Peter D'Hondt

Increased neopterin and interferon-gamma secretion and lower availability of L-tryptophan in major depression: further evidence for an immune response.

There is now some evidence that major depression may be accompanied by an immune response. The latter condition is suggested by elevated secretion of neopterin and interferon-gamma (IFN gamma) and by lower L-tryptophan (L-TRP) plasma levels. This study investigated the plasma levels of neopterin, L-TRP, and the L-TRP/competing amino acids (CAA) ratio in 30 normal control subjects and 47 depressed subjects (16 minor depressed, 13 simple major depressed, and 18 melancholic subjects), and IFN gamma secretion by mitogen-stimulated peripheral blood mononuclear cells in 7 normal control subjects and 13 major depressed subjects. Plasma neopterin levels were significantly higher in depressed subjects than in normal controls; 61% of melancholic patients had increased neopterin levels (> or = 7 nmol/l) with a specificity of 90%. Patients with major depression had significantly lower L-TRP and L-TRP/CAA values compared with normal control subjects. The amino acid values were significantly and negatively correlated with plasma neopterin levels. Major depressed subjects exhibited significantly higher IFN gamma secretion than did normal control subjects. The results further support the hypothesis that major depression is accompanied by an immune response and that the lower L-TRP availability in that illness may be an epiphenomenon of immune activation.

Lower serum prolyl endopeptidase enzyme activity in major depression: Further evidence that peptidases play a role in the pathophysiology of depression☆

Prolyl endopeptidase (PEP) is a serine proteinase, which may cleave peptides that are involved in the pathophysiology of major depression, such as arginine vasopressin, beta-endorphin, luteinizing hormone-releasing hormone, thyrotropin-releasing hormone, and maybe corticotropin-releasing hormone. PEP may be involved in activation of cell-mediated immunity, autoimmune and inflammatory responses, which repeatedly occur in severe depression. The present study investigates serum PEP activity in 33 normal controls, 16 minor, 14 simple major, and 18 melancholic depressed subjects. Pre-dexamethasone and post-dexamethasone (DST) intact adrenocorticotropic hormone (ACTH) and cortisol values were determined in 33 depressed subjects. Serum PEP activity was significantly lower in depressed subjects compared to normal controls and in melancholic depressed subjects compared to minor and simple major depressed subjects. Up to 61.1% of the melancholic patients had serum PEP activities below the mean PEP values of normal controls minus two SDs. In the depressed study group, significant negative correlations between serum PEP activity and severity of illness, post-DST cortisol, and ACTH values were observed. There was a trend toward higher serum PEP activity with increasing age. It is hypothesized that lower serum PEP activity, and lower serum activity of other peptidases, may play a role in the neuroendocrine and immune pathophysiology of major depression.

Seasonal variation in peripheral blood leukocyte subsets and in serum interleukin-6, and soluble interleukin-2 and-6 receptor concentrations in normal volunteers

This study has been carried out in order to investigate seasonal variation in peripheral blood immune cells, such as leukocytes, monocytes, neutrophils, lymphocytes, CD3+ T, CD4+ T, CD8+ t, CD25+ T, CD20+ B, and serum interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R) and sIL-2R levels in normal volunteers. Toward this end, 26 normal volunteers (13 men, 13 women) had monthly blood samplings during one calendar year for peripheral blood count, flow cytometric enumeration of peripheral leukocyte subsets and immunoassays of IL-6, sIL-6R and sIL-2R. It was found that most of the immune variables change rhythmically during the seasons as a group phenomenon. Statistically significant yearly variations with seasonal rhythms, i.e. annual rhythms or harmonics, such as semiannual, tetramensual and trimensual rhythms, were found in the number of leukocytes, neutrophils, monocytes, lymphocytes, CD4+ T, CD8+ T, CD25+ T, CD20+ B cells, in the CD4+/CD8+ ratio, and serum IL-6 and sIL-6R levels. It is concluded that the immune system is characterized by a multifrequency time-structure with significant high-amplitude yearly variations in the number of some peripheral blood leukocyte subsets.

Total serum protein and serum protein fractions in depression: relationships to depressive symptoms and glucocorticoid activity

Recently, it has been reported that major depression is accompanied by changes in plasma protein concentrations indicative of an acute-phase protein (APP) response. The purpose of the present study was to examine total serum protein (TSP) and the electrophoretically separated major fractions of serum proteins (SP), i.e., albumin (Alb), alpha 1, alpha 2, beta and gamma globulin, in depression. Highly significant differences were found in TSP and the separated SP fractions between major depressed patients and normal controls and between melancholic and minor depressed patients. Major depressed subjects showed significantly lower TSP and Alb concentrations and a higher percentage of the alpha 1 globulin fraction than normal controls and minor depressed subjects. Major depressed subjects had significantly higher and lower percentages, respectively, of alpha 2 and gamma globulin fractions than normal controls. In depressed subjects, there were significant negative correlations between TSP or Alb concentrations and severity of illness. Psychomotor retardation and anorexia were psychopathological correlates of lower TSP and Alb concentrations while middle insomnia and psychomotor retardation were related to changes in the alpha 2 globulin fractions. Basal plasma cortisol values were significantly and positively related to serum alpha 2 globulin. The results support the view that major depression is accompanied by an APP response.

Effects of serotonin precursors on the negative feedback effects of glucocorticoids on hypothalamic-pituitary-adrenal axis function in depression

In order to investigate the relationships between brain serotonergic turnover and hypothalamic-pituitary-adrenal (HPA) axis function in unipolar depression, the authors measured intact adrenocorticotropic hormone (ACTH) and cortisol levels in baseline conditions and after combined dexamethasone (1 mg PO) and L-5-hydroxytryptophan (L-5-HTP, 200 mg PO) administration in 13 minor, 17 simple major, and 17 melancholic subjects. L-5-HTP significantly enhanced post-DST ACTH and cortisol secretion in major--but not in minor--depressed subjects. Major depressed subjects with or without melancholia exhibited significantly higher post-DST ACTH and cortisol responses to L-5-HTP than minor depressed subjects. L-5-HTP administration converted some major depressed ACTH or cortisol suppressors into nonsuppressors. L-5-HTP stimulated ACTH or cortisol secretion to the same extent in major depressed HPA-axis suppressors and nonsuppressors. It is concluded that L-5-HTP loading may augment ACTH and, consequently, cortisol escape from suppression by dexamethasone in major but not in minor depressed subjects. The findings show that serotonergic mechanisms modulate the negative feedback of glucocorticoids on central HPA-axis regulation. It is hypothesized that the higher L-5-HTP-induced post-DST HPA-axis hormone responses in major depression reflect upregulated 5-HT2 receptor-driven breakthrough secretion of pituitary ACTH from suppression by dexamethasone.

Biochemical, metabolic and immune correlates of seasonal variation in violent suicide: a chronoepidemiologic study

The purpose of this chronoepidemiologic study was to investigate the time-relationships between the yearly variations in occurrence of violent suicide in Belgium and the yearly variations in various biochemical, metabolic and immune variables in the Belgian population. The weekly mean number of deaths due to violent suicide for all of Belgium for the period 1979-1987 was computed. Twenty-six normal volunteers had monthly blood samplings during one calendar year for assays of plasma L-tryptophan (L-TRP), competing amino acids (CAA), and melatonin levels, maximal [3H]paroxetine binding to platelets, serum total cholesterol, calcium, magnesium, and soluble interleukin-2 receptor concentrations, and number of CD4+ T, CD8+ T and CD20+ B lymphocytes. The annual rhythm in violent suicide rate is highly significantly synchronized with the annual rhythms in L-TRP, [3H]paroxetine binding, cholesterol, calcium, magnesium, CD20+ B cells, and CD4+/CD8+ ratio; the mean peak (violent suicide, [3H]paroxetine binding) or nadir (all other variables) occurs around 3 May. There were significant inverse time-relationships between the time series of violent suicide rate and L-TRP, L-TRP/CAA ratio, total cholesterol, calcium and magnesium, CD4+/CD8+ T cell ratio and number of CD20+ B cells. Maximal [3H]paroxetine binding to platelets was significantly and positively related to the time series of violent suicide. An important part (56.4%) of the variance in mean weekly number of violent suicide rate was explained by the time series of L-TRP, cholesterol and melatonin.

Clinical subtypes of unipolar depression: Part I. A validation of the vital and nonvital clusters

Cluster analyses were carried out on a sample of 100 depressed females. The study was based on the 14 items relevant to depressive phenomenology of the Structured Clinical Interview for DSM-III-R (SCID). Our findings support the existence of two classes, i.e., a vital (melancholic) vs. a nonvital cluster. The vital cluster is characterized by the following symptoms: a distinct quality of depressed mood, nonreactivity, early morning awakening, anorexia-weight loss, and cognitive and psychomotor disturbances. Patients belonging to the vital cluster exhibit disorders in the hypothalamic-pituitary-adrenal and thyroid axes and a markedly decreased availability of L-tryptophan to the brain. The vital depressives score significantly higher on the Hamilton Rating Scale for Depression as compared to those suffering from nonvital depression. The cluster-analytically derived class of vital depression and the DSM-III subtype of melancholia tend to be quite similar. Our findings support the isolation and the descriptive validity of a vital (melancholic) depressive syndrome.

Components of biological, including seasonal, variation in hematological measurements and plasma fibrinogen concentrations in normal humans

This study has been carried out in order to examine the components of biologicalaand, in particular, seasonal variation in hematologic measurements in normal humans. Toward this end, 26 normal volunteers had monthly blood samplings during one calendar year for determination of number of red blood cells (RBC) and platelets, hemoglobin (Hb), hematocrit (Ht), mean corpuscular volume (MCV), MC Hb (MCH), MC Hb concentration (MCHC), RBC distribution width (RDW), mean platelet volume (MPV), platelet distribution width (PDW), plateletcrit (PCT), and plasma fibrinogen concentrations. The data were analyzed by means of spectral analyses of a group of time series or a single time series, and by means of repeated measures analyses of variance. Most of the hematologic variables show seasonal rhythms, such as annual rhythms or harmonics, which are expressed as a group phenomenon. An important part of the variance (>15%) in Ht, MCV, MCH, MCHC, RDW, number of platelets, MPV and plasma fibrinogen was explained by a yearly variation. The peak-trough differences (expressed as a percentage of the mean) in the yearly variations in number of RBC, Ht, MCV, MCH, MCHC and RDW were very low (all<8.5%). Number of platelets (14.4%) and plasma fibrinogen values (28%) showed a high-amplitude yearly variation. All hematological variables, except MCHC, show a high interindividual variability which exceeds by far the intraindividual variability.

Components of biological variation in serum soluble transferrin receptor : relationships to serum iron, transferrin and ferritin concentrations, and immune and haematological variables

We investigated the components of biological variation in serum soluble transferrin receptor (TfR) in relation to serum iron, transferrin (Tf), ferritin, soluble interleukin-2 receptor (sIL-2R), sIL-6R, and number of erythrocytes, haemoglobin (Hb), haematocrit (Ht), mean corpuscular volume (MCV), mean cell haemoglobin (MCH), and erythrocyte distribution width (RDW). We took monthly blood samples during 1 calendar year from 26 healthy subjects for assay of the above variables. The estimated CVs for TfR were interindividual CVg = 20.8%, and intra-individual CVi = 13.6%; for Tf, CVg = 14.4% and CVi = 6.7%; for iron, CVg = 16.8% and CVi = 29.2%; and for ferritin, CVg = 71.1% and CVi = 26.5%. There was a statistically significant seasonal pattern in the four variables with significant annual, biannual and/or trimonthly rhythms, which were expressed as a group phenomenon. The peak-trough differences in the yearly variations, expressed as a percentage of the mean, were: for TfR, 11.7%; for iron, 39.2%; for Tf, 11.7%; and for ferritin, 29.3%. Up to 34.2% of the within-subject variability in TfR (which reflects changes over time) could be explained by the regression on iron, ferritin, Tf, sIL-2R, sIL-6R and MCH values. Up to 67.2% of the between-subject variability in TfR (which reflects differences in the homeostatic setpoint during the study year) could be explained by the regression on gender, iron, Tf, and ferritin values.

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.