The dexamethasone suppression test and pituitary-adrenocortical function

The dexamethasone suppression test (DST) as now commonly carried out in psychiatric settings yields "abnormal" results in many conditions including the healthy state. To determine whether the DST accurately identifies patients with physiologically meaningful increases in pituitary-adrenocortical activity, we compared DST results to baseline urinary cortisol level. Thirty-four psychiatric inpatients underwent a 24-hour urine collection and then a DST using 1 or 2 mg of dexamethasone. With the common 1-mg DST, 24-hour urinary cortisol levels in nonsuppressors and suppressors did not differ. With the 2-mg DST, however, nonsuppressors had significantly higher urinary cortisol levels than suppressors, and all nonsuppressors had urinary cortisol levels above the normal range. Thus, the 1-mg DST may not identify the heuristically important subgroup of psychiatric patients who have a pathophysiologically meaningful alteration in pituitary-adrenal regulation.     

Use of the dexamethasone suppression test in an inpatient setting: a replication and new findings

The dexamethasone suppression test (DST) was administered to 131 depressed and 109 nondepressed psychiatric inpatients. The depressed patients were categorized according to DSM-III as minor depression, major depression without melancholia, and major depression with melancholia and/or with psychotic features. The nondepressed patients were stratified over several DSM-III subcategories. DST nonsuppression was nonspecific for major depression: the mean post-dexamethasone cortisol value and the number of nonsuppressors were not significantly different between the major depressives and the nondepressed psychiatric controls. Within the depressive sample the DST was a significant (p less than 0.01) discriminator between major and minor depression. Postdexamethasone plasma greater than or equal to 3.5 micrograms/dl at 0800h was the most sensitive (39%) and specific (94%) criterion; cortisol values at 1600h and 2300h showed no significant discriminating power for major vs. minor depression. The diagnostic utility of the DST thus appears to be limited to confirming the diagnosis of major depression, once the clinical diagnosis of depression is made. There was no significant influence of age or gender on postdexamethasone cortisol values.     

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.     

The dexamethasone suppression test: its relationship to diagnoses, severity of depression and response to treatment

1. The dexamethasone suppression test (DST) was applied to 40 depressed patients, 40 healthy volunteers and 40 patients with other psychiatric disorders. 2. The post-dexamethasone cortisol level, adopted as the non-suppression criterion and established locally, was 3.0 micrograms/dl. 3. The DST sensitivity in depression was 45%, with a specificity of 95% and a positive predictive value of 90%. 4. There was a significant correlation (r = 0.38, p less than 0.05) between HDRS scores of depressed patients and their post-dexamethasone cortisol levels. 5. A prospective study of the depressed group, which was assessed with three depression rating scales, showed differences between non-suppressors and suppressors regarding to the symptoms severity and response to the treatment. It suggests that an abnormal DST result could have a prognostic value to antidepressant drugs and ECT. 6. The DST specificity in depression was also calculated from its performance in the group with other psychiatric disorders, and their diagnoses as well as the abnormal DST results were critically discussed.     

Mean 14.00-17.00 h plasma cortisol concentration and its relationship to the 1 mg-dexamethasone suppression response in depressives and controls

Three-hour cortisol-profiles and cortisol responses to a 1 mg dose of dexamethasone were recorded in 31 depressed patients and nine controls. The data indicate that the likelihood of detecting non-suppressible cortisol concentrations after dexamethasone is significantly increased in depressed patients with a hypersecretion of cortisol. However, a considerable subsample of normosecretors shows abnormal DST results. Conversely, hypersecretion is often associated with dexamethasone suppression. In this study a 1 mg-DST did not reflect the adrenocortical activity with ultimate accuracy. Therefore any attempts which correlate psychopathological or biological data with pituitary-adrenal activity and use a DST-result as measure are criticizable . Data derived from volunteers illustrate that medical factors such as weight-loss, steroid-containing contraceptives and sleep deprivation can make a pituitary-adrenal activity test ambiguous.     

Direct radioimmunoassay of cortisol in saliva and its application to the dexamethasone suppression test in affective disorders

In order to perform the dexamethasone suppression test (DST) with saliva as an alternative to serum, we assayed directly the cortisol concentrations in 25 microliters saliva samples, using a commercial radioimmunoassay kit for serum cortisol with minor modifications. Cortisol in saliva showed a diurnal rhythm parallel to that of cortisol in serum samples collected simultaneously. Saliva cortisol levels increased significantly after ACTH injection, but with a 60 min delay in reaching their peak compared to peak serum cortisol levels. The increase in saliva cortisol was five-fold, while that in serum was two-fold. Saliva cortisol levels continued to increase in some subjects while serum total cortisol levels already had begun to decline. In those subjects, the correlation of saliva with serum cortisol was greater when a quadratic curve was fitted than when calculated for a linear correlation. Considerable variation was observed for within-subject correlations, ranging from + 0.48 to + 0.999. The DST with saliva sample collection was performed on 43 inpatients with affective disorders. Sensitivity, specificity and diagnostic confidence of the DST for major depressive episode with melancholia were 33%, 91%, and 78%, respectively, at the criterion value of 0.3 microgram/100 ml for saliva cortisol, which are similar to those most often reported for the DST with serum cortisol determination. These results indicate that saliva cortisol levels do not always parallel serum cortisol levels and thus are not an unequivocal substitute. The findings for the DST in psychiatric patients, however, support the practical clinical usefulness of saliva cortisol measurements.     

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.     

Use of saliva cortisol in the dexamethasone suppression test

In a sample of 26 inpatients (15 primary endogenous depressives and a heterogeneous comparison group of 11 psychiatric patients), results of the dexamethasone suppression test (DST) for endogenous depression were compared when cortisol was measured in plasma (total and free) and in saliva. Results showed a close linear relationship among plasma total and free cortisol, plasma total cortisol, and saliva cortisol, and between free plasma and saliva cortisol. A saliva cortisol cutoff point of 70 ng/dl achieved the same sensitivity (67%), specificity (91%), and diagnostic confidence (91%) as the best cutoff scores of plasma total cortisol (5 μ/dl) and plasma free cortisol (0.15 μ/dl). These results suggest that saliva cortisol, which directly reflects the biologically active fraction of cortisol, can be used as a reliable and more practical index in the DST, especially in outpatients.     

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.     

The dex/CRH test-Is it better than the DST?

The dexamethasone suppression test (DST), frequently abnormal in mood disorder patients, is considered to measure glucocorticoid receptor-mediated negative feedback. We examined the hypothesis that the, apparently more sensitive, dexamethasone/corticotrophin-releasing-hormone (dex/CRH) test unveils subtle hypothalamic-pituitary-adrenal axis disturbance not detected by the DST in 82 patients with mood disorders and 28 controls. There was a close correlation between the cortisol responses on the two tests (r(s)=0.73, p<0.0005). However, ROC analysis revealed that the dex/CRH test had better diagnostic performance than the DST (p=0.031). The sensitivity of delta cortisol (from the dex/CRH) was 61.9% and the specificity 71.4%. The sensitivity of 1500 h cortisol (the DST) was 66.6% and the specificity was 47.6%. This suggests that the two tests measure common pathology but that the dex/CRH test has better diagnostic utility.     

Plasma corticosterone and cortisol following dexamethasone in psychiatric patients

Radioimmunoassays of cortisol (F) and corticosterone (B) were carried out in 133 plasma specimens, obtained at 0800 or 1600 h on the day following administration of dexamethasone (1.0 mg), from 69 patients admitted to a psychiatric inpatient service, to test suggestions that assays of B might complement those of F in the dexamethasone suppression test (DST) in a psychiatric setting. The overall correlation between F and B was +0.80. Concentrations of B averaged 5-8% those of F. We found close agreement (80-85%) between positive (F greater than or equal to 4.5 micrograms/dl) and negative DST results for both steroids assayed by radioimmunoassay at a criterion of greater than or equal to 1.5 ng/ml for B, as well as a reasonable compromise between sensitivity and specificity of the B-DST at that criterion. Post-dexamethasone samples obtained at 1600 h showed somewhat closer agreement between the B-DST and the F-DST than at 0800 h. Inclusion of 0800 h samples added little to the rate of positive results with the F-DST but did add to those of the B-DST by about 10% or more, depending on the criterion selected for a positive B-DST. The rate of positive DSTs among 44 patients who had both steroids assayed at both times was approximately 61%, and the agreement between positive test results among these patients was 92%. In a mixed population of acutely ill, hospitalized patients with various DSM-III diagnoses, but excluding those with medical or pharmacologic contraindications to the DST, high rates of positive DST results were obtained in patients with major depressive disorders (47-58%), with little difference found among those with bipolar, non-bipolar or melancholic characteristics. High rates also were found among manic and other acutely psychotic patients, as well as others with neurotic or characterological diagnoses, but rarely in a small group of chronic schizophrenics. Thus, a positive DST as evaluated with B or F is evidently not specific for cases of major depression, but may be indicative of acute illness, possibly with affective features. The results support suggestions that a steroid suppression test based on corticosterone may be useful to aid in diagnosis of major psychiatric illnesses and might complement or substitute for the F-DST. It may be possible to avoid certain pharmacologic complications in the DST by use of a test based on suppression of B by F rather than by dexamethasone.     

Neopterin levels and dexamethasone suppression test in posttraumatic stress disorder

Neopterin has recently gained growing importance as an immunological marker in psychiatric disorders. In the present study, we aimed to evaluate whether the dexamethasone suppression test (DST) and neopterin were associated with posttraumatic stress disorder (PTSD). Fourteen patients with PTSD and 14 controls were enrolled in the study. A clinical evaluation and measurements of cortisol and neopterin levels before and after DST were performed. Additionally, all patients were assessed by Clinician Administered PTSD Scale (CAPS). There was a significantly higher DST nonsuppression in the patient group than control group. There were positive correlations between the duration of illness and CAPS, basal cortisol or postdexamethasone cortisol levels in the patient group. The mean neopterin levels for both before and after DST were significantly lower in the patient group than control group. In conclusion, our results suggest that not only the patients with PTSD have considerable DST nonsuppression but also PTSD may be associated with neopterin. Received: 13 February 2002 / Accepted: 13 June 2002     

Clinical,endocrine and neurochemical effects of moclobemide in depressed patients

The clinical efficacy of the monoamine oxidase A inhibitor moclobemide and its effect on the dexamethasone suppression test (DST) and plasma and urine methoxyhydroxyphenylglycol (MHPG) were investigated in 26 depressed patients during a 4-week clinical trial. Fourteen patients (54%) responded favourably to the treatment (50% or more reduction of the Hamilton Rating Scale for Depression score). All (8) patients with an abnormal DST responded to treatment; 11 of 16 patients with a normal DST did not respond. Patients with low pretreatment MHPG excretion, according to the median value, were more frequently treatment responders. Plasma and urine MHPG were significantly decreased by treatment. The results indicate that low excretion of MHPG and cortisol nonsuppression may be considered as predictors of favourable clinical response to moclobemide treatment.     

Urinary free cortisol levels and dexamethasone suppression testing in organic affective disorder associated with hyperthyroidism

Eleven of 32 newly diagnosed untreated patients with hyperthyroidism met DSM-III criteria for organic affective syndrome. Thirty of these patients submitted 24-hour urine specimens for measurement of urinary free cortisol levels, and 31 were given a 1-mg dexamethasone suppression test (DST) before antihyperthyroidism therapy was started. There was no difference in the mean +/- SD urinary free cortisol excretion levels between depressed and nondepressed hyperthyroid patients. One nondepressed patient demonstrated nonsuppression (greater than 5 micrograms/dl) at 8:00 a.m. These results suggest that cortisol abnormalities as reflected by urinary free cortisol levels and DST findings are uncommon in patients with hyperthyroidism whether they are depressed or nondepressed.     

Dexamethasone suppression test and plasma dexamethasone levels in bulimia

A 1-mg dexamethasone suppression test (DST) was carried out in 66 women with bulimia and in 26 age- and sex-matched controls. Blood samples were obtained at 4 PM on the day following dexamethasone ingestion, and levels of cortisol and of dexamethasone in the plasma were measured. Thirty-two percent of the patients vs only 7% of the controls had plasma cortisol levels of 140 nmol/L (5 micrograms/dL) or greater following the DST (a positive DST). The plasma levels of dexamethasone varied substantially, and there was a significant inverse relationship between the plasma level of cortisol and that of dexamethasone. Patients with positive DST results had lower levels of plasma dexamethasone than did those with negative DST results, and the mean plasma level of dexamethasone was lower in the bulimic group than in the control group. These results suggest that factors other than a disturbance of hypothalamic-pituitary-adrenal activity may contribute to positive DST results in bulimia.     

Laboratory evaluation for Cushing's syndrome in psychiatric patients with cortisol nonsuppression following the overnight dexamethasone suppression test

Laboratory tests used for the differential diagnosis of Cushing's syndrome have infrequently been employed in investigations of psychiatric patients who demonstrate hypothalamic-pituitary-adrenal (HPA) overactivity, and these laboratory procedures have not previously been applied for the specific purpose of further evaluating the endocrine function of psychiatric patients with serum cortisol nonsuppression following the standard 1-mg overnight Dexamethasone Suppression Test (DST). Low-dose (4 mg/48 hr) and high-dose (16 mg/48 hr) DSTs were administered to 10 psychiatric patients who exhibited cortisol nonsuppression after the overnight DST. Patients all had normal suppression to both the low-dose and high-dose tests. HPA overactivity in these patients was thus not sufficient to meet laboratory criteria for the diagnosis of Cushing's syndrome. Study results suggest that psychiatric patients with abnormal cortisol suppression following the 1-mg overnight DST are likely to have normal responses when assessed by standard laboratory protocols used for the diagnosis of Cushing's syndrome.     

Plasma L-tryptophan/neutral amino acid ratio and dexamethasone suppression in depression

We examined the ratio of plasma L-tryptophan (L-TRP) to other neutral amino acids (NAA) in normal controls and depressed patients undergoing a dexamethsone suppression test (DST). The L-TRP/NAA ratio discriminated controls from patients; however, there was no difference in the mean L-TRP/NAA ratio between DST suppressors and nonsuppressors. The cortisol level measured at 1600h postdexamethasone and the L-TRP/NAA ratio were positively correlated. The 1600h postdexamethasone cortisol levels accounted for 24% of the variance of Hamilton Depression Rating Scale ( HDRS ) scores. The inclusion of L-TRP/NAA ratios with 1600h postdexamethasone cortisol levels in a multiple regression equation resulted in an increase in this value and accounted for 65% of the variance in HDRS scores. The finding supports the use of multivariate biological models in depression.     

Effect of hospital admission on DST results

The authors examined the dexamethasone suppression test (DST) responses of 41 patients with primary major depressive disorder and 40 patients with other psychiatric disorders who were tested within 2-6 days of hospital admission. Significantly more patients with primary depression who were tested on day 2 demonstrated abnormal cortisol suppression than those who were tested on days 3, 4, or 3-6 and than patients with other psychiatric disorders regardless of test day. These results suggest that patients with primary depression may be sensitive to psychophysiologic stresses associated with hospital admission and that the utility of the DST may require further evaluation vis-à-vis the day of DST administration.     

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.     

Plasma dexamethasone kinetics during the DST after oral and intravenous administration of the test drug

We compared early biophase kinetics of dexamethasone in 33 patients with a major depression who received a DST either by an oral (n = 20) or an intravenous (n = 13) route. After an oral DST, the dexamethasone kinetics between 14 suppressors and 6 nonsuppressors were indistinguishable during the early distribution phase. However, elimination of dexamethasone from the circulation was significantly enhanced in DST nonsuppressors, resulting in an association of decreased plasma dexamethasone with elevated post-DST cortisol levels. Following intravenous DST administration, we identified 5 nonsuppressors and 8 suppressors whose plasma dexamethasone kinetics were indistinguishable, and during the elimination phase, were in the same order of magnitude as those of nonsuppressors after an oral DST. We suggest that the actual plasma concentration at the conventional post-DST sampling times does not reflect the biopotency of the test drug to suppress the pituitary adrenocortical activity. Plasma dexamethasone concentrations after an oral DST that were associated with nonsuppressed cortisol seem to be coherent phenomena of the underlying endocrine disturbance, the precise nature of which deserves further study.