wyhlen, Germany) at 9:00 a.m. and noon on the first and second days of the study, respectively. On both study days an intravenous catheter ...
Brief Report

Mineralocorticoid Receptor Function in Patients With Posttraumatic Stress Disorder Michael Kellner, M.D. Dewleen G. Baker, M.D. Alexander Yassouridis, Ph.D. Silke Bettinger Christian Otte, M.D. Dieter Naber, M.D. Klaus Wiedemann, M.D.

Method: The effects of acute antimineralocorticoid (spironolactone) versus placebo pretreatment on levels of plasma cortisol at baseline and after stimulations with corticotropin-releasing hormone (CRH) and on adrenocorticotropic hormone (ACTH) level were measured in 12 PTSD patients and 12 healthy comparison subjects.

Objective: The study examined whether enhanced limbic mineralocorticoid receptor activity resulting in negative glucocorticoid feedback could contribute to the diminished basal and stress-induced cortisol output reported in patients with posttraumatic stress disorder (PTSD).

Conclusions: The results indicate intact, but not enhanced, mineralocorticoid receptor function in PTSD. The study’s experimental conditions did not allow determination of whether other compensatory factors might have masked the putative mineralocorticoid receptor changes.

Results: Spironolactone significantly elevated basal cortisol and ACTH concentrations as well as cortisol secretion after CRH stimulation, but no differential effect between PTSD patients and comparison subjects was detected.

(Am J Psychiatry 2002; 159:1938–1940)

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n patients with posttraumatic stress disorder (PTSD), low cortisol levels have repeatedly been reported despite high central nervous system corticotropin-releasing hormone (CRH) activity (1–3). An enhancement of glucocorticoid-receptor-mediated negative feedback in the pituitary of PTSD patients, as demonstrated with the dexamethasone suppression test (4), might explain this phenomenon. However, hippocampal mineralocorticoid receptors, which have a higher affinity for cortisol than do glucocorticoid receptors, exert an inhibitory influence on hypothalamic-pituitary-adrenal (HPA) axis activity (5, 6). Recently, the possibility of dynamic regulation of mineralocorticoid receptors was demonstrated in a preclinical study showing an increase in hippocampal mineralocorticoid receptor density after psychological stress (7). However, so far no investigation has characterized the role of mineralocorticoid receptors in PTSD. Based on our hypothesis that PTSD patients exhibit an elevated mineralocorticoid receptor function, we predicted an amplified cortisol response in PTSD patients compared to healthy subjects after administration of the mineralocorticoid receptor antagonist spironolactone, and enhanced cortisol secretion after subsequent stimulation with CRH.

Method Subjects were 12 outpatients with PTSD (seven women, five men, mean age=37.2 years, range=24–52) who had no other primary anxiety or primary mood disorder and no psychotic, organic, or substance-related disorders, as assessed with the Structured Clinical Interview for DSM-IV, and 12 healthy sex- and agematched comparison subjects (mean age=36.3 years, range=22– 54). The subjects had been free of medication for at least 14 days

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and had undergone a thorough medical examination to rule out other illnesses, drug intake, or lifestyle factors that could interfere with the study. The comparison subjects had no personal or family history of any major psychiatric disorder. The protocol was approved by the local institutional review board, and each participant provided written informed consent before the investigation. In a single-blind, fixed-order design, subjects were pretreated orally with placebo and 200 mg of spironolactone (Hoffmann-La Roche, Grenzach-Wyhlen, Germany) at 9:00 a.m. and noon on the first and second days of the study, respectively. On both study days an intravenous catheter was placed in the subject’s arm at 1:00 p.m., and the subject remained supine in a soundproof room at the hospital until 5:00 p.m. A bolus injection of 100 µg of human CRH (Clinalfa, Läufelfingen, Switzerland) was given at 3:00 p.m. Blood samples were drawn at 2:30, 2:45, 3:00, 3:15, 3:30, 3:45, 4:00, 4:30, and 5:00 p.m. to determine cortisol and adrenocorticotropic hormone (ACTH) levels. Samples were placed on ice, plasma was separated immediately, and specimens were stored at –80°C until analysis. Blood pressure was registered at blood sampling times with an automatic device. Plasma cortisol levels were determined by using a radioimmunoassay (ICN Biomedicals, Carson, Calif.). ACTH concentrations were determined with an immunoradiometric assay (Nichols Institute, San Juan Capistrano, Calif.). Intra- and interassay coefficients of variation were less than 8% for both assays. Cross-reactions of spironolactone and the spironolactone metabolite canrenoate at concentrations up to 4.0×105 ng/ml were below 0.2% in the cortisol assay. For statistical comparisons by multivariate analyses of variance (MANOVA), the following variables were calculated from the endocrine and blood pressure data: the mean basal levels from 2:30 to 3:00 p.m. and the maximal change in level and the area under the curve minus linear background between 3:00 and 5:00 p.m., i.e., after CRH stimulation. Data are given as means and standard deviations. The factors in the MANOVA were treatment (spironolactone versus placebo, as the within-subjects factor) and group (PTSD versus comparison subjects, as the between-subjects facAm J Psychiatry 159:11, November 2002

BRIEF REPORTS tor). To avoid colinearities, the parameters of cortisol level, ACTH level, and systolic and diastolic blood pressure were tested in separate MANOVAs. When a significant main or interaction effect was found, a univariate F test was used to identify the variables that contributed significantly to the effect. An alpha of 0.05 was accepted as the level of significance. All post hoc tests were performed at a reduced level of significance according to the Bonferroni procedure.

Results Cortisol parameters revealed significant treatment effects of spironolactone, compared with placebo (F=22.3, df=3, 20, p=0.001), for mean basal cortisol level and the area under the curve (F=43.2 and F=35.1, respectively, df=1, 22, p=0.001 each) but not for the change in level (F=0.6, df= 1, 22, p=0.47). However, neither a significant group effect (F=0.4, df=3, 20, p=0.76) nor a significant group-by-treatment effect (F=0.7, df=3, 20, p=0.54) was detected (Table 1). For ACTH parameters a significant treatment effect emerged (F=83.8, df=1, 22, p=0.001) for mean basal level (F=83.8, df=1, 22, p=0.001) but not for the area under the curve (F=0.0, df=1, 22, p=0.93) or the change in level (F= 2.2, df=1, 22, p=0.15). The mean basal ACTH levels in the placebo versus spironolactone condition were 16.6 pg/ml (SD=9.7) versus 33.0 pg/ml (SD=11.8) in PTSD patients and 15.9 pg/ml (SD=8.0) versus 31.1 pg/ml (SD=10.4) in comparison subjects. No group effect (F=0.9, df=3, 20, p= 0.51) or group-by-treatment effect (F=0.9, df=3, 20, p= 0.78) was found. The spironolactone action on cortisol and on ACTH was not caused by blood pressure effects, since systolic and diastolic blood pressure showed no treatment effect (F=0.9, df=3, 20, p=0.62 and F=0.9, df=3, 20, p=0.46, respectively) or group-by-treatment effect (F=0.9, df=3, 20, p=0.40 and F=0.9, df=3,20, p=0.50, respectively).

TABLE 1. Effects of Placebo and Spironolactone on Plasma Cortisol Levels at Baseline and After Stimulation With Corticotropin-Releasing Hormone (CRH) in Patients With PTSD and Healthy Comparison Subjects Subject Group and Cortisol Parameter PTSD patients (N=12) Basal cortisol level (ng/ml) Cortisol level after CRH stimulation Area under the curve (arbitrary units) Change in level (ng/ml) Comparison subjects (N=12) Basal cortisol level (ng/ml) Cortisol level after CRH stimulation Area under the curve (arbitrary units) Change in level (ng/ml)

Placebo Mean

SD

Spironolactone Mean

SD

96.6

31.2

212.1

48.5

1400.1 146.0

266.7 55.4

1660.5 150.5

400.1 53.0

102.6

55.1

225.9

94.9

1343.2 125.9

528.3 43.3

1763.5 137.7

751.0 72.7

Further investigation of mineralocorticoid receptor function in PTSD may be indicated, since mineralocorticoid receptors modulate pertinent cognitive and behavioral effects (5). In particular, given an anxiolytic action of hippocampal mineralocorticoid receptor blockade in rodents (10), mineralocorticoid receptor function might be a potential target for psychopharmacological intervention. Received Dec. 11, 2001; revision received May 31, 2002; accepted June 10, 2002. From the Department of Psychiatry and Psychotherapy, University Hospital Hamburg-Eppendorf; the Department of Psychiatry, University of Cincinnati and Cincinnati VA Medical Center, Cincinnati, and the Max Planck Institute of Psychiatry, Munich, Germany. Address reprint requests to PD Dr. Kellner, Department of Psychiatry and Psychotherapy, University Hospital Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany; kellner@uke. uni-hamburg.de (e-mail). Supported by Deutsche Forschungsgemeinschaft (grant Ke 595/51). Work on this research is part of the M.D. thesis of Silke Bettinger. The authors thank Mrs. H. Kloss and Ms. K. Knaudt for technical help.

Discussion Our findings of increased spontaneous and CRH-stimulated plasma cortisol after acute treatment with the mineralocorticoid receptor antagonist spironolactone are similar to those of previous studies in humans (8, 9). However, no differential effects of spironolactone in PTSD patients versus healthy comparison subjects were detected. Due to the limitations in our study design, we were unable to determine whether the lack of group differences was related to a lack of mineralocorticoid receptor up-regulation in PTSD or to factors such as compensatory neuropeptide regulation or hyperactive pituitary glucocorticoid receptor-mediated negative feedback (4) masking the putative mineralocorticoid receptor changes in our patient group. Also, in contrast to expectation, postplacebo basal cortisol levels in the patients were indistinguishable from those in the normal comparison subjects. Spironolactone administration closer to the circadian nadir of cortisol levels, when HPA axis tone is primarily driven by mineralocorticoid receptors, might better distinguish the groups. Am J Psychiatry 159:11, November 2002

References 1. Yehuda R, Teicher MH, Trestman RL, Levengood RA, Siever LJ: Cortisol regulation in posttraumatic stress disorder and major depression: a chronobiological analysis. Biol Psychiatry 1996; 40:79–88 2. Kellner M, Yehuda R: Do panic disorder and posttraumatic stress disorder share a common psychoneuroendocrinology? Psychoneuroendocrinology 1999; 24:485–504 3. Baker DG, West SA, Nicholson WE, Ekhator NN, Kasckow JW, Hill KK, Bruce AB, Orth DN, Geracioti TD Jr: Serial CSF corticotropinreleasing hormone levels and adrenocortical activity in combat veterans with posttraumatic stress disorder. Am J Psychiatry 1999; 156:585–588; correction, 156:986 4. Yehuda R, Boisoneau D, Lowy MT, Giller EL Jr: Dose-response changes in plasma cortisol and lymphocyte glucocorticoid receptors following dexamethasone administration in combat veterans with and without posttraumatic stress disorder. Arch Gen Psychiatry 1995; 52:583–593 5. De Kloet ER, Vreugdenhil E, Oitzl MS, Joëls M: Brain corticosteroid receptor balance in health and disease. Endocrinol Rev 1998; 19:269–301

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BRIEF REPORTS 6. Spencer RL, Kim PJ, Kalman BA, Cole MA: Evidence for mineralocorticoid receptor facilitation of glucocorticoid receptor-dependent regulation of hypothalamic-pituitary-adrenal axis activity. Endocrinology 1998; 2718–2726 7. Gesing A, Bilang-Bleuel A, Droste SK, Linthorst ACE, Holsboer F, Reul JMHM: Psychological stress increases hippocampal mineralocorticoid receptor levels: involvement of corticotropin-releasing hormone. J Neurosci 2001; 21:4822–4829 8. Young EA, Lopez JF, Murphy-Weinberg V, Watson SJ, Akil H: The role of mineralocorticoid receptors in hypothalamic-pituitary-

adrenal axis regulation in humans. J Clin Endocrinol Metab 1998; 83:3339–3345 9. Arvat E, Maccagno B, Giordano R, Pellegrino M, Broglio F, Gianotti L, Maccario M, Camanni F, Ghigo E: Mineralocorticoid receptor blockade by canrenoate increases both spontaneous and stimulated adrenal function in humans. J Clin Endocrinol Metab 2001; 86:3176–3181 10. Smythe JW, Murphy D, Timothy C, Costall B: Hippocampal mineralocorticoid, but not glucocorticoid, receptors modulate anxiety-like behavior in rats. Pharmacol Biochem Behav 1997; 56: 507–513

Brief Report

Is Comorbidity of Posttraumatic Stress Disorder and Borderline Personality Disorder Related to Greater Pathology and Impairment? Caron Zlotnick, Ph.D. C. Laurel Franklin, Ph.D. Mark Zimmerman, M.D.

personality disorder (N=469) were assessed with structured interviews for psychiatric disorders and for degree of impairment.

Objective: The authors examined whether patients with comorbid borderline personality disorder and posttraumatic stress disorder (PTSD) have a more severe clinical profile than patients with either disorder without the other.

Results: Outpatients with diagnoses of comorbid borderline personality disorder and PTSD were not significantly different from outpatients with borderline personality disorder without PTSD, PTSD without borderline personality disorder, or major depression without PTSD or borderline personality disorder in severity of PTSD-related symptoms, borderline-related traits, or impairment.

Method: Outpatients with borderline personality disorder without PTSD (N=101), PTSD without borderline personality disorder (N=121), comorbid borderline personality disorder and PTSD (N=48), and major depression without PTSD or borderline

Conclusions: The additional diagnosis of PTSD or borderline personality disorder does little to augment the pathology or dysfunction of patients who have either disorder without the other. (Am J Psychiatry 2002; 159:1940–1943)

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osttraumatic stress disorder (PTSD) and borderline personality disorder are DSM-IV diagnoses that are grounded independently in well-articulated theoretical and empirical frameworks. The more recent literature has suggested a possible relationship between these disorders. Comorbidity studies have shown a high frequency of PTSD among patients with borderline personality disorder (56%) (1) and a high frequency of borderline personality disorder among patients with PTSD (68%) (2). Among individuals in the community, it has been estimated that one-third of those with borderline personality disorder meet criteria for PTSD (3). In addition, it has been proposed that both disorders share a common pathogenesis, in that childhood sexual abuse has been found to have a strong association with both borderline personality disorder and PTSD (4, 5).

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Trauma experts (e.g., Herman et al. [5]) have suggested that borderline personality disorder may be a complex variant of PTSD because many core borderline personality disorder features, such as affective instability, anger, dissociative symptoms, and impulsivity, are present in individuals with chronic PTSD. The concept that the effects of trauma can lead to personality disturbances is reflected in the provisional inclusion in the ICD-10 diagnostic system of the diagnosis of enduring personality changes after catastrophic stress. A competing view is that the overlap between borderline personality disorder and PTSD is often the result of a premorbid borderline personality disorder, which increases vulnerability to the deleterious effects of trauma exposure (6). This view postulates that a distinction between the symptoms of PTSD and the traits of borderline personality disorder can be drawn on the basis of long-standing develAm J Psychiatry 159:11, November 2002