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.     

DST and TRH stimulation test in mood disorder subtypes

Both the dexamethasone suppression test (DST) and the thyrotropin-releasing hormone (TRH) stimulation test have been reported to be useful in subtyping some depression diagnoses. Whether the DST discriminates delusional from nondelusional depression remains controversial, but this possibility has not been studied for the TRH test. The authors evaluated DST and TRH test results in 29 depressed hospitalized patients; both tests significantly discriminated patients with nonendogenous depression from those with endogenous depression. Furthermore, postdexamethasone cortisol levels but not the change in thyroid-stimulating hormone discriminated the patients with endogenous delusional depression from those with endogenous nondelusional depression.     

Pre- and post-dexamethasone salivary cortisol concentrations in major depression

Seventy patients fulfilling DSM-III criteria for major depression were given the 1.0 mg overnight dexamethasone suppression test, with salivary cortisol concentrations being measured as the dependent variable. Using both the DSM-III and the Research Diagnostic Criteria, we categorized the patients into four groups based on increasing frequency of endogenous symptomatology. Among these four groups there were no significant differences in salivary cortisol concentrations either before dexamethasone or eight, 16, and 24 h after dexamethasone. Similarly, there were no significant differences among the groups in either the ratios of post- to pre-dexamethasone salivary cortisol or the frequencies of positive tests based on several criterion levels of cortisol for the three post-dexamethasone samples. Multiple regression analyses indicated that the Hamilton depression rating scale item “somatic anxiety” was significantly negatively related to post-dexamethasone cortisol concentrations. We conclude that, for our sample of major depressives, the salivary cortisol dexamethasone suppression test showed no utility as a laboratory correlate of depressive episodes with endogenous features.     

Hypothalamo-pituitary-adrenal activity in endogenously depressed post-traumatic stress disorder patients

We studied the hypothalamo-pituitary-adrenal (HPA) system in Vietnam veterans with post-traumatic stress disorder (PTSD) who also met Research Diagnostic Criteria for endogenous depression (MDD-ED). Over half also abused alcohol, and many complained of pain-confounding factors usually associated with increased HPA activity. Nonetheless, not even one patient had elevated basal plasma cortisol concentrations or an abnormal dexamethasone suppression test (DST); the subjects' post-dexamethasone cortisol values and plasma cortisol per ng plasma dexamethasone were in the low-normal range. These results highlight the biological heterogeneity of endogenous depression and its possible influence by past psychological trauma, and they raise questions about the use of current typological criteria for research purposes.     

Inositol treatment has no effect on the dexamethasone suppression test.

The dexamethasone suppression test (DST) is a widely studied state marker for endogenous depression. Several drugs cause false positives or negatives in this test. Since inositol is a new treatment for depression it is important to determine if it causes artifacts in the DST. Five patients with major depression diagnosed according to DSM-IV underwent a dexamethasone suppression test before and after one and two weeks of 12 grams daily inositol treatment. Three normal subjects underwent the same procedure before and after one week of inositol treatment. Four depressed patients and all three normal subjects demonstrated pretreatment dexamethasone suppression of plasma cortisol. One or two weeks of inositol treatment had no effect on post-dexamethasone cortisol plasma levels in patients or subjects. One depressed patient was a non-suppressor before treatment and continued to show elevated post dexamethasone cortisol levels after one week of inositol treatment. However, after two weeks on inositol, when substantial clinical improvement was noted, he converted to a normal DST. Chronic inositol treatment does not seem to induce false positive DST results.     

Escape from dexamethasone suppression: Possible role of an impaired inhibitory opioid mechanism

1. 1. Several lines of evidence indicate that the activity of the hypothalamus-pituitary-adrenal (HPA) axis in depression is disinhibited.

2. 2. Escape from dexamethasone suppression, although not limited to is more frequent in patients with endogenous depression compared to normals or patients with other psychiatric diagnoses.

3. 3. Norepinephrine, serotonin and acetylcholine have been implicated in the pathophysiology of this neuroendocrine abnormality.

4. 4. Morphine, 5 mg intravenously, suppressed Cortisol secretion in healthy volunteers (n = 4) and the majority of 32 psychiatric inpatients.

5. 5. However, patients with endogenous depression abnormal dexamethasone suppression test results show early resumption (escape) of cortisol secretion following the initial suppression induced by morphine.

6. 6. It is concluded that the pathophysiology of this neuroendocrine abnormality is not limited to classical neurotransmitter-HPA axis interaction but that it also involves opioid inhibitory mechanisms.

Neuroendocrine aspects of primary endogenous depression: IX. Receiver operating characteristic analysis of the dexamethasone suppression index vs. the dexamethasone suppression test in patients and controls

The dexamethasone suppression index (DSI), which is the product of the postdexamethasone (DEX) serum DEX concentration and the post-DEX serum cortisol concentration, has been suggested to be a more sensitive discriminative test for depression than the standard DEX suppression test (DST). We used receiver operating characteristic (ROC) analysis to examine the DSI, calculated in several ways, versus the standard DST in a sample of 40 endogenous major depressives and 40 matched normal control subjects. The ROC analysis indicated that the DSI offers no advantage over the standard DST, regardless of which criterion values are used to define cortisol nonsuppression. Serum DEX determinations appear to have value primarily as an indicator of the minimum DEX concentration necessary for an accurate DST.     

Plasma cortisol, catecholamine and cyclic AMP levels, response to dexamethasone suppression test and platelet MAO activity in manic-depressive patients. A longitudinal study

Plasma cortisol, catecholamine and cyclic AMP levels, response to dexamethasone suppression test and platelet MAO activity have been determined in 15 patients suffering from bipolar affective psychosis, each examined during a depressive, a manic and an euthymic phase, and in 15 sex- and age-matched normal controls. Mean basal and post-dexamethasone cortisol levels have been found to be enhanced in patients during depression, but not during mania or free intervals. Non-suppression of cortisol secretion after dexamethasone has been observed in 46.7% of patients while in a state of depression, but in none of them during mania or euthymia. Mean plasma noradrenaline and adrenaline levels, which are thought to be the most reliable biochemical indices of emotional arousal, have been found to be increased in patients during mania, but not during depression. No significant difference has been observed between patients during any phase of their illness and controls with regard to mean plasma cyclic AMP levels and platelet MAO activity. These results confirm the state-dependent overactivity of HPA axis in endogenous depression, and suggest that it should not be regarded as a correlate of emotional hyperarousal. Moreover, they do not support the postulated role of plasma cyclic AMP as a state variable and of platelet MAO activity as a trait variable for manic-depressive illness.     

Cortisol secretion in endogenous depression. II. Time-related functions

Plasma levels of cortisol were sampled for 24 hours in 32 endogenously depressed (ED) patients and 72 controls to examine mean 24-hour plasma levels of cortisol, intervention in the feedback mechanism of the hypothalamic-pituitary-adrenal system (the dexamethasone suppression test), the circadian rhythm of cortisol secretion and its magnitude, and the ultradian rhythm of cortisol secretion. The main difference in the pattern of cortisol secretion in ED patients, as compared with controls, was in the ultradian rhythm. No acrophase or nadir advance of cortisol secretion in endogenous depression was found when age was controlled, but there was an earlier timing of first secretory episode of cortisol (during night). Only some ED patients have abnormalities in each of the functions studied, and they only partially overlap each other. The results suggest that abnormal cortisol secretion in depression should not be viewed as a monolithic malfunction characteristic of endogenous depression.     

Abnormal dexamethasone suppression test in daily chronic headache sufferers

The dexamethasone suppression test (DST) was administered in 48 daily chronic headache (DCH) sufferers, 37 of whom also suffered from mild to severe depression. In 14 of 48 subjects (29.2%), cortisol values at 1600h were greater than 50 ng/ml, despite normal suppression at 0800h. The escapers showed basal cortisol values and (Depression scale) scores on the Minnesota Multiphasic Personality Inventory higher than suppressors. Thus, a group of DCH sufferers appeared to share a biochemical defect often seen in endogenous depression. The escape from dexamethasone suppression could be a psychobiological indicator of vulnerability to develop depressive disorder and/or chronic pain complaints.     

Serial dexamethasone suppression tests and plasma dexamethasone levels. Effects of clinical response to electroconvulsive therapy in major depression

Serial 1-mg dexamethasone suppression tests with concurrent plasma dexamethasone assessments were conducted in 58 patients with endogenous depression treated with electroconvulsive therapy (ECT). Plasma cortisol levels decreased significantly from pretreatment to immediately posttreatment, and they declined further during the first week after the ECT course, when patients remained drug free. Plasma dexamethasone levels showed an opposite pattern of progressive increases over these three time points. The progressive changes in plasma dexamethasone and cortisol levels seen during the week after ECT indicate that alterations in the bioavailability of dexamethasone and in hypothalamic-pituitary-adrenal axis function may be incomplete immediately after the ECT course. This may partly account for previous inconsistencies in serial dexamethasone suppression test findings with this treatment modality. The major finding was that clinical response was associated with increased plasma dexamethasone levels, whereas changes in cortisol levels were independent of clinical outcome. With ECT, changes in plasma dexamethasone levels may be more related to changes in clinical state than changes in postdexamethasone cortisol levels. The extent to which clinical recovery with other treatments in depression is associated with altered bioavailability of dexamethasone and perhaps other compounds is unknown and in need of investigation.     

Plasma 3,4-dihydroxyphenylethyleneglycol levels in depressed patients with and without abnormal dexamethasone suppression

Escape from dexamethasone-induced suppression of plasma cortisol is an abnormality found in about half of patients with major depression. It has been hypothesized that this hyperactivity of the hypothalamo-pituitary-adrenal axis might be related to a central noradrenergic hypofunction. The present study was designed to test this hypothesis by measuring plasma 3,4-dihydroxyphenylethyleneglycol (DOPEG) levels (free and conjugated forms), an index of central noradrenergic activity, and by simultaneously carrying out a dexamethasone suppression test. Forty-five patients with a diagnosis of major depression (according to the DSM-III) were investigated. Plasma DOPEG levels (measured at 8 a.m.) were found to be similar in dexamethasone suppressor and nonsuppressor depressed patients. These results do not support the hypothesis that central noradrenergic hypoactivity underlies nonsuppression of dexamethasone in major depression.     

Dynamics of the cortisol suppression index in depression

The cortisol suppression index (CSI), a ratio of predexamethasone to postdexamethasone plasma cortisol levels, has been suggested as an alternate approach to the use of the DST in the diagnosis of depression. Forty-eight psychiatric inpatients were prospectively studied to compare the utility of the CSI to results obtained using Carroll's fixed values at 4 p.m. and 11 p.m. Eighty-eight percent (22/25) of depressed patients had an 8 a.m. CSI below 7.0; 73% (16/22) had a 4 p.m. CSI less than 2.5. This compared to a 76% detection rate using Carroll's criteria for nonsuppression. In this study the CSI provided a sensitive and specific interpretation of the dexamethasone suppression test in depression.     

Dexamethasone suppression test findings in subjects with personality disorders: associations with posttraumatic stress disorder and major depression

OBJECTIVE: Previous studies using the 1.0-mg dexamethasone suppression test (DST) in subjects with personality disorders have produced mixed results. However, these studies focused on major depression and did not consider the possible effects of the comorbidity of posttraumatic stress disorder (PTSD). PTSD has been shown to be associated with increased cortisol suppression. To investigate the effect of PTSD, the authors conducted a 0.5-mg DST, which is more sensitive than the 1.0-mg DST for detection of increased cortisol suppression, in a group of subjects with personality disorders. METHOD: Subjects with personality disorders (N=52) ingested 0.5 mg of dexamethasone. Pre- and postfasting blood samples were drawn for measurement of cortisol levels. A three-way analysis of covariance was used to test for the main effects of major depression, PTSD, and gender on percent cortisol suppression, with plasma dexamethasone concentration as a covariate. Secondary analyses assessed for main and interaction effects of age at which trauma(s) occurred and a diagnosis of borderline personality disorder. RESULTS: Neither major depression nor gender had a significant effect on percent cortisol suppression. Subjects with PTSD had significantly higher percent cortisol suppression than subjects with major depression. Age at which trauma(s) occurred and a borderline personality disorder diagnosis had no significant main or interaction effects on cortisol suppression. CONCLUSIONS: A high level of cortisol suppression was associated with PTSD in subjects with personality disorder. This finding is similar to published findings for PTSD subjects without personality disorders. Major depression, gender, age when trauma(s) occurred, and a diagnosis of borderline personality disorder did not have significant main or interaction effects on cortisol suppression.     

The clinical use of the dexamethasone suppression test in DSM-III affective disorders: Correlation with the severe depressive subtypes of melancholia and psychosis

The utility of the dexamethasone suppression test (DST) as an adjunct in the diagnosis of major depression remains controversial. While the research utility of the DST has been confirmed, the clinical utility has been questioned. We studied 166 consecutive admissions to a general, non-research unit who either met DSM-III criteria for major depression or had depressive symptoms associated with other DSM-III diagnoses. Using a 5 μg/dl criterion, non-suppression of serum cortisol after dexamethasone was observed in 63% of patients with DSM-III major depression. Patients with the most severe subtypes of major depression (melancholia and psychosis) showed both the highest rate of serum cortisol non-suppression and the highest post-DST serum cortisol concentrations. These findings from the clinical setting where the test, if found useful, will be used ultimately suggest that the DST is both sensitive and specific for the diagnosis of major depression. Future research will determine the potential role of the DST as an adjunct to the clinical assessment and management of patients with major affective disorder.     

A comparison of the cortisol suppression index and the dexamethasone suppression test

The cortisol suppression index (CSI) (the ratio of pre- to postdexamethasone serum cortisol concentrations) was compared to the dexamethasone suppression test (DST) in endogenously depressed DST suppressors (N = 20) and nonsuppressors (N = 21) and in normal controls (N = 23). The 8 a.m. CSI detected 17.1% and 31.7% of endogenous depressives at the 4.0 and 6.0 thresholds; for the 4 p.m. CSI, rates were 48.8% and 65.9%. The 4 p.m. CSI produced 17.4% and 39.1% false positives in normal controls at the two thresholds, whereas the false positive rate for the DST was 4.3%. These data suggest that the CSI is not as specific as the standard DST for the detection of endogenous depression.     

Prediction of the DST results in depressives by means of urinary-free cortisol excretion, dexamethasone levels, and age

This study investigates the relationships between cortisol escape from suppression by dexamethasone during a depressive episode, and the baseline activity of the hypothalamic-pituitary-adrenal (HPA) axis, circulating dexamethasone levels, and age. To this end, we measured urinary-free cortisol (UFC) excretion in 24-hr urine samples and the 8 AM cortisol and dexamethasone levels after administration of 1 mg dexamethasone in 50 depressive patients. We found that up to 54% of the variance in the postdexamethasone cortisol values could be explained by the multiple regression on UFC, age, and dexamethasone levels. By utilizing these three parameters, the dexamethasone suppression test (DST) nonsuppressor/suppressor state was correctly identified in 92% of the subjects. It was shown that an important part of the variance in postdexamethasone cortisol is actually background variance, irrelevant to depression and produced by the cumulative effects of the three aforementioned parameters. Only a small part (less than 20%) of the variance in postdexamethasone cortisol is determined by the actual depressive state. It was concluded that (1) baseline hypersecretion of cortisol, (2) decrements in the bioavailability of the test substance, (3) increasing age, and (4) the depressive state per se--all of which are cumulative--contribute independently to cortisol escape from suppression by 1 mg dexamethasone.     

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.     

The dexamethasone suppression test in adolescent psychiatric patients

The authors administered a structured psychiatric interview, the Kiddie-SADS, and the dexamethasone suppression test (DST) to 42 adolescent psychiatric inpatients. Of the 26 adolescents diagnosed as depressed, nine (36.4%) failed to suppress cortisol, and of the 16 nondepressed adolescents, three (18.8%) also failed to suppress cortisol. There was no significant association between the diagnosis of depression and the failure to suppress cortisol during the DST. The use of the DST to diagnose endogenous major depressive illness in adolescents seems to be a premature clinical application of an important investigative finding.     

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.