Altered Hypothalamic-Pituitary-Adrenocortical Regulation in Healthy Subjects at High Familial Risk for Affective Disorders

Abstract

Altered negative feedback control of the hypothalamic-pituitary-adrenocortical (HPA) system is a frequent laboratory sign of major depression. It coincides with depressive episodes and partially reverses after recovery from psychopathology. Such an HPA disturbance in feedback control can be acquired as a result of stressful life experiences and be compounded by age or it can be genetically predetermined at all levels involved in fine-tuned neuroendo-crine regulation. Major psychiatric disorders run in families and a high familial load for an affective illness therefore increases an individual’s risk of becoming affected. We investigated whether the HPA feedback disturbance observed among patients with depression is present in otherwise healthy individuals who are at high risk for psychiatric disorders because they have a first-degree relative with an affective illness. Using rigid psychodiagnostic techniques, we screened 431 consecutively admitted patients with depression and identified 35 families with one or more high-risk probands (HRPs). The results of a combined dexamethasone/human corticotropin-releasing hormone (DEX-CRH) test showed that the group of dexamethasone-pretreated (1.5 mg; 23.00 h) HRPs released more cortisol after stimulation with human CRH (100 µg; 15.00 h the next day) than a control group (CPs), but less than a group of patients with an acute major depressive episode (DPs). The peak cortisol values were 146.1 ± 147.7 nmol/l (mean ± SD) (HRPs), 75.3 ± 47.9 nmol/l (CPs) and 278.2 ± 199.2 nmol/l (DPs), yielding significant (F = 9.66, p < 0.001) group differences, with values for HRPs vs. CPs and HRPs vs. DPs being significant at the 1 % level (t test). The adrenocorticotropin (ACTH) responses of the HRPs did not exceed control levels, suggesting that over time the adrenocortical gland had developed a hypersensitivity, possibly secondary to long-term overexposure to ACTH. A linear discriminant analysis identified 32% of the HRPs as showing cortisol response patterns indistinguishable from those of DPs. These and other data analyses revealed the presence of an HPA feedback disturbance in a substantial number of subjects at risk for affective illness. Our findings suggest that the negative feedback defect in a number of healthy probands at risk for affective disorder is caused by a disturbed corticosteroid receptor function. In the absence of current or previous psychiatric disorder or environmental factors such as specific lifestyles that could have led to adaptive changes in corticosteroid receptor function in our subjects, we conclude that our findings are best understood as indicating a genetically transmitted risk factor, possibly rendering these individuals susceptible to affective disorders.

Pharmacological and Nonpharmacological Factors Influencing Hypothalamic–Pituitary–Adrenocortical Axis Reactivity in Acutely Depressed Psychiatric In-patients, Measured by the Dex-CRH Test

“…In our own sample, peak cortisol values range from 3.9 to 332.4 ng/ml (mean/ SD ¼ 62.6/55.3). These values are still significantly higher than the ones reported for healthy controls in Holsboer et al (1995) (mean peak cortisol value 27.3 ng/ml (SD ¼ 17.4), p ¼ 0.005 for a two-sided t-test).…”

Importance of Studying the Contributions of Early Adverse Experience to Neurobiological Findings in Depression

“…Blunted ACTH responses to CRF stimulation provide indirect evidence for CRF hypersecretion in patients with depression (Holsboer et al, 1984;Gold et al, 1986) and parallel findings of blunted responses in abused women with depression and findings of downregulated pituitary CRF receptors in maternally separated rats. Escape from cortisol suppression in the combined dexamethasone/CRH test, as recently observed in humans in relation to ELS, is believed to be the most sensitive marker for HPA axis dysfunction in major depression and also detects vulnerability to depression in first-degree relatives of depressed patients (Holsboer et al, 1995). In addition, many other CNS features of depression parallel the effects of ELS.…”

Discovering Endophenotypes for Major Depression

“…Abnormal cortisol responses in MDD patients, MDD highrisk probands, and healthy controls were found to be surprisingly constant over time (Modell et al, 1998), and independent of the actual depressive state (Zobel et al, 1999), suggesting that this marker is state-independent. Findings in healthy subjects at high familial risk for affective disorders (Holsboer et al, 1995) suggest familial association and cosegregation.…”