Occurrence of high concentrations of postdexamethasone cortisol in elderly psychiatric inpatients

The authors retrospectively studied 161 psychiatric inpatients who had received a dexamethasone suppression test (DST). The majority of the patients were over 60 years old, female, and had concurrent chronic medical illnesses. Age was significantly correlated with log-transformed postdexamethasone cortisol concentrations in the 118 nondemented patients with major depression. Four p.m. cortisol concentrations greater than 15 micrograms/dl occurred in 15 patients. All were over 60 years old; all but one had major depressive disorder (MDD); and five had dementia plus MDD. In the same population, a 5 micrograms/dl criterion did not distinguish MDD from non-MDD patients. The results support the existence of a clinically relevant age effect on the DST in patients with MDD. Elderly depressed patients with markedly elevated cortisol concentrations occur frequently, and warrant further clinical and pathophysiological study.     

The dexamethasone suppression test in dementia: a review of the literature

To examine the utility of the dexamethasone suppression test (DST) in the differential diagnosis of depression in elderly demented patients, we reviewed the literature and focused on four components of this question: (1) cortisol nonsuppression rates in dementia; (2) cortisol nonsuppression and dementia severity; (3) cortisol nonsuppression in demented versus depressed patients; and (4) cortisol nonsuppression following antidepressant treatment. A combined analysis of 27 articles showed cortisol nonsuppression in 60% of patients with concurrent dementia and depression, in 47% of patients with depression only, in 41% of patients with dementia only, in 46% of patients with multi-infarct dementia, in 36% of patients with primary degenerative dementia, and in 10% of controls. The abnormal DST rate in demented patients was not significantly different from the abnormal DST rate in depressed patients. Eight of 12 studies (67%) did not find a significant relationship between DST results and dementia severity dementia patients without depression. Twelve of 13 studies (92%) did not find a relationship between age and DST outcome. The data we reviewed do not support the use of the DST in discriminating between depression and dementia or between dementia subtypes.     

Cortisol suppression per nanogram per milliliter of plasma dexamethasone in depressive and normal subjects

It has been suggested that dexamethasone pharmacokinetics may affect cortisol suppression during the Dexamethasone Suppression Test (DST). In depressed patients the cortisol response has been shown to negatively correlate with dexamethasone plasma concentrations, which also influence the sensitivity and specificity of the DST. These findings have been interpreted as weakening the utility of the DST. However, the analysis of pre- and post-1 mg DST cortisol concentrations corrected for plasma dexamethasone concentrations suggest that compared with normals (n = 52), patients with major depressive disorder (MDD) as a group (n = 71) had less suppressibility of cortisol to the same plasma dexamethasone concentrations. Moreover, when the MDD patients were evaluated based on DST status, the suppressors had cortisol/dexamethasone ratios (micrograms/dl of cortisol per ng/ml of plasma dexamethasone) similar to the normal controls, whereas the nonsuppressors had ratios that were significantly higher. These data suggest that DST non-suppression, as well as sensitivity and specificity of the DST in depression, is not only attributable to altered dexamethasone disposition, but indeed, there is a genuine reduced sensitivity of cortisol to dexamethasone that still points to an abnormality of the delayed feedback mechanism of the hypothalamic-pituitary-adrenal system in some depressed patients.     

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.     

Suicidal intent and the HPA-axis characteristics of suicide attempters with major depressive disorder and adjustment disorders

The main purpose of the study was to investigate Hypothalamic-Pituitary-Adrenal (HPA) axis characteristics in relation to suicidal intent among suicide attempters with Major Depressive Disorder (MDD) and Adjustment Disorders (AD). The relationship between suicidal intent, assessed by means of the Suicidal Intent Scale (SIS), and serum cortisol after a Dexamethasone Suppression Test (DST) was investigated in 78 suicide attempters, divided into diagnostic subgroups. There was a significant negative correlation between suicidal intent and post DST cortisol in patients with MDD. Our findings may be attributed to pathophysiological processes, where a high suicidal intent is revealed during a potential chronic course of MDD, which in turn results in a seemingly normal stress system.     

Suicidal Intent and the HPA-Axis Characteristics of Suicide Attempters with Major Depressive Disorder and Adjustment Disorders

The main purpose of the study was to investigate Hypothalamic-Pituitary-Adrenal (HPA) axis characteristics in relation to suicidal intent among suicide attempters with Major Depressive Disorder (MDD) and Adjustment Disorders (AD). The relationship between suicidal intent, assessed by means of the Suicidal Intent Scale (SIS), and serum cortisol after a Dexamethasone Suppression Test (DST) was investigated in 78 suicide attempters, divided into diagnostic subgroups. There was a significant negative correlation between suicidal intent and post DST cortisol in patients with MDD. Our findings may be attributed to pathophysiological processes, where a high suicidal intent is revealed during a potential chronic course of MDD, which in turnresults in a seemingly normal stress system.     

Enhanced adrenal sensitivity to exogenous cosyntropin (ACTH alpha 1-24) stimulation in major depression. Relationship to dexamethasone suppression test results

ACTH alpha 1-24 (cosyntropin) (250 micrograms by intravenous bolus) was given to 38 medicated patients with major depressive disorder (MDD) and to 34 normal control subjects. Patients with MDD had significantly higher plasma cortisol concentrations and significantly higher increases in plasma cortisol levels 60 minutes after cosyntropin infusion than did control subjects. Patients who were nonsuppressors in the dexamethasone suppression test had significantly higher 60-minute cortisol concentrations and cortisol increases than did normal subjects and patients with MDD who were suppressors. There were significant, strongly positive correlations between cortisol secretory responses to cosyntropin and postdexamethasone cortisol concentrations in patients with MDD. These findings confirm that adrenal sensitivity to corticotropin (ACTH) is enhanced in MDD and suggest that this endocrine abnormality may be related pathophysiologically to the resistance of cortisol secretion to dexamethasone suppression.     

Dexamethasone suppression in depressed elderly outpatients

The dexamethasone suppression test (DST) was performed as part of the preliminary workup in 85 previously untreated outpatients with major affective disorder, unipolar depressive type, who were over age 60. All patients were given a systematic structured interview (NIMH-DIS), and all had scores over 20 on the 21-item Hamilton Depression Rating Scale (HAM-D). Only 12 patients (14%) had positive DSTs; more of the non-melancholic (6 of 25; 24%) than melancholic (6 of 60; 10%) patients failed to suppress serum cortisol following standard dexamethasone challenge (p less than .10). DST results did not correlate with patients' HAM-D or Zung depression scores, gender, response to treatment, or any other variable studied. These findings suggest that, in comparison to previous reports, a positive DST may be 1) less common in major depressive disorders, 2) no more common in more severely depressed patients, and 3) less relevant to indications for specific treatment.     

Relationships of the dexamethasone suppression test to clinical severity and degree of melancholia

Investigators continue to debate whether the Dexamethasone Suppression Test (DST) reflects clinical severity or degree of melancholia ("endogeneity"). To evaluate this question, we studied 73 drug-free inpatients diagnosed with Schedule for Affective Disorders and Schizophrenia/Research Diagnostic Criteria (SADS/RDC) as having major depressive disorder (MDD). We compared absolute and dichotomous DST values (DST suppression versus nonsuppression) with absolute and dichotomous measures of endogeneity (as measured by operationally defined RDC items) and with Hamilton Rating Scale for Depression (HRSD) scores that were collected immediately prior to treatment. We found that degree of endogeneity correlated moderately (r = 0.27) but significantly (p = 0.02) with absolute DST values; DST nonsuppression increased proportionately with changes in categorical endogenous subtype (0% of the nonendogenous patients were nonsuppressives, 52% of probable endogenous, and 61% of subjects definitely endogenous); mean values for maximum DST concentrations increased steadily with categorical endogeneity (nonendogenous, 1.44 microgram/dl; probable endogenous, 7.65 micrograms/dl; definite, 10.93 micrograms/dl; p = 0.01); HRSD scores correlated more strongly (r = 0.45, p = 0.000) with maximum DST levels than did the degree of endogeneity. Age and weight changes did not account for the relationship of endogeneity to DST values. These data suggest that maximum postdexamethasone plasma cortisol levels reflect overall severity of depression and endogeneity and that endogeneity per se is highly confounded with severity.     

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.     

The dexamethasone suppression test and thyrotropin-releasing hormone stimulation test in posttraumatic stress disorder

Male veterans with posttraumatic stress disorder (PTSD) (n = 11), including 6 with concurrent major depressive disorder (MDD), were compared to veterans with MDD alone (n = 18) and to 28 controls in their response to the dexamethasone suppression test (DST) and thyrotropin-releasing hormone (TRH) stimulation tests. We found higher levels of 4 PM serum cortisol and lower peak thyroid-stimulating hormone (TSH) response to TRH in the MDD patients than in either the PTSD patients or controls, in spite of equivalent levels of depression for MDD and PTSD. DST suppression (cortisol less than 5 mg/dl) occurred in 90% of control, 90% of PTSD, and 78% of MDD subjects, whereas TRH blunting (dTSHmax less than 7 microU/ml) occurred in 28% of control, 27% of PTSD, and 67% of MDD subjects. Rather than blunting, four PTSD patients (36%) and only 10% of the control and MDD subjects had high TSH responses (13-24 microU/ml), which may be linked to high noradrenergic activity, since subclinical hypothyroidism seemed unlikely.     

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.     

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 in children and adolescents: a review and a controlled study.

Dexamethasone Suppression Test (DST) studies conducted in children and adolescents are reviewed, together with factors hypothesized to explain discrepancies in rates of DST nonsuppression across studies. These factors are then examined in a controlled study of 27 adolescents with major depressive disorder (MDD) and 34 normal controls (NC). Subjects were given 1 mg of dexamethasone at 11:00 PM, and the following day serum samples for cortisol were collected each hr from 8 AM to 11 PM through an indwelling catheter. There were no significant differences found between the MDD and NC subjects on any postdexamethasone cortisol measure. Further, cortisol suppressors and nonsuppressors were not distinguished by any of the hypothesized factors identified from the review, including inpatient status, presence of suicidality, endogenous features, psychotic symptoms, or prior history of MDD. Questions about the appropriateness of the 1 mg dose of dexamethasone (currently the standard dose used with adolescents) are raised, together with a discussion of the effects of stress on DST findings.     

The dexamethasone suppression test in borderlines: is it useful?

The relationship between borderline personality disorders (BPD) and major depressive disorder (MDD) continues to be controversial. A reliable biological marker for depressed BPD patients would not only support the diagnosis but could also help in predicting treatment outcome. A large sample of psychiatric patients was screened and data on the Dexamethasone Suppression Test (DST) were obtained for 67 patients who met the criteria for BPD by scoring 7 or greater on the Diagnostic Interview for Borderlines. The DST was positive in 23.9% of the cases. Fifty cases of BPD also met the Research Diagnostic Criteria for MDD. The DST was positive in 26.0%. Of the 50 patients with MDD, 34 also met the criteria for endogenous depression. Only 17.6% of this subgroup had positive results on the DST. The low sensitivity and specificity of the DST for depression in BPD patients suggests that the DST is not a useful test in differentiating BPD patients with MDD from those without MDD. The possible reasons for the DST not being useful in this population are discussed. These findings raises further questions about the nature of the depression suffered by BPD patients.     

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.     

Dexamethasone suppression test and the levels of serum growth hormone, plasma vasopressin and plasma homovanillic acid in depressed in- and outpatients

A total of 206 depressive patients (176 outpatients and 30 inpatients) underwent a dexamethasone suppression test (DST). Resting levels of serum growth hormone (GH), plasma vasopressin (AVP) and plasma homovanillic acid (HVA) were also measured in a proportion of the patients. Fifty-seven per cent of the endogenous patients showed nonsuppression of cortisol in the DST, while 92% in the nonendogenous group showed normal suppression. The diagnostic confidence of a positive test was 83%. The sensitivity and specificity of the test was slightly higher among inpatients than out-patients, and serum cortisol value at 4 p.m. was more useful than the morning value. No significant correlation was found between severity of the depression as measured by the Hamilton Rating Scale for Depression and serum cortisol. In single subjects there was, however, an obvious correlation. The levels of serum GH, plasma AVP and plasma HVA did not differ in the endogenous and nonendogenous groups, and there was no correlation between serum cortisol in the DST and the concentrations of the other hormones or HVA in plasma.     

Vasopressin-neurophysin and DST in major depression: relationship with suicidal behavior

The purpose of the present study was to assess if AVP-neurophysin is associated with hypercortisolemia and suicidal behaviour in depressed patients. The study included 28 patients subgrouped into suicide attempters (n=13) and nonattempters (n=15). We assessed basal AVP-neurophysins concentrations and post-dexamethasone (DST) cortisol levels. Concentrations of AVP-neurophysins did not differ between DST suppressors and nonsuppressors: 0.29+/-0.13 ng/ml vs 0.36+/-0.21 ng/ml, (F=1.1, df=1, 27, p=0.30). Suicide attempters did not differ from nonattempters for AVP-neurophysins levels. Our results fail to support a role of AVP in the early cortisol escape.     

Anatomic evaluation of the orbitofrontal cortex in major depressive disorder.

BACKGROUND: The orbitofrontal cortex (OFC) plays a major role in neuropsychologic functioning including exteroceptive and interoceptive information coding, reward-guided behavior, impulse control, and mood regulation. This study examined the OFC and its subdivisions in patients with MDD and matched healthy control subjects. METHODS: Magnetic resonance imaging (MRI) was performed on 31 unmedicated MDD and 34 control subjects matched for age, gender, and race. Gray matter volumes of the OFC and its lateral and medial subdivisions were measured blindly. RESULTS: The MDD patients had smaller gray matter volumes in right medial [two-way analysis of covariance F(1,60) = 4.285; p =.043] and left lateral OFC [F(1,60) = 4.252; p =.044]. Left lateral OFC volume correlated negatively with age in patients but not in control subjects. Male, but not female patients exhibited smaller left and right medial OFC volumes compared with healthy control subjects of the same gender. CONCLUSIONS: These findings suggest that patients with MDD have reduced OFC gray matter volumes. Although this reduction might be important in understanding the pathophysiology of MDD, its functional and psychopathologic consequences are as yet unclear. Future studies examining the relationship between specific symptomatic dimensions of MDD and OFC volumes could be especially informative.     

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.