The Stress Axis Gone Awry: A Possible Neuroendocrine Explanation for Increased Risk of Completed Suicide

• While not useful as a screening tool or specific diagnostic indicator, a patient’s DST status provides useful information about the character of the depressive state, particularly as it relates to agitation and anxiety. The HPA Axis and Mental Status The HPA axis is crucial to survival. At baseline, it maintains homeostasis and circadian rhythms through a finetuned feedback loop, consisting of the paraventricular nucleus (PVN) of the hypothalamus, the anterior pituitary, and the adrenal cortex. The PVN is the HPA axis master controller, receiving modifying input from the hippocampus, the prefrontal cortex, and other brain regions, as well as the axis itself (Figure). In humans, cortisol is the hormone messenger that feeds back to the PVN via two receptors. High-potency, type-I mineralocorticoid receptors that preferentially bind cortisol in low-concentration environments give predominantly positive feedback at baseline, fine tuning homeostasis in cardiovascular, metabolic, and immune systems.2 Under stressful conditions, however, massive amounts of cortisol are produced. Mineralocorticoid receptors are saturated, and low-potency glucocorticoid receptors located on the PVN and anterior pituitary dominate. They offer negative feedback to contain the all-out stress response. At these times, hyperarousal trumps homeostasis. The individual demonstrates heightened alertness, decreased libido, insomnia, and cognitive changes in the throes of a “fight-or-flight” mode. The HPA axis, the so-called “stress axis,” has long been linked to effects on mental status. Cannon3 observed as early as 1939 that the adrenal glands Abstract While the dexamethasone suppression test (DST) has not proven useful as a diagnostic test for “true” depression, it shows increasing promise as a potential indicator of psychiatric patients at increased risk for suicide. An indicator of the activity level of the hypothalamic-pituitary-adrenal (HPA) axis, the DST is an endocrine test that has caught the interest of psychiatric researchers throughout the last century because of the role of the HPA axis in managing an organism’s homeostasis and stress response. This article will present a brief literature review of the role of the DST in psychiatry. It will propose a hypothesis, supported by data from two recent small studies, that suggests that chronic overdrive in the HPA axis, as manifested in a nonsuppressing DST, may result in an increased likelihood of suicide when the individual is acutely stressed.