Effect of prolactin on plasma DHEA (s) levels.

Plasma DHEA and DHEA-S levels were significantly higher (P less than 0.001) in women with elevated prolactin levels, due either to chronic treatment with psychotropic drugs or to a prolactinoma, than in untreated controls. This increase was also observed in 3 male patients with prolactinoma. It is suggested that this increase is the consequence of a direct effect of prolactin on the adrenal cortex and that prolactin might be responsible for the ACTH independent andrenocortical androgen secretion.

Prediction of subtype and severity of depression by means of dexamethasone suppression test, L-tryptophan: competing amino acid ratio, and MHPG flow.

The score on the Hamilton Depression Rating Scale (HDRS), the L-tryptophan:competing amino acid (valine + leucine) (L-TRP:CAA) ratio, and the 3-methoxy-4-hydroxyphenylglycol (MHPG) flow in 24-hr urine were recorded in 83 depressed patients undergoing a Dexamethasone Suppression Test (DST). The subjects were diagnostically subdivided according to DSM-III into minor depression (296.82, 300.40, 309.00), major depression without melancholia (296.X2), with melancholia (296.X3), or with psychotic features (296.X4). Minor depression, major depression with melancholia, and major depression with psychotic features can be regarded as distinct biological entities. Major depression without melancholia is a heterogeneous group with reference to the biological markers. By combining these biological data with age in a discriminant function analysis, 81.9% of all depressed patients can be correctly classified into minor or major depression groups. The combined biological markers can also be used to predict the severity of the depression; 42.5% of the variance in the HDRS score is accounted for by multiple regression on the biological figures. Multivariate statistical techniques considerably improve prediction for both subtype and severity of 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.

Effects of dexamethasone on the availability of L-tryptophan and on the insulin and FFA concentrations in unipolar depressed patients.

Several authors have shown that the availability of L-tryptophan (L-TRP) in the serum is lower in patients with major depression than in controls. It has recently been reported that the administration of a dose of dexamethasone sufficient to cause cortisol suppression also caused significant decrements in the availability of L-TRP. In order to elucidate the putative pathophysiological mechanisms underlying this decreased L-TRP disposition, the authors examined 37 depressed women categorized according to the DSM-III. L-TRP, the sum of five competing amino acids (CAA), the L-TRP/CAA ratio, and insulin and free fatty acid (FFA) levels were determined both before and after oral administration of 1 mg dexamethasone. The availability of L-TRP was significantly lower in depressed women with melancholia compared with simple major and minor depressives. The baseline disposal of L-TRP was related neither to insulin nor to FFA concentrations Dexamethasone administration significantly reduced the L-TRP and L-TRP/CAA values and increased FFA and insulin levels. Postdexamethasone L-TRP and FFA levels were significantly and positively correlated.

Decreased serum dipeptidyl peptidase IV activity in major depression.

It has been recently shown that severe depression is characterized by immune dysfunctions such as blunted mitogen-induced blast transformation, which is linked to interleukin-2 (IL-2) mechanisms, and to autoimmune responses. In order to explore one of the putative pathophysiological mechanisms underlying both factors, we have measured the predexamethasone and postdexamethasone serum dipeptidyl-peptidase IV (DPP IV) activity in depressed inpatients and normal controls. This enzyme is an important mediator of IL-2-related blast proliferation, and it may play a role in autoimmunity. We found significantly lower DPP IV levels in major depressives as compared with healthy controls, and melancholics exhibited significantly lower enzyme activity than minor depressives. There was a significant negative correlation between serum DPP IV activity and the severity of illness. However, we were unable to detect any significant relationships between DPP IV on the one hand, and mitogen-induced blast transformation, soluble IL-2 receptor accumulation in PHA culture supernatant, total number of leukocytes and lymphocytes, T lymphocytes, CD4+ and CD25+ cells, on the other. Men exhibited significantly higher serum DPP IV levels than women.

Interleukin-1 beta: a putative mediator of HPA axis hyperactivity in major depression?

OBJECTIVE: There is extensive evidence that major depression, and particularly melancholia, is characterized by hypothalamic-pituitary-adrenal (HPA) axis hyperactivity as well as systemic immune activation, which may be accompanied by increased interleukin-1 beta production. Interleukin-1 beta is known to enhance HPA axis activity during an immune response. This study investigated whether interleukin-1 beta production is related to HPA axis activity in depressed subjects. METHOD: The subjects were 28 inpatients with major or minor depression and 10 normal comparison subjects. The authors measured 1) the subjects' cortisol levels after an overnight 1-mg dexamethasone suppression test (DST) and 2) mitogen-stimulated supernatant interleukin-1 beta production by peripheral blood mononuclear cells. RESULTS: Statistically significant positive correlations between interleukin-1 beta production and post-DST cortisol values were found in the study group as a whole and in the depressed and normal subgroups separately. CONCLUSIONS: It is suggested that constituents of the immune response (such as interleukin-1 beta) in major depression may contribute to HPA axis hyperfunction in that illness.

Haptoglobin phenotypes and gene frequencies in unipolar major depression.

OBJECTIVE: Studies from the authors' laboratory have shown that major depression is accompanied by significantly increased plasma concentrations of positive acute-phase proteins such as haptoglobin. Haptoglobin is characterized by a molecular variation with three known phenotypes (Hp 1-1, Hp 2-1, and Hp 2-2). This study investigated haptoglobin plasma levels and phenotype and gene frequencies in unipolar major depression. METHOD: Haptoglobin plasma levels of 22 healthy volunteers, 32 patients with minor depression, and 72 patients with major depression were determined by means of a laser nephelometric method. Haptoglobin phenotyping of these 126 subjects and 200 healthy blood donors was also carried out. RESULTS: The patients with major depression exhibited significantly higher haptoglobin plasma levels than the healthy comparison subjects and the patients with minor depression. Subjects with the haptoglobin phenotype Hp 2-2 had significantly lower haptoglobin levels than the phenotype Hp 1-1 and Hp 2-1 carriers. The frequencies of haptoglobin phenotypes Hp 2-1 (61.1%) and Hp 2-2 (20.8%) in the patients with major depression were significantly higher and lower, respectively, than the frequencies in the normal population (i.e., the blood donors: 48.0% and 37.0%, respectively). The frequency of the Hp-1 gene was significantly greater in the patients with major depression (48.6%) than in the normal population (39.0%). CONCLUSIONS: Major depression is characterized by a hyperhaptoglobinemia that is largely independent of haptoglobin phenotypes. This altered distribution of haptoglobin phenotypes and genes suggests that genetic variation on chromosome 16 may be associated with that illness.

Symptom profiles of biological markers in depression: a multivariate study.

The dexamethasone suppression test (DST), the thyrotropin releasing hormone (TRH) test, and the ratio of plasma L-tryptophan to competing amino acids (L-TRP/CAA) were studied in relation to the 21 items of the Hamilton Depression Rating Scale (HDRS) in 123 depressed patients categorized according to DSM-III. The relationships between the biological data and the items or item clusters of the HDRS were assessed by multivariate analyses. The psychopathological correlates of increased post-dexamethasone cortisol and decreased thyroid stimulating hormone (TSH) responsivity to TRH were middle and delayed insomnia and weight loss. The symptom correlates of decreased availability of L-TRP to the brain were psychic anxiety, depersonalization, obsessions and paranoid symptoms. Core depressive symptoms, i.e. depression, loss of interest, feelings of guilt and suicidal thoughts, were not related to the biological markers.

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.

An evaluation of basal hypothalamic-pituitary-thyroid axis function in depression: results of a large-scaled and controlled study.

In order to evaluate the function of the hypothalamic-pituitary-thyroid (HPT)-axis in unipolar depression, the authors measured basal 0800h plasma levels of free thyroxine (FT4), free triiodothyronine (FT3), and thyroid stimulating hormone (TSH) by means of the new, ultrasensitive assays (TSH-IRMA) in 69 healthy controls, 62 minor, 101 simple major, and 57 melancholic depressed subjects. Basal HPT-axis hormone levels of almost all (96.8%) unipolar depressed patients fell within the normal, euthyroid range. None of the major depressed subjects showed subclinical hypothyroidism. It was found that 8.8% of the melancholic subjects exhibited some degree of subclinical hyperthyroidism. Basal TSH-IRMA values were significantly lower in melancholic patients than in healthy controls, minor and simple major depressed patients, and in major vs. minor depressed subjects. FT4 circulating levels were significantly higher in melancholic patients than in all other subjects. Basal TSH-IRMA and FT4 levels were significantly correlated with severity of illness. In depression, there was a significant and negative correlation between basal TSH-IRMA values and FT4 concentrations. No significant gender- or age-related differences in TSH-IRMA or thyroid hormones were detected in depression. It is argued that--in depression research--the assays of basal TSH-IRMA should replace thyrotropin releasing hormone tests.

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.

Therapeutic effect and safety of increasing doses of risperidone (R 64766) in psychotic patients.

Risperidone (R 64766) was administered during 4 weeks in increasing doses to 17 psychotic patients, to evaluate the hematological and cardiovascular safety, the therapeutic effect, side effects, effects upon endocrinological parameters and the pharmacokinetic profile. Following a placebo wash-out period of 1 week, the initial dose was 10 mg daily, increasing with 5 mg per week until the maximal dose of 25 mg daily was reached during the 4th week of treatment. Doses up to 20 mg daily resulted in a significant improvement of the total BPRS score and of the different BPRS factor scores; with higher doses, no further clinical benefit was achieved except for the hostility and anxiety-depression factor, while sedation became more prominent. No increase of extrapyramidal symptoms was noticed. Except for the sedation observed with higher doses, risperidone was well tolerated. No clinically relevant effects on cardiovascular and ECG parameters were noticed, and except for a slight increase of aspartate aminotransferase and alanine aminotransferase in one patient, no laboratory abnormalities were observed. Prolactin showed an expected increase, while the other endocrinological parameters revealed no changes. Risperidone had a linear pharmacokinetic profile.

Serum postdexamethasone prolactin measures in depressive patients and control subjects.

Recently, some researchers noted significant positive relationships between postdexamethasone serum cortisol and prolactin levels, whilst endogenous depressives exhibited a significantly lower suppression of prolactin by dexamethasone than non-endogenous patients or normal controls. To ascertain the extent of prolactin responses to dexamethasone in severely depressed patients, we measured 8 a.m. pre- and postdexamethasone prolactin levels in 104 depressed and 42 normal subjects. Serum cortisol levels were also determined in depressed patients before and after dexamethasone administration. We found a significant suppressive effect of dexamethasone on prolactin levels. There were no significant differences either in pre- or postdexamethasone prolactin, or in actual dexamethasone-induced decrements in prolactin between normal controls, melancholics, simple major or minor depressed subjects. We have not found any significant relationships between cortisol and prolactin, either under baseline or postdexamethasone conditions.

HPA-axis hormones and prolactin responses to dextro-fenfluramine in depressed patients and healthy controls.

1. Like other authors we have established disturbances in central serotonergic neurotransmission in severely depressed patients by implementing hypothalamic pituitary adrenal (HPA)-axis hormones and prolactin responses to serotonin agonists or precursors. 2. Challenge probes with D,L fenfluramine have yielded controversial results. This substance, however, is not as serotonin-selective as previously believed. 3. Dextro(D)-fenfluramine, the dextrorotatory isomer of fenfluramine, constitutes a specific and potent serotonergic agonist. 4. In the present study the authors determined the following in healthy volunteers, and in depressed inpatients: the adrenocorticotropic hormone (ACTH), beta endorphin, prolactin and cortisol responses to D-fenfluramine administration (45 mg orally), total L-tryptophan and the 8 a.m. postdexamethasone cortisol values. 5. We found no significant differences in any of the post-D-fenfluramine hormone levels across healthy controls, minor, simple major and melancholic depressives. There were no significant correlations between L-tryptophan or postdexamethasone cortisol on the one hand, and any of the post-D-fenfluramine hormone values on the other.

Disturbances in acute phase plasma proteins during melancholia: additional evidence for the presence of an inflammatory process during that illness.

1. Leukocyte enumeration through flow cytometry has revealed that severe depression may be accompanied by a systemic immune activation, indicative of an inflammatory response. The latter condition allegedly involves an important modification of acute phase plasma protein (APP) equilibrium. 2. In order to elucidate whether the state of severe depression is represented by alterations in APPs, the authors measured: alpha 1 antitrypsin (alpha 1 AT), alpha 2 macroglobulin (alpha 2 M), haptoglobin (Hp), alpha 1 acid glycoprotein (alpha 1 S), transferrin (Tf), complement component 4 (C4) and C-reactive protein (CRP). Interleukin-1-beta (II-1 beta) and interleukin-6 (II-6) circulating levels were determined. 3. Hyperhaptoglobinemia and hypotransferrinemia are hallmarks for major depression and depression per se, respectively. The disorders in Hp and Tf circulating levels are highly sensitive to (83%) and specific for (100%) melancholia as opposed to the healthy state. 4. Disorders in both APPs are significantly related to the absolute number of blood monocytes. 5. The authors observed a trend towards lower alpha 2M and higher alpha 1S values in severely depressed subjects. Severity of depression was significantly related to Hp and alpha 1S (both positively) and to alpha 2M and Tf (both negatively) values. 6. No significant intercategory differences in C4 could be established, whilst only a few subjects exhibited measurable CRP, II-1 beta and II-6 circulating levels. 7. Our findings may support the hypothesis that depression is accompanied by an inflammatory response.

Influences on cortisol and noradrenergic turnover of healthy controls and depressed patients during L-tryptophan loading.

To investigate the interrelationships between the noradrenergic and serotonergic systems and the hypothalamic-pituitary-adrenal (HPA) axis, we measured the excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG) and free cortisol (UFC) in 24-h urine both before and after loading with 2 g L-tryptophan (L-TRP) orally in 24 healthy controls and 33 depressed patients categorized according to DSM-III. Loading with L-TRP reduced MHPG excretion significantly by 56% in major depressives, whereas in healthy controls and in minor depressives no significant effects were observed. Although basal MHPG did not differ among these study groups, loading with L-TRP resulted in MHPG excretion in major depressives being significantly lower than in healthy controls and minor depressives. Loading with L-TRP increased UFC significantly by 49% only in major depressives with associated features. After L-TRP those patients exhibited significantly increased UFC as compared with all other depressives and controls, whereas basal UFC values did not differ among the study groups. In baseline conditions there were no significant correlations between MHPG and UFC excretion.

The influences of dexamethasone levels on the predictive value of the DST for unipolar major depression and the relationships between post-dexamethasone cortisol and ACTH levels.

To investigate the relationships between dexamethasone (DEX) and post-DEX cortisol and adrenocorticotropic hormone (ACTH) levels, the authors measured DEX at 8.00 a.m. and post-DEX cortisol and ACTH levels at 8.00 a.m. and 4.00 p.m. in 72 depressed patients categorized according to DSM-III. Cortisol non-suppressors exhibited significantly (P = 0.0006) decreased levels of DEX compared to suppressors. DEX levels at 8.00 a.m. explained 21.1% of the variance in the post-DEX cortisol values at 8.00 a.m. and 34.5% of those at 4.00 p.m. DEX levels were not significantly different among minor depressives (300.40, 309.00), major depressives without melancholia (296.X2) or with melancholia and/or psychotic features (296.X3, 296.X4). In the latter the post-DEX cortisol was significantly increased compared to all other depressives and these differences remained significant even after adjusting for the variations in DEX (by means of regression analysis). Also the diagnostic performance of the post-DEX cortisol values for major depression with associated features versus minor depression was not substantially affected when the DEX levels were accounted for. ACTH levels after DEX were shown to correlate significantly (P less than 0.05) and negatively with DEX. Although post-DEX ACTH levels did not differ among the DSM-III diagnostic categories, cortisol non-suppressors averaged significantly (P = 0.0004) higher ACTH levels than suppressors.

The importance of creatinine flow, age and 24 h urinary output in the interpretation of the MHPG flow.

The 3-methoxy-4-hydroxyphenylglycol (MHPG) flow, the creatinine flow in 24 h urine and the plasma creatinine level were determined in 42 psychiatric control patients. The creatinine clearance was calculated. The relationship between MHPG flow in 24 h urine and creatinine clearance, creatinine flow, 24 h urinary output, age, sex and weight of the patient were studied by means of single and multiple regression methods. The MHPG flow was significantly correlated with creatinine clearance (r = 0.597), creatinine flow (r = 0.646) and sex of the patient (rpb = 0.434). The variance of the MHPG flow can be explained by the regression with creatinine flow, age and urinary output for a maximum 51.5%. These variables have to be taken into account for the interpretation of data concerning the MHPG flow in subsequent experimental designs. The results of the measurements of the MHPG flow can best be expressed as the residual values obtained after partialling out the predictable component calculated by multiple regression with creatinine flow, age and 24 h urine output.

Immune cell parameters in severely depressed patients: negative findings.

Cross-sectional population studies reported decreased mitogen-induced lymphocyte responsiveness in severely depressed patients. This immunologic impairment, indicative of T- and/or B-cell dysfunction, was related to disturbances in the dexamethasone suppression test (DST) and to age effects. Glucocorticoid overdrive, a hallmark for severe depression, exerts immunosuppressive effects through the impact on neutrophils, lymphocytes, and monocytes and natural killer cells (NKC). This paper has analyzed the relation of peripheral blood immune parameters to severe depression, DST results and age. The population consisted of 37 inpatients categorized according to DSM-III as minor depression (300.40, 309.00), simple major depression (296.X2) or major depression with melancholia and/or with psychotic features (296.X3, 296.X4). The number of leukocytes, neutrophils, lymphocytes and monocytes was counted. T-cell (total T-cell, T-helper, T-suppressor, HLA-DR), B-cell (LN1 and immunoglobulin (Ig) receptors), monocytes (M1 and M3 membrane antigens) and NKC activity were identified by phenotype using monoclonal antibodies. No differences were detected between the depressive subgroups for any of the parameters examined. There were no relationships between these immune variables and the severity of illness, DST results or age.

Repeated dexamethasone suppression test in depressed patients.

In 17 depressed patients with initially abnormal results on the dexamethasone suppression test (DST), serial plasma samples for the determination of cortisol concentrations were taken every 10 days, following overnight dexamethasone administration at 11 p.m. Severity ratings were repeated on the days of blood sampling. There was a gradual normalization of the DST and progressive clinical improvement during selective antidepressant therapy. The DST was closely related (r = 0.573, P less than 0.005) to the patients' clinical mood level during the depressive episode. At the point where normalization of the DST occurred, the patients were still moderately severely ill. DST conversion occurred early in the treatment, i.e. after 23.9 (+/- 15.1) days, and preceded symptomatic improvement by 24.5 (+/- 18.1) days. Normalization of the DST was a predictor (r = 0.691, P less than 0.005) of the time of clinical improvement, but not of clinical recovery. The test was a biological discriminator between severe and less severe depressions. The time of symptomatic improvement (r = 0.505, P less than 0.05), but not of biological remission, depended on age; severe depressions lasted longer in the elderly patients.