Plasma endogenous opioids and dexamethasone suppression test in depression

Plasma levels of beta-endorphin plus beta-lipotropin were determined in 35 hospital patients with depression and in 23 controls before and after administration of 1 mg of dexamethasone (dxm). Dxm suppressed opioid secretion in both groups. The opioid levels of the patients were significantly higher than those of the controls both before and after dxm. All the controls were cortisol suppressors. Among the patients the post-dxm opioid levels of cortisol nonsuppressors (n = 14) were higher than those of cortisol suppressors (n = 21). A significant correlation between the opioid and cortisol levels was found in the patients. There was a significant association between the use of neuroleptics and high opioid levels, but the difference between the patients and the controls was not explained by the effect of any single class of drugs. The results support the concept of hypersecretion of corticotropin-releasing factor in depression.     

A modified dexamethasone suppression test for endogenous depression

In order to simplify the dexamethasone suppression test (DST), we have administered a lower dosage of dexamethasone (DEX) and shortened the sampling time to a single morning blood sample. DEX (in dosage increments from 0.125 to 1.0 mg, p.o.) was administered at 2300 h to normal volunteers in a double-blind randomized fashion, and blood samples were taken at 0700 h the following morning. While significant cortisol suppression occurred after the 0.375 mg, 0.5 mg, and 1.0 mg doses of DEX, the 0.5 mg dose was the smallest that clearly suppressed cortisol in all eight subjects. This dose then was used to test the feedback sensitivity of the central nervous system (CNS)-pituitary-adrenal axis in endogenously depressed patients. Twenty endogenously depressed patients and 20 normal volunteers were given both the standard 1.0 mg DST, with post-DEX serum cortisol determined at 1500 h, and the simplified 0.5 mg DST, with post-DEX serum cortisol determined at 0700 h. Four patients (20%) and one control (5%) were nonsuppressors after the 1.0 mg DST, and nine patients (45%) and one control (5%) were nonsuppressors after the 0.5 mg DST. In addition, nine patients with major depression (nonendogenous subtype) and 15 patients with panic attacks also were studied using the 0.5 mg DST. Only 2 of these 24 patients (8%) were nonsuppressors. The results suggest that the single-sample 0.5 mg DST is more sensitive than the standard 1.0 mg DST, and the specificity of the modified test appears comparable to the standard form of the test.     

Resistance to inhibiting effect of dexamethasone in patients with endogenous depression

Suppression of 11-hydroxycorticosteroids (11-OHCS) release with dexamethasone (0.5 mg) has been investigated in 52 patients with endogenous depression and also in normals and in patients with other mental diseases. The suppression was considerably less in depressives (-19 +/- 5%) than in control groups (approx. -60%). The dexamethasone test indices were normalized during remission. The elucidate mechanisms of the dexamethasone inhibiting effect, the influence of tryptophan, DOPA and benzodiazepines on the 11-OHCS level and the degree of its suppression with dexamethasone have been studied. The data indicate a dual effect of serotonin on the regulation of the adrenal function: it stimulates CRF secretion and increases the inhibiting effect of corticosteroids on CRF release. It is suggested that during depression the negative feedback is disturbed in the system - brain monoamines-glucocorticoids. The possible role of this impairment in depression pathogenesis is considered.     

beta-Endorphin hypersecretion in depression: possible cholinergic mechanisms

Morning plasma concentrations of beta-endorphin immunoreactivity were significantly higher in a group of depressed patients meeting the Research Diagnostic Criteria for Major Depressive disorder or Schizo-affective disorder, depressed, than in age- and sex-matched groups of normal controls and psychiatric patients without affective disorders. Furthermore, physostigmine-stimulated release of beta-endorphin immunoreactivity was also significantly greater in the depressed patients. These results provide the first evidence for elevated plasma concentrations of beta-endorphin in depression and also represent further evidence for cholinergic supersensitivity in depression. These results suggest that elevated plasma concentrations of beta-endorphin and cholinergically stimulated hypothalamic-pituitary beta-endorphin release, might potentially represent biological state or trait markers for depression.     

Neuroendocrine aspects of primary endogenous depression. II. Serum dexamethasone concentrations and hypothalamic-pituitary-adrenal cortical activity as determinants of the dexamethasone suppression test response

To determine the contribution of serum dexamethasone concentrations and hypothalamic-pituitary-adrenal cortical activity before dexamethasone administration to the dexamethasone suppression test (DST) response, a series of stepwise discriminant function analyses were performed for 40 patients with definite endogenous depression and 40 matched normal control subjects. The 24-hour serum cortisol concentration before dexamethasone administration and the serum dexamethasone concentrations at 8, 16, and 24 hours after administration served as the independent variables, and the DST "escaper"/"suppressor" dichotomy served as the dependent variable. While both types of independent variables significantly influenced the DST response, the major factor that contributed to the discrimination of escapers from suppressors was the 24-hour cortisol concentration before dexamethasone administration. Sixteen hours after dexamethasone administration, when the DST had the highest positive predictive value, serum dexamethasone concentrations significantly influenced DST outcome only when they were below a certain threshold level. At this time, hypothalamic-pituitary-adrenal cortical hyperactivity before dexamethasone administration accounted for approximately two thirds of the incidence of DST nonsuppression.     

The validity of the dexamethasone suppression test as a marker for endogenous depression

The validity of the dexamethasone suppression test (DST) as an indicator of endogenous depression has been most frequently tested by examining its relationship to operational criteria of endogenous depression. However, these criteria sets themselves have not been empirically validated. We examined the DST in terms of a series of hypotheses and predictions that are consistent with the theoretical construct of endogenous depression. In a consecutively admitted sample of 187 primary unipolar depressed inpatients, the DST nonsuppressors were older, had less premobid personality disorder, better social support, less frequent marital separations or divorces, fewer nonindependent stressful life events during the year prior to admission, made fewer nonserious suicide attempts during the index episode, had fewer dysfunctional attitudes, and had a lower rate of treated alcoholism and antisocial personality in their first-degree relatives. The only clearly negative finding was the lack of association between DST results and family history of depression. Our results strongly support the construct validity of the DST as a marker of endogenous depression.     

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.     

Ventricular size, the dexamethasone suppression test and outcome of severe endogenous depression following psychosurgery

To assess the possible significance of cerebral ventricular size and the dexamethasone suppression test (DST) in the outcome of severe endogenous depression, 28 patients were followed up and reviewed 1 year after stereotactic subcaudate tractotomy. Neither ventricular size nor the dexamethasone suppression test predicted either a good or poor outcome. There was no relationship between ventricular size and the DST results.     

The psychopathology of anancastic endogenous depression.

From a sample of 1,005 patients admitted to the Psychiatric Hospital in Aarhus for the first time during the period 1950-1959 and diagnosed as suffering from manic-depressive psychosis or endogenous depression (affective psychoses), a subsample of 104 manic-depressive patients with anancastic symptoms in the history was selected. The 104 probands were individually matched with 104 non-anancastic probands with affective psychoses. The study was designed as a follow-up study, and the patients who were still living were seen personally. In the search for factors which could be used to distinguish affective psychoses with anancastic symptoms from affective psychoses without these traits, the incidence of a number of psychopathological features was evaluated based on the case histories and the information given by the patients at the follow-up. There was no difference as far as atypical, schizophrenia-like symptoms were concerned between the anancastic probands and the controls. Manic and hypomanic features were more frequent among the controls, corresponding to a greater number of bipolar psychoses among them. At the same time, the controls showed a significant preponderance of decidedly psychotic symptoms such as disturbances of consciousness, delusions and delusion-like ideas and hallucinations. Furthermore, retardation was more frequent among the controls. There was no difference in the suicidal behaviour of the two groups. Symptoms which were more often met among the anancastic depressives were: anxiety, agitation, diurnal variation of mood and early awakening. Seasonal variation in symptomatology was also more frequent among the anancastic probands. The same held true for depersonalization. The anancastic probands showed a significant preponderance of anancastic premorbid personality features. A positive correlation was found between the number of anancastic personality features and the following symptoms: agitation, anxiety, diurnal fluctuation, seasonal variation, hypochondriacal attitude and depersonalization. On the other hand, objective retardation or flight of ideas showed a significant negative correlation. The pattern of the anancastic symptoms was rather uniform; aggressive obsessions, mostly in the form of suicidal and homicidal obsessions, were present in more than two thirds of the cases. The anancastic depressions were often less severe than non-anancastic depressions in that the latter were more often complicated by decidedly psychotic symptoms. It is possible to interpret the symptomatology of anancastic depressions as a pathoplastic influence of the anancastic personality, but it cannot be excluded that some of the symptoms like anxiety and agitation are linked to the presence of anancastic symptoms as such.     

Electroconvulsive therapy-induced cortisol release after dexamethasone in depression.

ECT-induced cortisol release was distinctly seen, and fell along a course of ECT in each of 12 inpatient male melancholics (p = 0.00024, binomial), with dexamethasone given to diminish the elevated baseline cortisol levels typically seen in depression. Cortisol release dropped on average by 55% (p = 0.015), from 16.6 +/- 6.8 micrograms/dl (p = 0.000002) with the first ECT to 8.0 +/- 7.7 micrograms/dl (p = 0.000003) after 6 or more ECTs. The fall along the course was larger with unilateral ECT than bilateral ECT (p = 0.042), although significant regardless of electrode placement, suggesting that unilateral ECT tends to lose therapeutic impact along a course in comparison to bilateral ECT.     

The dexamethasone suppression test in depression. Critical review

Within the investigation of the neuroendocrinology of depression, the HPA axis exploration brings the most definite results. Biological measurements indicate an hyperactivity of this system in the endogenous depressions. The dexamethasone cortisol suppression test has been described by Liddle and Nugent and has been used by Carroll since 1970. A standardisation of the protocol is required; thus, within the endogenous deficiencies, either lack of cortisol suppression or cortisol suppression with an early escape are noticed. The various and hazardous reasons that make the results vary are discussed. The dexamethasone suppression test is a practical and useful tool for the diagnosis of endogenous depression (sensitivity above 65%, specificity and diagnostical value near 95%); for treatment management; and prognostic evaluation. From a theoretical aspect, the dexamethasone test enables us to delineate the nosology of the depressive disorder and to detect in childhood depression the same neuro-endocrinological features as noticed in adulthood depression. Physiopathological hypotheses within the norepinephrinergic and serotoninergic depression theories are detailed.     

The dexamethasone/corticotropin-releasing hormone test in depression in bipolar and unipolar affective illness.

The combined dexamethasone/corticotropin-releasing hormone (DEX/CRH) test was performed in forty patients with depression (12 male, 28 female), aged 20-68 years, in the course of affective illness (16 bipolar, 24 unipolar) both during acute depressive episode and in remission. The results were compared with those of 20 healthy control subjects (10 male, 10 female), aged 22-52 years. During acute depressive episode, cortisol concentration at 16 h after dexamethasone, 1.5 mg, and cortisol release after subsequent infusion of CRH, 100 microg, were significantly elevated in bipolar patients compared with unipolar ones and with control subjects. Patients with multiple episodes of unipolar depression exhibited greater cortisol levels after CRH than control subjects. In remission, significantly higher cortisol concentrations measured at 30 min(-1) h after CRH infusion were found in bipolar than in unipolar patients. Male bipolar patients had significantly higher cortisol level than bipolar females before and at 1.5 h after CRH. First episode unipolar patients during remission had lower levels of cortisol than control subjects before and at 1.5 h after CRH. Correlation between the magnitude of cortisol response and age was found within unipolar depressed patients but not in bipolar ones. On the other hand, correlation of test results with intensity of depression measured by Hamilton scale as well as with insomnia and anxiety subscales was more robust in bipolar subjects than in unipolar ones. It is concluded that the dysregulation of hypothalamic-pituitary-adrenal (HPA) axis activity, detected by DEX/CRH test is significantly more marked in patients with depression in the course of bipolar affective illness than in unipolar depression. Within unipolar depression, this dysregulation may increase with the time course of the illness.     

Melancholic/endogenous depression and response to somatic treatment and placebo.

OBJECTIVE: The authors' goals were to examine the effects of somatic treatment and placebo in patients with and without endogenous/melancholic depression. METHOD: Before entry into one of four trials of antidepressant drugs versus placebo, 231 patients were assessed as to whether they met Research Diagnostic Criteria for definite endogenous depression and/or DSM-III criteria for major depressive episode with melancholia. These patients were prospectively assessed for subsequent response to antidepressant treatment or placebo. Previous studies of the effect of endogenous/melancholic depression on treatment response were also reviewed. RESULTS: Of the 76 patients with DSM-III melancholia given active medication, 41 (54%) had a complete or partial response, but only 10 (23%) of the 44 patients with melancholia given placebo had a complete or partial response. Of the 76 depressed patients without melancholia given active medication, 46 (61%) had a complete or partial response, and 15 (43%) of the 35 depressed patients without melancholia given placebo had a complete or partial response. Moderately depressed patients with DSM-III melancholia had a significantly better response to active medication than did severely depressed patients with melancholia and showed the greatest difference between response to active medication and response to placebo. The results of the review of previous studies of the effect of endogenous/melancholic depression on treatment response were mixed. CONCLUSIONS: Depressed patients with melancholia were not particularly different from depressed patients without melancholia in their responses to antidepressant medication but did differ from patients without melancholia in their responses to active medication versus placebo, particularly if their depression was moderate and not severe. This suggests that patients with DSM-III melancholia may be unresponsive to nonsomatic treatments.     

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.     

Comparison of masked and endogenous depression using psychometric scales, endocrinological markers and pharmacological responses. Masked depression versus endogenous depression

Masked depression refers to a concept of a phenomenological state, either endogenous or psychogenic where somatic symptoms replace sadness: Thirty patients were evaluated by RDC (22 endogenous and 8 masked depressions) wherein in the latter dysphoria was replaced by a nonreactive persistent somatic complaint. They were rated on Beck and Hamilton Depression Scales, on Hamilton and Trait-State Anxiety Scales and the NOSIE. All patients presented with insomnia, anorexia, loss of weight, diminished libido and anhedonia. Initial ratings were similar for both diagnostic groups except for a significantly higher agitation factor and lower retardation in masked depression. Although 59.9 percent of the subjects are positive on the dexamethasone test, only 1 masked depression did not suppress secretion of cortisol. After a randomized 30-day drug trial where patients were assigned to Clomipramine or Desipramine, patients in both groups show significant improvement on rating scales but diagnostic group drug treatment interaction exists on anxiety and agitation criteria.