Ulrike Gotthardt

CEREBROSPINAL FLUID CONCENTRATIONS OF CORTICOTROPIN-RELEASING HORMONE, VASOPRESSIN, AND SOMATOSTATIN IN DEPRESSED PATIENTS AND HEALTHY CONTROLS: RESPONSE TO AMITRIPTYLINE TREATMENT

The effect of amitriptyline upon hypothalamic‐pituitary‐adrenal [HPA]‐system‐regulating neuropeptides (corticotropin‐releasing hormone [CRH], vasopressin, somatostatin) was studied in a group of depressed elderly patients and controls. A first lumbar puncture was performed in 37 depressed in‐patients. This was followed by a 6‐week medication phase with amitriptyline. Upon its completion a second cerebrospinal fluid (CSF) sample was obtained in 18 of these 37 patients. In 25 healthy controls a first lumbar puncture was done; eleven of these individuals agreed to take 75 mg/d amitriptyline for 6 weeks and to participate in the follow‐up CSF study. Within the group of depressed patients amitriptyline led to a significant decrease of CSF CRH in treatment responders only (F1,16 = 5.2; P < 0.02). Also, in normal controls CSF CRH concentration tended to decrease with amitriptyline treatment (t‐test; P < 0.09). No effects of amitriptyline upon vasopressin or somatostatin were observed. In normal controls (r = 0.4; P < 0.02) and in patients (r = 0.4; P < 0.03) age correlated positively with baseline CSF somatostatin. A trend for CSF CRH to increase with aging was found only in controls (r = 0.3; P < 0.09); patients did not show a significant association here. Finally, CSF neuropeptide concentration at baseline did not differ between the group of depressed patients and healthy controls. Our study corroborates the evolving concept that antidepressants effect various components of the HPA system with the net result of a reduction in its activity. In addition, we found CSF CRH and CSF somatostatin concentrations to be better reflections of age than of depression and, finally, that during aging and during depression the HPA system changes in similar directions. Depression and Anxiety 8:71–79, 1998.

With aging in humans the activity of the hypothalamus-pituitary-adrenal system increases and its diurnal amplitude flattens.

There is compelling evidence for feedback disturbances in the hypothalamus-pituitary-adrenal system associated with human aging as assessed by challenge tests. However, reports about age-related changes in human basal activity are ambiguous and to date little is known about changes in the pulsatile features of the HPA system. To investigate these changes we studied twenty-two healthy male and eleven healthy female subjects ranging from 23 to 85 and 24 to 81 years respectively. 24-hour blood sampling with 30 minute sampling intervals was performed. From 18.00 to 24.00 hours blood was sampled every 10 minutes for analysis of pulsatile features of HPA activity. Statistical analysis revealed that age in particular had major effects upon basal HPA-system activity: there was a significant age-associated increase in minimal (p < 0.0001) and mean (p < 0.02) cortisol plasma concentrations, but no alteration in pulsatile features. We found no age-cortisol correlation during daytime, but were able to demonstrate a strong impact of age upon cortisol plasma levels from 20.00 to 1.30 hours. The diurnal amplitude of cortisol (p < 0.005) and ACTH (p < 0.006), relative to the 24-hour mean of the hormones, showed an age-associated decline. Additionally, the evening cortisol quiescent period (p < 0.01) was shortened in the elderly, suggesting increasingly impaired circadian function in aging. Our results suggest an increased basal activity and a flattened diurnal amplitude of the HPA system in the elderly.

Combined dexamethasone/corticotropin-releasing hormone test in acute and remitted manic patients, in acute depression and in normal controls: I

Hypothalamic-pituitary-adrenal system (HPA)-function in patients with mania (n = 11), depression (n = 11, unipolar) and in control subjects (n = 11) was studied; six of the acutely manic patients were reevaluated after a symptom-free interval of at least 6 months. The combined dexamethasone-suppression/human CRH-challenge test was used to probe HPA-system function. After CRH and dexamethasone pretreatment, ACTH and cortisol release were significantly increased in both manic and depressed patients in comparison to the control group. In the remitted patients with mania, a significant decrease in hormonal release after DEX and CRH was evident when compared to the acute manic episode, but the degree of CRH-stimulated hormone secretion in these remitted patients was still significantly larger than in normal controls. This study demonstrates that acute and remitted manic episodes are associated with a profoundly dysregulated HPA-system activity.

Combined dexamethasone/corticotropin-releasing hormone test in patients with schizophrenia and in normal controls: II.

Hypothalamic-pituitary-adrenal system (HPA) function was tested in 24 patients with schizophrenia and compared to 24 age-matched healthy volunteers using the combined dexamethasone-suppression (DST/CRH) corticotropin-releasing hormone stimulation test (DST/CRH). After stimulation with CRH, the dexamethasone-pretreated patients released significantly more cortisol, but a similar amount of adrenocorticotropic hormone (ACTH) in comparison to controls. No association between DST status and degree of severity of illness and/or current medication was found. However, in comparison to unmedicated patients, those patients currently receiving antipsychotics, who were also those with a lesser degree of severity of illness, showed a decreased release of CRH-stimulated cortisol and ACTH. This study demonstrates that schizophrenic patients have a dysregulation of the HPA system as assessed with the DEX/CRH test. Overall, however, the degree of HPA-system dysfunction in schizophrenic patients seems to be of a lesser magnitude than in patients with affective disorders.

Testosterone, gonadotropin, and cortisol secretion in male patients with major depression.

OBJECTIVE Previous studies of sex hormone concentrations in depression yielded inconsistent results. However, the activation of the hypothalamic-pituitary-adrenal system seen in depression may negatively affect gonadal function at every level of regulation. The objective of this study was to explore whether major depressive episodes are indeed associated with an alteration of gonadal function. METHODS Testosterone, pulsatile LH secretion, FSH, and cortisol were assessed using frequent sampling during a 24-hour period in 15 male inpatients with major depression of moderate to high severity and in 22 healthy comparison subjects (age range 22-85 years). RESULTS An analysis of covariance model showed that after adjustment for age only, daytime testosterone (p < .01), nighttime testosterone (p < .05), and 24-hour mean testosterone secretion (p < .01) were significantly lower in the depressed male inpatients. There was also a trend for a decreased LH pulse frequency in the depressed patients (p < .08). CONCLUSIONS Gonadal function may be disturbed in men with a depressive episode of moderate to high severity.

Insulin-like growth factor-I (IGF-I) plasma concentrations are increased in depressed patients

There is some evidence that the somatotrophic system in depression, as assessed by basal growth hormone (GH) concentrations and by GH releasing hormone (GHRH) challenge, might be dysfunctional. However, the rather limited data have been inconclusive so far and plasma concentrations of both insulin-like growth factor-1 (IGF-I) and binding proteins (IGFBP 1 to IGFBP-6) have not been measured simultaneously in depressed patients. We studied 24 severely depressed patients and 33 healthy controls and estimated 24-hour mean plasma cortisol, six-hour evening mean plasma growth hormone (GH), morning plasma IGF-I, IGFBP 2 and 3 and GH-binding protein (GH-BP). Twenty-four-hour mean cortisol (306 +/- 69 vs. 196 +/- 30 nmol/l, p < .001) and IGF-I (157 +/- 40 vs. 120 +/- 33 micrograms/l, p < .01) plasma concentrations were found to be significantly increased in depressed patients, while there was no difference in GH or binding proteins between both groups. MANOVA analysis revealed age and diagnosis to have main effects upon plasma IGF-I. Especially young age and a diagnosis of major depression are associated with higher plasma IGF-I. After treatment only patients in remission had attenuated IGF-I plasma concentrations. We conclude that plasma IGF-I is increased in acutely depressed patients similar to other states of hypercortisolemia.

The combined dexamethasone/corticotropin-releasing hormone stimulation test is more closely associated with features of diurnal activity of the hypothalamo-pituitary-adrenocortical system than the dexamethasone suppression test.

BACKGROUND The dexamethasone suppression test (DST) is a widely used endocrine test in psychiatry, but was reported to not allow reliable inferences with regard to the basal activity of the hypothalamo-pituitary-adrenocortical (HPA) system. We compared the association of the standard DST and the combined dexamethasone/corticotropin-releasing hormone (DEX/CRH) challenge with parameters of diurnal cortisol profiles. METHODS We performed a DEX/CRH challenge and 24-hour cortisol profiles in 25 depressed patients (mean age: 47.4 +/- 16.0 years) and 33 age-matched healthy controls (mean age: 51.4 +/- 19.3 years). RESULTS A path analysis showed cortisol area under the curve (AUC) after CRH (= DEX/CRH status) to be dependent upon minimal 24-hour cortisol and evening frequency of pulsatile cortisol release. In contrast, postdexamethasone cortisol (= DST status) was related to 24-hour mean cortisol. Simple linear regressions supported an association of cortisol AUC with several parameters of the diurnal cortisol profiles, which was not true for the standard DST. CONCLUSIONS We conclude that the combined DEX/CRH challenge test is more closely associated with the activity of the HPA system than the standard DST in healthy and depressed subjects.

Amitriptyline metabolism in elderly depressed patients and normal controls in relation to hypothalamic-pituitary-adrenal system function

The pharmacokinetics of amitriptyline (AMI) have been extensively studied, and a large interindividual variability between oral dose and concentration of the drug in plasma has been documented. The aim of this study was twofold: first, to compare AMI kinetics in depressed patients with those of healthy controls and, second, to describe the relationship between AMI levels in plasma and hypothalamic-pituitary-adrenal (HPA) system changes during depression. Thirty-eight patients with a DSM-III-R diagnosis of major depression and 13 healthy control persons received 75 mg of AMI daily for 6 weeks. Levels of AMI and nortriptyline in plasma were determined, and neuroendocrine testing with the combined dexamethasone-suppression/CRH-stimulation test (DST) was done before AMI administration and after weeks 1, 3, and 6 of medication. AMI levels in plasma were significantly higher in the patient group compared with controls during the entire treatment period, whereas nortriptyline levels did not differ between the two groups. Drug levels correlated significantly with age, but gender had no effect on the concentration of the drug in plasma. Twenty-two patients remitted after treatment. There was no difference in drug levels between responders and nonresponders. Fifteen patients were DST nonsuppressors before treatment; 23 patients and all controls suppressed cortisol after dexamethasone. DST suppressors had significantly higher AMI levels in plasma at weeks 3, 5, and 6 compared with DST nonsuppressors. In comparison to patients with high AMI levels in plasma, those with low drug concentration had higher postdexamethasone cortisol and adrenocorticotropic hormone levels and an increased hormone release after additional CRH.(ABSTRACT TRUNCATED AT 250 WORDS)

Behavioral effects of a synthetic corticotropin 4-9 analog in patients with depression and patients with Alzheimer`s disease

In an acute trial, three different dosages (60, 300, and 600 micrograms) of the endocrinologically inert but behaviorally active corticotropin 4-9 (ACTH4-9) fragment ebiratide were given to three patients with clinically probable Alzheimers disease and five patients with a major depressive episode who were psychomotorly retarded. The drug was given intravenously in a double-blind, placebo-controlled, crossover design, and cognitive as well as psychopathologic assessments were carried out predrug and postdrug treatment. In summary, no adverse effect of the ACTH fragment was detected. In this explorative study, none of the patients improved cognitively, as measured by neuropsychologic testing. However, all patients, regardless of underlying disorder, reported a decrease of the feeling of tiredness or loss of energy, respectively. They felt more vigorous and alert. This occurred after any of the three doses of ACTH4-9, but not after placebo. In concert with reports from other studies, it is concluded that the ACTH4-9 fragment ebiratide may have activating properties in humans. However, given acutely, it does not seem to have antidementia or antidepressive efficacy.

Hypothalamic-Pituitary-Adrenocortical Dysfunction in Elderly, Male Marathon Runners: Feedback Sensitivity, Stress Response, and Effects on Verbal Memory

Animal studies suggest that repeated episodes of elevated glucocorticoids lead to a dysregulation of the hypothalamic-pituitary-adrenal (HPA) system at a suprapituitary level, and to impaired mnemonic function. We compared cognitive tests, as well as feedback integrity and stress responsivity of the HPA system, between 11 elderly, male marathon runners - a model of repeated HPA system activation - and 10 sedentary controls. The marathon runners had significantly increased baseline, stress, and post-stress ACTH - but not cortisol - concentrations. Also, suppression of ACTH by 3 mg dexamethasone was impaired in the athletes compared to the control subjects, while the ACTH and cortisol response to additional CRH did not differ between the 2 groups. Finally, long-term verbal memory was impaired in the athletes compared to the controls. Regarding the HPA system, these findings are in accordance with an acquired suprapituitary feedback disturbance in marathon runners; however, the similar glucocorticoid concentrations in the 2 groups may be due to reduced adrenal sensitivity to ACTH. Together with impaired verbal memory, these data support the assumption that repeated episodes of HPA system activity may exert negative effects at the level of the hippocampus.