THE PHYSIOLOGICAL STRESS SYSTEM

The hypothalamic-pituitary-adrenal (HPA) axis is one of the body’s major systems modulating physiological responses to actual, anticipated, or perceived harm, and is a major component of adaptation to stresses of all types. The HPA axis functioning reflects acute, chronic, and developmental stressors and trauma. The influence of long-term stressors on the HPA axis is reviewed in a recent IOM report on the links between health and behavior (IOM, 2001). Briefly, acute stress activates the HPA axis and increases levels of glucocorticoids—a family of hormones that mediates stress. Adaptation to chronic stress activates a negative feedback loop that causes: (1) decreased resting glucocorticoid levels, (2) decreased glucocorticoid secretion in response to subsequent stress, (3) increased density of glucocorticoid receptors in the hippocampus (Sapolsky et al., 1984; Yehuda et al., 1991). Chapter 5 provides a detailed description of the role early adverse experiences play in HPA axis functioning and how this may reflect a physiological mechanism for socioenvironmental influences on psychopathology. Dysregulation of the HPA axis has been found to be significantly associated with severe affective disorders (e.g., Plotsky et al., 1998) and with post-traumatic stress disorder (e.g., van der Kolk, 1996), although findings suggest that this dysregulation may take different forms for specific disorders (Yehuda et al., 1991). Irregularities in HPA axis function also appear to correlate with suicide regardless of psychiatric diagnosis, as described below.

Links between corticosteroids and suicide have been proposed for many years. In the late 1960s it was first noted that urinary 17-hydroxy-corticosteroids were elevated in patients who completed suicide (Bunney et al., 1969; Fawcett and Bunney, 1967). Subsequently, several other cases were published (Krieger, 1970), although not all reports were in concurrence (Levy and Hansen, 1969). Other postmortem findings implicated an overactive HPA axis with suicide: individuals who died from suicide were reported to have enlarged adrenal glands compared to controls who died from other violence (Dorovini-Zis and Zis, 1987; Szigethy et al., 1994). Increased levels of corticotropin-releasing factor (CRF) in the cerebrospinal fluid (Arató et al., 1989; Brunner and Bronisch, 1999) and fewer binding sites for CRF in the frontal cortex (Nemeroff et al., 1988) in victims of suicide suggested HPA axis hyperactivity. In patients who had attempted suicide, levels of corticotropin-releasing hormone (CRH), another component of the HPA axis feedback loop, were noted to be lower than other psychiatric patients in cerebrospinal fluid (Brunner et al., 2001; Träskman-Bendz et al., 1992) and in plasma (Westrin et al., 1999), a pattern associated with chronic stress.

A depressed cortisol release following challenge with a corticosteroid, dexamethasone, represents a normal HPA axis response. Non-sup-



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