Stuart Checkley

A novel prednisolone suppression test for the hypothalamic-pituitary-adrenal axis.

We have developed a suppressive test for the hypothalamic-pituitary-adrenal (HPA) axis using prednisolone, which is similar to endogenous glucocorticoids. We used a single-blind, repeated-measure design in healthy volunteers. In the first phase of the study, we compared placebo or prednisolone 2.5 mg, 5 mg, or 10 mg; in the second phase of the study, we compared placebo or prednisolone 5 mg or dexamethasone.5 mg. On the following day, we collected plasma and salivary cortisol levels from 9 AM to 5 PM. Maximal average prednisolone plasma levels (at 9 AM after the 10-mg dose) were 30 to 35 ng/mL. At all doses, prednisolone caused a larger suppression of salivary cortisol (approximately 20% after 2.5 mg, 30% to 35% after 5 mg, and 70% to 75% after 10 mg) than of plasma cortisol (approximately 5% after 2.5 mg, 10% after 5 mg, and 35% after 10 mg). Dexamethasone.5 mg gave 80% suppression of plasma cortisol and 90% suppression of salivary cortisol. Plasma and salivary cortisol levels were more consistently correlated in each subject after prednisolone than after dexamethasone. We propose that prednisolone at the 5-mg dosage (which gave partial HPA suppression), together with the assessment of salivary cortisol, can be used to investigate both impaired and enhanced glucocorticoid-mediated negative feedback in large samples of patients with psychiatric disorders.

Salivary Cortisol Profiles in Chronic Fatigue Syndrome

Salivary cortisol profiles (hourly sampling over a 16-hour period) of 10 patients with chronic fatigue syndrome (CFS) but without concurrent depressive disorder were compared with those of 10 healthy volunteers matched for age, sex and menstrual cycle. The mean saliva cortisol concentration over the 16-hour period was slightly but significantly greater in the patients than the controls (p < 0.05). These findings are at variance with earlier reports that CFS is a hypocortisolaemic state and suggest that in CFS the symptom of fatigue is not caused by hypocortisolaemia.

Four days of citalopram increase suppression of cortisol secretion by prednisolone in healthy volunteers

RationaleChronic antidepressant treatment increases glucocorticoid-mediated negative feedback on the hypothalamic-pituitary-adrenal (HPA) axis, and thus reduces HPA axis activity, in depressed patients and healthy controls. In contrast, acute antidepressant treatment induces an activation of basal HPA axis activity.ObjectivesWe examined the effects of 4 days of treatment with the selective serotonin reuptake inhibitor, citalopram, on basal salivary cortisol and on suppression of salivary cortisol by prednisolone.MethodsWe used a single-blind, placebo-controlled, repeated-measure design. Salivary cortisol was measured from 0900 to 1700xa0hours. In the first phase of the study, basal salivary cortisol secretion was measured on 2 study days, before and after 4 days of treatment with citalopram (orally, 20xa0mg/day). In the second phase, salivary cortisol secretion after suppression by prednisolone (5xa0mg, given at 2200xa0hours the night before) was measured on 2 study days, again before and after 4 days of treatment with citalopram (orally, 20xa0mg/day). Eight volunteers participated to the study.ResultsCitalopram increased basal salivary cortisol in the morning (0900–1100xa0hours) by approximately 47% (P=0.003). Moreover, citalopram increased suppression by prednisolone in the morning (0900–1100xa0hours): suppression was approximately 22% before citalopram and 45% after citalopram (P=0.05).ConclusionsCitalopram increases glucocorticoid-mediated negative feedback on the HPA axis after as little as 4 days of treatment. This effect could be due to an increased function of the corticosteroid receptors. Our findings further support the notion that one of the mechanisms by which antidepressants exert their therapeutic effects is by normalizing HPA axis hyperactivity in depressed patients.

Dexamethasone-induced effects on lymphocyte distribution and expression of adhesion molecules in treatment-resistant depression

Alterations in immune function are associated with major depression and have been related to changes in endocrine function. We investigated whether alterations in immune function were associated with altered basal hypothalamic-pituitary-adrenal (HPA) function (salivary cortisol) and lymphocyte sensitivity to dexamethasone (DEX) intake (1 mg PO). The latter was explored by comparing the impact of DEX-induced changes on peripheral lymphocyte redistribution and expression of adhesion molecules (beta2 integrins and L-selectin). The study included 36 inpatients with treatment-resistant major depression (unipolar subtype) and 31 matched healthy controls. The dexamethasone suppression test (DST) was carried out and used to classify 10 patients as HPA axis non-suppressors. The latter presented significantly higher post-DEX salivary cortisol levels than DST suppressors, 82.0 vs. 8.9 nM l(-1) h(-1). No differences in basal salivary cortisol levels were found between patients and controls. Changes in cell redistribution (CD4(+), CD8(+), CD19(+), CD56(+) and HLADR(+) cells) after DEX administration were more prominent in controls than in patients, but the effects of DEX varied dependent on whether patients exhibited DEX-induced suppression of cortisol secretion. Glucocorticoid-induced suppression of adhesion molecule expression was also generally less marked in patients than controls. Our data indicate that alterations in immune function and steroid regulation associated with depression are not related to elevated basal levels of cortisol and further suggest that lymphocyte steroid resistance is associated with drug-resistant depression.

Characterization of platelet alpha2 adrenoceptors and measurement in control and depressed subjects

The alpha-adrenoceptor on platelets has been characterized using 3H-yohimbine, 3H-dihydroergocriptine, and 3H-clonidine. The receptor, which exhibits the characteristics of an alpha 2-type, has a Bmax for dihydroergocriptine of 330 fmoles/mg protein, for yohimbine of 178 fmoles/mg protein, and for clonidine of 38 fmoles/mg protein. Clonidine, but not yohimbine binding, is decreased by the presence of K+, Na+, or Li+. Adenosine triphosphate (ATP) and the guanosine triphosphate (GTP) analogue, Gpp(NH)p, reduce the affinity of clonidine for its binding site. Acute exercise, such as playing squash, does not apparently alter the Bmax or Kd of 3H-yohimbine binding to platelet membranes, and in vitro studies, with intact platelets or platelet membranes, show that incubation with adrenalin (10 microM) does not induce alterations in Bmax or Kd. In the present study, no correlation was found between age and alpha 2-adrenoceptor numbers. There was no significant difference in the Bmax for 3H-yohimbine binding to platelet membranes from control and depressed subjects, although the mean value for the depressed group was some 10% lower than that for the corresponding control group. There were no overall significant and consistent effects of desipramine (DMI) treatment. After 2-3 days of treatment, the Bmax was reduced by 20%, after 7 days by 14%, and after 21 days it was 8% above the control value. When an additional group of patients on DMI (7 days of treatment) was analyzed using one supramaximal concentration of 3H-yohimbine, there was a significant decrease (25%) in binding.

Menstrual Cycle Effects on Hypothalamic Dopamine Receptor Function in Women with a History of Puerperal Bipolar Disorder

Neuroendocrine challenge tests of hypothalamic dopamine receptor function in the early postpartum period suggest that the sensitivity of these receptors is increased in women with a history of bipolar disorder after childbirth. We tested the hypothesis that, in women predisposed to bipolar disorder in the puerperium, hypothalamic dopamine receptor function is more sensitive to changes in circulating ovarian hormone concentrations than in women without such histories. Eight fully recovered and drug-free women who had had at least one episode of bipolar illness following childbirth were compared with nine normal controls. Growth hormone (GH) responses to apomorphine (APO 0.005 mg s.c.) were measured in the early follicular phase, when plasma concentrations of ovarian hormones are low, and in the mid-luteal phase, when they are relatively high. The recovered bipolar subjects and the controls did not differ from each other in their follicular and midluteal oestrogen and progesterone concentrations. In the midluteal phase, both groups had increased oestrogen and progesterone levels. The recovered bipolar subjects did not differ from controls in baseline concentrations of GH in either of the menstrual phases. The APO-GH responses of the two groups did not differ in the follicular phase, but in the midluteal phase, when female sex steroids are relatively increased, the recovered group had significantly enhanced APO-GH responses [MANOVA for repeated measures: (i) area under the curve, group by phase effect: p < 0.04; (ii) GH peak rise after APO, group by phase effect: p < 0.056] and the responses were not related to concurrent measures of mood. The results of this small study of women predisposed to bipolar disorder in the puerperium shows an increased dopaminergic receptor sensitivity in the luteal phase of the menstrual cycle. It suggests that their dopaminergic systems have increased sensitivity to changes in circulating female sex steroids. This may be aetiologically relevant to the pathogenesis of puerperal bipolar disorder.

Neuroendocrine and psychosocial mechanisms in post-partum psychosis.

(1) Results from a study investigating psychosocial and neuroendocrine influences on post-partum psychosis are presented. Subjects were 43 pregnant women with histories of affective disorder (bipolar or schizoaffective disorder, n = 26; major depressive disorder, n = 17), together with 45 pregnant women without any psychiatric history. (2) At 36 weeks antenatal assessments were carried out of the womens psychiatric histories, current psychiatric state and also the occurrence of life events in the preceding year. They were then monitored for 6 months after delivery during which time psychiatric state and any further life events were recorded. Illness was defined according to Research Diagnostic Criteria (RDC); 22 high risk women and 3 control women were categorised as RDC cases during the post-partum follow-up period. Fifteen of the bipolar/schizoaffective women (8 of whom subsequently became ill within 3 months of delivery) and 15 controls (all of whom remained well) also participated in a neuroendocrine test at 4 days post-partum when their growth hormone response to a challenge dose of the dopamine agonist, apomorphine, was measured. (3) The results showed that women with histories of depression and control women who became ill after delivery were three times more likely to have had a life event in the year preceding onset of illness than women from these subgroups who remained well. In contrast, for women with histories of bipolar or schizoaffective disorder, life events appeared to be unimportant. Instead bipolar/schizoaffective women who became ill showed an enhanced growth hormone response to the apomorphine challenge test compared to those who remained well and controls.(ABSTRACT TRUNCATED AT 250 WORDS)

No effect of naloxone on plasma oxytocin in normal men

The role of endogenous opiates in the control of the secretion of oxytocin in the basal state in healthy male volunteers was investigated with the opiate antagonist naloxone. There was no change in plasma oxytocin levels, assessed for a 120 min period following the intravenous administration of naloxone (10 mg). Although there was no effect of opiate receptor blockade with naloxone in this basal situation, further studies are needed to evaluate the possible role of opioid regulation of oxytocin during lactation and parturition.

MEASUREMENT OF THE GH AND OTHER RESPONSES TO CLONIDINE AT DIFFERENT TIMES OF THE DAY IN NORMAL SUBJECTS

The growth hormone response to clonidine may be impaired in some patients with endogenous depression. To determine whether or not this change is due to a circadian variation in the GH response to clonidine, this measure has been studied in normal subjects at 0900, 1800 and 2100 hr. Similar responses were obtained at 0900 and 1800 hr. The responses at 2100 hr could not be interpreted, as the baseline plasma GH was raised. At no time of day were there impaired GH responses similar to those found in endogenous depression. The effects of clonidine upon blood pressure and alertness were similar at the three times studied, providing no support for any circadian rhythm in the function of the alpha 2-adrenoceptors that mediate these effects of clonidine.

Effects of sex steroids on protein synthesis in cultured human lymphocytes

In cultured human lymphocytes, oestrogen and progesterone at concentrations found in plasma during the normal menstrual cycle, significantly increase the incorporation of [35S] methionine into protein and, in addition, both hormones significantly alter the relative synthesis of certain proteins. At concentrations found in plasma during pregnancy, some changes are augmented while others are reversed. These specific sex-steroid-induced changes in protein synthesis provide possible peripheral biological markers of hormone action which may be tested for their association with predisposition to, and/or onset of, conditions such as postpartum psychiatric illness.