Rachel Yehuda

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Psychiatry Department and Division of Traumatic Stress Studies, Mount Sinai, School of Medicine and Bronx Veterans Affairs, Bronx, NY, USA

Abstract: This chapter discusses how neuroendocrine findings in posttraumatic stress disorder (PTSD) potentially inform us about hypothalamic -pituitary-adrenal (HPA) alterations in PTSD and highlight alterations relevant to the identification of targets for drug development. The majority of studies demonstrate alterations consistent with an enhanced negative feedback inhibition of Cortisol on the pituitary, and/or an overall hyperreactivity of other target tissues (adrenal gland, hypothalamus) in PTSD. However, findings of low Cortisol and increased reactivity of the pituitary in PTSD are also consistent with reduced adrenal output. The observations in PTSD are part of a growing body of neuroendocrine data providing evidence of insufficient glucocorticoid signaling in stress-related neuropsychiatric disorders.

Introduction

The development of drugs that might be effective in treating anxiety disorders in part depends on the ability of clinical neuroscience to identify biological alterations that might serve as targets for drug development. Unfortunately, an observable biological change - even one that is directly correlated with severity of symptoms or the absence or presence of a disorder -- does not always constitute a core pathophysiological process requiring biological "repair." Biological alterations may be present in specific anxiety disorders because they are correlates of, or proxies for, other pathophysiologic processes, or even because they represent compensatory mechanisms of adaptation.

The study of the neuroendocrinology of posttraumatic stress disorder (PTSD) has been illuminating in highlighting alterations that have not historically been associated with pathologic processes. The most infamous of these findings - low Cortisol levels - has been subjected to much discussion and scrutiny, likely because it has been a counterintuitive result

* E-mail: Rachel.yehuda(aimed.va.gov given modern interpretations of the damaging effects of stress hormones. Indeed, the initial observation of low Cortisol in a disorder precipitated by extreme stress directly contradicted the emerging and popular formulation of hormonal responses to stress, the "glucocorticoid cascade hypothesis" (Sapolsky et al, 1986) which was emerging as a cogent rationale for antiglucocorticoid treatments in depression, and other psychiatric disorders thought to be driven by hypercortisolism.

This chapter discusses how Cortisol findings in PTSD potentially inform us about hypothalamic-pituitary-adrenal (HPA) alterations in PTSD and highlight what might be true targets of drug development. The observations in PTSD are part of a growing body of neuroendocrine data providing evidence of insufficient glucocorticoid signaling in stress-related neuropsychiatric disorders (Raison and Miller, 2003). The majority of studies demonstrate alterations consistent with an enhanced negative feedback inhibition of Cortisol on the pituitary, and/or an overall hyperreactivity of other target tissues (adrenal gland, hypothalamus) in PTSD. This model explains most of the reported observations in PTSD. Theoretically, however, findings of low

Cortisol and increased reactivity of the pituitary in PTSD are also consistent with reduced adrenal output (Maes et al, 1998; Heim et al, 2000), but this latter model is only supported by the minority of HPA alterations observed in PTSD.

It may be that models of enhanced negative feedback, increased HPA reactivity, and reduced adrenal capacity explain different facets of the neuroendocrinology of PTSD, or that the tendency for reduced adrenal output represents a pre-existing risk factor that may be related to certain types of early experiences, at least in some persons who develop PTSD. On the other hand, alterations associated with enhanced negative feedback inhibition may develop over time in response to the complex biological demands of extreme trauma and its aftermath. The findings of increased HPA reactivity may also reflect a more nonspecific response to ongoing environmental challenges associated with having chronic PTSD. Furthermore, the absence of Cortisol alterations in some studies imply that alterations associated with low Cortisol and enhanced negative feedback are only present in a biological subtype of PTSD. The observations in the aggregate, and the alternative models of pathology or adaptation suggested by them, must be clearly understood in using neuroendocrine data in PTSD to identify targets for drug development.

Basal HPA hormone levels in PTSD

The first observation reporting on Cortisol levels in PTSD was that of Mason et al. (1986), who found that the mean 24-h urinary excretion of Cortisol was significantly lower in combat Vietnam veterans with PTSD compared to psychiatric patients in four other diagnostic groups. The authors were surprised at the fact that Cortisol levels were low since "certain clinical features such as depression and anxiety (in PTSD) might have been expected to be associated with increased activity of the pituitary-adrenal cortical system." Since this initial observation, the majority of the evidence supports the conclusion that Cortisol alterations in PTSD are different from observed in acute and chronic stress, and major depression, but more importantly, that the hypothalamic-pituitary-adrenal (HPA) axis appears to be regulated differently.

Urinary Cortisol levels in PTSD

The initial report of sustained, lower urinary Cortisol levels in PTSD highlighted the disassociation between Cortisol and catecholamine levels in PTSD. Noradrenaline and epinephrine levels assayed from the same urine specimens revealed elevations in both of these catecholamines, and that Cortisol levels in PTSD fell within the "normal range" of 20-90 ug/day, indicating that the alteration was not in the "hypoadrenal" or endocrinopathological range (Mason et al, 1986). This finding established the expectation that alterations in basal levels of Cortisol might be subtle, and not easily differentiated from normal values (Mason et al, 1986).

Table 1 shows that this is in fact the case. Whereas the majority of studies have found evidence of low-cortisol in PTSD, it is clear that group differences are not always present between subjects with and without PTSD. The inconsistency in published reports examining urinary 24-h Cortisol levels has been widely noted. There are numerous sources of potential variability in such studies related to selection of subjects and comparison groups, adequate sample size and inclusion/exclusion criteria, as well as considerations that are specific to the methods of collecting and assaying Cortisol levels that can explain the discrepant finding. However, the simplest explanation for disparate observations is that Cortisol levels may not represent stable markers, and are likely to fluctuate, making it difficult to consistently observe group differences.

Cortisol levels over the diurnal cycle in PTSD

Among the many potential methodological problems associated with 24-h urine collections is the possibility that persons who are asked to collect 24-h samples at home may not provide complete collections. To the extent that there may be a systematic bias in protocol nonadherence between subjects with and without PTSD, in that the former might be more likely to miss collections than the latter, this could contribute to observed low Cortisol levels. One of the

Table 1. Summary of data from studies of 24-h urinary Cortisol excretion in adults with PTSD Author(s), year Cortisol ng/day (n)

Trauma survivors Trauma with/without Normal Psychiatric with PTSD (n) PTSD comparison comparison

Table 1. Summary of data from studies of 24-h urinary Cortisol excretion in adults with PTSD Author(s), year Cortisol ng/day (n)

Trauma survivors Trauma with/without Normal Psychiatric with PTSD (n) PTSD comparison comparison

Mason et al., 1986*

33.3 (9)

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