The thyrotropin-releasing hormone and dexamethasone suppression tests in the familial classification of depression

Eighty-eight depressed patients who had received a dexamethasone suppression test (DST) and thyrotropin-releasing hormone (TRH) test were divided into four subgroups based on family history of psychiatric illness. Nonsuppression on the DST was found in 46% of familial pure depressive disease (FPDD) patients, 38% of sporadic depressive disease (SDD) patients, 38% of depressive spectrum disease (DSD) patients, and 50% of mixed depressive disease patients (patients with both a first degree relative with alcoholism and one with depression). A blunted thyroid-stimulating hormone response to TRH was found in 50% of FPDD patients, 56% of SDD patients, 47% of DSD patients, and 56% of mixed depressive disease patients. Neither the DST nor TRH test was found to distinguish significantly among the four familial subgroups of depression.     

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.     

Evaluation of depression in a general hospital: utility and limitations of the dexamethasone suppression test

Use of the DST was studied in medically hospitalized, depressed patients. Although complicating medical factors necessarily excluded nearly 60% of referrals, post-dexamethasone plasma cortisol values were significantly higher in 14 major depressives appropriate for the DST as compared to 12 patients with milder, subsyndromal depressive conditions. Using a plasma cortisol criterion of greater than 7 micrograms/dl, the DST identified major depression with 57% sensitivity and 92% specificity in this subsample (p less than 0.005). While limited by a high exclusion rate, the DST may be useful for confirmation of major depression in carefully screened general hospital patients. Implications for research and practice are discussed.     

HPA-axis hyperactivity and mortality in psychotic depressive disorder: preliminary findings

BACKGROUND: The excess mortality associated with depressive disorders has been most often attributed to risks for suicide but diverse findings indicate that depressive disorders also increase risks for cardiovascular (CV) mortality. Among the possible mediators is the hypothalamic-pituitary-adrenal (HPA)-axis hyperactivity that characterizes many cases of relatively severe depressive disorder and severity is characteristic of psychotic depressive disorder. METHODS: The following describes a 17-year mortality follow-up of 54 patients with Research Diagnostic Criteria (RDC) psychotic major depression or schizoaffective, mainly affective, depression. All had baseline assessments that included a 1mg dexamethasone suppression test with post-dexamethasone samples at 8 a.m., 4 p.m. and 11 p.m. RESULTS: Regression analyses showed that both greater age and higher maximum post-dexamethasone cortisol concentrations predicted deaths due to CV causes (t=4.01, p<0.001 and t=3.03, p=0.004, respectively). The 4 who died from CV disease had a mean (SD) post-dexamethasone cortisol concentration of 18.0 (6.0)microg/dl while the mean (SD) value for the remaining 50 patients was 7.6 (6.6)microg/dl (t=3.03, df=53, p=0.004). Regression analyses showed the 11 p.m. post-dexamethasone value to be predictive of suicide (t=2.05, p=0.048). CONCLUSIONS: Conclusions should be tentative because an earlier follow-up of a more heterogeneous, but larger, sample did not find a relationship between DST results and CV mortality, and because only 4 CV deaths occurred in the present study. HPA-axis hyperactivity is probably only one of a number of factors that link depressive disorder to CV mortality.     

Measurement of ACTH and prolactin in the dexamethasone suppression test

Plasma concentrations of ACTH and prolactin were measured in psychiatric inpatients at 8 a.m. and 4 p.m. before and after the standard 1 mg overnight Dexamethasone Suppression Test (DST). Plasma concentrations of cortisol were measured at 8 a.m. and 4 p.m., and 11 p.m. before and after 1 mg dexamethasone. Dexamethasone suppressed plasma concentrations of ACTH, prolactin and cortisol in the subject group as a whole. "Cut Points" obtained using Fisher's Exact Test identified plasma ACTH values at 8 a.m. baseline, 4 p.m. baseline and 8 a.m. post-dexamethasone and plasma prolactin values at all four times that significantly differentiated patients with bipolar depressive disorder and major depressive disorder from other psychiatric patients. There were no cut points found at any of the six times for plasma levels of cortisol that significantly differentiated between these two diagnostic groups. Of interest in this subject population, basal (pre-dexamethasone) plasma concentrations were of more diagnostic information than post-dexamethasone values. These pilot findings suggest that monitoring plasma prolactin and ACTH concentrations before and after dexamethasone might increase the sensitivity and specificity of this laboratory test for depression.     

Cortisol escape from suppression by dexamethasone during depression is strongly predicted by basal cortisol hypersecretion and increasing age combined.

We determined baseline 0800h plasma cortisol concentrations, 24-hr urinary free cortisol (UFC) excretion, the post-dexamethasone cortisol values at 0800h and 1600h, and the 0800h dexamethasone concentrations in 60 depressed patients categorized according to the DSM-III. Up to 59% of the variability in the 0800h post-dexamethasone cortisol values could be explained by the multiple regression on UFC, 0800h basal plasma cortisol, age (all positively related), and dexamethasone concentrations (negatively related). The 1600h post-dexamethasone cortisol data were best explained (i.e., 55% of the variance) by the multiple regression on basal plasma cortisol, UFC (positive) and dexamethasone (negative). After controlling for UFC, baseline plasma cortisol, and age no significant effects of the depressive state (diagnostic classification or severity of illness) on the post-dexamethasone cortisol values could be detected. It can be deduced that cortisol non-suppression during depression is related strongly to baseline cortisol hypersecretion and increasing age. These factors are additive and contribute independently towards cortisol escape from suppression by dexamethasone.     

Effect of dexamethasone on cortisol and prolactin responses to meals in bulimic and normal women

In normal individuals, serum cortisol and prolactin concentrations have been shown to rise following a mid-day meal. To determine whether abnormalities of the hypothalamo-pituitary-adrenal axis in bulimics lead to a disrupted hormonal response to eating, cortisol and prolactin responses to meals (600 kcal, 30% protein, 30% fat, 40% carbohydrate) were studied on two consecutive days in six normal weight bulimics and six normal volunteers. Dexamethasone (1 mg orally) was administered at 2330 h after baseline sampling. During baseline sampling, cortisol concentrations were significantly higher in the bulimics (18.2 +/- 0.9 micrograms/dl, mean +/- SEM) than in the normals (12.1 +/- 0.4 micrograms/dl) (p less than 0.001). Post-dexamethasone cortisol concentrations also were higher in the bulimics (5.7 +/- 0.3 micrograms/dl) than in the normals (1.2 +/- 0.2 micrograms/dl) (p less than 0.001). The three bulimics with a major depressive disorder had higher peak post-dexamethasone cortisol concentrations than the nondepressed bulimics. Dexamethasone significantly enhanced the prolactin response to meals among both bulimics (at 90 min post onset of eating) and normals (at 60, 75 and 90 min post onset of eating). This enhancement of the prolactin response to meals by dexamethasone is opposite to the inhibitory effect of dexamethasone on stress-induced prolactin release and suggesting that stress-induced and meal-induced prolactin release involve different neuroendocrine mechanisms.     

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.     

The predictive power of the salivary cortisol dexamethasone suppression test for three-year outcome in major depressive illness

Seventy patients satisfying DSM-III and Research Diagnostic Criteria for major depression were given a salivary cortisol dexamethasone suppression test, with samples collected at 0700 h, 1500 h and 2300 h after dexamethasone. The patients were classified as nonsuppressors (mean post-dexamethasone salivary cortisol concentration greater than or equal to 2.0 ng/ml, N = 27) and suppressors (mean post-dexamethasone salivary cortisol concentration less than 2.0 ng/ml, N = 43). At 3-yr follow-up there was no difference in illness outcome as assessed by the life table method or by the length of rehospitalisation for several periods after the index episode. In multiple regression and discriminant function analyses, with outcome as the dependent variable (readmitted within 1 yr, readmitted between 1 and 3 yr, not readmitted), the mean post-dexamethasone salivary cortisol concentration was not significantly predictive of outcome.     

Simple laboratory test of neuroendocrine disturbance in depression: 11 p.m. saliva cortisol

Saliva cortisol was measured at 11 p.m. in a sample of 74 psychiatric inpatients composed of 24 primary endogenous depressives, 40 secondary depressives and 20 nondepressives (DSM III and Saint-Louis criteria). Primary depressives had significantly higher 11 p.m. saliva cortisol levels than nondepressives (p less than 0.02) and secondary depressives (p less than 0.05). In contrast, there were no significant differences between secondary depressive and nondepressive saliva cortisol levels. A saliva cortisol cutoff limit of 3.45 nmol/l identified primary depressives with a sensitivity of 62.5% and with a specificity of 75% in the depressive group, and 90% in the nondepressive group. The measurement of saliva cortisol at 11 p.m. could be used alone as a reliable and practical index of hypothalamic-pituitary-adrenal axis activity in depression, especially in outpatients.     

Increased activity of the hypothalamus-pituitary-adrenal system after treatment with the mineralocorticoid receptor antagonist spironolactone

The hippocampal mineralocorticoid receptor (MR) is critical for the regulation of the basal activity of the hypothalamus-pituitary-adrenocortical (HPA) system. It has been hypothesized that reduced capacity of the hippocampal MR is involved in the HPA-system dysregulation found in depression and aging. We applied the combined dexamethasone suppression/corticotropin releasing hormone stimulation (DEX/CRH) test to six healthy young females both before and after 12 days of treatment with the MR antagonist spironolactone to assess HPA regulation. Treatment with spironolactone caused a significant increase in post-dexamethasone cortisol concentrations (75.1+/-56.7 vs. 36.6+/-24.6 nmol/l, p<0.05). Furthermore, we observed a significant rise in peak cortisol concentration after additional human CRH (hCRH) application (223. 6+/-139.1 vs. 126.7+/-73.3 nmol/l, p<0.02). There was no change in ACTH plasma concentrations. We thus conclude that (1) the MR antagonist spironolactone affects HPA system regulation as reflected in the DEX/CRH test and (2) these findings are in accordance with the assumption that MR dysfunction may underlie HPA-system dysfunction in depression and/or aging.     

Plasma cortisol and 11-deoxycortisol activity in depressed patients and normal volunteers.

Plasma cortisol and 11-deoxycortisol were measured in 30 depressed patients and 110 normal volunteers before and after a 1.0 mg dexamethasone suppression test (DST). Post-dexamethasone plasma cortisol, 11-deoxycortisol and the cortisol/11-deoxycortisol ratio were significantly higher in the depressives compared to the controls, even when age and sex were taken into account. Pre-dexamethasone plasma cortisol, post-dexamethasone cortisol, 11-deoxycortisol and their ratio were significantly higher in the cortisol nonsuppressors than in the suppressors. The measurement of post-dexamethasone 11-deoxycortisol and the ratio did not differentiate between endogenous and reactive depression. Using the normative data, we explored several methods for determining a criterion value to define abnormal post-dexamethasone plasma 11-deoxycortisol and the cortisol/11-deoxycortisol ratio in depressed patients. All showed poor sensitivity and a low positive predictive value for depression. The measurement of 11-deoxycortisol thus does not enhance the clinical utility of the DST.     

Depression and anxiety inventories, and the dexamethasone suppression test

Twenty-one psychiatric inpatients with prominent depressive symptoms underwent dexamethasone suppression tests and assessment with observer-rated and self-rated anxiety, depression, and somatic symptom inventories. This was done to test the hypothesis that anxiety, more than depression, was related to cortisol nonsuppression seen in psychiatric patients including those diagnosed as having major depressive disorders. Nonsuppressors were significantly more depressed but not more anxious on the symptom inventories. In addition, it was noted retrospectively that the depression symptom inventory scores predicted nonsuppression. Several individual items from the symptom scales which correlated with post-dexamethasone cortisol levels were also identified.     

Cortisol levels and depression in men and women using heroin and cocaine

Abnormalities in the hypothalamic-pituitary-adrenal (HPA) axis are well documented in men using illicit drugs and/or infected with HIV; however, less is known about HPA function, or the health consequence of HPA dysfunction, in their female counterparts. People with depression exhibit hypercortisolemia, and depression is common in people with HIV or substance use problems. The current study investigated cortisol secretion in 209 demographically matched men and women, stratified by their HIV and drug use status. Self-reported depressive symptoms were evaluated using a standardized, validated questionnaire (CES-D). Women reported more depressive symptoms than men (p=.01). Male and female drug users exhibited higher cortisol concentrations (p=.03), and were more likely to report depressive symptoms (p=.04), than non-users. Depression was related to elevated cortisol concentrations for the study population (p=.03), and women with elevated cortisol concentrations were significantly more depressed than all other participants (p=.05). While it is unknown whether high cortisol concentrations precede depressive symptoms or vice versa, these data indicate that higher cortisol concentrations are associated with depressive symptoms in heroin and cocaine users, and that this association is more pronounced in women than men. HIV status did not act in an additive or synergistic way with drug use for either cortisol or CES-D measures in the current study. Unique therapies to treat the endocrine and mental health consequences of illicit drug use in men and women deserve consideration as depressive symptoms, and high cortisol concentrations associated with depressive symptoms, differ by gender.     

Endocrinological studies in alcoholics during withdrawal and after abstinence

Several endocrine parameters were assessed in 35 alcoholic inpatients after admission to hospital, and 17 of the 35 were retested after several weeks of sobriety. No difference was found in clonidine-stimulated growth hormone (GH) secretion between male alcoholics and male healthy controls, but significant positive correlations of GH secretion and alcohol content in expired breath on admission and gamma-GT values after abstinence were observed. Nonsuppression in the dexamethasone suppression test was found in 17% of the patients on admission, which seemed to be due to alcohol withdrawal. Postdexamethasone cortisol levels were significantly positively correlated with the "apathic syndrome" (r = 0.40; p less than or equal to 0.05). About one-third of the patients showed a blunted response in the TRH-test both on admission and after abstinence. No significant influence of alcohol intake, withdrawal or familial disposition on prolactin values could be detected. The results of the TRH test and the DST point to similar endocrinological patterns in alcoholics as in depressive patients and thus support the hypothesis of a link between alcoholism and 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.     

Mood state and salivary cortisol levels following overtraining in female swimmers

Mood, as measured by the Profile of Mood States questionnaire, and resting salivary cortisol levels were examined in 14 female college swimmers during progressive increases and decreases in training volume, and were compared to the same measures in eight active college women who served as controls. Training volume increased from 2,000 yards/day in September (baseline) to a peak of 12,000 yards/day in January (overtraining), followed by a reduction in training (taper) to 4,500 yards/day by February. The swimmers experienced significant (p less than 0.01) alterations in tension, depression, anger, vigor, fatigue and global mood across the training season compared to the controls. Salivary cortisol was significantly (p less than 0.01) greater in the swimmers compared to the controls during baseline and overtraining, but was not different between the groups following the taper. Salivary cortisol was significantly correlated with depressed mood during overtraining (r = .50; p less than 0.05) but not at baseline or taper. Global mood, depression, and salivary cortisol were significantly (p less than 0.05) higher during the overtraining phase in those swimmers classified as stale, compared to those swimmers who did not exhibit large performance decrements.     

Cortisol response to ACTH infusion in depressed patients: comparison with age-, sex-, and weight-matched normal subjects

Adrenal responsiveness to Cosyntropin (synthetic ACTH_1–24) was investigated in five patients with major depression and five individually matched normal subjects. Three hours following suppression of endogenous ACTH secretion with dexamethasone (1 mg orally), the adrenal response to a 10-min infusion of Cosyntropin (0.05 μg/kg body weight) was monitored for hr by plasma cortisol measured at 15-min intervals. The depressed patients had significantly higher baseline plasma cortisol, but not higher baseline ACTH, than the controls. During the 3-hr post-dexamethasone (and prior to Cosyntropin infusion), the depressed patients maintained significantly higher cortisol secretion, but not higher ACTH secretion, than the controls. After Cosyntropin infusion, there were no differences in ACTH and cortisol increases between the two groups. These findings stand in contrast to previous reports of enhanced adrenal responsiveness to the administration of much larger amounts of Cosyntropin in major depression.     

Sleep disturbance in unipolar and bipolar depression: relationship to psychiatric family history

Eighty depressed patients (40 bipolar and 40 unipolar) were personally interviewed in order to assess the relationship of disturbed sleep with psychiatric family history. Complaints of unsatisfactory sleep quantity and/or quality were more common among patients with a negative than among those with a positive family history for either any major psychiatric disorder (74.5 vs. 43.3%, p < 0.01) or only a mood disorder (68.4 vs. 43.5%, p < 0.05); this was more pronounced in bipolar patients. Results were confirmed when demographic variables and clinical characteristics of the disease were taken into consideration through the use of multiple logistic regression analysis. It is, thus, suggested that the mechanisms underlying disturbed sleep during a major depressive episode are different to those associated with the familial predisposition for depression.     

Plasma 11-deoxycortisol and cortisol following dexamethasone in psychiatric patients

As it has been suggested that calculating the ratio of cortisol to its biosynthetic precursor, 11-deoxycortisol, may enhance the sensitivity of the dexamethasone suppression test (DST) for depression, cortisol and 11-deoxycortisol were measured in 90 subjects undergoing this test. Among these subjects, post-dexamethasone cortisol and 11-deoxycortisol levels were significantly correlated (r = 0.65, P less than 0.001) and evaluating the ratio of cortisol to 11-deoxycortisol decreased rather than enhanced sensitivity of the DST.