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.     

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.     

Postdexamethasone prolactin and cortisol: a biological state variable in depression

In 70 inpatients with major depressive disorder postdexamethasone cortisol and prolactin, but not baseline cortisol and prolactin, was found to correlate significantly with various state variables of depression. Postdexamethasone prolactin appeared to be a more specific state variable of depression compared with postdexamethasone cortisol. While prolactin was decreased following dexamethasone in controls and nonendogenous depressed patients, in endogenous depressed patients prolactin was increased by 30%. Due to this inverse prolactin response to dexamethasone, the sensitivity of this test should be considerably increased by using a higher dexamethasone dosage. The DST failed to be a diagnostic marker for any subgroup of depression.     

A multivariate study of simultaneous escape from suppression by dexamethasone of urinary free cortisol, plasma cortisol, adrenocorticotropic hormone and beta-endorphin in melancholic patients.

To investigate the relationships between pre- and postdexamethasone hypothalamic-pituitary-adrenal (HPA) axis functioning in depression, we measured the levels of baseline and postdexamethasone urinary free cortisol (UFC), plasma cortisol, adrenocorticotropic hormone (ACTH) and beta-endorphin. We found that dexamethasone significantly suppressed all hormone levels. All 4 postdexamethasone hormones--but not their baseline levels--were significantly higher in melancholic subjects than in minor and simple major depressives. We have accumulated evidence that the melancholic and minor depression groups form discrete classes in postdexamethasone HPA axis hormone levels; this supports the biological heterogeneity hypothesis of melancholia. We found that a combination of the postdexamethasone UFC and beta-endorphin values yielded the most significant diagnostic tool for melancholia. Our results suggest that the measurements of both hormones may constitute the most accurate index reflecting the HPA axis escape from suppression by dexamethasone in melancholia. By means of pathway analysis, we determined the causal relationships between age, dexamethasone circulating levels, diagnostic depression classification and the various baseline and postdexamethasone hormone values.     

beta-Endorphin/beta-lipotropin immunoreactivity in endogenous depression. Effect of dexamethasone

This study addresses the question of whether pituitary peptides (ie, beta-endorphin) show regulatory disruption in endogenous depression and, if so, does it co-occur in the same subjects who show cortisol dysregulation. Endogenously depressed patients and psychiatric controls from three centers were evaluated, when not taking medications, and studied for plasma cortisol and beta-endorphin levels. Plasma samples were taken at four time points over one hour, on the basal day, and 16 hours after 1 mg of dexamethasone. From 33% to 69% of the endogenous patients were abnormal in their postdexamethasone cortisol levels, and from 50% to 69% were abnormal on postdexamethasone beta-endorphin values (vs 0% and 8%, respectively, for controls). When endogenous subjects were evaluated for abnormality on both cortisol and beta-endorphin, after dexamethasone, it was found that the two measures of hypothalamic-pituitary-adrenal dysfunction did not necessarily co-vary. In fact when having either abnormal beta-endorphin or cortisol levels (or both) was used as a biological marker a larger number of the endogenous patients were detected than with either measure alone. Our conclusions are as follows: Plasma beta-endorphin shows a circadian rhythm similar to that seen with corticotropin (ACTH) and is suppressable by dexamethasone. In many endogenous patients plasma beta-endorphin levels escape from dexamethasone suppression. Many of these subjects are not cortisol escapers. When abnormality of either the beta-endorphin or cortisol is considered it is clear that both levels of the hypothalamic-pituitary-adrenal axis can be dysregulated in endogenous depression.     

Psychotic and nonpsychotic depressions: I. Comparison of plasma catecholamines and cortisol measures

Unconjugated plasma catecholamines and cortisol were measured before and after a 1 mg dose of dexamethasone in 22 medication-free depressed patients and 6 healthy, medication-free control subjects. Plasma dopamine (DA) levels in the psychotically depressed subgroup (n = 4) were significantly higher both before and after dexamethasone than those in the nonpsychotic depressed group and higher before dexamethasone than in the control group. Similarly, the psychotically depressed group exhibited significantly higher cortisol levels both before and after dexamethasone than the nonpsychotic depressed group or the control group. In contrast, the psychotically depressed group had significantly lower postdexamethasone plasma norepinephrine levels compared to the nonpsychotic depressed group. In both patients and controls, plasma DA was significantly higher after dexamethasone administration than before, but the magnitude of the increase was 10 times greater in controls than in patients.     

The dexamethasone suppression test in panic disorder

The dexamethasone suppression test (DST) was performed in 35 patients with panic disorder and 21 normal control subjects. Non-suppression of plasma cortisol was determined as 4 micrograms/dl and using this figure 29% of panic patients and 9.5% of controls were non-suppressors. There was no significant difference in the number of suppressors and non-suppressors between patient and control groups (chi 2 = 1.81; P greater than 0.05). Both pre- and postdexamethasone cortisol concentrations were significantly different between the two groups possible indicating a cortisol hypersecretion in some panic patients.     

The effects of dexamethasone on plasma homovanillic acid and 3-methoxy-4-hydroxyphenylglycol. Evidence for abnormal corticosteroid-catecholamine interactions in major depression

We investigated the possible interactions between corticosteroids and catecholamines in depression by studying the effects of the synthetic glucocorticoid dexamethasone on plasma levels of homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) in a group of depressed patients and normal controls. In comparison with metabolite levels on a control day, normal controls showed a significant dexamethasone-induced increase in the plasma HVA level and a trend toward a decrease in the plasma MHPG level at 4 PM following dexamethasone administration (1 mg orally at 11 PM). Conversely, depressed patients, particularly those with psychotic features, showed a significant dexamethasone-induced increase in the plasma MHPG level and a blunting of the plasma HVA response relative to the normal controls. Dexamethasone-induced increases in the plasma MHPG level were directly correlated with the severity of depressive symptoms and with postdexamethasone cortisol levels in the depressed patients. These data suggest abnormal corticosteroid-catecholamine interactions in depression and, specifically, in depressed patients with psychotic features.     

Immunoendocrine aspects of major depression

Recently, a complete bidirectional circuit between the immune and neuroendocrine systems has been documented. Previous reports from this laboratory have shown that there are complex reciprocal relationships between immune and hypothalamic-pituitary-adrenal (HPA)-axis function in major depression. To further examine the immune-endocrine relationships, this study investigates plasma baseline cortisol and prolactin secretion in relation to plasma interleukin-6 (IL-6) and soluble IL-2 receptor (sIL-2R) levels in 34 healthy controls and 56 major depressed patients. There were significant positive correlations between IL-6 or sIL-2R and plasma cortisol in major depressed subjects and in the combined group of major depressed and healthy subjects. There were also significant positive correlations between plasma prolactin and sIL-2R concentrations in major depressed subjects and in the combined groups of normal and major depressed subjects.     

Neuroendocrine aspects of primary endogenous depression. V. Serum prolactin measures in patients and matched control subjects

To ascertain the extent of dysregulation of prolactin (PRL) secretion in endogenous depression, we determined nocturnal serum PRL concentrations and PRL responses to thyrotropin-releasing hormone (TRH), gonadotropin-releasing hormone (LHRH), and dexamethasone administration in 40 Research Diagnostic Criteria (RDC) primary, definite endogenous depressives and 40 individually matched normal control subjects. Compared to their matched controls, the patients showed no difference in basal nocturnal PRL concentrations, a marginally significant 20%-25% increase in the PRL response to TRH, and no differences in post-LHRH or postdexamethasone PRL concentrations. In the patients, there was a weak, negative correlation between age and PRL (r = -0.30), but none of the other subject characteristics or specific dimensions of depressive symptomatology were significantly related to the PRL measures. The PRL measures also were unrelated to pre- and postdexamethasone cortisol concentrations and to the thyrotropin (TSH) responses to TRH in both groups of subjects. In contrast to the previously reported hypothalamo-pituitary-adrenal cortical and thyroid axis abnormalities in these patients, our findings suggest that PRL secretion was relatively normal.     

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 dexamethasone suppression test: importance of dexamethasone concentrations

Plasma dexamethasone concentrations and cortisol response to dexamethasone were measured in 29 normal healthy volunteers, 23 depressed patients, and 10 patients with anorexia nervosa at 4:00 PM postdexamethasone. In each of the 3 groups, nonsuppressors had lower dexamethasone concentrations than suppressors. Of the subjects with plasma dexamethasone at or below 0.7 ng/ml, a significantly higher proportion (48%) were nonsuppressors compared to the proportion above 0.7 ng/ml (14%), all of whom were patients. Plasma dexamethasone concentrations in a subgroup of depressed nonsuppressors were high (mean 1.35 ng/ml), whereas the remainder were low (0.42 ng/ml) and were similar to the normal nonsuppressors (0.35 ng/ml), suggesting different mechanisms for nonsuppression in the subgroups. Plasma dexamethasone concentrations were similar in nonendogenous and endogenous depressives, in men and women, and in medicated and drug-free patients. None of the variables of age, weight, history of weight loss, Hamilton depression rating score, predexamethasone cortisol, or postdexamethasone cortisol were significantly correlated with plasma dexamethasone, except for body weight and a history of weight loss in the depressed group only. Mean plasma dexamethasone concentrations increased significantly from week 1 to week 2 in 7 depressed patients, whereas plasma cortisol decreased; however, the relationship between dexamethasone and cortisol varied considerably for individual patients.     

HPA-Axis hormones and prolactin responses to dextro-fenfluramine in depressed patients and healthy controls

1. Like other authors we have established disturbances in central serotonergic neurotransmission in severely depressed patients by implementing hypothalamic pituitary adrenal (HPA)-axis hormones and prolactin responses to serotonin agonists or precursors.

2. Challenge probes with D,L fenfluramine have yielded controversial results. This substance, however, is not as serotonin-selective as previously believed.

3. Dextro(D)-fenfluramine, the dextrorotatory isomer of fenfluramine, constitutes a specific and potent serotonergic agonist.

4. In the present study the authors determined the following in healthy volunteers, and in depressed inpatients: the adrenocorticotropic hormone (ACTH), B endorphin, prolactin and cortisol responses to D-fenfluramine administration (45 mg orally), total L-tryptophan and the 8 a.m. postdexamethasone cortisol values.

5. We found no significant differences in any of the post-D-fenfluramine hormone levels across healthy controls, minor, simple major and melancholic depressives. There were no significant correlations between L-tryptophan or postdexamethasone cortisol on the one hand, and any of the post-D-fenfluramine hormone values on the other.     

Differences in plasma ACTH and cortisol between depressed patients and normal controls

Although studies have repeatedly demonstrated that depressed patients average higher baseline and postdexamethasone serum cortisol than normal controls, studies examining similar trends in adrenocorticotrophic hormone (ACTH) have produced conflicting results. The current study uniquely employs 48 hr of every 20-min serum sampling: the first 24 hr prior to dexamethasone administration and the second 24 hr subsequent. The depressed patients showed higher baseline cortisol levels than normal controls, with the greatest differences between 2 AM and 6 AM. After an 11 PM dose of dexamethasone, the difference was greatest between the hours of 8 AM and 4 PM. Among the depressed patients, those who reported recent weight loss had significantly higher plasma ACTH and cortisol levels than those without weight loss. Depressed patients without weight loss had higher baseline plasma ACTH than normal controls, and the differences reached significance during some time periods.     

Dexamethasone suppression in dementia, depression, and normal aging

Dexamethasone suppression tests (DSTs) were performed for 18 moderately demented elderly patients, 66 depressed elderly outpatients, and 25 age- and sex-matched healthy elderly control subjects. Seventeen percent of the demented patients and 4% of the normal subjects were DST nonsuppressors, compared to 38% of the total depressed group. The postdexamethasone plasma cortisol levels of the dementia group fell between those of the normal and the depressed subjects. In addition, demented patients had postdexamethasone cortisol levels significantly lower than those of depressed patients with high Hamilton depression scores. Older subjects in all diagnostic categories, including normal subjects, had higher postdexamethasone plasma cortisol levels.     

Neuroendocrine aspects of primary endogenous depression. I. Cortisol secretory dynamics in patients and matched controls

To examine both predexamethasone and postdexamethasone cortisol measures in depression, we determined circadian serum cortisol patterns, cortisol responses to dexamethasone, and 24-hour urinary free cortisol excretion before and after dexamethasone administration in 40 patients with primary, definite endogenous depression diagnosed by Research Diagnostic Criteria and in 40 individually matched normal control subjects. Fifteen patients (38%) were dexamethasone nonsuppressors; they had significantly higher predexamethasone serum and urine cortisol measures than both their matched controls and the 25 suppressor patients. Both the predexamethasone and postdexamethasone cortisol measures were unimodally distributed across the patients and the controls. Circadian cortisol rhythms of similar magnitude occurred in both groups. The cortisol measures before and after dexamethasone administration were positively correlated to a similar degree in the patients and their controls, suggesting that predexamethasone hypothalamic-pituitary-adrenocortical hyperactivity and postdexamethasone cortisol nonsuppression are not independently determined in endogenous depression.     

Neuroendocrine responses to intravenous tryptophan in major depression

The increases in plasma levels of prolactin (PRL) and growth hormone (GH) following intravenous administration of the 5-hydroxytryptamine precursor tryptophan (100 mg/kg) were assessed in 30 depressed patients and 30 control subjects. In depressed patients who lost less than 10 lb, PRL responses were significantly reduced compared with controls. In contrast, the PRL responses of patients with weight loss exceeding 10 lb were significantly greater than those of either controls or the other depressed patients. Growth hormone responses to tryptophan were significantly decreased in patients who lost less than 10 lb. Prolactin, but not GH, responses correlated significantly with the postdexamethasone plasma cortisol concentration; however, an apparent relationship between GH and PRL responses and suicidal behavior was probably due to the common factor of weight loss. The results suggest that depressed patients have different types of abnormal 5-hydroxytryptamine-mediated neuroendocrine responses that correlate with the presence or absence of severe weight loss and cortisol hypersecretion. Further investigations are needed to establish if these abnormalities are central to the depressive disorder or have implications for treatment response.     

Growth hormone, cortisol and prolactin responses to physical exercise: higher prolactin response in depressed patients

This study was designed to compare growth hormone, cortisol and prolactin responses to physical exercise in depressed patients and healthy comparison subjects. Patients fulfilled the DSM-IV diagnostic criteria for current major depressive disorder; subjective depressive symptoms were rated with Montgomery-Asberg Depression Rating Scale (MADRS) immediately before the experiment. Growth hormone, cortisol and prolactin were measured before and immediately after physiologically stressful bicycle cardiopulmonary exercise test. After exercise, there were three additional hormone measurements, with 30-min intervals. No significant difference was found in baseline growth hormone, cortisol or prolactin levels between patients and the control group. Plasma growth hormone and cortisol levels increased significantly during physical exercise in both patients and controls and returned to baseline in 90 min. There was no significant difference in growth hormone or cortisol responses to physical exercise between the two groups. However, prolactin levels increased only in the depressed patients group during the exercise. We hypothesize that acute exercise may have a stronger effect on serotonin (5-HT) release in depressed patients, which is reflected in increased plasma prolactin concentration.     

The dexamethasone suppression test in normal control subjects: comparison of two assays and effect of age

he authors used competitive protein binding assay and radioimmunoassay to measure cortisol levels in 38 normal control subjects three times before and three times after administration of 1 mg of dexamethasone. They found significant interassay differences at 11:00 p.m. before dexamethasone and at all three postdexamethasone times. Analysis of variance revealed significant overall positive relationships between age and cortisol levels measured by both techniques. Age correlated significantly with postdexamethasone cortisol levels measured by radioimmunoassay but not when measured by competitive protein binding assay. Clinicians should obtain data from their laboratories as to appropriate cutoffs for cortisol suppression on the specific assay used.     

CSF corticotropin-releasing hormone in depressed patients and normal control subjects

The authors studied CSF corticotropin-releasing hormone (CRH) and plasma cortisol in 22 depressed patients and 18 normal control subjects. CRH levels were similar in the two groups. Depressed patients who were nonsuppressors on the dexamethasone suppression test had significantly higher levels of CRH than suppressors did. The depressed patients' CRH levels were significantly correlated with 4:00 p.m. postdexamethasone plasma cortisol levels. While the inclusion of a depressed patient with an outlier CRH value resulted in the loss of statistical significance for both of these findings, the authors suggest that these results support the hypothesis that hypercortisolism in depressed patients in part reflects a defect at or above the hypothalamus, resulting in hypersecretion of CRH.