Elizabeth A. Young

Twenty-Four-Hour ACTH and Cortisol Pulsatility in Depressed Women

Increased plasma cortisol in patients with major depression is a well documented finding, although it is present in only 25–30% of subjects with major depression. However, ACTH and cortisol are secreted in a pulsatile manner, so it is unclear if increased ACTH secretion occurs in depression and if there are changes in the pulsatile components of ACTH secretion. Ten-minute sampling for ACTH and cortisol was performed for 24 hr in 25 premenopausal depressed women, whose age and menstrual cycle day matched control women. As a group, the depressed women demonstrated a trend to increase cortisol secretion (p = 0.089). There was no difference in mean cortisol between the patient group as a whole (8.36 ± 2.9 μg/dl) and those patients meeting criteria for atypical depression (8.38 ± 1.9 μg/dl), but patients meeting criteria for endogenous showed increased cortisol (12.17 ± 4 μg/dl) Mean ACTH was not significantly different between patients and controls. Pulse analyses revealed similar number of secretory events and similar amplitudes for cortisol secretory bursts in patients and controls. The baseline component area under the curve of cortisol secretion was increased at a trend level (p = .064) in depressed patients, and the baseline AUC for ACTH was significantly increased in depressed patients (p = .045). No differences were found in pulsatile components of ACTH secretion between patients and matched controls. Harmonic analyses indicated no significant differences between patients and controls on any detected rhythm for ACTH or cortisol. These data suggest that the pulsatile and circadian components of the HPA axis are normal in premenopausal depressed women and that only 24% of depressed women demonstrate hypercortisolemia.

Selective forebrain fiber tract lesions implicate ventral hippocampal structures in tonic regulation of paraventricular nucleus corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) mRNA expression

The hippocampus appears to be involved in tonic regulation of the hypothalamo-pituitary-adrenocortical axis via interactions with corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP)-containing neurons of the hypothalamic paraventricular nucleus (PVN). To further investigate the anatomical basis of such interactions, lesions were made to forebrain fiber tracts in position to communicate inhibitory information from the hippocampus to the PVN. Total fimbria-fornix transections (TFF) and lateral fimbria-fornix lesions (LFF) both significantly increased CRH mRNA levels in the medial parvocellular PVN, as assayed by semi-quantitative in situ hybridization histochemistry. Medial fimbria-fornix lesions or section of the medial corticohypothalamic tracts (MCHT) did not influence CRH mRNA levels. The LFF group showed increases in both AVP mRNA and ACTH secretion, whereas no other lesion was effective in this regard. The results suggest: (1) hippocampal efferents conferring tonic inhibition of the HPA axis probably originate in regions contributing to the lateral extent of the fornix, representing structures in the ventral subiculum and ventral extent of CA1; (2) projections from the hippocampus to the medial basal hypothalamus (travelling in the MCHT) are unlikely to affect HPA function; (3) hippocampus may influence the PVN CRH/AVP neuron at multiple levels, in that LFF and TFF lesions have differential effects on PVN AVP mRNA levels and ACTH secretion.

HPA axis activation in major depression and response to fluoxetine: a pilot study

Hypothalamic-pituitary-adrenal (HPA) axis activation is a frequently observed phenomenon in major depression. However, whether this activation has any implications for treatment is unknown. To address this question, we examined baseline response to metyrapone and 6-week response to fluoxetine. Premenopausal women (n = 20) who met criteria for major depression with no other confounding Axis I disorders, medications, or medical illnesses and were not taking hormonal contraceptives were evaluated with an evening metyrapone challenge before the onset of treatment. Twenty-one normal women were also studied with the evening metyrapone challenge. The depressed patients then entered an open label treatment with fluoxetine for 6 weeks. Subjects were classified as responders if they demonstrated a 50% or greater decrease in Hamilton Depression Rating Scale rating. As a group, the depressed women demonstrated significantly increased ACTH secretion compared to control women before the onset of treatment, during the metyrapone challenge. Before treatment, women who were non-responders to fluoxetine showed increased HPA axis activation compared to controls, while the fluoxetine responders did not differ significantly from normal subjects in their ACTH levels during metyrapone challenge. These results suggest that overactivity of the HPA axis may be one factor associated with slower response to fluoxetine. This may reflect the greater severity of subjects with HPA axis dysregulation or the need to normalize the HPA axis with medications for optimal response.

Serotonin 1A receptor messenger RNA regulation in the hippocampus after acute stress.

BACKGROUND When rats are subjected to chronic stress for 2 weeks, a significant decrease in hippocampal serotonin (5-HT)1A messenger RNA (mRNA) is observed. We wanted to investigate whether stress, administered for shorter periods of time, would result in decreases in 5-HT1A gene expression in hippocampus. METHODS In one experiment, rats were either stressed daily for 1 week or implanted with two corticosterone pellets to produce elevated corticosterone levels. In another experiment, rats were subjected to a severe acute stressor and sacrificed 1 day or 1 week after the stressor. RESULTS We found that 24 hours after the acute stress, rats showed a significant decrease in 5-HT1A mRNA levels in CA1 and the dentate gyrus compared to controls. No significant changes in 5-HT1A mRNA levels were detected in any of the other groups. CONCLUSIONS Although 1 week of chronic stress is not sufficient to cause significant decreases in hippocampal 5-HT1A mRNA levels, a severe and prolonged acute stress is capable of down-regulating, at least transiently, 5-HT1A mRNA gene expression in hippocampus.

Effect of ruminations on the saliva cortisol response to a social stressor

Depression is generally precipitated by stressful life events, which suggests that there could be differences in response to stress in individuals at risk for depression compared to normal subjects. To test this hypothesis, we compared individuals who scored high on ruminative coping, a risk factor for depression, to individuals low on ruminative coping. We used the Trier Social Stress Test (TSST), a mock job interview in front of a panel of judges, and collected saliva cortisol to assess neuroendocrine response. While we observed a clear effect of the stressor on saliva cortisol secretion, we observed no differences in this response between high and low ruminators. However, the task itself failed to cause a significant increase in rumination in either group, suggesting the task itself may not be optimal for testing the hypothesis. Finally, a modified version of the TSST in which the subjects were allowed a longer preparatory period resulted in a markedly diminished saliva cortisol response to the TSST.

Hyperactivity of the hypothalamic–pituitary–adrenal axis and mortality in major depressive disorder

Convergent evidence indicates that HPA-axis hyperactivity is a risk factor for suicide in major depressive disorder, and seven independent reports have shown that patients with abnormal dexamethasone suppression test (DST) results have significantly higher rates of eventual suicide. The identification of interactions between DST results and other clinical predictors would enhance risk assessment, but modest sample sizes have limited such analyses in earlier cohorts. Subjects with major depressive disorder who participated in research protocols at the University of Michigan between 1980 and 1991, who had fully structured diagnostic interviews, and who underwent a 1-mg DST while actively depressed were screened with the National Death Index for a mean (S.D.) follow-up period of 18.0 (5.5) years. Of 334 subjects, 69 (20.7%) were identified as having died. Of these, 13 (18.8%) had died by suicide and 32 (46.4%) from cardiovascular causes. Baseline DST results did not significantly predict death from suicide or from cardiovascular disease for the sample as a whole. Significant relationships between DST results and later suicide did exist for inpatients, for patients with manifest suicidality and, in particular, for inpatients with manifest suicidality. Because nearly all previous reports of DST results and suicide described depressed inpatients, it is possible that the DST is a useful predictor only within this population.

Interaction of brain noradrenergic system and the hypothalamic–pituitary–adrenal (HPA) axis in man

BACKGROUND Numerous interactions between the brainstem locus coeruleus system and the HPA axis have been shown in experimental animals. This relationship is less well characterized in humans and little is known about the influence of psychiatric disorders, which disturb one of these systems, on this relationship. METHODS Untreated subjects with pure MDD (n = 13), MDD with comorbid anxiety disorders (n = 17), and pure anxiety disorders (n = 15) were recruited by advertising. Age and sex matched control subjects were recruited for each subject with a psychiatric diagnosis (n = 45). All subjects underwent a social stressor, the Trier Social Stress Test (TSST), and blood was collected for ACTH assay. These same subjects also underwent a clonidine challenge study for assessment of growth hormone release as a marker of tonic noradrenergic activation. RESULTS Examining log transformed area under the curve response for each hormone, a significant negative relationship (simple regression) was observed between systems in normal subjects. This relationship was preserved in anxiety subjects. However, both pure depressed and comorbid depressed and anxiety subjects demonstrated disruption of this relationship. CONCLUSIONS Under normal circumstances, noradrenergic systems can influence the magnitude of the HPA axis response to stress. However, in subjects with major depression, HPA axis activation appears autonomous of noradrenergic influence.

Saliva Cortisol and Response to Dexamethasone in Children of Depressed Parents

BACKGROUND Major depression (MDD) is heritable, and children of depressed parents are at higher risk for the development of depression. However, depression in a parent might also act as a stressor leading to increased activation of neuroendocrine stress circuits. To address this question we examined saliva cortisol in children whose parents have a history of MDD. METHODS We recruited 15 families with one parent with MDD (26 prepubertal children) and 16 control families without history of parental MDD (32 prepubertal children). All parents and children underwent Structured Clinical Interview for DSM-IV and Kiddie Schedule For Affective Disorders And Schizophrenia interviews, respectively. Families were asked to collect morning, afternoon, and bedtime saliva samples for 4 days for 2 weeks. At bedtime of the 3rd day, dexamethasone was administered. Two doses, standard and low, were used in each family. RESULTS The majority of children demonstrated no psychiatric diagnosis. Children with MDD parents showed higher cortisol basally and higher cortisol after both 25 mg and 5 mg dexamethasone. However, this effect occurred predominantly in children whose parents were currently depressed. There were strong correlations for cortisol between parents and children (r = 52 in depressed; r = 499 in control). CONCLUSIONS Elevated cortisol and impaired feedback seemed to reflect an environmental effect of MDD in a parent.

Degradation of [3H]β-endorphin in rat plasma is increased with chronic stress

With a number of acute stressors beta-endorphin is released into plasma. It is unclear if beta-endorphin is converted into any other biologically active products, nor is it clear if the rate or pathways of degradation are changed during chronic stress. To explore these issues, we incubated [3H]beta-endorphin h labeled in positions 1 and 27 with plasma from normal and chronically footshocked rats and measured the rate of conversion of the label from beta-endorphin size material to smaller size material. Initial separations were done using a G-50 molecular sieving column, with subsequent characterization and identification on HPLC. By G-50 sieving, there is a time dependent formation of only one radioactive peak. HPLC identification demonstrates gamma-endorphin and another unidentified peak. This enzymatic activity is increased in the plasma of chronically stressed rats.

Hypothalamic-pituitary adrenal response to cholecystokinin-B receptor agonism is resistant to cortisol feedback inhibition.

Intravenous injection of the cholecystokinin (CCK)-B receptor agonist, pentagastrin, produces robust, dose-dependent release of adrenocorticotropin (ACTH) and cortisol, supporting the hypothesis that CCK-B agonists pharmacologically activate the hypothalamic-pituitary-adrenal (HPA) axis. The mechanism of activation and its physiological relevance remain uncertain. Preliminary data suggest that the ACTH response to pentagastrin may be differentiated from the response to exogenous corticotropin releasing hormone (CRH) by its relative resistance to cortisol feedback inhibition. To more directly test the relationship between cortisol levels and ACTH response to pentagastrin, this study examined responses to pentagastrin (a) during a peak (8 a.m.) and a nadir (4 p.m.) period of endogenous cortisol secretion and (b) when cortisol levels were artificially reduced to low levels by administration of metyrapone. ACTH responses to pentagastrin were identical in the morning and afternoon, despite substantial differences in basal cortisol levels. Suppression of cortisol with metyrapone had little impact on ACTH response to pentagastrin. These data support the hypothesis that CCK-B receptor mediated activation of the HPA axis is relatively resistant to cortisol feedback inhibition. This differentiates it from CRH-mediated activation and raises the possibility that CCK could contribute to acute activation of the HPA axis even in the face of elevated basal cortisol levels, such as those seen in chronic stress or some psychiatric disorders.