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

Abstract

The most consistent biological findings in patients with depression are abnormalities in the hypothalamic-pituitary-adrenal (HPA)-axis, which can be measured using the combined dexamethasone-suppression/CRH-stimulation (Dex-CRH) test. The reactivity of the HPAaxis in this test, however, ranges over several orders of magnitude in depressed patients with comparable severity of symptoms. In this present study, we investigate which factors influence the magnitude of the response in the Dex-CRH test in 235 acutely depressed inpatients. We first examined the effects of common confounders shown to influence the HPA-axis, such as caffeine and nicotine consumption, acute stressors during the test, weight, gender, and age. Of all these variables, only female sex and nicotine consumption were positively correlated with the cortisol or ACTH response, respectively. As for the effects of psychopharmacological treatment, only the intake of carbamazepine and the fact of having relapsed under an established pharmacotherapy significantly increased the response in the Dex-CRH test, whereas the presence or absence of antidepressant treatment, the type of antidepressant treatment, or the number of ineffective antidepressant treatment trials during the index episode up to admission did not have any effect. We also found a positive correlation of the number of previous episodes, the overall HAM-D score and the severity of somatic/vegetative symptoms with the results in the Dex-CRH test. These results underline that in depressed patients this test is not majorly influenced by disease-unrelated factors. In addition, current antidepressant treatment does not appear to affect test outcome in the absence of clinical response. The influence of the number of previous episodes and relapse under pharmacotherapy suggests that HPA-axis reactivity may be altered by repetitive states of hypercortisolemia or continuous antidepressant treatment. Finally, more severe vegetative symptoms are associated with an enhanced HPA-axis activity.

Increased Pituitary Volume in Antipsychotic-Free and Antipsychotic-Treated Patients of the Æsop First-Onset Psychosis Study

“…Studies of patients in the acute relapse phase of a psychotic disorder (with florid symptoms, newly hospitalized or unmedicated) have also found elevated cortisol levels that correlate with the severity of psychotic and arousal symptoms (Lammers et al, 1995;Tandon et al, 1991;Walder et al, 2000), nonsuppression of cortisol secretion by dexamethasone in the dexamethasone suppression test and in the dexamethasone/CRH test (Coryell and Tsuang, 1992;Herz et al, 1985;Lammers et al, 1995), and elevated levels of CRH in the cerebrospinal fluid (Banki et al, 1987). Finally, patients with bipolar disorder also show HPA axis hyperactivity (Kunzel et al, 2003;Linkowski et al, 1994;Watson et al, 2004). It is of note that a smaller pituitary volume has been described in psychiatric patients with long duration of illness and whose mental state is stable or less severely affected at the time of the MRI scan: for example, in euthymic and depressed bipolar patients, or in patients with chronic, treated schizophrenia (Pariante et al, 2004).…”

The Antidepressant Desipramine Requires the ABCB1 (Mdr1)-Type p-Glycoprotein to Upregulate the Glucocorticoid Receptor in Mice

“…Moreover, several lines of evidence indicate that these HPA axis abnormalities contribute to the development of the depressive symptoms. First, treatment with antidepressants reduces HPA axis activity, and this reduction is associated with the clinical response in depressed patients (Kunzel et al, 2003). Second, genes that regulate the HPA axis also influence the likelihood of developing depression (van West et al, 2006).…”

Regulation of the Hypothalamic–Pituitary–Adrenocortical System in Patients with Panic Disorder

“…This test is aimed at detecting impaired glucocorticoid feedback signaling at the pituitary and to evaluate the effects of an altered release of central neuropeptides involved in the regulation of the HPA system, such as CRH and vasopressin (AVP) . Moreover, the Dex-CRH test was shown to be rather refractory against disease-unrelated factors such as cigarette smoking, weight, age and test-concomitant acute stress and a current psychopharmacological treatment does not appear to affect test outcome in acutely ill patients (Künzel et al, 2003).…”

“…Profound changes in hypothalamic-pituitary-adrenocortical (HPA) system regulation have been demonstrated in major depression, and the dexamethasone-suppression/ corticotropin-releasing hormone-stimulation (Dex-CRH) test has proven to be a sensitive tool for detecting such altered HPA regulation (Heuser et al, 1994;Holsboer, 2000;Künzel et al, 2003;Ising et al, 2005). One of the major modulators of the HPA system is corticotropin releasing hormone (CRH) (review: Engelmann et al (2004); Nemeroff and Vale (2005)), which elicits the release of pituitary ACTH and subsequently cortisol under basal conditions and in response to stress.…”

“…We also examined the effects of different psychopathological phenotypes upon Dex-CRH test induced hormone response. We used the Dex-CRH test in our study because this test was consistently shown to have high sensitivity in detecting even subtle HPA system dysregulations which are not necessarily reflected in differences in basal peripheral plasma ACTH and corticosteroid concentrations (Holsboer, 2000;Pariante et al, 2004;Ising et al, 2005;Künzel et al, 2003). This test is aimed at detecting impaired glucocorticoid feedback signaling at the pituitary and to evaluate the effects of an altered release of central neuropeptides involved in the regulation of the HPA system, such as CRH and vasopressin (AVP) .…”