Platelet MAO activity and the dexamethasone suppression test in bipolar depression

The correlation between postdexamethasone cortisol levels after the dexamethasone suppression test (DST) and platelet monoamine oxidase (MAO) activity was studied in 31 depressed female inpatients with Research Diagnostic Criteria primary, endogenous, bipolar depression (12 bipolar 1 and 19 bipolar 11). Out of the 31 patients, 25 showed abnormal DST results. Platelet MAO activity did not differ significantly from the matched control group. There was a trend that patients with higher MAO activity had lower postdexamethasone cortisol levels, but it was significant only for the 0800 hr cortisol levels.     

Dexamethasone suppression test in schizophrenic patients before and during neuroleptic treatment

The dexamethasone suppression test (DST) was performed in 21 drug-free schizophrenic patients. The patients satisfied DSM-III and Research Diagnostic Criteria for schizophrenia and were in an acute phase of the disease. In 15 of the patients the DST was repeated after about 5 weeks of treatment with neuroleptics. DST compliance was checked by analysis of dexamethasone concentrations in plasma. In the acute phase 71% (at 04 p.m.) of the patients were nonsuppressors. After neuroleptic treatment the frequency of abnormal responders had decreased to 20%. The decrease in nonsuppressors was not due to alteration of the dexamethasone concentration between the two test occasions. Prolactin levels were markedly increased at the second test occasion compared with the first. There were no significant relationships between cortisol levels, cortisol suppression and prolactin levels. The high frequency of nonsuppressors among schizophrenic patients in the acute phase of the disease indicates that acute stress may be a confounding factor in the outcome of DST.     

Results of the 8 a.m. dexamethasone suppression test constitute a suitable tool for confirming the diagnosis of melancholia. A test unaffected by the variations in the bioavailability of dexamethasone

This prospective study was conducted in order (1) to examine which postdexamethasone cortisol value i.e., 8 a.m., 4 p.m. or peak cortisol - is most suitable as a laboratory test to help confirm the diagnosis of melancholia and (2) to investigate the influence of the dexamethasone levels in the results of the dexamethasone suppression test (DST). To this end we administered the DST to 48 controls and 115 depressed inpatients categorized according to DSM-III. The 8 a.m. and 4 p.m. dexamethasone levels were determined in 100 subjects. We found that an 8 a.m. postdexamethasone cortisol value greater than or equal to 3.5 micrograms/dl was of the most significant diagnostic value in order to separate melancholia from normal controls and/or minor depressives. The 8 a.m. and 4 p.m. dexamethasone values did not differ between healthy controls, minor and severely depressed patients. Although cortisol nonsuppressors exhibited significantly lower dexamethasone values, the predictive value of the DST for melancholia was not affected by the large variation in the bioavailability of dexamethasone.     

Platelet serotonin, plasma cortisol, and dexamethasone suppression test in schizophrenic patients.

BACKGROUND: Serotonin (5-HT) regulates hypothalamic-pituitary-adrenal (HPA) axis activity. Abnormal response to the dexamethasone suppression test (DST) and altered platelet 5-HT concentration have been shown in some schizophrenic patients. METHODS: Platelet 5-HT and plasma cortisol concentrations were determined simultaneously in 86 male schizophrenic patients before and after DST. Basal plasma cortisol and platelet 5-HT levels were also determined in 69 healthy male persons. RESULTS: Schizophrenic patients had higher plasma cortisol and platelet 5-HT concentrations than healthy persons. An abnormal escape from dexamethasone suppression was observed in 50% of patients. In these patients predexamethasone cortisol and platelet 5-HT concentrations were higher than in patients with normal DST. CONCLUSIONS: This study demonstrates that schizophrenic patients have the HPA axis dysregulation that could be connected with a disturbance in the 5-HT system.     

Lack of effect of HPA axis hyperactivity on hormonal responses to d-fenfluramine in major depressed patients: implications for pathogenesis of suicidal behaviour

There is evidence for inhibitory effects of adrenocorticosteroids on serotonergic (5-HT) activity. However, in depression the relationship between altered cortisol levels and brain 5-HT function remains to be clarified. The aim of this study was to investigate whether hypothalamic-pituitary-adrenal (HPA) axis hyperactivity is associated with 5-HT dysfunction in depressed patients, especially in those with suicidal behaviour. Cortisol levels following the dexamethasone suppression test (DST, 1 mg PO) and prolactin, corticotropin and cortisol responses to the d-fenfluramine test (d-FEN, 45 mg PO) - a specific 5-HT releaser/uptake inhibitor - were measured in 71 drug-free DSM-IV major depressed inpatients (40 with a history of suicide attempt, 31 without) and 34 hospitalized healthy control subjects. Depressed patients showed higher post-DST cortisol levels but similar responses to d-FEN compared with control subjects. Hormonal responses to d-FEN were not correlated with cortisol levels (basal or post-DST). Among the depressed patients, DST suppressors and DST nonsuppressors exhibited no significant difference in endocrine responses to d-FEN. However, patients with a history of suicide attempt, when compared with patients without such a history, showed lower hormonal responses to d-FEN but comparable basal and post-DST cortisol levels. Taken together these results suggest that, in depression, HPA axis hyperactivity is not responsible for the reduced 5-HT activity found in patients with a history of suicidal behavior.     

Plasma ACTH and cortisol concentrations before and after dexamethasone

Alteration in the hypothalamic-pituitary-adrenal (HPA) axis occurs in up to 50% of depressed patients and is demonstrated by the failure to suppress cortisol concentrations after dexamethasone administration. Evidence suggesting that these cortisol abnormalities reflect hypothalamic-pituitary dysfunction has been inconsistent. We administered the dexamethasone suppression test to 28 psychiatric inpatients, including 17 cortisol suppressors and 11 nonsuppressors. Adrenocorticotropic hormone (ACTH) concentrations at 8 a.m. pre- and postdexamethasone were significantly greater in cortisol nonsuppressors than in suppressors. Our data support the hypothesis that pituitary ACTH secretion is altered in depressed patients who have HPA axis abnormalities demonstrated by plasma cortisol measurements.     

Stable adrenocorticotropin-stimulated 11-beta-hydroxylase activity but loss of age-related changes in patients with hypercortisolemia

Eleven-beta-hydroxylase activity was measured before and after acute adrenocorticotrophic hormone (ACTH) stimulation in 28 controls, 25 depressed Dexamethasone Suppression Test (DST) suppressors, 13 DST nonsuppressor patients, and 8 patients with Cushing's syndrome to investigate changes in states of cortisol hypersecretion. Eleven-beta-hydroxylase activity was equivalent among groups both before and after stimulation. Such 11-beta-hydroxylase stability, however, resulted in higher cortisol and 11-deoxycortisol poststimulation levels in both depressed DST nonsuppressors and Cushing's patients than in controls. Basal 11-beta-hydroxylase activity is positively correlated and 11-deoxycortisol is negatively correlated with age in controls and DST suppressors, but not in the patients tested with evidence of cortisol hypersecretion. These findings suggest that in vivo basal 11-beta-hydroxylase activity rises gradually with age, but does not rise after acute administration of exogenous ACTH. The age relationship is lost in states of cortisol hypersecretion, but the lack of response to acute exogenous ACTH is not affected.     

Platelet MAO activity in clinical subtypes of depression and DST suppression

Platelet MAO activity was measured in 75 hospitalized depressed patients and in 31 healthy subjects. Plasmas post dexamethasone cortisol levels were examined in 73 patients. Results indicate that higher platelet MAO activity does not occur in all, but only in male major depressed patients. No relationship between changes of MAO activity and specific clinical subtypes was found. Platelet MAO activity is not different between DST suppressors and DST non suppressors. The authors suggest that platelet MAO activity may be related to non specific factors such as sex, age, but not to diagnosis of depression.     

Baseline plasma cortisol and dexamethasone test in unselected psychiatric inpatients

The plasma cortisol (PC) level at 08.00 a.m. was assessed in 250 unselected psychiatric inpatients suffering from various disorders, assorted in 8 diagnostic groups. Endogenously depressive patients showed a significantly higher rate of cortisol hypersecretion (PC greater than 560 nmol/l = 20 micrograms/dl) than the neurotically or reactively depressed patients and than schizophrenics or paranoid psychotics. The PC level after the midnight dose of 1 mg dexamethasone was examined in 125 patients at 08.00 a.m. (group I) and in 125 patients at 04.00 p.m. (group II). There was no statistical difference in the rate of dexamethasone test (DST) nonsuppressors (PC greater than 140 nmol/l = 5 micrograms/dl) in the separate diagnostic groups between group I and II, but in the postdexamethasone blood samples at 04.00 p.m., significantly more DST nonsuppressors were detected than in the samples at 08.00 a.m. in the total number of all patients, regardless of their diagnosis. DST nonsuppressors were found in all of our diagnostic groups with the exception of manic syndrome, and their various rates will be discussed and compared with the results of previous studies. The DST shows a high sensitivity in endogenous depression, but its diagnostic value is limited as a result of its relative lack of specificity.     

Platelet serotonin and plasma prolactin and cortisol in healthy, depressed and schizophrenic women

Serotonin (5-hydroxytryptamine, 5-HT) is involved in the regulation of hypothalamic-pituitary-adrenal axis (HPA) activity and prolactin (PRL) secretion. The present study examined the relationship between platelet 5-HT and plasma cortisol and PRL concentrations in 20 schizophrenic, 25 depressed, and 25 healthy women. At the time of blood sampling, the schizophrenic and depressed patients had been drug-free for at least 7 days. Platelet 5-HT, plasma cortisol and PRL concentrations were determined by spectrofluorimetric, radioimmunoassay and immunoradiometric methods, respectively. Platelet 5-HT concentration was significantly higher in schizophrenic patients than in depressed patients or in healthy controls, while it was significantly lower in depressed patients than in healthy controls or in schizophrenic patients. Plasma cortisol levels were significantly increased both in schizophrenic and in depressed patients compared with values in healthy controls. Values of plasma PRL were similar across groups. A significant correlation was found between platelet 5-HT and plasma cortisol, and platelet 5-HT and plasma PRL concentrations in healthy controls, but not in schizophrenic or depressed patients. There was no significant relationship between plasma PRL and cortisol levels in any of the groups. Our data, although obtained on peripheral biochemical markers, indicate that depression and schizophrenia are characterized by disturbed 5-HT transmission and dysregulated HPA axis activity.     

Sleep deprivation and hypothalamic-pituitary-adrenal (HPA) axis activity in depressed patients

In the present study we investigated HPA axis activity in depressed patients treated with partial sleep deprivation (PSD) in order to identify endocrinological characteristics related to PSD responsiveness. Thirty-three drug-free patients (14 men, 19 women) suffering from major depression according to DSM-IV criteria were treated with PSD. Response to PSD was defined as a reduction of at least 30% according to the 6-item version of the Hamilton Depression Scale (6-HAMD). Subsequently, the combined dexamethasone-suppression/CRH-stimulation test (DEX/CRH test) was performed. Patients were pretreated with 1.5 mg dexamethasone (DEX) at 23:00 h and challenged with 100 microg corticotropin-releasing hormone (CRH) the following day. Postdexamethasone cortisol concentrations (before CRH administration) served as parameters for the DST status (dexamethasone suppression test). The cortisol stimulation after CRH was used as measurement for the DEX/CRH test status. Of the depressive patients, 54.5% (18 out of 33) responded to PSD. DST suppressors (postdexamethasone cortisol levels < 15 ng/ml) showed a significantly greater reduction in 6-HAMD scores after PSD than DST nonsuppressors. Furthermore, a significant negative correlation between postdexamethasone cortisol levels and reduction in 6-HAMD scores after PSD could be established. However, there was no relationship between the cortisol stimulation following CRH challenge and response to PSD. Although the combined DEX/CRH challenge test is a more sensitive marker for HPA axis dysregulation in depression than the standard DST, the negative feedback of the HPA system reflected by the DST status is apparently more closely associated with response to partial sleep deprivation in major depressive disorder.     

Dexamethasone suppression test in schizophrenia: its relation to monoamine metabolism in hypothalamic-pituitary-adrenal axis

The metabolic disturbances of monoamine in the hypothalamic-pituitary-adrenal axis (HPA axis) was examined in patients with chronic schizophrenia showing nonsuppression of the dexamethasone suppression test (DST). Subjects were 16 male chronic schizophrenics consisting of 8 DST suppressors and 8 nonsuppressors. All the patients were orally given the 5HT precursor, L-5-hydroxytryptophan (L-5HTP, 3 mg/kg) and the alpha 2-adrenergic agonist, clonidine (3 micrograms/kg), and the concentrations of plasma prolactin, cortisol, human growth hormone, and blood 5HT were measured chronologically. As a result, all of the DST nonsuppressors showed no increased response of prolactin after L-5HTP loading. Moreover, in the DST nonsuppressors, the secretion response of cortisol after L-5HTP loading was delayed compared with that of the suppressors. However, no different response between the DST suppressors and the nonsuppressors was observed after a loading dose of clonidine. These results suggest that there might be a metabolic disturbance of 5HT in the HPA axis of chronic schizophrenics showing DST nonsuppression.     

Hypercortisolemia decreases dexamethasone half-life in rabbit

The pharmacokinetics of dexamethasone have been found to be related to endogenous hypothalamic-pituitary-adrenal (HPA) axis activity. Lower plasma dexamethasone levels in psychiatric patients (especially depressed) who are dexamethasone suppression test (DST) nonsuppressors have previously been reported. Since DST nonsuppression is one measure of HPA axis hyperactivity and is usually associated with relatively increased plasma cortisol levels and lower post dose plasma dexamethasone levels, we hypothesized that hypercortisolemia can induce a more rapid disappearance of dexamethasone from plasma. We therefore studied the kinetics of dexamethasone in rabbits before and after a period of sustained hypercortisolemia produced by administration of IM hydrocortisone acetate, a slowly absorbed salt of cortisol. Mean dexamethasone half-life decreased significantly from baseline of 1.92 h on day zero in seven rabbits to 1.17 h on experimental day 17 of induced hypercortisolemia (P<0.001), while there was no significant change in saline treated controls (n=3). Dexamethasone half-life had returned to the baseline levels when retested 88 days later on experimental day 105. The results indicate that pronounced hypercortisolemia decreases dexamethasone half-life in rabbits, and support the concept that increased circulating cortisol levels induce hepatic enzymes that metabolize dexamethasone. Thus, the lower postdexamethasone plasma dexamethasone levels and decreased dexamethasone half-life in DST nonsuppressors may in part reflect the effect of prior or coincident hypercortisolemia.     

Specificity of plasma HVA response to dexamethasone in psychotic depression

Earlier reports have suggested that dexamethasone significantly increases levels of plasma homovanillic acid (HVA) in normal subjects, but that this effect may be altered in some depressed patients. To investigate the specificity of such alterations, we administered dexamethasone (1 mg p.o. at 11 p.m.) to 33 normal subjects, 27 depressed patients (8 with psychotic features), and 16 schizophrenic patients. Plasma for assay of cortisol and HVA was obtained at 4 p.m. before and on the day following dexamethasone administration. Dexamethasone induced significant increases in plasma HVA in the normal subjects and in the schizophrenic patients, but not in the depressed patients. Indeed, psychotically depressed patients tended to show a dexamethasone-associated decrease in plasma levels of HVA. In contrast to cortisol "suppression" or "nonsuppression," dexamethasone-induced changes in plasma levels of HVA (i.e., increases or decreases) sensitively and specifically discriminated between patients with affective and nonaffective psychoses.     

Platelet MAO activity and the cortisol response to dexamethasone in major depression

Previous studies have sometimes found a positive relationship between platelet monoamine oxidase (MAO) activity and dexamethasone nonsuppression in depressed patients. To assess this relationship in more detail, we examined the association between these two biological variables in unmedicated depressed patients. A positive correlation between platelet MAO activity and 8:00 AM serum cortisol levels following an overnight dexamethasone test (1 mg) was observed. The relationship between high and low platelet MAO activity (median split) and suppression of serum cortisol levels was also significant. These relationships were stronger in bipolar patients. Multiple regression revealed that postdexamethasone 8:00 AM dexamethasone levels and platelet MAO activity were independent predictors of the 8:00 AM cortisol levels following dexamethasone. The possibility that platelet MAO activity may be a peripheral marker of brain serotonergic activity which in turn may affect various aspects of the hypothalamo-pituitary-adrenal axis activity, is discussed. We also found that all nine depressed patients studied greater than or equal to 15 days after admission were suppressors. Platelet MAO activity, but not 8:00 AM pre- or postdexamethasone serum cortisol, was related to the severity of depression.     

Plasma dexamethasone concentrations and the dexamethasone suppression test

Altered bioavailability or altered pharmacokinetics of dexamethasone (dex) may contribute to a positive Dexamethasone Suppression Test (DST) in psychiatric patients. We measured plasma dex and plasma cortisol concentrations in 32 patients with primary major depressive disorder (MDD), 14 patients with other psychiatric disorders, and 16 normal controls. Cortisol was measured by the competitive protein binding (CPB) assay and dex by RIA (IgG Corp.). Additionally, cortisol was measured by a fluorescent polarization immunoassay (FPIA) available on the Abbott TDx analyzer in an attempt to validate this method for use in the DST. The agreement between FPIA and CPB cortisol results was excellent. Depressed nonsuppressors, by definition, had significantly higher mean plasma cortisol concentrations than depressed suppressors, psychiatric controls, and normal volunteers at 8:00 AM, 3:00 PM, and 10:00 PM postdex. When DST nonsuppressors and suppressors were compared regardless of diagnostic group, plasma dex concentrations were significantly lower (p less than 0.01) in the DST nonsuppressors. There was a significant negative correlation between plasma cortisol levels and plasma dex levels across all subjects at 8:00 AM (r = -0.365, n = 44, p less than 0.05). When the subjects were sorted by diagnostic category, there was a strong, but not statistically significant, trend toward lower plasma dex concentrations in the melancholic nonsuppressors versus the melancholic suppressors and between the psychiatric control non-suppressors and the corresponding suppressor group. These relationships disappeared when we restricted our analyses to an empirically derived middle range of plasma dex concentrations within which the DST results were considered to be valid. We conclude that bioavailability or pharmacokinetics of dex may significantly contribute to DST results. Further investigation is needed to determine whether or not the quantification of dex and its metabolites and their determination at which specific timepoints during the DST will enhance the predictive or interpretive value of the DST in psychiatric patients.     

Cortisol response to dexamethasone and noradrenergic function in depression

Positive correlations between measures of hypothalamic-pituitary-adrenal (HPA)-axis activity and noradrenergic turnover have been reported in depression. To investigate this relationship the authors measured peak postdexamethasone cortisol levels (8 a.m., 4 p.m. and 11 p.m.) and the 24-hour urinary 3-methoxy-4-hydroxy-phenylglycol (MHPG) flow in 84 depressed patients. The results show that there is no positive association between those measures of HPA-axis and noradrenergic activity. On the contrary, patients with severe non-suppression (greater than or equal to 10 micrograms/dl or 277 nmol/l) tended to have a lower MHPG-excretion.     

Plasma dexamethasone levels in children given the dexamethasone suppression test

To determine whether children who demonstrate dexamethasone suppression test (DST) nonsuppression have lower plasma dexamethasone levels than DST suppressors, we administered the DST to 73 patients ranging in age from 5-14 years. Plasma dexamethasone levels and postdexamethasone cortisol levels were measured at 4:00 PM on day 2. We found: (1) DST nonsuppressors had significantly lower plasma dexamethasone levels (p less than 0.03) than suppressors; similar trends were observed when the population was divided into depressed and nondepressed patients; (2) mg/m2 dose of dexamethasone was directly correlated with plasma dexamethasone (p less than 0.003) and inversely correlated with postdexamethasone plasma cortisol levels (p less than 0.04); and (3) a statistically significant inverse correlation between plasma dexamethasone levels and postdexamethasone cortisol levels (p less than 0.04). Our findings show that plasma dexamethasone levels are important in evaluating DST results in psychiatrically disturbed children and suggest that dexamethasone dosage for use in the DST in children might be better calculated in terms of body surface area.     

The ACTH stimulation test before and after clinical recovery from depression

Excessive cortisol secretion after cosyntropin (adrenocorticotropic hormone; ACTH) infusion in some depressed patients has suggested the possibility that the adrenal cortex may have heightened responsiveness to ACTH, and that this may contribute, in part, to activation of the hypothalamic-pituitary-adrenocortical axis. We administered an ACTH test and dexamethasone suppression test (DST) to 32 patients before and after treatment. Maximal cortisol response to ACTH demonstrated a significant decrease after treatment in the subgroup of melancholic/DST nonsuppressors (p = 0.04). When the cumulative cortisol response (CCR) to ACTH was examined, the DST nonsuppressors had a greater CCR decrease than suppressors (p = 0.03), and the melancholics a greater decrease than nonmelancholics (p = 0.02). The melancholic/DST nonsuppressor subgroup had the largest CCR decrease after treatment (p = 0.03), and these patients may represent a group of depressives with altered adrenocortical function that tends to "normalize" with clinical recovery.     

A modified dexamethasone suppression test for endogenous depression

In order to simplify the dexamethasone suppression test (DST), we have administered a lower dosage of dexamethasone (DEX) and shortened the sampling time to a single morning blood sample. DEX (in dosage increments from 0.125 to 1.0 mg, p.o.) was administered at 2300 h to normal volunteers in a double-blind randomized fashion, and blood samples were taken at 0700 h the following morning. While significant cortisol suppression occurred after the 0.375 mg, 0.5 mg, and 1.0 mg doses of DEX, the 0.5 mg dose was the smallest that clearly suppressed cortisol in all eight subjects. This dose then was used to test the feedback sensitivity of the central nervous system (CNS)-pituitary-adrenal axis in endogenously depressed patients. Twenty endogenously depressed patients and 20 normal volunteers were given both the standard 1.0 mg DST, with post-DEX serum cortisol determined at 1500 h, and the simplified 0.5 mg DST, with post-DEX serum cortisol determined at 0700 h. Four patients (20%) and one control (5%) were nonsuppressors after the 1.0 mg DST, and nine patients (45%) and one control (5%) were nonsuppressors after the 0.5 mg DST. In addition, nine patients with major depression (nonendogenous subtype) and 15 patients with panic attacks also were studied using the 0.5 mg DST. Only 2 of these 24 patients (8%) were nonsuppressors. The results suggest that the single-sample 0.5 mg DST is more sensitive than the standard 1.0 mg DST, and the specificity of the modified test appears comparable to the standard form of the test.