Pharmacological modulation of cortisol secretion and dexamethasone suppression in Alzheimer's disease

We have investigated the dexamethasone suppression of cortisol release in a group of 28 patients with senile dementia of the Alzheimer type (SDAT) after stimulation by physostigmine and clonidine, as compared with basal conditions. All patients but one had previously been evaluated with a depression symptom checklist and had submitted to a standard Dexamethasone Suppression Test (DST). SDAT patients showed normal baseline cortisol values measured at 4:00 PM. DST was reproducible, but nonsuppression did not appear to be a feature of the disease, nor of the dementia syndrome, although a majority of the most demented patients were found to be nonsuppressors. Physostigmine stimulated cortisol secretion in 20 of 24 cases, irrespective of the severity of dementia. Clonidine induced a secretion in 12 of 15 cases, but this was less than that observed after cholinergic stimulation. Physostigmine made cortisol release significantly less sensitive to the suppressive effect of dexamethasone than clonidine in SDAT. This double response should be tested as a possible predictor of a cholinergic therapeutic effect.     

The dexamethasone suppression test in Alzheimer's disease and major depression: relationship to dementia severity, depression, and CSF monoamines.

Patients with Alzheimer's disease (AD) have been reported to have a rate of nonsuppression on the dexamethasone suppression test (DST) comparable to that of patients with major depression. With symptoms of depression being increasingly recognized in patients with AD, studying their DST response may provide clues to the etiology of the abnormal response in both diagnostic groups. A correlation between dementia severity and post-dexamethasone cortisol was found within the group of male, but not female AD patients. Within the group of elderly depressives, a correlation between post-dexamethasone cortisol and ratings of depression was found. Serum dexamethasone levels were not significantly lower in the nonsuppressors as compared with suppressors in either diagnostic group. Within the AD group, dexamethasone levels themselves correlated significantly with ratings of dementia severity and with the Wechsler Memory Scale score. Cerebrospinal fluid (CSF) 3-methoxy-4-hydroxyphenylglycol (MHPG) correlated positively with 4:00 pm post-dexamethasone cortisol level and with ratings of dementia severity in the AD patients. Findings are discussed in light of the known clinical and other biological similarities between AD and major depression, followed by a review of theories regarding the etiology of the hypothalamic-pituitary-adrenal abnormalities in these two illnesses.     

Serial dexamethasone suppression tests in psychiatric illness: Part II. A study in major depressive disorder

Weekly dexamethasone suppression tests (DSTs) were performed in 35 patients with major depressive disorder until clinical response. At initial evaluation, 65% of the patients showed nonsuppression, and 85.7% showed nonsuppression at least once during the treatment period. Normalization of the DST results usually coincided with or occurred before clinical recovery, although isolated "peaks" of DST nonsuppression occurred in 45.7% of the patients, irrespective of the clinical course. The test was not useful as a predictor of clinical recovery or relapse. Moderately ill depressed patients had significantly higher nonsuppression rates than schizophrenic or manic patients with corresponding severity scores, indicating that different factors might be associated with nonsuppression in different diagnoses. However, many abnormal DST results could neither be related to the course of the depression nor to the severity of illness; thus other factors must also be responsible for DST nonsuppression.     

Does the dexamethasone suppression test relate to subtypes, factors, symptoms, or severity?

Results of the dexamethasone suppression test (DST) are frequently abnormal in depression but not always. We performed the DST in 95 depressed inpatients to determine whether abnormal DST results were associated with individual symptoms of depression, latent behavioral "factors," melancholia, or severity of depression. Initial insomnia, agitation, loss of sexual interest, and weight loss correlated significantly with nonsuppression. Using multiple regression, these four symptoms contributed independently to the variance in DST results and more closely associated with the DST results than did severity or the diagnosis of melancholia or endogenous subtype. Factor analysis failed to identify a factor that correlated with the DST results more significantly than did the individual symptoms. Our findings and a literature review suggest that DST nonsuppression associates with certain vegetative signs of depression but not with such symptoms as loss of interest or anhedonia nor with "psychological" symptoms such as guilt, worthlessness, helplessness, hopelessness, or suicidal ideation.     

Depression, negative and positive symptoms, and the DST in schizophrenia

It has been suggested that the presence of depression is a major determinant of abnormal dexamethasone suppression in patients with schizophrenia. It has been reported that negative symptoms in patients with schizophrenia are associated with increased rates of nonsuppression. In this study of schizophrenic inpatients, the Dexamethasone Suppression Test (DST), depression and negative and positive symptom ratings were carried out in two phases of the acute episode, in the second week after administration to, and in the week prior to discharge from, hospital. There was no association between depression and cortisol nonsuppression or between negative and positive symptoms and cortisol nonsuppression either early or late in the acute episode. It is concluded that the DST has no clinical utility in identifying the non-melancholic depression which occurs commonly in schizophrenia.     

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.     

The dexamethasone suppression test in demented outpatients with and without depression

The dexamethasone suppression test (DST) was given to 33 elderly, male outpatients, previously diagnosed by DSM-III criteria as having dementia. Fifteen of these patients also had signs and symptoms of depression and, except for the presence of organic mental syndrome, would have met DSM-III criteria for major depressive episode. Of these 15 depressed, demented patients, 40% had abnormal DST results. None of the 18 patients who had dementia alone had abnormal DSTs. Our data suggest that in elderly, demented outpatients, an abnormal DST may be associated with concomitant depression.     

Adrenocortical hyperactivity in depression: effects of agitation, delusions, melancholia, and other illness variables

In an attempt to determine the relative contributions to adrenocortical hyperactivity in depression of agitation, delusions, and melancholic subtype, we measured cortisol levels before and after dexamethasone in 93 unipolar major depressed inpatients. Stepwise multiple regression showed that agitation predicted 22% of the variance in a.m. cortisol level after dexamethasone. Addition of the variables melancholia and delusionality to the regression model accounted for 27% and 34%, respectively, of the variance in the same cortisol variable. Age, illness severity, and weight loss added no further significant predictive value. Age, weight loss, and illness severity did affect cortisol levels when examined separately from the other variables. Rate of nonsuppression on the dexamethasone suppression test (DST) differed between the nonmelancholic major depressive group and any other group with melancholia. These results suggest why some discrepancies may exist between studies of the DST in delusional depression and indicate that agitation merits careful assessment in future studies of DST response.     

Cortisol, ACTH, and beta-endorphin after dexamethasone administration in Parkinson's dementia

The dexamethasone suppression test (DST) has been suggested as an effective tool for differentiating between depression and dementia. After administering 1 mg dexamethasone, we measured cortisol, ACTH, and beta-endorphin levels in 32 nondepressed patients with idiopathic Parkinson's disease (PD) (14 also with dementia) and 20 healthy, age-matched controls. Four of the 20 controls, 9 of the 18 with PD alone, and 8 of the 14 with PD and dementia were dexamethasone nonsuppressors (cortisol value greater than or equal to 5 micrograms/100 ml). PD patients without dementia (nonsuppressors) showed higher basal plasma values of cortisol (22.06 +/- 5.30 micrograms/100 ml) compared with the suppressors (13.38 +/- 3.30 micrograms/100 ml). Plasma ACTH and beta-endorphin responded in a coupled way to dexamethasone challenge. Higher basal levels of both peptides were found among PD patients (demented and nondemented), nonresponders to DST. Thus, the DST does not appear to be effective in differentiating between depression and dementia in PD. In addition, PD nonsuppressors showed higher basal values of plasma ACTH, beta-endorphin, and cortisol (similar to patients with major depression). This suggests that although the depression is clinically undetectable, both disorders may share some pathophysiological features at the hypothalamic hypophyseal adrenal level.     

Dexamethasone suppression in dementia, depression, and normal aging

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

Chronic caffeine consumption and the dexamethasone suppression test in depression

Acute caffeine administration increases cortisol and converts the dexamethasone suppression test (DST) to nonsuppression in normal humans; data concerning chronic administration as well as effects in depressed patients are minimal. To determine whether caffeine intake influenced DST results in depression, we retrospectively studied the relationship between regular daily caffeine consumption and pretreatment DST status in major depressives. Daily intake was not correlated with either post-DST cortisol levels or symptom ratings. These data suggest that chronic caffeine use is unlikely to be a major factor in dysregulation of the hypothalamic-pituitary-adrenal axis in depression, perhaps because of the development of tolerance.     

The dexamethasone suppression test in the clinical setting

The authors administered the dexamethasone suppression test (DST) to 47 inpatients on a clinical, nonresearch psychiatric unit who had been diagnosed according to DSM-III. Of the 30 patients with major depression, 23 (77%) exhibited nonsuppression (serum cortisol concentrations greater than 5 micrograms/dl); only 1 of the 17 patients with other diagnoses and depressive symptoms exhibited nonsuppression. There was no difference in the rate of nonsuppression between the patients with subgroups of major depression, but those with major depression and psychosis had significantly higher postdexamethasone cortisol levels than those with major depression with and without melancholia and those with diagnoses other than major depression.     

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.     

Hypothalamic-pituitary-adrenal axis function in chronic schizophrenia: association with clinical features.

The function of the hypothalamic-pituitary-adrenal axis (HPA-axis) and its association with clinical features in chronic schizophrenia were investigated. Twenty of 33 chronic schizophrenics exhibited an abnormal diurnal variation of the saliva cortisol level. The patients with abnormal diurnal variation gave higher scores for some negative symptoms than those with normal diurnal variation. On the dexamethasone suppression test (DST) of saliva samples, 13 of 34 chronic schizophrenics were abnormal. The patients with DST nonsuppression were more frequently classified into disorganized type and exhibited low scores of anxiety compared with the patients with normal suppression. The 9 patients who showed abnormal diurnal variation and DST nonsuppression were more frequently classified into disorganized type and showed higher scores of negative symptoms than the 9 patients who did not show any abnormal cortisol data. These results suggest that there might be some disturbance in the function of the HPA-axis in a group of chronic schizophrenics and that these patients might have severe negative symptoms.     

DST in chronic pain patients not suffering from major depression

The relationship between chronic pain and depression is complex, and nonorganic chronic pain has been hypothesised (at least in some cases) as the expression of an underlying affective disturbance. Postdexamethasone cortisol nonsuppression was assessed in two groups of patients with chronic organic (n = 43) and nonorganic (n = 20) pain, none of them suffering from a major depressive disorder. Non-suppression occurred in 16.3% of the organic group and 20% of the nonorganic one. No difference emerged between the two groups for mean postdexamethasone cortisol values. The DST test results did not suggest the existence of a close relationship between chronic pain and major depressive disorder; however, a wider relationship between chronic pain and affective disturbances, at least in a subgroup of patients, cannot be ruled out.     

Serial dexamethasone suppression tests in psychiatric illness: Part III. The influence of intervening variables

The effects of different intervening variables on dexamethasone suppression test (DST) results were evaluated in depressed, schizophrenic, and manic patients. There was a significant correlation between age and DST results in major depression. Some "isolated peaks" of DST nonsuppression were explained by low dexamethasone serum levels. In schizophrenic and manic patients, the dexamethasone concentrations increased to above the normal range during the study period. A significant negative correlation between dexamethasone concentrations and DST results was found in schizophrenia and mania, but not in depression. Dexamethasone levels were generally higher in men than in women. Weight loss and hospital admission affected the DST in individual cases, whereas length of episode and drug withdrawal did not. Thus, the intervening variables accounted for some of the abnormal DST results, but other factors such as severity of illness, nonspecific stress, or possibly depression itself emerged as the main causes of abnormal DST results.     

Cortisol and corticosterone response after syn-corticotropin in relationship to dexamethasone suppressibility of cortisol

The current study was designed to investigate whether glucocorticoid output after syn-ACTH stimulation is different in depression associated with dexamethasone suppression test (DST) nonsuppression from the euthymic state and DST suppression. We gave 28 depressives a DST and an adrenocortical challenge with synthetic ACTH. Fourteen patients were nonsuppressors on the DST. After successful drug treatment, the subjects were reinvestigated by both tests; all DSTs revealed plasma cortisol concentrations below the criterion value of 50 ng/ml. Cortisol and corticosterone responses after syn-ACTH tended to be higher during depression. After clinical remission, higher cortisol and corticosterone responses occurred in those patients who were DST nonsuppressors during depression. This finding suggests that patients who suffer from a depression which is linked to an abnormal pituitary--adrenocortical regulation develop an enhanced sensitivity of the adrenal cortex to ACTH.     

The lack of relationship between DST nonsuppression in the dexamethasone suppression test and EEG abnormalities

As a recent study suggested a relationship between cortisol escape following dexamethasone suppression test (DST) and electroencephalogram (EEG) abnormalities, we tried to replicate these findings in 52 major depressive inpatients. A total of 23 patients exhibited DST nonsuppression (44%) and 18 patients had EEG abnormalities (35%). No relationship existed between DST and EEG results.     

Comparison of early and delayed inpatient dexamethasone suppression tests

Ninety-five inpatients completed a dexamethasone suppression test (DST) within 72 hours after admission and again after at least 1 week of medication-free hospital care. The frequency of cortisol nonsuppression in patients with endogenous depression (ED) was high and not significantly different at both tests. In patients with diagnoses other than ED, the higher rate of cortisol nonsuppression at the first DST was associated with a significant decrease in test specificity. Change in postdexamethasone cortisol levels at repeat testing was associated with a decrease in depressive symptomatology, but was not related to weight change during hospitalization.     

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.