Eric Vandoolaeghe

Increased plasma concentrations of interleukin-6, soluble interleukin-6, soluble interleukin-2 and transferrin receptor in major depression

Recently, it was found that major depression may be accompanied by significant changes in cell-mediated and humoral immunity. The purpose of this study was to investigate the plasma concentrations of interleukin (IL)-6, soluble IL-6 receptor (sIL-6R), sIL-2R and transferrin receptor (TfR) in patients with major depression in an acute phase of illness, in remission and during antidepressive treatment. Plasma concentrations of IL-6, sIL-6R, sIL-2R and TfR were significantly higher in major depressed subjects than in healthy controls. In major depressed subjects, but not in normal controls, there were significant positive correlations between the plasma concentrations of IL-6 and sIL-6R, IL-6 and sIL-2R, IL-6 and TfR, and between sIL-2R and TfR. Subchronic treatment with antidepressive drugs, such as fluoxetine or tricyclic antidepressants, did not significantly affect plasma IL-6, sIL-6R, sIL-2R or TfR. The latter did not significantly differ between major depressed patients in an acute phase of illness or in complete clinical remission. It is suggested that: (1) a coordinated and upregulated production of IL-6, sIL-6R, sIL-2R and TfR may constitute a trait marker of major depression; and that (2) an upregulated production of IL-6 may represent a contributing factor to the various immune disorders encountered in major depression and maybe to the pathophysiology or pathogenesis of that illness.

Lower serum zinc in major depression is a sensitive marker of treatment resistance and of the immune/inflammatory response in that illness

The aims of the present study were to examine i) serum zinc (Zn) and copper (Cu) in treatment resistant depression (TRD); ii) the effects of subchronic antidepressant therapy on these trace elements; and iii) the relationships between serum Zn and Cu and immune/inflammatory markers. Serum Zn was significantly lower in TRD than in normal controls. There was a significant inverse correlation between baseline serum Zn and staging of depression based on severity of prior treatment resistance. There were no significant effects of antidepressive treatment on serum Zn, whereas serum Cu was significantly reduced. There were highly significant correlations between serum Zn and the CD4+/CD8+ T-cell ratio (negative), and total serum protein, serum albumin, and transferrin (all positive). The results suggest that lower serum Zn is a marker of TRD and of the immune/inflammatory response in depression. It is suggested that treatment resistance may bear a relationship with the immune/inflammatory alterations in major depression.

Lower serum high‐density lipoprotein cholesterol (HDL‐C) in major depression and in depressed men with serious suicidal attempts: relationship with immune‐inflammatory markers

Recently, there have been some reports that changes in serum lipid composition may be related to suicide, major depression and immune‐inflammatory responses. Findings from our laboratory suggest that major depression is accompanied by reduced formation of cholesteryl esters and perhaps by impairment of reverse cholesterol transport. The latter is reportedly accompanied by lower serum high‐density lipoprotein cholesterol (HDL‐C). The aim of this study was to examine whether (i) major depression is accompanied by lower serum HDL‐C or by abnormal levels of serum total cholesterol, triglycerides, low‐density lipoprotein‐C (LDL‐C) or vitamin E, (ii) suicidal attempts are related to lower serum HDL‐C and (iii) there are significant associations between serum HDL‐C and immune/inflammatory markers. A total of 36 subjects with major depression, of whom 28 patients showed treatment resistance, as well as 28 normal control subjects, had blood sampled for the assay of the above lipids, serum zinc (Zn), albumin (Alb) and flow cytometric determination of the T‐helper/T‐suppressor (CD4+/ CD8+) T‐cell ratio. In total, 28 depressed subjects had repeated measures of these variables both before and after treatment with antidepressants. Serum HDL‐C and total cholesterol, as well as the HDL‐C/cholesterol ratio, were significantly lower in subjects with major depression than in normal controls. Serum HDL‐C levels were significantly lower in depressed men who had at some time made serious suicidal attempts than in those without such suicidal behaviour. Treatment with antidepressants for 5 weeks did not significantly alter either serum HDL‐C or other lipid variables. Serum HDL‐C levels were significantly and negatively correlated with the (CD4+/CD8+) T‐cell ratio, and positively correlated with serum Alb and Zn. These results suggest that (i) lower serum HDL‐C levels are a marker for major depression and suicidal behaviour in depressed men, (ii) lower serum HDL‐C levels are probably induced by the immune/inflammatory response in depression and (iii) there is impairment of reverse cholesterol transport from the body tissues to the liver.

Serum levels of excitatory amino acids, serine, glycine, histidine, threonine, taurine alanine and arginine in treatment-resistant depression : modulation by treatment with antidepressants and prediction of clinical responsivity

Previous research has revealed that major depression is accompanied by disorders in excitatory amino acids, e.g. glutamate and aspartate, and alterations in serum levels of other amino acids, e.g. serine, glycine and taurine. The aim of the present study was to examine serum levels of aspartate, asparagine, glutamate, glutamine, serine, glycine, threonine, histidine, alanine, taurine and arginine in major depression patients with treatment‐resistant depression (TRD). No significant differences in the serum concentrations of any of the above amino acids could be found between patients with and without TRD and normal controls. Non‐responders to treatment with antidepressants during a period of 5 weeks were characterized by significantly lower serum levels of aspartate, asparagine, serine, threonine and taurine. A 5‐week period of treatment with antidepressants significantly reduced the serum levels of aspartate, glutamate and taurine, and significantly increased the serum concentrations of glutamine. The results suggest that alterations in serum levels of aspartate, asparagine, serine, threonine and taurine may predict the subsequent response to treatment with antidepressants, and that the latter may modulate serum levels of excitatory amino acids and taurine.

Efficacy of treatment with trazodone in combination with pindolol or fluoxetine in major depression

Fluoxetine, a selective serotonin (5-HT) reuptake inhibitor (SSRI), and trazodone, a heterocyclic antidepressant, are effective in the treatment of major depression and treatment resistant depression (TRD). Chronic treatment with both drugs causes increases in extracellular 5-HT through 5-HT reuptake inhibition and desensitization of inhibitory 5-HT1A autoreceptors. It has been shown that pindolol, a serotonin (5-HT)1A-receptor antagonist, may shorten the latency of onset of SSRIs in depression. The aim of the present study was to examine whether pindolol may increase the efficacy of a subtherapeutical dosage of trazodone in the treatment of major depression and TRD, defined according to the Thase and Rush criteria (1995). Thirty-three major depressed inpatients of whom 26 with TRD participated in this study. Ten days after hospitalization, treatment with trazodone 100 mg/day was started. After 1 week trazodone treatment, patients were randomized-using a double blind placebo controlled design-to receive trazodone 100 mg/day+placebo; trazodone 100 mg/day+pindolol 7.5 mg/day: or trazodone 100 mg/day+fluoxetine 20 mg/day and treated during 4 weeks. The 17-item Hamilton Depression Rating Scale (HDRS) was used as outcome measure. It was found that trazodone+pindolol was as effective as trazodone+fluoxetine in the treatment of major depression and TRD and significantly more effective than trazodone+placebo. Using an outcome measure of 50% reduction in the HDRS, we found that 72.5% of the depressed patients treated with trazodone+pindolol and 75% of depressed patients treated with trazodone+fluoxetine showed a clinically significant response compared with 20.0% of trazodone+placebo-treated patients.

Increased serum interleukin-1-receptor-antagonist concentrations in major depression

Recently, it has been shown that major depression may be accompanied by an increased production of interleukin-1 beta (IL-1 beta), an acute phase (AP) response and simultaneous signs of activation and suppression of cell-mediated immunity. The interleukin-1-receptor antagonist (IL-1-rA) is released in vivo during an AP response and serum levels are increased in many immune disorders. The release of IL-1-rA may limit the pro-inflammatory effects of IL-1. This study has been carried out to examine serum IL-1-Ra in 68 depressed subjects (21 minor, 25 simple major and 22 melancholic subjects) vs. 22 normal controls. Depressed subjects showed significantly higher serum IL-1-rA concentrations than healthy controls. 29% of all depressed subjects had serum IL-1-rA levels higher than the mean value +2 standard deviations of normal controls; 44% depressed subjects had IL-1-rA values greater than 0.215 ng/ml with a specificity of 90%. In depressed subjects, there was a significant and positive relationship between serum IL-1-rA and severity of illness. In depression, there were no significant relationships between serum IL-1-rA concentrations and indicants of hypothalamic-pituitary-adrenal (HPA)-axis activity, such as 24-h urinary cortisol and postdexamethasone cortisol values. Women had significantly higher serum IL-1-rA levels than men. The findings support the thesis that depression is accompanied by an immune-inflammatory response.

Lower plasma CC16, a natural anti-inflammatory protein, and increased plasma interleukin-1 receptor antagonist in schizophrenia: effects of antipsychotic drugs

Recently, it was suggested that in vivo activation of the monocytic and T-lymphocytic arms of cell-mediated immunity (CMI) may occur in schizophrenia and that antipsychotic drugs may modify CMI. The aim of the present study was to examine plasma soluble interleukin-2 receptor (sIL-2R), soluble suppressor/cytotoxic antigen (sCD8), interleukin-1 receptor antagonist (IL-1RA), and Clara cell protein (CC16) concentrations in normal controls, nonmedicated schizophrenic patients, and schizophrenic patients treated with risperidone or loxapine. Plasma concentrations of IL-1RA were significantly higher in nonmedicated schizophrenic patients than in normal controls. Plasma CC16 was significantly lower in nonmedicated and loxapine-treated schizophrenic patients than in normal controls, whereas risperidone-treated patients had plasma CC16 levels which were not significantly different from normal controls. Plasma CC16 levels were significantly and positively related to age at onset of schizophrenia. Plasma sIL-2R was significantly higher in schizophrenic patients who were treated with risperidone than in normal controls and nonmedicated schizophrenic patients. The results show that (i) schizophrenia is accompanied by an activation of the monocytic arm of CMI (i.e., increased plasma IL-1RA) and lower plasma levels of a natural anti-inflammatory and immunosuppressive agent, i.e. CC16, and that the latter may constitute a trait market of schizophrenia; and that (ii) chronic treatment with atypical antipsychotic agents, i.e., risperidone, may normalize lower plasma CC16 and increase plasma sIL-2R.

Alterations in iron metabolism and the erythron in major depression: Further evidence for a chronic inflammatory process

There is now some evidence that major depression is accompanied by biochemical and immune changes pointing to the presence of a chronic inflammatory response. The latter condition is reportedly characterized by changes in iron (Fe) metabolism and the erythron, such as decreased serum Fe and transferrin (Tf) and increased serum ferritin, lower number of red blood cells (RBC), lower hematocrit (Htc) and hemoglobin (Hb). The aim of the present study was to examine Fe metabolism and the erythron in 38 major depressed subjects versus 15 normal volunteers, as well as the effects of antidepressant treatments on these variables. Major depressed subjects had significantly lower serum Fe and Tf, a lower number of RBC, lower Htc and Hb, and a significantly increased number of reticulocytes than normal controls. Serum ferritin was significantly higher in major depressed patients with melancholia than in those with simple major depression and normal controls. Mean corpuscular volume (MCV), MC Hb (MCH), MC Hb concentration (MCHC) and RBC distribution width (RDW) were not significantly different between major depressed subjects and normal controls. Treatment with antidepressants during 5 weeks had no significant effect on the alterations in number of RBC and reticulocytes, Htc, Hb, Fe and Tf. There were significant relationships between the above Fe and erythron variables and established immune-inflammatory markers of major depression, e.g., lowered serum albumin and zinc and the increased electrophoretically-separated alpha 1-globulin fraction. The results suggest that the disorders in Fe metabolism and the erythron during major depression may be induced by the immune-inflammatory response in that illness.

Effects of trazodone and fluoxetine in the treatment of major depression: Therapeutic pharmacokinetic and pharmacodynamic interactions through formation of meta-chlorophenylpiperazine

It has been suggested that (1) the clinical efficacy of the heterocyclic antidepressant trazodone in depression may, in part, be attributed to its metabolite meta-chlorophenylpiperazine (mCPP); and (2) the enhancement of the efficacy of trazodone by the addition of fluoxetine, a selective serotonin reuptake inhibitor, may, in part, be ascribed to fluoxetine-induced plasma concentrations of trazodone. After a washout period of 10 days, 27 inpatients with major depression were treated with trazodone 100 mg/day (orally). One week later (T0), fluoxetine 20 mg/day, placebo, or pindolol 7.5 mg/day was added. Plasma concentrations of mCPP and trazodone were determined at T0 and 2 and 4 weeks later. Although placebo pindolol had no significant effect on the plasma concentrations of mCPP and trazodone, there was a significant increase of the concentrations of these compounds associated with the combination of trazodone + fluoxetine. The results suggest that fluoxetine-induced increases in plasma mCPP and trazodone concentrations contribute to the clinical efficacy of the combination of fluoxetine + trazodone. It is suggested that desensitization of 5-HT2C receptor function by mCPP as well as fluoxetine may contribute to the antidepressant effects of this combination.

Serotonin-immune interactions in major depression: lower serum tryptophan as a marker of an immune-inflammatory response

Serum total tryptophan and the five competing amino acids (CAA), i.e., valine, leucine, tyrosine, phenylalanine, and isoleucine were determined in 35 major depressed subjects of whom 27 with treatment resistant depression (TRD), and 15 normal controls. Twenty-five of the depressed subjects had repeated measurements of the amino acids both before and after antidepressive treatment. The following immune-inflammatory variables were assayed in the above subjects: serum zinc (Zn), total serum protein (TSP), albumin (Alb), transferrin (Tf), iron (Fe), high-density lipoprotein cholesterol (HDL-C), number of peripheral blood leukocytes, and the CD4+/CD8+ T cell (T-helper/T-suppressor) ratio. Serum tryptophan and the tryptophan/CAA ratio were significantly lower in major depressed subjects than in normal controls. The tryptophan/CAA ratio was significantly lower in patients with TRD than in patients without TRD and normal controls. There were no significant alterations in any of the amino acids upon successful therapy. There were significant correlations between serum tryptophan and serum Zn, TSP, Alb, Tf, Fe, and HDL-C (all positive), and number of leukocytes and the CD4+/CD8+ T-cell ratio (all negative). The tryptophan/CAA ratio was significantly and negatively related to the number of leukocytes and the CD4+/CD8+ T-cell ratio. The results suggest that (a) TRD is characterized by lower availability of serum tryptophan; (b) the availability of tryptophan may remain decreased despite clinical recovery; and (c) the lower availability of tryptophan is probably a marker of the immuneinflammatory response during major depression.