Joel A. Posener

Diurnal variation of plasma cortisol and homovanillic acid in healthy subjects

We investigated the relationship between plasma levels of cortisol, the dopamine metabolite homovanillic acid (HVA) and norepinephrine in healthy human subjects. Plasma cortisol and HVA levels were measured at 0800h, and in an integrated sampling procedure involving samples every 15 min between 1300 and 1600h. Plasma norepinephrine was measured at 0800 and 1300h. Cortisol, HVA and norepinephrine indices did not show significant correlations with each other. Both cortisol and HVA showed significant decreases over time. Longitudinal Random Effects (LRE) models were used to test whether individual cortisol and HVA curves over time were correlated; significant correlations were not found with this procedure. While significant correlations between cortisol and catecholamine indices have been reported in depressed patients, our results do not suggest such correlations in healthy subjects.

Effects of major depression diagnosis and cortisol levels on indices of neurocognitive function

Although many studies have examined separately the effects of depression and cortisol on cognition, no study has examined their relative or potentially additive effects. Our study simultaneously investigated the contributions of clinical status [major depression (MD) versus psychiatrically healthy controls (HC)] and cortisol on a hippocampal/mediotemporal mediated verbal memory task (Paragraph Recall) and a prefrontal cortex/cingulate mediated executive functioning task (Stroop). Thirty-seven unmedicated nondelusional MDs and 18 HCs underwent psychiatric ratings, hourly assessments of cortisol activity over 24 h, and neuropsychological assessments. Hierarchical multiple regressions indicated a significant effect of cortisol but not of diagnosis on verbal memory. Greater cortisol levels were related to poorer memory performance independent of group. In contrast, a significant interaction between cortisol and diagnosis was found for a color-word index of response inhibition. This interaction suggests that the detrimental effect of elevated cortisol level on this type of executive functioning exists only in the healthy control group but not in MDs. On an Interference score, another measure of response inhibition, cortisol had a significant independent effect, but neither the effects of diagnosis and the interaction attained full significance. Our study suggests that cortisol has an independent effect on verbal memory. Also, our study produced evidence of an interaction between diagnosis and cortisol on response inhibition.

Process irregularity of cortisol and adrenocorticotropin secretion in men with major depressive disorder.

Although evidence suggests that major depressive disorder (MDD) is associated with hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, research on basal HPA axis hormone levels in MDD patients has been inconclusive. Definitive characterization of basal cortisol and adrenocorticotropin (ACTH) secretion may be important for understanding the pathophysiology of this disorder. In recent years, a new approach to the analysis of basal hormone secretion has been developed involving the approximate entropy (ApEn) statistic, which represents the degree of disorderliness or serial irregularity in a time series of hormone levels. ApEn has been shown to reflect the degree of coordination in integrated network systems and has provided new insights into the pathophysiology of a number of endocrine conditions. In the study reported here, 15 medication-free men with MDD and 15 healthy control men were admitted to a General Clinical Research Center and had blood sampled for cortisol and ACTH determinations every hour over a 24-h period. The cortisol and ACTH time series were characterized with a cosinor analysis and with analysis of ApEn. Depressed patients and control subjects did not differ significantly on any parameter derived from the cosinor analysis or on several other standard indices of basal hormone secretion. However, the depressed men had significantly increased cortisol ApEn and significantly decreased ACTH ApEn compared with the healthy subjects. The ApEn findings suggest a loss of regulatory control over cortisol secretion, and possibly increased cortisol feedback on the pituitary in the depressed patients. Together, these results are most consistent with a primary abnormality of the adrenal gland and suggest that further investigation of adrenal gland physiology may be informative for the pathophysiology of depression.

Acute and delayed effects of corticotropin-releasing hormone on dopamine activity in man ☆

Interactions between the hypothalamic-pituitary-adrenal (HPA) axis and central dopamine systems have been hypothesized to play a role in the pathophysiology of psychosis, but the normal physiology of HPA axis-dopamine interactions has not been fully defined. We report results from two uncontrolled pilot studies which explored the effects of ovine corticotropin-releasing hormone (CRH) on dopamine activity in healthy human subjects. Administration of CRH did not produce changes in plasma levels of homovanillic acid (HVA), the major dopamine metabolite, over the subsequent 3.5 hours. However, when the effects of CRH were followed over a longer period in a small subgroup, we found that CRH administration produced a two-fold rise in plasma HVA levels 20 hours later, without affecting plasma levels of 3-methoxy-4-hydroxyphenylglycol (MHPG), a major metabolite of norepinephrine. Thus, the findings of these pilot studies suggest that CRH may exert delayed but not acute effects on dopamine activity in man.

Hypothalamic–pituitary–adrenal axis effects on plasma homovanillic acid in man

BACKGROUND Effects of the hypothalamic-pituitary-adrenal (HPA) axis on central dopaminergic systems have been proposed to underlie the development of psychotic symptoms in depression. This study examined HPA axis hormone effects on plasma levels of homovanillic acid (HVA), the dopamine metabolite, in healthy volunteers, using a placebo-controlled, double-blind, random-assignment, crossover design. On the basis of preliminary studies, we hypothesized that HPA axis hormones would produce delayed effects on plasma HVA levels measured in the afternoon. METHODS Ten healthy subjects underwent a standard protocol on four occasions and each time received ovine corticotropin-releasing hormone, synthetic adrenocorticotropic hormone (ACTH), cortisol, or placebo. Plasma HVA was measured at 9 AM and 4 PM on Day 1, immediately prior to administration of the test substance at 7 PM, then at 30-60-min intervals until 11 PM. Plasma HVA levels were subsequently obtained at 9 AM and 4 PM on Days 2 and 3. RESULTS As predicted, there were significant differences between test substances in delayed effects on afternoon HVA levels measured on Days 2 and 3, with cortisol and ACTH producing greater increases in HVA than placebo. Acute effects of HPA axis hormones on HVA were not found, while differences between test substances in delayed effects on morning HVA levels approached significance. CONCLUSIONS HPA axis hormones exert delayed effects on plasma HVA levels in healthy humans.

Cortisol feedback effects on plasma corticotropin levels in healthy subjects.

An abnormality of rapid cortisol feedback on activity of the hypothalamic-pituitary-adrenal axis has been reported in depression. However, there is controversy regarding the existence of rapid cortisol feedback on corticotropin (ACTH) secretion in humans. We investigated the effects of cortisol on ACTH levels in healthy subjects using a placebo-controlled, double blind, random assignment, cross-over design. Ten medication-free volunteers with no psychiatric history and no active medical problems underwent a standard protocol on two occasions separated by at least 2 weeks. Each time, subjects were admitted to a General Clinical Research Center and had infusion of 15 mg cortisol (hydrocortisone sodium succinate) over 120 min or placebo. Serum levels of cortisol and plasma ACTH levels were determined at baseline and over the 4 h after the start of the infusion. Over the two GCRC admissions subjects received both cortisol and placebo infusions, and the order of the two infusions was randomized. Compared to placebo, cortisol infusion produced a significant decrease in plasma ACTH levels beginning within 60 min from the start of the infusion. We conclude that cortisol infusion produces early inhibition of ACTH secretion in normal humans.

LATE FEEDBACK EFFECTS OF HYPOTHALAMIC-PITUITARY-ADRENAL AXIS HORMONES IN HEALTHY SUBJECTS

We tested the hypothesis that hypothalamic-pituitary-adrenal (HPA) axis hormones exert prolonged negative feedback on corticotropin (ACTH) secretion. Ten healthy subjects underwent a standard protocol 4 x and each time received i.v., under double blind conditions and in random order, corticotropin-releasing hormone (CRH) 1 microgram/kg, co-syntropin (ACTH1-24) 0.25 mg, cortisol (hydrocortisone) 15 mg, or placebo. Subjects had a venipuncture for cortisol and ACTH levels at 0900h on Day 1, then had i.v. insertion and cortisol and ACTH levels measured at 1600 and 1855h. The test substance was given at 1900h and cortisol and ACTH levels were monitored until 2300h, when the i.v.s were discontinued. Subjects then had venipunctures for cortisol and ACTH levels at 0900 and 1600h on Day 2 and 3. Hormones had the expected acute effects. Hormones did not differ from placebo in effects on cortisol levels measured over Days 2 and 3. There were significant differences between test substances in effects on afternoon ACTH levels on Days 2 and 3, with ACTH levels increasing significantly less from baseline to Day 2 and 3 after CRH administration than after placebo, and tending to increase less from baseline to Day 3 after ACTH administration than after placebo. Examination of Day 2 and 3 morning ACTH levels showed a significant interaction between the test substances and time (Day 2 vs. 3), and interpretation of this interaction is not straightforward. We conclude that CRH and possibly ACTH exert late inhibitory effects on ACTH secretion measured in the afternoon of the 2 days following hormone administration.