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An Increased Capacity for Adrenal DHEA Release Is Associated with Decreased Avoidance and Negative Mood Symptoms in Women with PTSD

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An Increased Capacity for Adrenal DHEA Release Is Associated with Decreased Avoidance and Negative Mood Symptoms in Women with PTSD Neuropsychopharmacology (2004) 29, 1546–1557 & 2004 Nature Publishing Group All rights reserved 0893-133X/04 $30.00 www.neuropsychopharmacology.org An Increased Capacity for Adrenal DHEA Release is Associated with Decreased Avoidance and Negative Mood Symptoms in Women with PTSD ,1 2 1 1 2 Ann M Rasmusson* , Jitka Vasek , Deborah S Lipschitz , Dolores Vojvoda , Mary Ellen Mustone , 3 2 1 2 4 Quihu Shi , Gretchen Gudmundsen , Charles A Morgan , Jessica Wolfe and Dennis S Charney 1 Department of Psychiatry, Yale University School of Medicine & VA National Center for PTSD, Clinical Neuroscience Division, VA Boston 2 Healthcare System, West Haven, CT, USA; Department of Psychiatry, Boston University School of Medicine & VA National Center for PTSD, 3 Womens’ Health Sciences Division, VA Boston Healthcare System, Boston, MA, USA; School of Public Health, New York Medical College, The Learning Center, Valhalla, NY, USA; 4Mood and Anxiety Disorders Branch, National Institute of Mental Health, Bethesda, MD, USA We recently found increased adrenal cortisol responses to adrenocorticotropic hormone (ACTH)1–24 and increased pituitary ACTH and adrenal cortisol responses to corticotropin-releasing factor in premenopausal women with chronic post-traumatic stress disorder (PTSD) compared to healthy nontraumatized subjects. This pattern of hypothalamic–pituitary–adrenal axis (HPA) hyper-reactivity has been previously seen in healthy individuals treated with the antiglucocorticoid mifepristone. We therefore investigated whether endogenous plasma levels of antiglucocorticoids such as dehydroepiandrosteroine (DHEA) and progesterone were increased in premenopausal women with PTSD at baseline or in response to adrenal activation by ACTH . The study revealed that DHEA responses to 250 mg 1À24 ACTH were increased in 13 PTSD subjects compared to 13 healthy nontraumatized subjects, while DHEA levels were generally 1À24 increased in the PTSD subjects compared to seven healthy traumatized subjects. Cortisol responses to ACTH1À24 were also higher in the women with PTSD, while progesterone levels and responses were not different among the three groups. In addition, among the PTSD subjects, the peak change in DHEA in response to ACTH1À24 was negatively correlated with the total Clinician Administered PTSD Scale score, while the peak DHEA to cortisol ratio was inversely associated with negative mood symptoms measured by the Profile of Mood States scale. This work suggests that an increased capacity for DHEA release in response to extreme adrenal activation may influence the pattern of HPA axis adaptation to extreme stress, as well as mitigate the severity of PTSD and negative mood symptoms in premenopausal women with PTSD. Neuropsychopharmacology (2004) 29, 1546–1557, advance online publication, 16 June 2004; doi:10.1038/sj.npp.1300432 Keywords: post-traumatic stress disorder; PTSD; cortisol; DHEA; premenopausal women; HPA axis INTRODUCTION ovine corticotropin-releasing factor (CRF) in the PTSD group. While these findings are inconsistent with some We recently reported increased adrenal cortisol responses previous studies showing low (Mason et al, 1986, Yehuda to intravenously administered adrenocorticotropic hor- et al, 1990, 1993, 1995) or the same cortisol output (Kosten mone (ACTH)1À24 in premenopausal women with chronic et al, 1990; Baker et al, 1999; Mason et al, 2002) in PTSD post-traumatic stress disorder (PTSD) compared to healthy compared to healthy subjects, they are consistent with other nontraumatized subjects (Rasmusson et al, 2001). In studies finding relatively increased urinary free cortisol addition, we observed increased pituitary ACTH and output in premenopausal women (Rasmusson et al, 2001; adrenal cortisol responses to intravenously administered Lemieux and Coe, 1995; Friedman et al, 2001), mixed-sex samples of children (De Bellis et al, 1999) or adults (Maes *Correspondence: Dr A M Rasmusson, Psychiatry Service/116A, VA et al, 1998), and male combat veterans (Pitman and Orr, Connecticut Healthcare System, 950 Campbell Avenue, West Haven, 1990) with PTSD. Since high levels of cortisol may CT 06516, USA, Tel: 203-932-5711, ext. 2483 or 2464, Fax: 203-937- 3886, Page 203-867-3132, E-mail: [email protected] contribute to alterations in the structure and function of Received 22 September 2003; revised 8 January 2004; accepted 27 brain areas and neurotransmitter systems thought to be January 2004 involved in the mediation of PTSD symptoms (Sapolsky, Online publication: 13 February 2004 at http://www.acnp.org/citations/ 1985, 1986; McEwen, 2000; Schulkin et al, 1998; Grunde- Npp02130403432/default.pdf mann et al, 1998; Lupien et al, 1998, 1999; Newcomer et al, Increased DHEA release in women with PTSD AM Rasmusson et al 1547 1999; Gold et al, 2002), we decided it would be important METHODS to investigate the possible mechanisms underlying increased cortisol reactivity in premenopausal women with Subjects PTSD. Increased ACTH and cortisol responses to CRF admin- In all, 41 subjects were recruited via community and clinic istration have been observed in animals and humans treated advertisements in Connecticut and Boston to participate in with the antiglucocorticoid RU486 (Van Haarst et al, 1996; the study. The protocol was approved by the VA Connecti- Bertagna et al, 1994). Facilitation of HPA axis reactivity by cut and VA Boston Healthcare System Human Studies RU486 is thought to be mediated by antagonism of Subcommittees; written informed consent was obtained glucocorticoid negative feedback in the brain and pituitary, from each subject. a resulting increase in ACTH release, and trophic effects of Subjects were screened for current or significant past ACTH on the adrenal gland. Thus, we wondered whether medical illness and illicit drug use via medical history, endogenous, peripherally released steroids with antigluco- physical examination, and laboratory tests. None had corticoid activity might play a role in enhancing pituitary identifiable endocrine syndromes and only one healthy and adrenal responsiveness in our female subjects with subject reported irregular menses. All subjects were free PTSD. from psychotropic medications for months to years or had The endogenous steroids, dehydroepiandrosterone never been treated with such. Subjects abstained from other (DHEA) and progesterone, have been shown to have medications, alcohol, and illicit drugs for at least 4 weeks antiglucocorticoid activity in several tissues, including before testing, except for two PTSD and two TC subjects the brain (Chader and Reif-Leher, 1972; Kaiser et al, who used steroid hormone contraception. Two PTSD, one 1979; Bohus and DeKloet, 1981; Giesen and Beck, TC, and two NTC subjects smoked 1/2–1 pack of cigarettes 1982; Daynes et al, 1990; Blauer et al, 1991; Browne et al, per day. 1992; Araneo et al, 1993). DHEA and progesterone DSMIV PTSD Criterion A1/A2 trauma (American Psy- exert antiglucocorticoid effects at the glucocorticoid type chiatric Association, 1994) exposure was assessed by use of II receptor via mechanisms distinct from classical general and early trauma inventories (ETI) (Bremner et al, receptor antagonism (Chou and Luttge, 1998; Morfin and 2000) (Table 1). The A1 criterion requires that a person Starka, 2001), while progesterone acts as a classical experiences, witnesses or confronts an event or events antagonist at mineralocorticoid (type I glucocorticoid) involving actual or threatened death or serious injury or receptors (reviewed in Turner, 1997). Consistent with the threat to the physical integrity of self or others. The A2 antiglucocorticoid characteristics of these steroids, ACTH criterion requires that a person’s response involve intense responses to psychological stress have been shown to fear, helplessness, or horror. To qualify as a Criterion A2 increase after DHEA treatment in postmenopausal women trauma, we required that physical or sexual trauma (Kudielka et al, 1998) and dexamethasone suppression of ascertained by the ETI be scored as ‘very’ or ‘extremely’ plasma cortisol levels has been shown to be reduced during distressing and disruptive in at least two of three domains of the luteal phase of the menstrual cycle when progesterone function (emotional, interpersonal, or school performance). levels are high (Altemus et al, 1997). DHEA and its sulfated Healthy NTC subjects were evaluated psychiatrically metabolite, DHEAS, also positively modulate NMDA using the non-patient edition of the Structured Clinical receptor function and antagonize GABAA receptor- Interview for DSM-IV (SCID-NP) (First et al, 1995a); mediated chloride ion flux (Baulieu and Robel, 1998)Fef- subjects with a current Axis I diagnosis were excluded, fects that may contribute to increased HPA axis responses except for one subject with a simple phobia. PTSD and TC (Barbaccio et al, 2001). subjects were evaluated using the SCID-P (First et al, DHEA is secreted episodically and synchronously with 1995b); subjects with current or past psychotic disorders or cortisol in response to fluctuating ACTH levels (Rosenfeld bipolar disorder were excluded from participation. Current et al, 1971). In addition, the administration of CRF and co-morbid Axis I diagnoses are presented in Table 1. ACTH has been shown to increase plasma DHEA and Past psychiatric diagnoses among the PTSD subjects progesterone levels (Parker et al, 1985a, b; Genazzani et al, included major depression (n ¼ 11), panic disorder (n ¼ 2), 1998). We therefore hypothesized that premenopausal substance
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