Glucocorticoid resistance in depression: the dexamethasone suppression test and lymphocyte sensitivity to dexamethasone

Approximately 50% of depressed patients are resistant to the cortisol-suppressing effect of dexamethasone. To determine if glucocorticoid resistance could be a more generalized phenomenon in depressed patients, mitogen stimulation tests were performed on lymphocytes from 12 depressed patients and 12 control subjects before and after dexamethasone administration. Suppression of serum cortisol following administration of 1 mg of dexamethasone in four depressed patients and 11 control subjects was associated with a decreased lymphoproliferative response, but no such change occurred in the eight depressed patients and the single control subject who did not suppress cortisol. The dexamethasone-induced changes in the mitogen responses were positively correlated with the highest postdexamethasone serum cortisol values.     

Glucocorticoid receptors in depression: relationship to the dexamethasone suppression test

Cytoplasmic glucocorticoid receptor content wa quantitated in lymphocytes from unmedicated depressed patients and control subjects before and after a standardized dexamethasone suppression test. Depressed patients (N = 11) had significantly lower (32%) basal cytoplasmic glucocorticoid receptor content than the control group (N = 14). Suppression of serum cortisol (5.0 micrograms/dl or less) in both control and depressed subjects (N = 16) following dexamethasone (1 mg) was associated with a decrease in lymphocyte cytoplasmic glucocorticoid receptor number, whereas no such change occurred in cortisol nonsuppressors (N = 9). Changes in receptor concentration were positively correlated with postdexamethasone serum cortisol levels and with the inhibitory effect of dexamethasone on mitogen-induced lymphocyte proliferation.     

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.     

Plasma ACTH levels in depression before and after recovery: relationship to the dexamethasone suppression test

Sixteen patients with major depressive disorder who were nonsuppressors on the dexamethasone suppression test (DST) on hospital admission were studied for plasma levels of adrenocorticotropic hormone (ACTH). Eight patients reverted to normal suppression with clinical recovery, while eight remained nonsuppressors. There was a significant reduction of ACTH levels in those who normalized on their DST, while ACTH levels remained high in the group that continued to be nonsuppressors. The results favored the hypothesis that dexamethasone nonsuppression in depression is mediated by high ACTH levels.     

Situational depression and the dexamethasone suppression test

Neither baseline integrated 24 hr cortisol concentrations nor cortisol escape from dexamethasone suppression were able to distinguish a group of endogenously depressed patients who experienced precipitating events prior to their depression (situational) from a group of endogenously depressed patients with no discernible precipitating events (non-situational). Symptom severity, features of psychosis, and family history also were similar between the two groups. These results highlight the inadequacy of using the presence or absence of precipitating events for subtyping endogenous depression.     

Age and the dexamethasone suppression test in depression

The authors examined the effects of age on plasma cortisol concentrations of 81 depressed men after dexamethasone administration. Dexamethasone nonsuppression was significantly more frequent in patients older than age 55 than those younger. Similarly, older patients had significantly higher postdexamethasone cortisol concentrations than younger patients at all time points sampled. These differences could not be attributed to severity or to the prevalence of psychosis in older and younger depressed patients.     

The dexamethasone suppression test in depression

The DST does appear to be abnormal in a sizable subgroup of patients with major depressive disorder, particularly those characterized as "endogenomorphic" or "melancholic." At present the available data seem clear in indicating this abnormality is significantly less common in normal controls and patients without affective illness. The test holds considerable promise in helping to define new subgroups of depressed individuals for further study. In terms of its ability to predict treatment response to an adequate course of somatic therapy, the test does not appear to be of value, and the clinician should still be guided by the clinical presentation and history in initiating or choosing between various somatic treatments. With further attention to issues of diagnosis and DST methodology this strategy could help in addressing questions of differential diagnosis in potential "variants" of affective illness and providing a better understanding of the pathophysiology of depression.     

Number of cortisol time-points and dexamethasone suppression test sensitivity for major depression

Failure to suppress cortisol secretion after administration of dexamethasone has been reported to be a diagnostic marker for major depression and to have prognostic implications when repeated after antidepressant treatment. The pulsatile pattern of cortisol secretion suggested to us that increasing the number of post-dexamethasone cortisol determinations might significantly increase the sensitivity of the dexamethasone suppression test (DST) for major depression. With a conventional two-point DST (1600 h and midnight), 5% of 20 normal volunteers, 8% of 13 inpatients with non-major depressions, and 31% of 65 inpatients with primary major depression failed to suppress. With six post-dexamethasone points (0800 h, 1200 h, 1600 h, 2000 h, 2200 h, midnight), the respective percentages were 10, 15 and 44%. The additional points increased the sensitivity from 31 to 44%, mostly by identifying more major depressives with a "late escape" pattern. If a clinician is using the DST to establish a marker for major depression that can be repeated to monitor response to treatment and the likelihood of relapse, then perhaps the increased sensitivity of the six-point DST would be helpful, despite a modest decrease in specificity from 94 to 88%.     

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.     

Repeated dexamethasone suppression test in major depression

A review is made on the repeated dexamethasone suppression test (DST) in patients with a major depression. In those patients treated with conventional antidepressants the gradual normalization of the DST results is significantly correlated with the evolution of the clinical picture as measured with the Hamilton Depression Rating Scale. Normalization of the DST precedes symptomatic improvement and can be used as a predictor of good clinical outcome. Persistent dexamethasone non-suppression after treatment and complete clinical recovery predicts early clinical relapse. Patients with recurrent depression tend to have consistency of their response to dexamethasone over multiple depressive episodes.     

Thirty-four hour dexamethasone suppression test in depression

The utility of extending the dexamethasone suppression test past its usual 24 hr period to include a cortisol determination at 34 hr was investigated in 18 depressed patients. Conventional suppressors and non-suppressors differed significantly on their 34 hr cortisol values. However, this difference was small. Furthermore, 34 hr values generally returned close to baseline values, so that the 34 hr DST cannot now be recommended in the assessment of depressed patients without further study.     

Noradrenergic function and the dexamethasone suppression test in depression

We measured the plasma free 3-methoxy-4-hydroxyphenylglycol (MHPG) levels and the serum cortisol levels before and after the oral administration of dexamethasone. There was not a significant difference in the plasma free MHPG levels between the patients with major depression and normal subjects. There was a significant positive correlation between the plasma MHPG levels and postdexamethasone cortisol levels in patients with major depression. This indicates that there exists a certain relation between abnormalities of the central noradrenergic systems and hypothalamic-pituitary-adrenal axis in patients with major depression. The mean total scores of the Hamilton Rating Scale for Depression of the first (MHPG less than 5 ng/ml) and third (10 ng/ml less than or equal to MHPG) groups were significantly higher than those of the second (5 less than or equal to MHPG less than 10 ng/ml) group.     

Pharmacologic provocation and dexamethasone suppression test sensitivity

In expectation of improving sensitivity, the standard 1-mg dexamethasone suppression test (DST) was given to 10 depressed inpatients and repeated with theophylline or caffeine and again following 3 days of lorazepam with abrupt discontinuation. Two patients showed nonsuppression on the standard DST; 2 suppressors changed to nonsuppression after lorazepam discontinuation, and 1 also changed after theophylline. This increase from 20 to 40% sensitivity remains significantly less than a desirable minimum 80% sensitivity (p less than 0.001), which suggests that a consistent DST sensitivity of 80% in melancholia is unlikely to be attained.     

Agoraphobia and the dexamethasone suppression test: atypical depression?

The tricyclic antidepressants and the monoamine oxidase inhibitors have been shown to be effective in the treatment of some patients with phobic and panic disorders. To explain this action it has been suggested that a number of these patients may have an atypical biological depression. In an attempt to test this hypothesis we used the dexamethasone suppression test (DST), which has been proposed as a state dependent biological marker of depression. We compared the non-suppression rate of agoraphobic patients suffering panic attacks with controls and with patients suffering major depression. Twenty-nine per cent of the agoraphobics showed non-suppression compared with 12% of the control group and 64% of the depressives.     

The TRH stimulation test and the dexamethasone suppression test in depression

The thyrotropin-releasing hormone (TRH) stimulation test and the dexamethasone suppression test (DST) were performed in 40 depressive patients. More endogenously depressed patients than nonendogenously depressed patients showed a blunted response to TRH. No difference was found in delta max thyroid-stimulating hormone (TSH) between patients who responded to dexamethasone administration with a normal suppression of cortisol and those who responded with nonsuppression.     

Comparison of the ACTH suppression test and dexamethasone suppression test in depressed patients

Fourteen depressed patients were given the dexamethasone and ACTH suppression tests. The results of 71% agreed, suggesting that in a subgroup of depressed patients dexamethasone resistance reflects a central rather than peripheral dysfunction of the hypothalamic-pituitary-adrenal axis.     

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.