Mycoplasma pneumoniae IgG positivity is associated with tic severity in chronic tic disorders.

Infectious pathogens may represent an environmental risk factor for chronic tic disorders (CTD). This cross-sectional study aimed to determine whether Mycoplasma pneumoniae (M. pneumoniae) IgG positivity is associated with the presence or severity of tics. We compared M. pneumoniae IgG positivity across three groups: children and adolescents (3-16 years) with CTD (CTD group; n = 302); siblings (3-10 years) of people with CTD who developed tics within a seven-year follow-up period (tic onset group; n = 51); siblings (4-10 years) who did not develop tics within the study period and were ≥10-years-old at their last assessment (unaffected group; n = 88). The relationship between M. pneumoniae IgG positivity and the presence and severity of tics was analysed using multilevel models controlling for site, family relatedness, sex, age, presence of comorbid obsessive-compulsive and/or attention-deficit/hyperactivity disorder and use of psychotropic medication. M. pneumoniae IgG positivity was not associated with the presence of CTD, or the first onset of tics as compared to siblings who remained unaffected. M. pneumoniae IgG positivity was associated with a higher tic severity score within the CTD group (ß = 2.64, s.e. = 1.15, p = 0.02). It is possible that M. pneumoniae infection influences tic severity in CTD or, that having more severe tics, increases the risk of infection. However, it is more likely that the association observed in this study reflects a propensity toward enhanced immune responses in people with CTD and that, rather than a causal relationship, infection and greater tic severity are indirectly linked via shared underlying immune mechanisms.

[Patients with tic disorders: widely known, yet underserved]. / Patienten mit Tic-Störungen: weit bekannt, doch unterversorgt.

Tic disorders typically start in early childhood and can be classified into provisional tic disorder (tics last <12 months) and chronic tic disorders (tics last > 12 months). The widely known chronic tic disorder Tourette's syndrome is featuring multiple motor and vocal tics. Tics are typically waxing and waning in frequency and intensity. Concentration and relaxation might decrease tics, whereas stress and excitement might increase tics. Psychiatric comorbidities, like obsessive-compulsive disorder, ADHD, depression and anxiety are common. The etiology is multifactorial with genetic and environmental interactions leading to a dysregulation of cortico-striato-pallido-thalamo-cortical networks.A correct diagnosis and psychoeducation are essential for patients as well as their relatives. Additional therapies are needed for patients with severe tics that cause physical impairment or great psychosocial stress. It is crucial to also treat psychiatric comorbidities. Psychotherapeutic interventions for tics include progressive muscle relaxation, habit reversal training, exposure and response prevention and comprehensive behavioral intervention for tics. First-line psychopharmacological treatment in Europe contains aripiprazole, tiapride and risperidone, which are all used off-label for tic disorders. Haloperidol remains the only approved medication for the pharmacotherapy of tics in Germany, but is rarely used due to its side effects. Cannabinoids gain interest as a new pharmacological option, but are mainly offered within the frame of studies.

Oxytocin course over pregnancy and postpartum period and the association with postpartum depressive symptoms.

During the postpartum period, women are at higher risk of developing a mental disorder such as postpartum depression (PPD), a disorder that associates with mother-infant bonding and child development. Oxytocin is considered to play a key role in mother-infant bonding and social interactions and altered oxytocin plasma concentrations were found to be associated with PPD. In the present study, we evaluated oxytocin plasma levels and depressive symptoms during pregnancy and the postpartum period in healthy women. We evaluated 100 women twice during pregnancy (weeks 35 and 38) and three times in the postpartum period (within 2 days and 7 weeks and 6 months after delivery) by measuring oxytocin plasma levels with enzyme-linked immunosorbent assay (ELISA) and assessing depressive symptoms with the Montgomery-Asberg Depression Rating Scale. Oxytocin plasma levels significantly increased from the 35th week of gestation to 6 months postpartum in all women. However, levels decreased from the 38th week of gestation to 2 days after delivery in participants with postpartum depressive symptoms, whereas they continuously increased in the group without postpartum depressive symptoms; the difference between the course of oxytocin levels in the two groups was significant (Δt2-t3: t = 2.14; p = 0.036*). Previous depressive episodes and breastfeeding problems predicted postpartum depressive symptoms. Our results indicate that alterations in the oxytocin system during pregnancy might be specific for women who develop postpartum depressive symptoms. Future studies should investigate whether oxytocin plasma levels might have predictive value in women at high risk for PPD.

Transcutaneous noninvasive vagus nerve stimulation (tVNS) in the treatment of schizophrenia: a bicentric randomized controlled pilot study.

Despite many pharmacological and psychosocial treatment options, schizophrenia remains a debilitating disorder. Thus, new treatment strategies rooted in the pathophysiology of the disorder are needed. Recently, vagus nerve stimulation (VNS) has been proposed as a potential treatment option for various neuropsychiatric disorders including schizophrenia. The objective of this study was to investigate for the first time the feasibility, safety and efficacy of transcutaneous VNS in stable schizophrenia. A bicentric randomized, sham-controlled, double-blind trial was conducted from 2010 to 2012. Twenty schizophrenia patients were randomly assigned to one of two treatment groups. The first group (active tVNS) received daily active stimulation of the left auricle for 26 weeks. The second group (sham tVNS) received daily sham stimulation for 12 weeks followed by 14 weeks of active stimulation. Primary outcome was defined as change in the Positive and Negative Symptom Scale total score between baseline and week 12. Various other secondary measures were assessed to investigate safety and efficacy. The intervention was well tolerated with no relevant adverse effects. We could not observe a statistically significant difference in the improvement of schizophrenia psychopathology during the observation period. Neither psychopathological and neurocognitive measures nor safety measures showed significant differences between study groups. Application of tVNS was well tolerated, but did not improve schizophrenia symptoms in our 26-week trial. While unsatisfactory compliance questions the feasibility of patient-controlled neurostimulation in schizophrenia, the overall pattern of symptom change might warrant further investigations in this population.

The Effect of Nabiximols on Driving Ability in Adults with Chronic Tic Disorders: Results of a Substudy Analysis of the Double-Blind, Randomized, Placebo-Controlled CANNA-TICS Trial.

Background: The multicenter, randomized, double-blind, parallel-group, phase IIIb CANNA-TICS (CANNAbinoids in the treatment of TICS) trial showed clear trends for improvement of tics, depression, and quality of life with nabiximols versus placebo in adult patients with Gilles de la Tourette syndrome and other chronic tic disorders. Although in general nabiximols was well tolerated, it is unclear whether treatment using this cannabis extract influences driving skills in patients with chronic tic disorders. Methods: Here we report results of the "Fitness to Drive" substudy of the CANNA-TICS trial. The key endpoint was fitness to drive as a binary criterion with a computerized assessment at baseline and after 9 weeks of stable treatment (week 13) with nabiximols or placebo. A patient was considered unfit to drive according to the German Federal Highway Research Institute guidelines. Results: In the substudy, a total of 64 patients (76.6% men, mean±standard deviation of age: 36.8±13.9) were recruited at two study sites. The number of patients who were fit to drive increased from 24 (55.8%) at baseline to 28 (71.8%) at week 13 among 43 patients treated with nabiximols, and decreased from 14 (66.7%) to 10 (52.6%) among 21 patients who received placebo. The risk difference (nabiximols - placebo) was 0.17 (95% confidence interval=-0.08 to 0.43) in favor of nabiximols. Specifically, only 2 of 24 (8.3%) patients in the nabiximols, but 4 of 14 (28.6%) patients in the placebo group changed for the worse from fit (at baseline) to unfit (at week 13) to drive, whereas 8 of 19 (42.1%) patients in the nabiximols, and only 2 of 7 (28.6%) patients in the placebo group improved from unfit to fit. Conclusion: Treatment with nabiximols does not impair skills relevant to driving in those patients with tic disorders who were fit to drive at baseline and even improved fitness to drive in a subset of patients who were unfit to drive before start of treatment. EudraCT number: 2016-000564-42.

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.

Intracellular monocytic cytokine levels in schizophrenia show an alteration of IL-6.

Several studies have shown an involvement of the immune system, in particular the monocytic system, in the pathophysiology of schizophrenia. Beside others, the monocyte-derived cytokines TNF-α, IL-6 and IL-10 were found to be affected. Since cytokines are secreted by several different cell types, the cellular source is only clear if intracellular levels are measured. Thus, in order to study the monocytic system in schizophrenia, the intracellular levels of TNF-α, IL-6 and IL-10 were determined. The intracellular concentration of TNF-α, IL-6 and IL-10 in CD33 positive monocytes was evaluated in schizophrenic patients and controls with monoclonal antibodies against these cytokines. In addition, in vitro stimulation with lipopolysaccharide (LPS) or poly I/C, which mimic a bacterial and viral infection, was performed before immunocytochemistry. At baseline, monocytic IL-6 levels were significantly lower in schizophrenic patients than in controls. After stimulation with LPS, compared with baseline, monocytic intracellular IL-6 production tended to increase more in schizophrenic patients. The present results provide further support for the hypothesis of an involvement of a dysfunction of the monocytic system in the pathophysiology of schizophrenia and indicate that especially the pro-inflammatory immune response seems to be impaired.

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.

Efficacy of Sertraline Plus Placebo or Add-On Celecoxib in Major Depressive Disorder: Macrophage Migration Inhibitory Factor as a Promising Biomarker for Remission After Sertraline-Results From a Randomized Controlled Clinical Trial.

Introduction: Previous research delivers strong indications that inflammatory activation leads to treatment resistance in a subgroup of patients with Major Depressive Disorder (MDD). Thus, tailored interventions are needed. The present study aimed to find potential biomarkers that may enable patients to be stratified according to immune activation. Methods: A phase IIa randomized placebo-controlled trial was performed to assess levels of inflammatory compounds in responders/remitters and non-responders/non-remitters to sertraline plus celecoxib (n = 20) and sertraline plus placebo (n = 23). Levels of macrophage migration inhibitory factor, neopterin, and tumor necrosis factor alpha were determined by enzyme-linked immunosorbent assay; response and remission were measured by reduction of the Montgomery Åsberg Depression Rating Scale score. Results: Both treatment groups showed a significant decline in depression symptoms, but no difference was found between groups. A clear pattern emerged only for macrophage migration inhibitory factor: placebo remitters showed significantly lower baseline levels than non-remitters (a similar trend was seen in responders and non-responders) while celecoxib responders showed a trend for higher baseline levels than non-responders. Conclusion: Small subsample sizes are a notable limitation, wherefore results are preliminary. However, the present study provides novel insights by suggesting macrophage migration inhibitory factor as a promising biomarker for treatment choice. The trial was registered in EU Clinical Trials Register (EU-CTR): https://www.clinicaltrialsregister.eu/ctr-search/trial/2009-011990-34/DE, EudraCT-No.: 2009-011990-34.

Activation and deactivation steps in the tryptophan breakdown pathway in major depressive disorder: A link to the monocyte inflammatory state of patients.

It is unclear how the tryptophan (TRP) breakdown pathway relates to the activated inflammatory state of patients with major depressive disorder (MDD). We determined in two different cohorts of patients with MDD (n = 281) and healthy controls (HCs) (n = 206) collected for the EU-MOODINFLAME project: We then correlated outcomes to each other, and to the clinical characteristics of patients. Both cohorts of patients differed clinically; patients of the Munich cohort (n = 50) were less overweight, less medicated, were less in the current episode and showed a higher HAM-D 17 score as compared with patients of the Muenster cohort (n = 231). An increased expression of ICCGs was found in the circulating monocytes of patients of both cohorts; this was in particular evident in the Munich cohort. In contrast, ISGs monocyte expression levels tended to be reduced (both cohorts). TRP serum levels were linked to the pro-inflammatory (ICCGs) monocyte state of patients; a decrease in TRP serum levels was found in the Munich cohort; TRP levels correlated negatively to patient's HAM-D 17 score. Contrary to what expected, KYN serum levels were not increased in patients (both cohorts); and an increased KYN/TRP ratio was only found in the Munich patients (who showed the lowest TRP serum levels). IDO-1 monocyte expression levels were decreased in patients (both cohorts) and negatively associated to their pro-inflammatory (ICCGs) monocyte state. Thus, a depletion of TRP via an ICCGs-inflammatory IDO activation is not likely in MDD. Downstream from KYN, and regarding compounds influencing glutamate receptors (GR), reduced serum levels of KYNA (NMDA-R antagonist), 3-HK (NMDA-R agonist), and XA (mGlu2/3 agonist) were found in patients of both cohorts; PIC serum levels (NMDA-R antagonist) were increased in patients of both cohorts. Reduced QUIN serum levels (NMDA-R agonist) were found in patients of the Muenster cohort,only. 3-HK levels correlated to the monocyte inflammatory ICCG state of patients. The ultimate effect on brain glutamate receptor triggering of this altered equilibrium between peripheral agonists and antagonists remains to be elucidated.

Association between intracellular infectious agents and Tourette's syndrome.

The underlying pathophysiological mechanisms in Tourette's syndrome (TS) are still unclear. Increasing evidence supports the involvement of infections, possibly on the basis of an altered immune status. Not only streptococci but also other infectious agents may be involved. This study investigates the association between the neurotrophic agents Chlamydia, Toxoplasma and TS. 32 patients with TS and 30 healthy matched controls were included. For each individual, IgA/IgG antibody titers against Chlamydia trachomatis/pneumoniae and Toxoplasma gondii were evaluated and analyzed with Fisher's exact test. We found a significantly higher rate of TS patients with elevated antibody titers against Chlamydia trachomatis (P = 0.017) as compared to controls. A trend toward a higher prevalence in the Tourette's group was shown for Toxoplasma (P = 0.069). In conclusion, within the TS patients a higher rate of antibody titers could be demonstrated, pointing to a possible role of Chlamydia and Toxoplasma in the pathogenesis of tic disorders. Because none of these agents has been linked with TS to date, a hypothesis is that infections could contribute to TS by triggering an immune response. It still remains unclear whether tic symptoms are partly due to the infection or to changes in the immune balance caused by an infection.

Childhood Adversity and Current Stress are related to Pro- and Anti-inflammatory Cytokines in Major Depression.

BACKGROUND: Stress during early childhood, for example as a result of maltreatment, can predict inflammation in adulthood. The association of depression with inflammation and current and long-term stress resulting from childhood maltreatment and threatening experiences in the past year has not yet been studied. Therefore, we assessed these variables in a group of patients with major depressive disorder (MDD) and measured levels of the pro-inflammatory cytokine IL-6 and the anti-inflammatory cytokine IL-10. High levels of IL-6 are associated with depression and of IL-10 with stress. METHODS: We included 44 patients who fulfilled DSM-IV diagnostic criteria for MDD and 44 age- and gender-matched healthy controls. We used Cohen's Perceived Stress Scale (PSS), the list of life-threatening experiences questionnaire (LTE-Q) and the childhood trauma questionnaire (CTQ) to assess the level of stress and analyzed IL-6 and IL-10 cytokines in venous blood plasma. RESULTS: The patient group showed significantly higher scores on the maltreatment scale LTE-Q (2.7 vs. 1.1; P = 0.001, and the stress scales CTQ (emotional abuse; P = 0.048 and physical neglect; P = 0.002) and PSS (35.2 vs 15.5; P < 0.001) as well as significantly higher levels of IL-6 (1.5pg/ml vs. 0.9pg/ml; P = 0.012). They also had significantly higher levels of IL-10 (1.1pg/ml vs. 0.7pg/ml; P < 0.001). Higher actual stress levels were associated with childhood maltreatment and higher IL-6 (tau = 0.004) and IL-10 (tau = 0.027) levels. LIMITATIONS: The results need to be replicated in a larger sample, and the study did not evaluate causal relationships. Although the assessment of childhood trauma was retrospective, the CTQ is a well-established assessment instrument. CONCLUSIONS: The patients with MDD in this study showed an immune activation in response to stress. This study highlights the association of childhood trauma and current and long-term stress with an increased immune activation in MDD.

Low-Grade Inflammation as a Predictor of Antidepressant and Anti-Inflammatory Therapy Response in MDD Patients: A Systematic Review of the Literature in Combination With an Analysis of Experimental Data Collected in the EU-MOODINFLAME Consortium.

Low-grade inflammation plays a role not only in the pathogenesis of major depressive disorder (MDD) but probably also in the poor responsiveness to regular antidepressants. There are also indications that anti-inflammatory agents improve the outcomes of antidepressants. Aim: To study whether the presence of low-grade inflammation predicts the outcome of antidepressants, anti-inflammatory agents, or combinations thereof. Methods: We carried out a systematic review of the literature on the prediction capability of the serum levels of inflammatory compounds and/or the inflammatory state of circulating leukocytes for the outcome of antidepressant/anti-inflammatory treatment in MDD. We compared outcomes of the review with original data (collected in two limited trials carried out in the EU project MOODINFLAME) on the prediction capability of the inflammatory state of monocytes (as measured by inflammatory gene expression) for the outcome of venlafaxine, imipramine, or sertraline treatment, the latter with and without celecoxib added. Results: Collectively, the literature and original data showed that: 1) raised serum levels of pro-inflammatory compounds (in particular of CRP/IL-6) characterize an inflammatory form of MDD with poor responsiveness to predominately serotonergic agents, but a better responsiveness to antidepressant regimens with a) (add-on) noradrenergic, dopaminergic, or glutamatergic action or b) (add-on) anti-inflammatory agents such as infliximab, minocycline, or eicosapentaenoic acid, showing-next to anti-inflammatory-dopaminergic or lipid corrective action; 2) these successful anti-inflammatory (add-on) agents, when used in patients with low serum levels of CRP/IL-6, decreased response rates in comparison to placebo. Add-on aspirin, in contrast, improved responsiveness in such "non-inflammatory" patients; 3) patients with increased inflammatory gene expression in circulating leukocytes had a poor responsiveness to serotonergic/noradrenergic agents. Conclusions: The presence of inflammation in patients with MDD heralds a poor outcome of first-line antidepressant therapies. Immediate step-ups to dopaminergic or glutamatergic regimens or to (add-on) anti-inflammatory agents are most likely indicated. However, at present, insufficient data exist to design protocols with reliable inflammation parameter cutoff points to guide such therapies, the more since detrimental outcomes are possible of anti-inflammatory agents in "non-inflamed" patients.

Transcranial Direct Current Stimulation (tDCS) for Depression during Pregnancy: Scientific Evidence and What Is Being Said in the Media-A Systematic Review.

Major depression is the most frequent morbidity in pregnancy. The first-line therapies, psychopharmacologic treatment and psychotherapy, are either insufficient or may cause severe or teratogenic adverse events. As a result of its local limitation to the patient's brain, transcranial direct current stimulation (tDCS) could potentially be an ideal treatment for pregnant women with depression. A literature search was conducted in medical databases, globally published newspapers, search engines, and clinical trial registers to collect all articles on tDCS for the treatment of depression during pregnancy. The aim of this review was to investigate the scientific evidence of tDCS use for depression during pregnancy and to compare these results with the textual and emotional perception in the media as interventions during pregnancy are under particular surveillance. We detected 13 medical articles dealing with tDCS for depression in pregnancy. Overall, the scientific evidence as well as articles in the media for tDCS in pregnancy are sparse, but promising. Further studies are required in this specifically vulnerable population of pregnant women to generate evidence. It is likely that public interest will increase when the results of a pilot study in Canada are published.

Cathodal tDCS Over Motor Cortex Does Not Improve Tourette Syndrome: Lessons Learned From a Case Series.

Introduction: Current pathophysiological hypotheses of Gilles de la Tourette Syndrome (GTS) refer to temporally abnormal neuronal activation in cortico-striato-thalamo-cortical (CSTC) networks. Modifying cortical activity by non-invasive brain-stimulation appears to be a new treatment option in GTS. Background: Previous studies suggested therapeutic effects of cathodal transcranial direct current stimulation (tDCS) to pre-supplementary motor areas (SMA), however, treatment modalities concerning electrode placement, current intensity and stimulation-rate have not been systematically explored. Aim of this study was to assess efficacy of an alternative stimulation regime on GTS symptoms in a pilot study. To test a treatment protocol with tDCS twice a day, we administered 10 sessions over 5 days of bilateral cathodal tDCS (30 min, 2 mA) over the pre-SMA in three patients with severe GTS. Tic severity as well as obsessive-compulsive (OC) symptoms and affective scales were rated before and after tDCS treatment. Discussion: Only one out of three patients showed a 34.5% reduction in tic severity. The two other patients showed an increase in tic severity. All patients showed a mild increase in positive affect and a reduction in negative affect, OC symptom changes were heterogeneous. Our results do not support earlier findings of extensive therapeutic effects of cathodal tDCS on tics in patients with GTS and show that prediction of stimulation effects on a targeted brain area remains inaccurate. Concluding Remarks: Future research will have to focus on the determination of most effective stimulation modes regarding site, polarity and frequency of tDCS in GTS patients.

The role of inflammation in schizophrenia.

High levels of pro-inflammatory substances such as cytokines have been described in the blood and cerebrospinal fluid of schizophrenia patients. Animal models of schizophrenia show that under certain conditions an immune disturbance during early life, such as an infection-triggered immune activation, might trigger lifelong increased immune reactivity. A large epidemiological study clearly demonstrated that severe infections and autoimmune disorders are risk factors for schizophrenia. Genetic studies have shown a strong signal for schizophrenia on chromosome 6p22.1, in a region related to the human leucocyte antigen (HLA) system and other immune functions. Another line of evidence demonstrates that chronic (dis)stress is associated with immune activation. The vulnerability-stress-inflammation model of schizophrenia includes the contribution of stress on the basis of increased genetic vulnerability for the pathogenesis of schizophrenia, because stress may increase pro-inflammatory cytokines and even contribute to a lasting pro-inflammatory state. Immune alterations influence the dopaminergic, serotonergic, noradrenergic, and glutamatergic neurotransmission. The activated immune system in turn activates the enzyme indoleamine 2,3-dioxygenase (IDO) of the tryptophan/kynurenine metabolism which influences the serotonergic and glutamatergic neurotransmission via neuroactive metabolites such as kynurenic acid. The described loss of central nervous system volume and the activation of microglia, both of which have been clearly demonstrated in neuroimaging studies of schizophrenia patients, match the assumption of a (low level) inflammatory neurotoxic process. Further support for the inflammatory hypothesis comes from the therapeutic benefit of anti-inflammatory medication. Metaanalyses have shown an advantageous effect of cyclo-oxygenase-2 inhibitors in early stages of schizophrenia. Moreover, intrinsic anti-inflammatory, and immunomodulatory effects of antipsychotic drugs are known since a long time. Anti-inflammatory effects of antipsychotics, therapeutic effects of anti-inflammtory compounds, genetic, biochemical, and immunological findings point to a major role of inflammation in schizophrenia.

Impaired activation of the innate immune response to bacterial challenge in Tourette syndrome.

OBJECTIVES: Infections resulting in immune activation have been proposed to play an etiological role in a subgroup of patients with Tourette syndrome (TS). METHODS: In order to further characterize the interaction between pathogens and the innate immune system the toll-like receptor (TLR) 4 on CD14 + monocytes and soluble CD14 (sCD14) levels were analyzed in the serum of 33 Tourette patients and 31 healthy controls. Moreover, collected blood samples were stimulated with lipopolysaccharide (LPS) mimicking a bacterial infection. TLR4 was analysed by flow cytometry, sCD14 was analysed by enzyme-linked immunosorbent assay. RESULTS: Patients had a lower receptor expression of TLR4 after stimulation with LPS (P = 0.045) and higher levels of sCD14 (unstimulated P = 0.014, after LPS P = 0.045). The increase in TLR4 expression after stimulation with LPS was significantly higher in the control group (P = 0.041). CONCLUSIONS: Higher levels of sCD14, lower levels of TLR4 expression after stimulation and a diminished up-regulation of TLR4 expression after LPS stimulation in patients might represent an impaired activation of the innate immune response in TS, especially in regard to bacterial infection. The impaired response to pathogens could eventually lead to a higher susceptibility for infections. Recurring infections and a chronic inflammation could trigger and maintain the symptoms of TS.

Anti-inflammatory treatment in schizophrenia.

Antipsychotics, which act predominantly as dopamine D2 receptor antagonists, have several shortcomings. The exact pathophysiological mechanism leading to dopaminergic dysfunction in schizophrenia is still unclear, but inflammation has been postulated to be a key player in the pathophysiology of the disorder. A dysfunction in activation of the type 1 immune response seems to be associated with an imbalance in tryptophan/kynurenine metabolism; the degrading enzymes involved in this metabolism are regulated by cytokines. Kynurenic acid (KYNA), an N-methyl-d-aspartate antagonist, was found to be increased in critical regions of the central nervous system (CNS) in schizophrenia, resulting in reduced glutamatergic neurotransmission. The differential activation of microglial cells and astrocytes as functional carriers of the immune system in the CNS may also contribute to this imbalance. The immunological effects of many existing antipsychotics, however, rebalance in part the immune imbalance and overproduction of KYNA. The immunological imbalance results in an inflammatory state combined with increased prostaglandin E(2) production and increased cyclo-oxygenase-2 (COX-2) expression. Growing evidence from clinical studies with COX-2 inhibitors points to favorable effects of anti-inflammatory therapy in schizophrenia, in particular in an early stage of the disorder. Further options for immunomodulating therapies in schizophrenia will be discussed.

Monocytic HLA DR antigens in schizophrenic patients.

A genetic association of specific human leukocyte antigens (HLA) DR genes and schizophrenia has recently been shown. These HLA play a fundamental role in the control of immune responses. Furthermore infectious agents have been proposed to be involved in the pathogenesis of schizophrenia. In this study we investigated the rate of HLA DR positive monocytes in schizophrenic patients compared to controls with a special focus on the adaption to in vitro stimulation with toll-like receptor ligands. Patients with schizophrenia and matched controls were included. For each individual, we evaluated the rate of HLA DR positive monocytes (either incubated at 37 °C or after stimulation with lipopolysaccharide or Poly I:C). We found a significantly higher percentage of schizophrenic patients with elevated HLA DR positive cells (p=0.045) as compared to controls. The adjustment rate from baseline levels of monocytic HLA DR positive cells to stimulation with Poly I:C was significantly lower in schizophrenic patients (p=0.038). The increased monocytic HLA DR in schizophrenic patients and the maladjustment of their monocytic HLA DR levels to an infectious stimulus might be a sign for a disturbed monocytic immune balance in schizophrenic individuals.