YEHUDA 2005 NEG FEEDBACK INIB ACTH RESP TO CORTIS PTSD

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Psychoneuroendocrinology (2006) 31, 447–451

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Alterations in cortisol negative feedback inhibition as examined using the ACTH response to cortisol administration in PTSD Rachel Yehuda*, Ren-Kui Yang, Monte S. Buchsbaum, Julia A. Golier The Traumatic Stress Studies Program, Psychiatry Department, Mount Sinai School of Medicine, and the Bronx Veterans Affairs Medical Center, NY, USA Received 6 July 2005; received in revised form 3 October 2005; accepted 31 October 2005

KEYWORDS PTSD; Cortisol; ACTH; Hypothalamic-pituitary-adrenal axis; Negative feedback inhibition; Glucocorticoid receptor

Summary Objective: Studies using the dexamethasone suppression test (DST) have demonstrated an enhanced negative feedback inhibition at the pituitary in PTSD, but have not provided information about central feedback effects, since dexamethasone (DEX) does not penetrate the brain well. The authors therefore examined the change in ACTH and cortisol before and after cortisol administration, which acts at central feedback sites in addition to peripheral targets. Method: Blood was obtained from 31 male veterans (18 with PTSD) before, and 8, 40 and 95 min following injection of 17.5 mg cortisol and placebo. Results: A greater decline in ACTH was observed after cortisol injection in PTSD. Conclusions: Central as well as peripheral negative feedback inhibition may be altered in PTSD. Published by Elsevier Ltd.

1. Introduction Although a greater ACTH decline in response to low doses of oral DEX (Yehuda et al., 2004) has been observed in PTSD, these findings have not been informative about central glucocorticoid responsiveness since DEX poorly penetrates the brain when administered peripherally, acting primarily on glucocorticoid receptors (GR) on the pituitary (Miller et al., 1992; Cole et al., 2000). In contrast, * Corresponding author. Address: Bronx VA OOMH, 130 West Kingsbridge Road, Bronx, NY 10468, USA. Tel.: C718 584 9000x6964; fax: C1 718 741 4775. E-mail address: [email protected] (R. Yehuda).

0306-4530/$ - see front matter Published by Elsevier Ltd. doi:10.1016/j.psyneuen.2005.10.007

cortisol has preferential access to the brain and affects feedback inhibition in multiple locations by binding to both mineralocorticoid receptors (MR) and GR (de Kloet et al., 1975). Understanding the extent to which alterations in negative feedback inhibition occur at the level of the pituitary versus the brain in PTSD is critical to evaluating the role of glucocorticoids in PTSD pathophysiology. That central and peripheral negative feedback effects are differentially regulated is implied by observations of CRF hypersecretion in the face of normal or lower plasma cortisol levels in PTSD (Baker et al., 1999), since stress-induced elevations in glucocorticoids would theoretically constrain both the release of ACTH from the pituitary and the release of CRH from the hypothalamus, and is further highlighted by

448 the uniformity in negative feedback effects on the peripheral HPA target organs — the pituitary and the adrenal—under conditions of CRF hypersecretion. Indeed, low doses of DEX produce comparable suppression of ACTH and cortisol in subjects with and without PTSD (Yehuda et al., 2004). Some regionally specific negative feedback effects may be consequences of differences in binding to MR or heterologous regulatory peptides such as vasopressin, and/or neurotransmitters that act differentially at discrete target organs of the HPA (de Kloet et al., 1975). In the current study, we examined the effects of exogenous cortisol in PTSD using a randomized, double—blind design, based on the methodology developed in the study of depression and dementia (Gispen-de Wied et al., 1998; de Leon et al., 1997).

2. Methods 2.1. Participants Thirty-one male veterans (age range 52–79 years) provided written informed consent to participate in a study approved by the IRB of Mount Sinai and Bronx Veterans Affairs. Subjects in the PTSD (C) group met diagnostic criteria for current or lifetime PTSD and were free of substance abuse/dependence, bipolar disorder, or psychosis. Subjects in the PTSD (K) group were free from any Axis I disorder. All participants were without medical, or neurological illness. Two subjects were taking antidepressants.

2.2. Procedure Psychiatric diagnoses were made using the structured clinical interview for DSM-IV (Spitzer et al., 1995); PTSD was diagnosed according to the clinician administered PTSD Scale (Blake et al., 1995). Participants received 17.5 mg cortisol (hydrocortisone sodium succinate (Solucortef) or placebo (counterbalanced to control for order effects) as an i.v. bolus within a two week period. This dose was chosen to produce a moderate suppression of the HPA axis (Gispen-de Wied et al., 1998; de Leon et al., 1997) and be within a range that is clinically acceptable (e.g. in the range of what is recommended for maintenance therapy of primary adrenocortical insufficiency (Oelkers et al., 2001). Samples were collected from an indwelling catheter 10 min before, and at 8, 40 and 95 min following injection. The mean (SD) injection times

R. Yehuda et al. for cortisol were 10:37 h (1:18) and 10:37 h (1:38) and for placebo were 10:51 h (1:17) and 10:45 h (1:08) in the PTSD(K) and PTSD(C) groups respectively. Plasma cortisol and ACTH levels were determined by radioimmunoassay (as previously described, Yehuda et al., 2004). The intra-assay and inter-assay coefficients of variation were 4.0 and 6.8%, for cortisol and 4.7 and 7.1% for ACTH.

2.3. Statistical analyses ACTH and cortisol responses to exogenous cortisol were evaluated using a group!time repeated measures ANCOVA correcting for injection time and the respective baseline hormone level.

3. Results 3.1. Characteristics of the sample Demographic and clinical characteristics of the sample are shown in Table 1. The groups were comparable in age, education, body mass index, and ages of their first, focal and most recent traumatic experience. A higher proportion of subjects in the PTSD(C) group than the PTSD(K) group had experienced combat trauma (78% (nZ14) vs. 31% (nZ4); (X2Z 6.85; dfZ1, pZ0.009). The PTSD(C) group had significantly higher rates of current (X2Z3.32, dfZ1, pZ0.07) and lifetime major depression (X2Z14.85, dfZ1, p!0.0005); the groups were comparable with respect to past alcohol abuse/dependence (X2Z0.68, dfZ1, pZ0.41) and past substance abuse/dependence (X2Z0.66, dfZ1, pZ0.42). Subjects in the PTSD(C) group had significantly higher scores on all subscales of the CAPS (intrusive (tZ4.26, dfZ29, p!0.0005), avoidance (tZ5.39, dfZ29, p!0.0005), and hyperarousal (tZ7.16, dfZ29, p!0.0005)). Fig. 1 shows mean plasma ACTH and cortisol levels in response to exogenous cortisol and placebo. For ACTH there was a significant group! time interaction (F(2,26)Z4.28, pZ.025) reflecting a greater decline in plasma ACTH to exogenous cortisol administration in the PTSD(C) compared to the PTSD(K) group. The adjusted mean (SE) ACTH values at C8,C40 and C95 min for the PTSD(C) group were 25.2 (1.3), 13.0 (2.1) and 6.4 (2.2) pg/ ml and for the PTSD(K) group were 25.2 (1.5), 18.6 (2.4), 14.3 (2.6) pg/ml. Post-hoc tests revealed there was a trend-level group difference in postcortisol ACTH levels at C40 min (F(1,29)Z3.45,

The ACTH response to cortisol administration in PTSD Table 1

449

Demographic and clinical characteristics in veterans with and without PTSD.

Demographics Age (years) Education (years) Ethnicity White Hispanic Black Asian Body mass index Trauma-related characteristics War zone exposure None WWII/Korea Vietnam Age of earliest trauma (years) Age of most recent trauma (years) Age of worst (focal) trauma (years) Diagnoses other than PTSD Current depressive disorder Lifetime depressive disorder Lifetime alcohol abuse or dependence Lifetime drug abuse or dependence Severity of current PTSD symptoms CAPS intrusive CAPS avoidance CAPS hyperarousal

PTSDK(NZ13)

PTSDC(NZ18)

M (SD) or % (n)

M (SD) or % (n)

64.4 (10.0) 15.5 (3.3)

60.4 (6.9) 14.1 (2.2)

84.6% (nZ11) 0% (nZ0) 15.4% (nZ2) 0% (nZ0) 26.2 (3.6)

61.1% (nZ11) 11.1% (nZ2) 16.7% (nZ3) 11.1% (nZ2) 28.2 (5.6)

69.2% (nZ9) 23.1% (nZ3) 7.7% (nZ1) 22.2 (14.3) 46.3 (14.6) 31.9 (18.6)

22.2% (nZ4) 22.2% (nZ4) 55.6% (nZ10) 15.9 (7.3) 47.1 (15.8) 26.2 (13.4)

0% (nZ0) 7.7% (nZ1) 46.2% (nZ6) 15.4% (nZ2)

22.2% (nZ4) 77.8% (nZ14) 61.1% (nZ11) 27.8% (nZ5)

0.08 (0.28) 1.00 (2.24) 0.62 (1.45)

9.47 (7.35) 19.59 (11.13) 19.76 (7.90)

plasma hormone level (for ACTH: pg/ml for cortisol: ug/dl)

pZ0.07) and a significant difference at C95 min (F(1,29)Z5.79, pZ0.02). There was a trend-level effect of time (F(2,26)Z2.66, pZ0.09) and no significant effect of group (F(1,27)Z2.94, pZ0.10).

This effect on ACTH levels did not result from group differences in cortisol levels as their were no group differences in cortisol (F(2,26)Z0.30, pZ0.74) or in the response to exogenous cortisol

50 45

ACTH before and after exogenous cortisol

Cortisol before and after exogenous cortisol

40 35 30 25 20 15 10 5 0 pre-

8 min 40 min 95 min

pre-

8 min 40 min 95 min

Figure 1 Solid lines represent H-cort administration and dotted lines represent placebo day in the PTSD(K) (open circles) and PTSD(C) (filled circles) groups.

450 administration (F(1,27)Z0.04, pZ0.84). There were no significant effects of time or group on ACTH or cortisol in the placebo condition.

4. Discussion The greater ACTH decline in response to exogenous cortisol administration reflects augmented negative feedback inhibition in PTSD. Although there is no way of assessing the relative proportion of cortisol effects occurring on sites influencing negative feedback inhibition in brain vs. those occurring in the pituitary, the findings suggest there may be PTSD-related difference in central feedback inhibition. The presence of alterations in central feedback inhibition would provide support for the use of pharmacologic strategies aimed at ameliorating PTSD symptoms by targeting central glucocorticoid mechanisms (e.g. Aerni et al., 2004). Although cortisol more readily enters the brain than DEX, recent studies in both intact rodents and post-mortem human brains have demonstrated that, like DEX, cortisol is also excreted from brain by means of steroid transporters, such as the P glycoproteins at the blood–brain–barrier, that limit access of glucocorticoids to brain (Karssen et al., 2001). Thus, although the dose administered yielded a two-three fold increase in circulating cortisol compared to baseline within a relatively short time frame, it is not known whether the concentration of cortisol was high enough to overwhelmed the capacity of steroid pumps (e.g. resulting in central effects). Still, it is reasonable to assume that some cortisol did get transported into the brain. Pariante et al. (2000) reported that 17–21.5% of plasma radioactive cortisol was present in guinea pig brain after perfusion with 3H-cortisol (2.5 nM). Furthermore, in PET-flurodeoxyglucose studies of these same subjects (unpublished data) we observed relative metabolic rate changes in discrete brain areas with the administration of cortisol as (de Leon et al 1997). Specific differential effects of DEX on verbal declarative memory in patients with PTSD and normal controls have also been observed (Bremner et al., 2004). This is consistent with, and most parsimoniously explained by, penetrance of cortisol into the brain, although complex indirect effects of cortisol cannot be excluded. It is of interest to know whether the response to exogenous cortisol involves intermediate or fast feedback mechanisms (Falkenstein et al., 2000) and nongenomic as well as genomic effects. It has not been possible to associate such mechanisms

R. Yehuda et al. with the response to DEX, which involves classic corticosteroid (genomic) actions at the GR, (i.e. entry of steroid into the cell, occupation of cytosolic GR, translocation into the nucleus, subsequent activation/repression of mRNA synthesis and protein synthesis and transport (Falkenstein et al., 2000), typical of delayed, slow feedback effects. Rapid fast feedback, consistent with non-GR mediated (nongenomic) actions, has been observed following exposure to higher doses of cortisol than those used in the current study, within 15 min of administration or sooner (Rees et al., 1977; Boscaro et al., 1998). Putative mechanisms of glucocorticoid action resulting in reduced ACTH secretion include those mediated by membrane-bound GR (Orchinik et al., 1991), or other rapidly acting channels, such as changes in the chloride channel via inhibition of GABA A receptors, prolongation of N-methyl-D-aspartate receptor-mediated CAC channels (Takahashi et al., 2002), observed in hippocampal tissue. In the present study such effects were not observed at 8 min post-injection and data at earlier time points was not obtained. Further studies are needed to clarify whether there are non-genomic effects in this response in PTSD by looking at earlier postcortisol time points (e.g. 5, 10 and 15 min post cortisol). Inferences regarding the adrenal response to exogenous cortisol cannot be made from the cortisol data presented since the radioimmunoassay could not detect differences between endogenous and injected cortisol. Thus, the lack of group difference in cortisol only demonstrates that ACTH effects were not a reflection of group differences in baseline or ambient circulating cortisol levels. Yet, in tandem with the reduced ACTH levels, the findings demonstrate enhanced glucocorticoid responsiveness in PTSD that might reflect central glucocorticoid alterations.

Acknowledgements This work was supported by a VA Merit Review Grant (RY), and, in part by a grant (5 M01 RR00071) for the Mount Sinai General Clinical Research Center from the National Institute of Health. In particular, Vivian Mitropoulou at the General Clinical Research Center assisted in the logistics of the project. The authors also wish to thank Karina Stavitsky for coordinating this study, Drs. Lisa Tischler, Ellen Labinsky, and Alicia Hirsch for providing psychiatric diagnostic assessments, Dr. Linda Bierer for performing medical clearance examinations of

The ACTH response to cortisol administration in PTSD subjects, Randall Newmark for assisting in executing the medication/placebo sessions, and Song-Ling Guo for performing cortisol and ACTH assays.

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