Plasma ACTH levels in primary depression: relationship to the 24-hour dexamethasone suppression test

The failure of adequate cortisol suppression after 1 mg dexamethasone in 50% of patients with endogenous depression has been attributed to abnormal hypothalamic-pituitary-adrenal axis regulation, resulting in high levels of adrenocorticotropic hormone (ACTH). Because studies of plasma ACTH have been conflicting, we studied plasma ACTH levels during the 24-hour dexamethasone suppression test in a homogeneous group of 29 hospitalized patients with primary endogenous depression and 19 normal volunteers. No differences were found in ACTH levels among normal volunteers, depressed cortisol suppressors, and depressed cortisol nonsuppressors at either 4 p.m. or 11 p.m.     

Effects of parental PTSD on the cortisol response to dexamethasone administration in their adult offspring

OBJECTIVE: The authors used a low-dose dexamethasone suppression test to examine the effect of a PTSD risk factor, parental PTSD, on cortisol negative feedback inhibition in adult offspring of Holocaust survivors with PTSD (N=13) versus without PTSD (N=12) as well as a comparison group of offspring whose parents had no Holocaust exposure (N=16). METHOD: Blood samples were obtained at 8:00 a.m. for the determination of baseline cortisol. Participants ingested 0.5 mg of dexamethasone at 11:00 p.m., and blood samples were obtained again at 8:00 a.m. the following day. RESULTS: Enhanced cortisol suppression in response to dexamethasone was associated primarily with parental PTSD status, with minimal contribution of subjects' own trauma-related symptoms. CONCLUSIONS: Enhanced cortisol negative feedback inhibition may be associated with PTSD because it is related to the PTSD risk factor of parental PTSD.     

Effect of endogenous cortisol levels on natural killer cell activity in healthy humans

The aim of this study was to examine the effects of increasing and decreasing endogenous cortisol levels on natural killer (NK) cell activity in vivo. Normal healthy volunteers participated in the following studies: baseline (n = 27), metyrapone challenge test (n = 10), dexamethasone suppression test (n = 10), and adrenocorticotropic hormone (ACTH) stimulation test (n = 8). Each subject served as his own control for each study. Each subject was tested for NK activity and plasma cortisol levels at 9 a.m., just before the challenge drug administration, and at 10 a.m., except for the dexamethasone study, in which only the 9 a.m. blood was drawn, 10 h after the dexamethasone administration. On the baseline study day, a significant decrease in plasma cortisol levels was found from 9 to 10 a.m. (p <.02) along with a significant increase in NK activity (p <.001). On the metyrapone test day, plasma cortisol levels at 10 a.m. were significantly reduced (p <.005) as expected, while NK activity at the same time point was not affected and was increased to an extent equivalent to the baseline study day. On the dexamethasone test day, plasma cortisol concentrations were significantly decreased (p <.0001) as compared to the same time point on the baseline day, without any significant change in the NK activity. On the ACTH test day, plasma cortisol rose significantly at 10 a.m. (p <.02), with no change in NK activity. We conclude that plasma cortisol alone has no significant effect on NK activity in vivo.     

Salivary cortisol responses to dexamethasone in adolescents with posttraumatic stress disorder

OBJECTIVE: Previous studies of adults with posttraumatic stress disorder (PTSD) have found various abnormalities in the regulation of the hypothalamic-pituitary-adrenal axis, including enhanced suppression of cortisol following low-dose dexamethasone. The purpose of the present study was to investigate salivary cortisol responses to low-dose dexamethasone in adolescents with PTSD. METHOD: Forty-eight adolescents (20 with current PTSD, 9 trauma controls without PTSD, and 19 healthy nontraumatized controls) were enrolled in the study. On day 1, baseline saliva samples were obtained at 8 a.m. and 0.5 mg of dexamethasone was administered at 11 p.m. Cortisol and dexamethasone levels were assessed at 8 a.m. the following day. RESULTS: Adolescents with current PTSD showed no difference in the suppression of salivary cortisol in response to low-dose (0.5 mg) dexamethasone compared to trauma controls without PTSD and nontraumatized controls. More severely affected PTSD subjects with co-occurring major depression showed higher pre- and post-dexamethasone salivary cortisol levels compared to controls. CONCLUSIONS: The present study did not find evidence for enhanced suppression of salivary cortisol at 8 a.m. following low-dose dexamethasone in multiply traumatized adolescents with PTSD. This result differs from findings in adults with PTSD. Further investigations of hypothalamic-pituitary-adrenal axis abnormalities in traumatized children and adolescents are needed.     

Judgement of the hypothalamic-pituitary-adrenocortical function in psychiatric patients by betamethasone-induced cortisol suppressibility

Summary Betamethasone induced cortisol suppressibility was examined in 62 drug free consecutively admitted psychiatric inpatients. Betamethasone was choosen instead of the commonly used dexamethasone, because its double half-life compared to dexamethasone and its higher tissue availability. After a base-line evaluation with blood samples drawn at 8 a.m., 4 p.m., and 11 p.m., 0.5 mg or 1.0 mg betamethasone was given orally at 11 p.m. Postbetamethasone cortisol as well as betamethasone blood levels were then measured at the same time points as on the baseline day. In the groups receiving 1.0 mg betamethasone non-depressed patients had significantly (p<0.05) lower postbetamethasone cortisol levels than depressed patients for each time point measured whereas 0.5 mg betamethasone did not differentiate depressed from non-depressed patients. Patients with other depressions like schizoaffective psychosis -depressive subtype- or organic brain syndrome with depressive symptomatology demonstrated similar postbetamethasone cortisol profiles as the group of patients with major depression. Betamethasone plasma concentrations differed significantly (p< 0.001) with respect to the oral dosage with higher values for the 1.0 mg betamethasone groups.     

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.     

Evidence for altered hypothalamus-pituitary-adrenal axis functioning in systemic hypertension: blunted cortisol response to awakening and lower negative feedback sensitivity

BACKGROUND: Hypothalamus-pituitary-adrenal (HPA) axis functioning in systemic hypertension is not fully understood. We explored HPA axis activity and feedback sensitivity to oral administration of dexamethasone in systemic hypertension via assessment of the cortisol awakening response (CAR) and the circadian cortisol profile. METHODS: The CAR and circadian cortisol profile were assessed in 20 unmedicated and otherwise healthy middle-aged hypertensive men and in 22 normotensive male controls. Salivary free cortisol measures for the CAR were obtained immediately after awakening and 15, 30, 45, and 60 min thereafter. Circadian cortisol secretion was sampled at 08:00, 11:00, 15:00, and 20:00 h. Assessment of the CAR was repeated on the next day after administration of 0.5mg dexamethasone at 23:00 h on the previous night. RESULTS: Hypertensives had a significantly lower CAR (p<0.02) and significantly reduced suppression of the CAR after dexamethasone administration (p<0.01) than normotensive controls. There were no significant differences in cortisol levels at awakening and in circadian cortisol profiles between hypertensives and normotensives. CONCLUSION: We found evidence for altered HPA axis activity in men with systemic hypertension evident with the CAR. Hypertensives showed relative attenuation in the CAR and in the HPA axis feedback sensitivity following dexamethasone suppression. Such alterations in HPA axis regulation might contribute to the atherosclerotic risk in hypertensive individuals.     

Comparison of the dexamethasone suppression test and the cortisol suppression index

Among 50 inpatients, the sensitivity and specificity of the dexamethasone suppression test (DST) were 51.7% and 85.7%, respectively. For the cortisol suppression index they were 10.3% and 91% at 8:00 a.m. and 51.7% and 57.1% at 4:00 p.m. Thus, the cortisol suppression index does not appear to be an adequate substitute for the DST.     

The effect of serum dexamethasone concentrations in the dexamethasone suppression test

Serum dexamethasone and cortisol concentrations were measured in a sample of 98 psychiatric inpatients during the course of the 1-mg oral overnight Dexamethasone Suppression Test (DST). Suppressors were found to have significantly higher serum dexamethasone concentrations than nonsuppressors at each time of sampling (8:00 AM, 4:00 PM, and 11:00 PM). There was a significant inverse curvilinear relationship between serum dexamethasone and cortisol concentrations at each sample time. Although serum dexamethasone concentration was a potent determinant of postdexamethasone serum cortisol concentration, there were still significantly higher serum concentrations of cortisol in patients with major depression compared with patients with other disorders when dexamethasone concentrations were statistically controlled. By taking serum dexamethasone concentrations into account in defining DST suppression status, a modest increase in diagnostic specificity was achieved, but no substantial change in sensitivity.     

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.     

Cortisol feedback during the HPA quiescent period in patients with major depression.

OBJECTIVE: The authors tested the hypothesis that patients with major depression have a defect in the mechanism by which cortisol exerts negative feedback on the hypothalamic-pituitary-adrenal (HPA) axis during the HPA axis quiescent period. METHOD: Twenty-nine patients with major depression and 25 healthy comparison subjects were randomly assigned to administration of 15 mg cortisol or placebo infused over 2 hours beginning at 7:00 p.m. Cortisol and ACTH levels were measured at baseline and every 30 minutes from 7:30 p.m. to 11:00 p.m. RESULTS: Differences between the patients and the comparison subjects in the ACTH response to the cortisol infusion, relative to the ACTH response to placebo, were not found. CONCLUSIONS: The results provide some evidence that patients with major depression do not have an abnormality of cortisol feedback during the HPA axis quiescent period.     

Effects of trauma exposure on the cortisol response to dexamethasone administration in PTSD and major depressive disorder

OBJECTIVE: To evaluate cortisol suppression following 0.5 mg of dexamethasone (DEX) in trauma survivors (N=52) with posttraumatic stress disorder (PTSD), major depressive disorder (MDD), both, or neither disorder, and in subjects never exposed to trauma (N=10), in order to examine interactions between diagnosis and trauma history on cortisol negative feedback inhibition. METHOD: Lifetime trauma exposure and psychiatric diagnoses were assessed and blood samples were obtained at 8:00 a.m. for the determination of baseline cortisol. Participants ingested 0.5 mg of DEX at 11:00 p.m. and blood samples for determination of cortisol and DEX were obtained at 8:00 a.m. the following day. RESULTS: PTSD was associated with enhanced cortisol suppression in response to DEX. Among trauma survivors, the presence of a traumatic event prior to the "focal" trauma had a substantial impact on cortisol suppression in subjects with MDD. Such subjects were more likely to show cortisol alterations similar to those associated with PTSD, whereas subjects with MDD with no prior trauma were more likely to show alterations in the opposite direction, i.e. relative non-suppression. CONCLUSIONS: Cortisol hypersuppression in PTSD appears not to be dependent on the presence of traumatic events prior to the focal trauma. However, prior trauma exposure may affect cortisol suppression in MDD. This finding may have implications for understanding why only some depressed patients show non-suppression on the DST.     

Salivary cortisol levels and their correlation with plasma ACTH levels in depressed patients before and after the DST.

OBJECTIVE: The aim of this work was to study the clinical utility of salivary cortisol concentrations in a group of depressed patients undergoing the dexamethasone suppression test (DST) and the correlation of these concentrations with plasma ACTH levels. METHOD: Twenty outpatients from the psychiatric department of a Barcelona hospital who were diagnosed as having nonendogenous (N = 9) or endogenous (N = 11) depression according to DSM-III criteria and the Newcastle scale participated in the study. The comparison group consisted of 12 healthy volunteers. Blood and saliva samples were taken before and after administration of 1 mg of dexamethasone Salivary cortisol and plasma ACTH concentrations were determined by direct iodine-125 radioimmunoassay with commercial kit reagents. RESULTS: Predexamethasone salivary cortisol concentrations were significantly higher in the group with endogenous depression than in the comparison group. A significant correlation was obtained between plasma ACTH and predexamethasone salivary cortisol levels in the group with nonendogenous depression and in the comparison subjects. CONCLUSIONS: These preliminary findings indicate that salivary cortisol could substitute for plasma cortisol in clinical studies in which the DST and hypercortisolemia are evaluated. The lack of correlation between ACTH and cortisol levels in saliva in the group of endogenously depressed patients could indicate a disturbance in the regulation of cortisol secretion in major depression.     

A comparison of the cortisol suppression index and the dexamethasone suppression test in prepubertal children

Results of the dexamethasone suppression test (DST) and the cortisol suppression index (CSI) were compared in 50 depressed prepubertal children and 36 control subjects. The 4:00 p.m. DST, the two-point DST, and the 8:00 a.m. revised criterion CSI yielded the best results and had similar clinical utility and diagnostic confidence values.     

Three tests of cortisol secretion in adult endogenous depressives

Seventy-nine drug-free adult patients fitting RDC criteria for major depressive disorder endogenous subtype (EMDD), and 64 normal adult volunteers, were studied at pretreatment with at least one of three tests of cortisol secretion. The tests were: 1) Mean half-hourly cortisol concentrations from 1 p.m. to 4 p.m. (1-4 PM CORT); 2) plasma cortisol response to 0.15 mg/kg of dextroamphetamine hydrochloride (DACT) in the afternoon; 3) dexamethasone suppression test (DST) using 1 or 2 mg. Thirty-six depressive and 27 volunteers underwent all three tests. Analysis of the data was performed for each test singly, for all pairs of tests and for all three tests in same subjects. Results show that the single most sensitive cortisol test for depressions is the DACT (72%), with a specificity of 88%. These tests may measure different underlying pathophysiologies associated with depression.     

Dexamethasone suppression test: use of two different dexamethasone doses

The endocrinologic methods used in the dexamethasone suppression test (DST) for depression were examined, by employing two different doses of dexamethasone (0.5 or 1.0 mg) at 11 p.m. Nonsuppression to the 1.0 mg DST (plasma cortisol criterion value of 5 micrograms/dl) was seen in 33% of major depressives and in 15% of schizophrenics. A similar result was obtained with the 0.5 mg DST when 12 micrograms/dl was employed as the plasma cortisol criterion value. Plasma cortisol levels 33 hours postdexamethasone did not distinguish between major depressives and schizophrenics.     

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.     

Resistance of beta-endorphin to dexamethasone inhibition in Parkinson's and Alzheimer's diseases.

The response of plasma beta-endorphin (beta-EP) to dexamethasone suppression was studied in 14 patients with Alzheimer's disease (AD), 14 patients with Parkinson's disease (PD), and 13 age-matched controls in order to evaluate whether an impairment of the opiate system is present in these neurodegenerative disorders. Basal circulating beta-EP was in normal range in all subjects, although the mean concentration was slightly reduced in the patients compared to controls. After 1 mg dexamethasone given at 11:00 p.m. the night before, plasma beta-EP concentration measured at 08:00 a.m. and 04:00 p.m. was not inhibited in AD and PD patients while it was significantly reduced in controls. Circulating ACTH and cortisol were similar in patients and controls and a normal inhibition of plasma cortisol after dexamethasone was observed in 13/14 AD and 12/14 PD patients. The resistance of beta-EP to dexamethasone inhibition is consistent with previous clinical and experimental data indicating a disorder of the opiate system in brain degenerative diseases.     

HPA hyperactivity with increased plasma cortisol affects dexamethasone metabolism and DST outcome

Data suggests that dexamethasone bioavailability or pharmacokinetic factors contribute importantly to the outcome of the dexamethasone suppression test, and a relationship between plasma cortisol and plasma dexamethasone levels has been shown. To evaluate these data further, we studied plasma dexamethasone pharmacokinetics in 24 patients with major depression (15 suppressors and nine nonsuppressors) who received a 1 mg IV dexamethasone bolus at 09:00 h with blood samples collected at intervals over the next 14 h. We found that nonsuppressors had significantly shorter plasma dexamethasone half-life (P=0.003) as well as significantly lower dexamethasone levels 10 h (P=0.02) following IV dexamethasone administration. Moreover, upon clinical improvement of patients, the shortened dexamethasone half-life and lower dexamethasone levels disappeared in the five patients who switched from nonsuppression to suppression and were restudied by IV bolus. These 10-h post IV plasma dexamethasone level findings paralleled the results of the 1 mg overnight oral DST performed in these depressed patients (N=22) where we found significantly lower 10 h plasma dexamethasone levels in nonsuppressors on admission compared to suppressors (P=0.002) and again at discharge (P=0.007). Interestingly, in the few patients who switched from suppression to nonsuppression over the course of hospitalization, 10-h post dose plasma dexamethasone levels simultaneously dropped. No difference in dexamethasone half-life was observed in the patients studied by oral and IV dexamethasone administration. These findings support the concept that metabolism of dexamethasone is significantly related to the activity of the HPA axis (particularly by plasma cortisol levels), and that dexamethasone pharmacokinetics can be modified by state-dependent phenomena.     

Comparison of solid-phase radioimmunoassay and competitive protein binding method for postdexamethasone cortisol levels in psychiatric patients

Results obtained by competitive protein binding assay (PBA) and a solid-phase radioimmunoassay (RIA) for cortisol were compared in 157 samples from 100 psychiatric patients given a dexamethasone suppression test (DST). Cortisol levels in plasma samples obtained at 8:00 a.m. or 4:00 p.m. the day following 1.0 mg dexamethasone orally at bedtime ranged from 0 to 30 micrograms/dl and correlated closely (r = 0.96). However, RIA gave values that were consistently and significantly lower (average = 8.9%) than those obtained by PBA. When samples were further assayed by a specific RIA for corticosterone, there was a strong correlation between cortisol and corticosterone RIA values (r = 0.79), and corticosterone (7.8% of cortisol levels) accounted for most of the difference between PBA and RIA for cortisol. The relationship between results of the two cortisol assay methods can be expressed (in micrograms/dl) by the equation: RIA = 0.92(PBA) - 0.10, based on findings obtained in a separate analysis of 127 samples with cortisol values in the 0-10 micrograms/dl range, critical to the valid interpretation of the DST in melancholia. A reported criterion of a "positive" DST in psychiatry, of plasma cortisol of greater than or equal to 5.0 micrograms/dl has been suggested by use of a PBA. Use of the present RIA required that this value be adjusted downward, at least to 4.5 micrograms/dl; application of this criterion increased the clinical sensitivity of the DST by 10%. We urge local, independent verification of criteria to define the DST as "positive" in each laboratory and with each method of assay.