Lucia Poon

Different responses to dexamethasone and prednisolone in the same depressed patients

RationalePatients with major depression show hypothalamic–pituitary–adrenal (HPA) axis hyperactivity, but the mechanisms underlying this abnormality are still unclear.ObjectivesWe have compared two synthetic glucorticoids, dexamethasone and prednisolone, in their ability to suppress the hypothalamic–pituitary–adrenal (HPA) axis in depressed patients. Dexamethasone probes glucocorticoid receptor (GR) function, while prednisolone probes both GR and mineralocorticoid receptor (MR) function.Materials and methodsWe used a single-blind, repeated-measure design. We administered placebo, prednisolone (5xa0mg) or dexamethasone (0.5xa0mg), at 22:00, to 18 severe, treatment-resistant depressed inpatients (15 of them with a history of childhood trauma) and 14 healthy volunteers. On the following days, we collected salivary cortisol from 9:00 to 22:00.ResultsDepressed patients had higher salivary cortisol levels compared with controls, at baseline and after both prednisolone and dexamethasone (p<0.001). Consistent with previous studies, depressed inpatients showed impaired suppression by dexamethasone: based on the analysis of the areas under the curve (AUCs), suppression by dexamethasone (0.5xa0mg) was −85% in controls vs −46% in depressed patients (p=0.018). However, the same depressed patients showed normal suppression by prednisolone (5xa0mg): suppression was −41% in controls and −36% in depressed patients (p=0.6).ConclusionsWe suggest that the additional effects of prednisolone on the MR explain the different responses to these glucocorticoids in the same depressed patients.

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.

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.

The prednisolone suppression test in depression: Dose—response and changes with antidepressant treatment

Depressed patients have reduced glucocorticoid receptor (GR) function, as demonstrated by resistance to the suppressive effects of the synthetic glucocorticoid hormone, and GR agonist, dexamethasone. We have developed a suppressive test with prednisolone, a synthetic glucocorticoid that is similar to cortisol in its pharmacodynamics and pharmacokinetics, and binds to both the GR and the mineralocorticoid receptor (MR). We have found that depressed patients suppress normally to prednisolone, unless they are particularly non-responsive to treatment. In the present study, we evaluated 28 inpatients with treatment-resistant depression (TRD), and compared salivary cortisol secretion (at 0900 h, 1200 h and 1700 h) after placebo or after prednisolone (5 mg), before and after an inpatient treatment admission. Half of the patients (n=14) reached treatment response. When comparing the assessment between admission and discharge, cortisol output after placebo fell (-26% of area under the curve; p=0.024) while the output after prednisolone did not change. Moreover, there was no change in the response to prednisolone (percentage suppression) between admission at discharge, and this was not influenced by treatment response. Finally, we could confirm and extend our previously published data with prednisolone (5 mg), showing that depressed patients (n=12) and controls (n=12) suppressed equally to both 5 and 10 mg doses of prednisolone. This study suggests that the response to prednisolone is similar in depressed patients and controls at different doses of prednisolone, and does not change with symptomatic improvement. This is in contrast with findings, from us and others, using other measures of hypothalamic-pituitary-adrenal axis function, such as basal cortisol levels or the response to dexamethasone. Thus, we propose that the prednisolone suppression test may offer specific biological and clinical information, related to its action at both the GR and the MR.

The role of mineralocorticoid receptor function in treatment-resistant depression.

Background: Treatment-resistant depression patients show both reduced glucocorticoid receptor function and a hyperactive hypothalamic-pituitary-adrenal axis. However, few studies have examined the role of the mineralocorticoid receptor. This study aimed to evaluate the functional activity of the mineralocorticoid receptor system in regulating the hypothalamic-pituitary-adrenal axis in well-defined treatment-resistant depression patients. Material and method: We recruited 24 subjects divided into: (a) treatment-resistant depression; (b) healthy controls. We evaluated: (a) the effect of combined glucocorticoid receptor/mineralocorticoid receptor stimulation with prednisolone; (b) the effect of prednisolone with the mineralocorticoid receptor antagonist spironolactone; and (c) the effect of spironolactone alone. The response of the hypothalamic-pituitary-adrenal axis was measured using salivary cortisol and plasma levels of drugs were also measured. Results: Treatment-resistant depression patients had higher cortisol compared with controls after all challenges. In controls, spironolactone increased cortisol compared to placebo. The co-administration of spironolactone with prednisolone in controls decreases the suppressive effects of prednisolone. In contrast, in treatment-resistant depression, spironolactone did not increase cortisol compared to placebo and spironolactone with prednisolone had no effect on the suppressive effects of prednisolone. Patients with treatment-resistant depression had a reduction in the conversation of spironolactone to the active metabolite canrenone. Conclusion: Our data confirmed that treatment-resistant depression is associated with hypercortisolism and these patients no longer show an hypothalamic-pituitary-adrenal response to the administration of a mineralocorticoid receptor antagonist, suggesting that there is a mineralocorticoid receptor malfunctioning, such as a down regulation, however, pharmacokinetics and pharmacodynamics in these subjects could also have had an effect on the lack of mineralocorticoid receptor response.

Confidence judgment in depression and dysphoria: The depressive realism vs. negativity hypotheses

BACKGROUND AND OBJECTIVESnAccording to the negativity hypothesis, depressed individuals are over-pessimistic due to negative self-concepts. In contrast, depressive realism suggests that depressed persons are realistic compared to their nondepressed controls. However, evidence supporting depressive realism predominantly comes from judgment comparisons between controls and nonclinical dysphoric samples when the controls showed overconfident bias. This study aimed to test the validity of the two accounts in clinical depression and dysphoria.nnnMETHODSnSixty-eight participants, including healthy controls (nxa0=xa032), patients with DSM-IV major depression (nxa0=xa020), and dysphoric participants with CDC-defined chronic fatigue syndrome (nxa0=xa016) performed an adjective recognition task and reported their item-by-item confidence judgments and post-test performance estimate (PTPE).nnnRESULTSnCompared to realistic PTPE made by the controls, patients with major depression showed significant underconfidence. The PTPE of the dysphoric participants was relatively accurate. Both the depressed and dysphoric participants displayed less item-by-item overconfidence as opposed to significant item-by-item overconfidence shown by the controls.nnnLIMITATIONSnThe judgment-accuracy patterns of the three groups need to be replicated with larger samples using non-memory task domains.nnnCONCLUSIONnThe present study confirms depressive realism in dysphoric individuals. However, toward a more severe depressive emotional state, the findings did not support depressive realism but are in line with the prediction of the negativity hypothesis. It is not possible to determine the validity of the two hypotheses when the controls are overconfident. Dissociation between item-by-item and retrospective confidence judgments is discussed.