Hormonal Evidence for Altered Responsiveness to Social Stress in Major Depression

Abstract

In patients with major depression, abnormalities in baseline cortisol secretion and resistance to negative feedback are well established. However, it is unclear if patients with major depression have alterations in the hypothalamicpituitary-adrenal (HPA) response to stressors. While other challenges to the HPA axis have used endocrine stimuli such as insulin-induced hypoglycemia, we now report of the response to a social stressor in patients withOver the last two decades, an extensive body of work has pointed to a close relationship between stress and major depression. Studies by numerous investigators including Frank et al. (1994) and Brown et al. (1994) have documented the role of stressful life events in the precipitation of depressive episodes. Studies in twins by Kendler et al. (1993) have demonstrated a clear interaction between genetic substrate and a recent stressful life event in the precipitation of a depressive episode. In addition, abnormalities in the hypothalamic-pituitary adrenal (HPA) axis are seen during depression. HPA measures have demonstrated different types of dysregulation at rest or following various endocrine challenges. For example, patients with major depression demonstrate elevated plasma cortisol levels at rest, a finding observed in approximately 50% of depressed patients. This increase in plasma cortisol is particularly evident in the evening, at the nadir of the circadian rhythm (Sachar et al. 1973; Carroll et al. 1976;Rubin et al. 1987;Halbreich et al. 1985;Pfohl et al. 1985). Furthermore, a number of studies have investigated abnormal glucocorticoid feedback, typically using the synthetic steroid dexamethasone but also using the naturally occurring glucocorticoid cortisol (Carroll et al. 1981;Young et al. 1993Young et al. , 1991. These studies generally support the view that there is significant dysregulation of NO . 4 steroid negative feedback mechanisms in major depression. Fewer studies have examined the activational circuits of the LHPA axis in depression, and these studies have been limited to endocrine challenges such as metyrapone, or insulin-induced hypoglycemia (Young et al. 1994;von Bardeleben et al. 1988;Kathol et al. 1992;Lopez et al. 1987). The metyrapone studies suggested increased central drive in the evening (Young et al. 1994), while insulin-induced hypoglycemia revealed elevated basal cortisol and an attenuated ACTH response to the challenge (Kathol et al. 1992;Lopez et al. 1987). Finally, there is evidence that corticotropin-releasinghormone, CRH, which represents the final common path of stress responsiveness in the brain, is elevated in CSF and hypothalamus, and that this elevation may contribute both to the endocrine and psychological profile seen in severe depression (Nemeroff et al. 1984;Roy et al. 1987;Raadsheer et al. 1995Raadsheer et al. , 1994Nemeroff, 1988;Nemeroff et al. 1988).In spite of these findings, it remains difficult to determine what these endocrine changes tell us about the alterations in key neuronal circuits which mediate stress resp...

Neurosteroids in the context of stress: Implications for depressive disorders

“…Moreover, to the extent that allopregnanolone negatively modulates the HPA axis following stress, then our results are also consistent with HPA axis abnormalities seen in depression, since it is well established that a large proportion of patients with melancholy depression are hypercortisolimic (Nemeroff, 1998) and show exaggerated HPA axis responses to mental stress (Heim et al, 2000;Young and Breslau, 2004). More relevant, euthymic women with a history of major depression show elevated diurnal salivary cortisol relative to never-depressed women (Young et al, 2000a(Young et al, , 2000b. Thus, the possibility exists that the hypercortisolimia frequently documented in depression may be an associated feature of the depleted allopregnanolone concentrations seen in patients with depression or the altered allopregnanolone response to stressors seen in our sample of women with depression histories.…”

“…Thus, this profile of diminished neurosteroid concentrations coupled with elevated glucocorticoids in socially isolated animals is strikingly similar to that seen in patients with melancholic depression, since many depressed patients are also hypercortisolimic relative to non-depressed controls (e.g., Nemeroff, 1998;Young et al, 2000aYoung et al, , 2000b. Chronic activation of the HPA axis, including greater CRF concentrations and gene expression in depressed patients (Roy et al, 1987;Raadsheer et al, 1995;Nemeroff, 1998), is clearly implicated in the pathophysiology of depressive disorders (Nemeroff, 1998).…”

“…Some of these initial studies are currently underway in our laboratory (e.g., Girdler et al, 2006). The establishment of a reliable neuroactive stress response profile in healthy humans, as has been done for the HPA axis response to social stress (e.g., Kirschbaum et al, 1993Kirschbaum et al, , 1995aKirschbaum et al, , 1995bYoung et al, 2000aYoung et al, , 2000b, will be needed to address questions suggested by some of the recent work from our laboratory. For example, whether depressive illness results in longterm alterations in neurosteroid responsivity, persisting beyond remission of the depressive episode, and whether such dysregulation results in altered stress responsiveness to even mild stressors later, either directly or indirectly via homeostatic forces affecting the HPA axis, setting the stage for the recurrence of a depressive episode with stress.…”

“…For example, Bloch et al (2000) demonstrated that euthymic women with a past history of postpartum depression experienced significant depression when exposed to high doses of hormone add-back and withdrawal, effects not seen in women with no prior history of depression. Divergent evidence suggests that in euthymic women, histories of depression are associated with persistent disturbance in HPA axis function (Young et al, 2000a(Young et al, , 2000b as well as thyroid axis function relative to never-depressed women.…”

Effect of Ethanol on Hypothalamic–Pituitary–Adrenal System Response to Psychosocial Stress in Sons of Alcohol-Dependent Fathers

“…This difference might be due to long-lasting effects of chronic alcohol intoxication on HPA functioning and suggests that endocrine abnormalities observed in alcoholics during early abstinence cannot be interpreted as pre-existing risk factors for the development of alcoholism. In untreated patients with major depression, basal cortisol was increased, but cortisol response to the TSST was equal to healthy controls matched for sex and age (Young et al, 2000). In another study investigating a nonclinical sample of adult women, HPA response to the TSST correlated with childhood abuse, adulthood traumas, and severity of depression, but not with severe negative life events (Heim et al, 2002).…”