The novel seizure quality index for the antidepressant outcome prediction in electroconvulsive therapy: association with biomarkers in the cerebrospinal fluid.

For patients with depression treated with electroconvulsive therapy (ECT), the novel seizure quality index (SQI) can predict the risk of non-response (and non-remission)-as early as after the second ECT session-based the extent of several ictal parameters of the seizure. We aim to test several CSF markers on their ability to predict the degree of seizure quality, measured by the SQI to identify possible factors, that could explain some variability of the seizure quality. Baseline CSF levels of metabolites from the kynurenine pathway, markers of neurodegeneration (tau proteins, ß-amyloids and neurogranin), elements of the innate immune system, endocannabinoids, sphingolipids, neurotrophic factors (VEGF) and Klotho were measured before ECT in patients with depression (n = 12) to identify possible correlations with the SQI by Pearson's partial correlation. Negative, linear relationships with the SQI for response were observed for CSF levels of T-tau (rpartial = - 0.69, p = 0.019), phosphatidylcholines (rpartial = - 0.52, p = 0.038) and IL-8 (rpartial = - 0.67, p = 0.047). Regarding the SQI for remission, a negative, linear relationship was noted with CSF levels of the endocannabinoid AEA (rpartial = - 0.70, p = 0.024) and CD163 (rpartial = - 0.68, p = 0.029). In sum, CSF Markers for the innate immune system, for neurodegeneration and from lipids were found to be associated with the SQI for response and remission after adjusting for age. Consistently, higher CSF levels of the markers were always associated with lower seizure quality. Based on these results, further research regarding the mechanism of seizure quality in ECT is suggested.

Anti-dopamine D2 receptor antibodies in chronic tic disorders.

AIM: To investigate the association between circulating anti-dopamine D2 receptor (D2R) autoantibodies and the exacerbation of tics in children with chronic tic disorders (CTDs). METHOD: One hundred and thirty-seven children with CTDs (108 males, 29 females; mean age [SD] 10y 0mo [2y 7mo], range 4-16y) were recruited over 18 months. Patients were assessed at baseline, at tic exacerbation, and at 2 months after exacerbation. Serum anti-D2R antibodies were evaluated using a cell-based assay and blinded immunofluorescence microscopy scoring was performed by two raters. The association between visit type and presence of anti-D2R antibodies was measured with McNemar's test and repeated-measure logistic regression models, adjusting for potential demographic and clinical confounders. RESULTS: At exacerbation, 11 (8%) participants became anti-D2R-positive ('early peri-exacerbation seroconverters'), and nine (6.6%) became anti-D2R-positive at post-exacerbation ('late peri-exacerbation seroconverters'). The anti-D2R antibodies were significantly associated with exacerbations when compared to baseline (McNemar's odds ratio=11, p=0.003) and conditional logistic regression confirmed this association (Z=3.49, p<0.001) after adjustment for demographic and clinical data and use of psychotropic drugs. INTERPRETATION: There is a potential association between immune mechanisms and the severity course of tics in adolescents with CTDs.

A step ahead: Exploring the gut microbiota in inpatients with bipolar disorder during a depressive episode.

OBJECTIVES: There is evidence that the gut microbiota plays a major role in the pathogenesis of diseases of the central nervous system through the gut-brain axis. The aim of the present study was to analyze gut microbiota composition in bipolar disorder (BD) and its relation to inflammation, serum lipids, oxidative stress, tryptophan (TRP)/kynurenine (KYN) levels, anthropometric measurements and parameters of metabolic syndrome. Further, microbial community differences of individuals with BD compared with healthy controls (HC) were explored. METHODS: In this cross-sectional study, we performed 16S rRNA gene sequencing of stool samples from 32 BD individuals and 10 HC. Laboratory parameters included inflammatory markers, serum lipids, KYN, oxidative stress and anthropometric measures. Microbial community analysis and correlation to clinical parameters was performed with QIIME, differential abundance analysis of taxa encompassed linear discriminant analysis effect size (LEfSe). RESULTS: We found a negative correlation between microbial alpha-diversity and illness duration in BD (R = -0.408, P = 0.021). Furthermore, we identified bacterial clades associated with inflammatory status, serum lipids, TRP, depressive symptoms, oxidative stress, anthropometrics and metabolic syndrome in individuals with BD. LEfSe identified the phylum Actinobacteria (LDA= 4.82, P = 0.007) and the class Coriobacteria (LDA= 4.75, P = 0.010) as significantly more abundant in BD when compared with HC, and Ruminococcaceae (LDA= 4.59, P = 0.018) and Faecalibacterium (LDA= 4.09, P = 0.039) as more abundant in HC when compared with BD. CONCLUSIONS: The present findings suggest that causes and/or consequences of BD may also lie outside the brain. Exploratory research of the gut microbiota in affective disorders like BD may identify previously unknown underlying causes, and offer new research and therapeutic approaches to mood disorders.

Biomarkers for Antidepressant Efficacy of Electroconvulsive Therapy: An Exploratory Cerebrospinal Fluid Study.

BACKGROUND: No candidate biomarkers based on cerebrospinal fluid (CSF) have been identified as prognostic factors in patients with major depression treated with electroconvulsive therapy (ECT), yet. METHOD: Following different underlying hypotheses, we analysed baseline CSF levels of markers of neurodegeneration (tau proteins, ß-amyloids and neurogranin), elements of the innate immune system (interleukin [IL]-6, neopterin, soluble CD14, soluble CD163, migration inhibitory factor and monocyte chemotactic protein 1), endocannabinoids, sphingolipids and Klotho before ECT in patients with depression (n = 12) to identify possible correlations with the clinical antidepressant response to ECT. RESULTS: Correlation with the reduction of the depressive symptoms could be observed especially for markers of neurodegeneration and elements of the innate immune system. Differences for CSF levels of several markers were found between the groups of responders and non-responders at the trend level. LIMITATIONS: The sample size is small and the -distribution of responders and non-responders is uneven. CONCLUSIONS: It is this first study on CSF biomarkers for antidepressant efficacy of ECT warrants further research regarding the mechanism of ECT and personalized antidepressant therapy.

European Multicentre Tics in Children Studies (EMTICS): protocol for two cohort studies to assess risk factors for tic onset and exacerbation in children and adolescents.

Genetic predisposition, autoimmunity and environmental factors [e.g. pre- and perinatal difficulties, Group A Streptococcal (GAS) and other infections, stress-inducing events] might interact to create a neurobiological vulnerability to the development of tics and associated behaviours. However, the existing evidence for this relies primarily on small prospective or larger retrospective population-based studies, and is therefore still inconclusive. This article describes the design and methodology of the EMTICS study, a longitudinal observational European multicentre study involving 16 clinical centres, with the following objectives: (1) to investigate the association of environmental factors (GAS exposure and psychosocial stress, primarily) with the onset and course of tics and/or obsessive-compulsive symptoms through the prospective observation of at-risk individuals (ONSET cohort: 260 children aged 3-10 years who are tic-free at study entry and have a first-degree relative with a chronic tic disorder) and affected individuals (COURSE cohort: 715 youth aged 3-16 years with a tic disorder); (2) to characterise the immune response to microbial antigens and the host's immune response regulation in association with onset and exacerbations of tics; (3) to increase knowledge of the human gene pathways influencing the pathogenesis of tic disorders; and (4) to develop prediction models for the risk of onset and exacerbations of tic disorders. The EMTICS study is, to our knowledge, the largest prospective cohort assessment of the contribution of different genetic and environmental factors to the risk of developing tics in putatively predisposed individuals and to the risk of exacerbating tics in young individuals with chronic tic disorders.

Increased Tryptophan Metabolism Is Associated With Activity of Inflammatory Bowel Diseases.

BACKGROUND & AIMS: Administration of tryptophan and some of its metabolites reduces the severity of colitis in mice, whereas removing tryptophan from the diet increases susceptibility to colitis. Transfer of the intestinal microbiome transfers the colitogenic phenotype from tryptophan starved animals to normally nourished mice. We aimed to systematically evaluate serum levels of tryptophan and its metabolites in patients with inflammatory bowel diseases (IBD), and study their association with clinical and serologic features. METHODS: We studied 535 consecutive patients with IBD (211 with ulcerative colitis [UC], 234 with Crohn's disease [CD]; 236 male), enrolled in Germany from August 2013 through April 2014 and followed until July 2016. Serum samples were collected from patients and 291 matched individuals without IBD (controls); levels of tryptophan were measured using high-performance liquid chromatography. Metabolites of tryptophan were measured in serum from 148 patients and 100 controls by mass spectrometry. We measured levels of interleukin 22 in serum from 28 patients by enzyme-linked immunosorbent assay. Paired stool and serum samples were collected from a subset of patients with active UC (n = 10) or CD (n = 8) to investigate associations between serum levels of tryptophan and composition of the fecal microbiota, analyzed by 16S ribosomal DNA amplicon sequencing. We used real-time polymerase chain reaction to measure levels of messenger RNAs in colonic biopsies from 60 patients with UC, 50 with CD, and 30 controls. We collected information on patients' disease activity scores, medications, laboratory assessments, and clinical examinations during recruitment and follow-up visits. RESULTS: Serum levels of tryptophan were significantly lower in patients with IBD than in controls (P = 5.3 × 10-6) with a stronger reduction in patients with CD (vs control; P = 1.1 × 10-10) than UC (vs control; P = 2.8 × 10-3). We found a negative correlation between serum levels of tryptophan and disease activity or levels of C-reactive protein. Levels of messenger RNAs encoding tryptophan 2,3-dioxygenase-2 and solute carrier family 6 member 19 (also called B0AT1) were significantly decreased in colonic biopsies from patients with IBD compared with controls, whereas level of messenger RNA encoding indoleamine 2,3-dioxygenase-1 was significantly increased. The composition of the fecal microbiota associated with serum levels of tryptophan. Analysis of tryptophan metabolites revealed activation of the kynurenine pathway, based on high levels of quinolinic acid, in patients with IBD compared with controls. Serum concentration of interleukin 22 associated with disease activity in patients with IBD; there was an inverse association between levels of interleukin 22 and serum levels of tryptophan. CONCLUSIONS: In an analysis of serum samples from more than 500 patients with IBD, we observed a negative correlation between serum levels of tryptophan and disease activity. Increased levels of tryptophan metabolites-especially of quinolinic acid-indicated a high activity of tryptophan degradation in patients with active IBD. Tryptophan deficiency could contribute to development of IBD or aggravate disease activity. Interventional clinical studies are needed to determine whether modification of intestinal tryptophan pathways affects the severity of IBD.

Stability of Cellular Immune Parameters over 12 Weeks in Patients with Major Depression or Somatoform Disorder and in Healthy Controls.

OBJECTIVE: Cellular immune status in major depression (MD) patients differs from that in somatoform disorder (SFD) patients and healthy controls (HC). It is still questionable whether the patterns of immune parameters remain stable over time. Therefore, we studied lymphocyte and monocyte cell counts and neopterin levels in peripheral blood of MD and SFD patients and HC over 12 weeks and tested for correlations between biochemical and psychometric parameters. METHODS: Thirty-nine patients with MD, 27 with SFD, and 51 HC were recruited. Peripheral blood was drawn at four visits, at 4-week intervals. We assessed the total cell count of B lymphocytes, natural killer (NK) cells, T lymphocyte subpopu-lations, and monocytes by flow cytometry, and neopterin serum levels by ELISA. Psychometric parameters were measured with questionnaires. RESULTS: Counts of lymphocytes, monocytes, and neopterin were stable in the SFD and HC groups. In the MD group, total CD3+, CD3+CD8+, NK cells, and CD3+CD25+ T cells showed inhomogeneous variances in Friedman tests, particularly in females. Neopterin correlated with depressed mood in MD patients, and with body mass index in HC. CONCLUSIONS: Cellular immune parameters are stable in HC and SFD. Our results may indicate influences of MD and gender on some cellular immune parameters. This may need to be considered in future immunological studies.

Inflammatory processes and schizophrenia: two independent lines of evidence from a study of twins discordant and concordant for schizophrenic disorders.

The concept of twin concordance involves quantifying the resemblance between co-twins in an "objective" and reproducible way. Yet, quantifying resemblance in the case of complex psychiatric traits like schizophrenic disorders leads to methodological problems, as the yes-no dichotomy of diagnostic schemata does not allow one to assess between-subject differences in psychopathology patterns sufficiently accurately. Therefore, we relied on a multidimensional, quantitative concordance measure that provided a high resolution and differentiation when assessing the resemblance of psychopathology patterns. This concordance measure was central to our investigations into the potential link between schizophrenic disorders and aberrancies of the inflammatory response system. Specifically, we aimed to determine the extent to which (1) the observed variation of between-subject psychopathology concordance among 100 schizophrenic patients and (2) the observed variation of within-pair psychopathology concordance among 71 twin pairs can be explained by immunoglobulin M (IgM) levels. To accomplish this goal, we had to "gauge" in a first step the concordance measure's performance by (1) comparing the psychopathology patterns of 269 index cases suffering from functional psychoses with the respective patterns of the 350 "affecteds" among their first-degree relatives; (2) systematically comparing the psychopathology patterns of 100 unrelated patients with a diagnosis of schizophrenic disorders with each other; and (3) detailing the within-pair concordance of elementary traits among 2734 healthy twin pairs. As to the role of active immune processes in the context of schizophrenic disorders, we found that there exists a 20-30% subgroup of patients for whom aberrancies of the inflammatory response system, as quantified through IgM levels, appeared to be linked to the pathogenesis of schizophrenic disorders (r = 0.7515/0.8184, p < 0.0001). The variation of within-pair psychopathology concordance among twins with schizophrenic disorders was found to be "explainable" in part by chronically elevated IgM levels (24.5% of observed phenotypic variance; p = 0.0434), thus suggesting that monozygotic twins concordant for schizophrenic disorders may possess a less "robust" variant of the inflammatory response system which can more easily be triggered by exogenous factors than the more "robust" variants of discordant pairs. Though the underlying biological mechanisms remain to be detected, our data have cleared the way for an early identification of patients with schizophrenic disorders for whom the inflammatory response system may be a target for therapeutic intervention. Moreover, our results will likely lead to new treatment strategies that involve elements of personalized medicine.

Insufficient glucocorticoid signaling and elevated inflammation in coronary heart disease patients with comorbid depression.

Coronary heart disease (CHD) and depression are very common and often co-existing disorders. In addition to psychological and social morbidity, depression exacerbates adverse cardiac outcomes in CHD patients. Inflammation has been proposed as one of the mechanisms involved in the association between these two debilitating diseases. Therefore, the present study aimed to evaluate inflammatory responses as well as to investigate the pathophysiological mechanisms underlying the putative inflammatory activation in CHD patients with and without depression, by assessing the function of two important biological factors regulating inflammation, the hypothalamus-pituitary-adrenal (HPA) axis and the glucocorticoid receptor (GR). Eighty-three CHD patients with (n=28) and without (n=55) comorbid depression were recruited from primary care services in South London. Depression status was assessed by means of Clinical Interview Schedule Revised for diagnosis of depression, and Beck Depression Inventory for the presence of depressive symptoms. Serum C-reactive protein (CRP), plasma vascular endothelial growth factor (VEGF), and plasma and salivary cortisol were measured using commercially available ELISA kits. Gene expression of GR and interleukin-6 (IL-6) were conducted via qPCR. GR sensitivity was evaluated in vitro in isolated peripheral blood mononuclear cells using the dexamethasone inhibition of lipopolysaccharide-stimulated IL-6 levels. Serum levels of kynurenine pathway metabolites were measured using high performance liquid chromatography. Our results show that CHD patients with depression had higher levels of CRP, IL-6 gene expression, and VEGF compared with CHD non-depressed, as well as lower plasma and saliva cortisol levels. The CHD depressed group also exhibited a reduction in GR expression and sensitivity. Finally, tryptophan levels were significantly lower in patients with depression, who also showed an increased kynurenine/tryptophan ratio. In conclusion, CHD patients with depression had elevated levels of inflammation in the context of HPA axis hypoactivity, GR resistance, and increased activation of the kynurenine pathway. Reduced cortisol bioavailability and attenuated glucocorticoid responsiveness due to decreased expression and sensitivity of GR may lead to insufficient glucocorticoid signaling and thus elevation of inflammation in these patients.

The impact of electroconvulsive therapy on the tryptophan-kynurenine metabolic pathway.

BACKGROUND: There is still limited knowledge about the mechanism of action of electroconvulsive therapy (ECT) in the treatment of depression. Substantial evidence suggests a role for the immune-moderated tryptophan (TRP)-kynurenine (KYN) pathway in depression; i.e. a depression-associated disturbance in the balance between the TRP-KYN metabolites towards a neurotoxic process. We, therefore, aimed to investigate the impact of ECT treatment on the TRP-KYN pathway, in association with ECT-related alterations in depressive symptoms. METHOD: Twenty-three patients with unipolar or bipolar depression, treated with bilateral ECT twice a week were recruited. Blood serum samples, and depression scores using the Hamilton Depression Rating Scale-17 items (HDRS) as well as the Beck Depression Inventory (BDI) were collected repeatedly during the period of ECT and until 6 weeks after the last ECT session. TRP and KYN metabolites were analyzed in serum using the High Performance Liquid Chromatography. Four patients could not complete the study; thereby yielding data of 19 patients. Analyses were performed using multilevel linear regression analysis. RESULTS: There was an increase in kynurenic acid (KYNA) (B=0.04, p=0.001), KYN/TRP ratio (B=0.14, p=0.001), KYNA/KYN ratio (B=0.07, p<0.0001), and KYNA/3-hydroxykynurenine ratio (B=0.01, p=0.008) over time during the study period. KYN (B=-0.02, p=0.003) and KYN/TRP (B=-0.19, p=0.003) were negatively associated with total HDRS over time. Baseline TRP metabolite concentrations did not predict time to ECT response. CONCLUSION: Our findings show that ECT influences the TRP-KYN pathway, with a shift in TRP-KYN metabolites balance towards molecules with neuroprotective properties correlating with antidepressant effects of ECT; thereby providing a first line of evidence that the mechanism of action of ECT is (co)mediated by the TRP-KYN pathway.

Prenatal immunologic predictors of postpartum depressive symptoms: a prospective study for potential diagnostic markers.

In postpartum depression (PPD), immunologic changes have been proposed to be involved in the disease pathology. The study evaluates the regulation of the innate and adaptive immune response over the course of late pregnancy and postpartum period and their association with the development of postpartum depressive symptoms. Furthermore, prenatal immunologic markers for a PPD were investigated. Hundred pregnant women were included. At 34th and 38th week of pregnancy as well as 2 days, 7 weeks and 6 months postpartum, immune parameters (neopterin, regulatory T cells, CXCR1, CCR2, MNP1 and CD11a) were measured by flow cytometry/ELISA, and the psychopathology was evaluated. We found that regulatory T cells were significantly increased prenatal (p=0.011) and postnatal (p=0.01) in mothers with postnatal depressive symptoms. The decrease in CXCR 1 after delivery was significantly higher in mother with postnatal depressive symptoms (p=0.032). Mothers with postnatal depressive symptoms showed already prenatal significantly elevated neopterin levels (p=0.049). Finally, regulatory T cells in pregnancy strongly predict postnatal depressive symptoms (p=0.004). The present study revealed that prenatal and postnatal immunologic parameters are associated with postpartum depressive symptoms in mothers. In addition, we found immune markers that could eventually be the base for a biomarker set that predicts postnatal depressive symptoms already during pregnancy.

Tryptophan metabolism and immunogenetics in major depression: a role for interferon-γ gene.

The tryptophan metabolism and immune activation play a role in pathophysiology of major depressive disorders. The pro-inflammatory cytokine interferon-γ transcriptionally induces the indoleamine 2,3-dioxygenase enzyme that degrades the tryptophan and thus induces serotonin depletion. The polymorphism of certain cytokine genes was reported to be associated with major depression. We investigated the association between interferon-γ (IFNγ) gene CA repeat polymorphism, the profile of serotonin and tryptophan pathway metabolites and clinical parameters in 125 depressed patients and 93 healthy controls. Compared to controls, serum tryptophan and 5-hydroxyindoleacetic acid (5HIAA) concentrations in the patients were significantly lower and serum kynurenine concentrations were significantly higher at baseline (p<0.0001). The presence of IFNγ CA repeat allele 2 homozygous has significant association with higher kynurenine concentrations in controls (F=4.47, p=0.038) as well as in patients (F=3.79, p=0.045). The existence of interferon-γ CA repeat allele 2 (homo- or heterozygous) showed significant association with increase of tryptophan breakdown over time during the study period (F=6.0, p=0.019). The results indicated the association between IFNγ CA repeat allele 2, tryptophan metabolism and the effect of medication.

Increased 3-hydroxykynurenine serum concentrations differentiate Alzheimer's disease patients from controls.

Increased degradation of tryptophan (TRP) through the kynurenine (KYN) pathway (KP) is known to be involved in the molecular mechanisms resulting in the neuropathogenesis of Alzheimer's disease (AD). Activation of the KP leads to the production of neurotoxic metabolites 3-hydroxykynurenine (3-HK) and quinolinic acid (QUIN) by immune cells and neuroprotective derivates kynurenic acid (KYNA) and picolinic acid (PIC) by astrocytes and neurons. We therefore investigated whether an imbalance between neurotoxic and neuroprotective kynurenine metabolites could be detected in patients with AD. We measured serum levels of TRP, KYNA, 3-HK, PIC and QUIN in 20 patients with AD and for comparison in 20 patients with major depression, and 19 subjectively cognitive impaired subjects. Serum levels of 3-HK were markedly increased in AD patients compared to the comparison groups (p < .0001). Serum levels of the other KP metabolites were not significantly different between groups. Our data indicate an increased production of the neurotoxic KP metabolite 3-HK in AD. In contrast to its downstream metabolites QUIN and PIC, 3-HK can cross the blood-brain barrier via an active transport process. Our data therefore indicate an enhanced availability of 3-HK in the brain of AD patients, which may be related to the previously reported higher production of QUIN in AD brains.

Impact of different antipsychotics on cytokines and tryptophan metabolites in stimulated cultures from patients with schizophrenia.

BACKGROUND: An imbalance of tryptophan metabolites plays a role in the pathophysiology of schizophrenia. Also cytokines seem to be involved and are able to enhance the tryptophan metabolism. In this study the impact of cytokines, tryptophan metabolites and antipsychotics was evaluated in schizophrenic patients/ healthy controls and correlated with the psychopathology of schizophrenia. SUBJECTS AND METHODS: This study investigated 12 patients with schizophrenia and 24 matched controls. Peripheral blood mononuclear cell cultures were stimulated in vitro with lipopolysaccharide (LPS) or polyinosine-polycytidylic acid (poly I:C) and different antipsychotics (quetiapine, risperidone, haloperidole and clozapine) were added. The cytokines IL-4, IL-10, IFN-γ and tryptophan metabolites were analysed. Symptom severity was assessed using the positive and negative syndrome scale (PANSS). RESULTS: Peripheral mononuclear cells of schizophrenia patients showed a reduced IFN-γ response to LPS (p=0.008). When quetiapine and risperidone were added this imbalance between patients and controls disappeared. Tryptophan levels were significantly lower in patients' cells cultures when the cells were stimulated with LPS (p=0.029). A group effect for lower levels in the patients' cell culture was evaluated for tryptophan and kynurenine (p=0.043; p=0.05). In addition, high tryptophan levels correlated with low PANSS negative scores in patients and higher kynurenine levels resulted in higher PANSS positive scores. CONCLUSIONS: Only two atypical antipsychotics were identified to reverse the imbalanced cytokine levels in schizophrenia. The low concentrations of tryptophan and kynurenine in these patients could be a sign of a fast degradation of tryptophan - yet tryptophan metabolites could not be changed by any of the investigated antipsychotics.

Increased soluble interleukin-2 receptor levels are related to somatic but not to cognitive-affective features in major depression.

Cell-mediated immune activation may play a role in the pathogenesis of depression as indicated by findings of increased soluble tumor necrosis factor receptor (sTNF-R) levels and meta-analytic evidence for elevated soluble interleukin-2 receptor (sIL-2R) concentrations. However, little research has been done on how these soluble cytokine receptors are differently related to specific features in patients with depression. We measured levels of the soluble cytokine receptors sIL-2R, sTNF-R1 and sTNF-R2 in 25 non-medicated patients with major depression (DSM-IV) and 22 healthy controls. Psychometric measures included cognitive-affective depressive symptoms, somatoform symptoms, somatic and cognitive dimensions of anxiety and current mood states. While patients with depression showed increased levels of sIL-2R (p<0.01), differences in sTNF-R1 (p=0.09) and sTNF-R2 (p=0.08) marginally failed to reach significance. Increased concentrations of sIL-2R were related to somatic measures such as the severity of somatoform symptoms and somatic anxiety symptoms but not to cognitive-affective measures or current mood states. Our findings may suggest some specificity in the relationship between sIL-2R and symptom dimensions and highlight potential pathways by which T cell mediated immune activation may underpin somatic symptoms in depression.

The role of the kynurenine metabolism in major depression.

There are circumferential evidences that major depression is associated with mild pro-inflammatory state. Both physiological and psychological stress can induce increased production of pro-inflammatory mediators, reactive oxygen species (ROS) and hypothalamo-hypophyseal-adrenal axis disturbances. While both pro-inflammatory mediators and ROS could activate the tryptophan breakdown and kynurenine pathway with a shift toward the neurotoxic arm, chronic hypercortisolism could also enhance tryptophan breakdown and induce neurodegenerative changes. The imbalanced kynurenine metabolism in terms of neuroprotective and neurotoxic effects was demonstrated in major depression, and in drug-induced neuropsychiatric side effects, such as interferon-treated depression. The changes in periphery are shown to be associated with central changes. Those changes might be partly contributed by genetic factors. While some of the currently available antidepressants could reverse the pro-inflammatory state of the depressed patients, these medications could not efficiently improve those metabolic and neurochemical changes within the period that could induce clinical improvement. In this review, the role of kynurenine metabolism which interacts with other neurochemicals is discussed as a major contributing pathophysiological mechanism in major depression. Moreover, the future therapeutic opportunities are also discussed in this review.

Psychobiological aspects of somatization syndromes: contributions of inflammatory cytokines and neopterin.

Previous research suggests a dysregulation of immune-to-brain communication in the pathophysiology of somatization syndromes (multiple somatoform symptoms). We compared blood levels of the inflammatory markers tumor necrosis factor-alpha (TNF-α), interleukin-1 receptor antagonist (IL-1ra), interleukin-6 (IL-6) and neopterin between 23 patients with somatization syndromes (Somatoform Symptom Index-8, SSI-8), 23 age- and sex-matched healthy controls and 23 patients with major depression. No group differences were found for IL-1ra and IL-6. While TNF-α was increased in both clinical groups, neopterin was only increased in somatization syndromes. Correlational analyses revealed that neopterin tended to be related to somatoform pain complaints in patients with somatization syndromes. This study is the first to demonstrate increased levels of TNF-α and neopterin in patients with somatization syndromes without a diagnosis of depression, which may support a role of immune alterations in somatization syndromes. Neopterin is a reliable indicator for interferon-γ (IFN-γ) which was identified as the only cytokine that induces significant production of neopterin. Considering recent research indicating that IFN-γ can lead to increased neuronal responsiveness and body perceptions by reducing inhibitory tone in the dorsal horn, the observed association between somatization syndromes and neopterin might support the idea of central sensitization in the pathogenesis of somatoform symptoms.

Altered monocyte activation markers in Tourette's syndrome: a case-control study.

BACKGROUND: Infections and immunological processes are likely to be involved in the pathogenesis of Tourette's syndrome (TS). To determine possible common underlying immunological mechanisms, we focused on innate immunity and studied markers of inflammation, monocytes, and monocyte-derived cytokines. METHODS: In a cross-sectional study, we used current methods to determine the number of monocytes and levels of C-reactive protein (CRP) in 46 children, adolescents, and adult patients suffering from TS and in 43 healthy controls matched for age and sex. Tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), soluble CD14 (sCD14), IL1-receptor antagonist (IL1-ra), and serum neopterin were detected by immunoassays. RESULTS: We found that CRP and neopterin levels and the number of monocytes were significantly higher in TS patients than in healthy controls. Serum concentrations of TNF-alpha, sIL1-ra, and sCD14 were significantly lower in TS patients. All measured values were within normal ranges and often close to detection limits. CONCLUSIONS: The present results point to a monocyte dysregulation in TS. This possible dysbalance in innate immunity could predispose to infections or autoimmune reactions.

Effects of antidepressants and cyclooxygenase-2 inhibitor on cytokines and kynurenines in stimulated in vitro blood culture from depressed patients.

BACKGROUND: Immune activation induces a pro-inflammatory state, which enhances the tryptophan degradation into kynurenine (KYN). The involvement of kynurenines has been shown in patients with major depression. Here, the effects of anti-inflammatory medication and antidepressants on cytokines and tryptophan metabolite changes in blood culture with immune challenge [bacterial mimetic lipopolysaccharide (LPS)] were investigated. MATERIALS AND METHODS: A total of 21 depressed patients and 38 matched controls were recruited. Whole blood cultures were stimulated with LPS and drugs were added (celecoxib, venlafaxine, reboxetine, imipramine and fluoxetine). Cytokines and kynurenines were analysed. RESULTS: After stimulation with LPS, the interferon-γ and interleukin (IL)-10 secretions were significantly higher in controls than in patients (p = 0.045, p = 0.032), respectively. Adding imipramine and celecoxib abolished the significance for IL-10. Challenge with LPS induced the kynurenine pathway in each group. Regarding the ratio KYNA/KYN, which indicated how much of KYN formed is further catabolised into the neuroprotective arm, the controls' blood cultures showed a significantly higher ratio (p = 0.045). DISCUSSION: Stimulation with LPS induced increased production of pro-inflammatory and anti-inflammatory cytokines in both groups, but higher responses in controls. This lower production of cytokine responses in depressed patients indicates that their immune cells are in a refractory phase, induced by a pre-existing pro-inflammatory state. For kynurenines, the whole metabolism was enhanced by LPS; however, an imbalance to neuroprotective metabolites was observed just in control blood. A drug effect could only be shown for imipramine and celecoxib, which were beneficial in terms of re-balancing the immune function but not in re-balancing neuroactive metabolites.

Attention-deficit hyperactivity disorder (ADHD) and glial integrity: an exploration of associations of cytokines and kynurenine metabolites with symptoms and attention.

BACKGROUND: In contrast to studies of depression and psychosis, the first part of this study showed no major differences in serum levels of cytokines and tryptophan metabolites between healthy children and those with attention-deficit/hyperactivity disorder of the combined type (ADHD). Yet, small decreases of potentially toxic kynurenine metabolites and increases of cytokines were evident in subgroups. Therefore we examined predictions of biochemical associations with the major symptom clusters, measures of attention and response variability. METHODS: We explored systematically associations of 8 cytokines (indicators of pro/anti-inflammatory function) and 5 tryptophan metabolites with symptom ratings (e.g. anxiety, opposition, inattention) and continuous performance test (CPT) measures (e.g. movement, response time (RT), variability) in 35 ADHD (14 on medication) and 21 control children. Predictions from linear regressions (controlled by the false discovery rate) confirmed or disconfirmed partial correlations accounting for age, body mass and socio-economic status. RESULTS: (1) Total symptom ratings were associated with increases of the interleukins IL-16 and IL-13, where relations of IL-16 (along with decreased S100B) with hyperactivity, and IL-13 with inattention were notable. Opposition ratings were predicted by increased IL-2 in ADHD and IL-6 in control children. (2) In the CPT, IL-16 related to motor measures and errors of commission, while IL-13 was associated with errors of omission. Increased RT variability related to lower TNF-alpha, but to higher IFN-gamma levels. (3) Tryptophan metabolites were not significantly related to symptoms. But increased tryptophan predicted errors of omission, its breakdown predicted errors of commission and kynurenine levels related to faster RTs. CONCLUSIONS: Many associations were found across diagnostic groups even though they were more marked in one group. This confirms the quantitative trait nature of these features. Conceptually the relationships of the pro- and antiinflammatory cytokines distinguished between behaviours associated more with cognitive or more with motor control respectively. Further study should extend the number of immunological and metabolic markers to confirm or refute the trends reported here and examine their stability from childhood to adolescence in a longitudinal design.