Schizophrenia, a neuropsychiatric disorder has been associated with aberrant neurotransmission affecting behaviors, social preference, and cognition. Limitations in understanding its pathogenesis via the dopamine hypothesis have engendered other hypotheses such as the glutamate hypothesis. That antagonism of the N-methyl-D-aspartate receptor (NMDAR) elicits schizophrenia-like behaviors indistinguishable from the disorder in animal and human models. There are growing concerns that redox imbalance and neuro-immuno dysfunction may play role in aggravating the symptomologies of this disorder. This 14-day treatment study was designed to investigate the effect of diosmin on lipopolysaccharide (LPS) plus ketamine (NMDAR antagonist). Mice were divided into 4 groups (n = 6). Group 1 was administered 5% DMSO (10 mL/kg, i.p) while group 2-4 received LPS (0.1 mg/kg, i.p) daily for 14 days. Diosmin (50 mg/kg, i.p) and risperidone (0.5 mg/kg, i.p) were given to groups 3 and 4 respectively. Groups 2-4 were given KET (20 mg/kg, i.p.) daily from days 8-14. Behavioral tests were done 30 min after the last dose, and oxidative stress and neuroinflammatory maker were assayed. LPS plus ketamine-induced hyperlocomotion, stereotypy, decreased social preference, and memory impairment. Furthermore, LPS plus-ketamine-induced oxidative stress (reduced GSH, CAT, SOD, and increased MDA and nitrite levels) and marked pro-inflammatory cytokines TNF-α and IL-6 suggesting neuroinflammation. However, diosmin attenuated behavioral deficits and improved memory. Additionally, diosmin potentiated antioxidant level via increased GSH, CAT, and SOD while reducing MDA and nitrite levels. Finally, diosmin reduced TNF-α and IL-6 suggesting anti-neuro-immuno activity. Conclusively, diosmin attenuated LPS plus ketamine-induced behavioral deficits, oxidative stress, neuroinflammation, and improved memory.

Schizophrenia (SZ) is a severe mental disease with highly heterogeneous clinical manifestations and pathological mechanisms. Schizophrenia is linked to abnormalities in cell membrane phospholipids and blunting of the niacin skin flush response, but the associations between these phenotypes and its molecular pathogenesis remain unclear. This study aimed to describe the PLA2/COX pathway, the key link between phospholipids and niacin flush, and to illustrate the pathogenic mechanisms in schizophrenia that mediate the above phenotypes.

A total of 166 patients with schizophrenia and 54 healthy controls were recruited in this study and assigned to a discovery set and a validation set. We assessed the mRNA levels of 19 genes related to the PLA2/COX cascade in leukocytes by real-time PCR. Plasma IL-6 levels were measured with an ELISA kit. Genetic association analysis was performed on PLA2G4A and PTGS2 to investigate their potential relationship with blunted niacin-skin response in an independent sample set.

Six of the 19 genes in the PLA2/COX pathway exhibited significant differences between schizophrenia and healthy controls. The disturbance of the pathway indicates the activation of arachidonic acid (AA) hydrolysis and metabolization, resulting in the abnormalities of membrane lipid homeostasis and immune function, further increasing the risk of schizophrenia. On the other hand, the active process of AA hydrolysis from cell membrane phospholipids and decreased transcription of CREB1, COX-2 and PTGER4 may explain the reported findings of a blunted niacin response in schizophrenia. The significant genetic associations between PLA2G4A and PTGS2 with the niacin-skin responses further support the inference.

These results suggested that the activation of AA hydrolysis and the imbalance in COX-1 and COX-2 expression are involved in the pathogenesis of schizophrenia and blunting of the niacin flush response.

This work was supported by the National Key R&D Program of China (2016YFC1306900, 2016YFC1306802); the National Natural Science Foundation of China (81971254, 81771440, 81901354); Interdisciplinary Program of Shanghai Jiao Tong University (ZH2018ZDA40, YG2019GD04, YG2016MS48); Grants of Shanghai Brain-Intelligence Project from STCSM (16JC1420500); Shanghai Key Laboratory of Psychotic Disorders (13DZ2260500); and Shanghai Municipal Science and Technology Major Project (2017SHZDZX01); China Postdoctoral Science Foundation (2018M642029, 2018M630442, 2019M661526, 2020T130407); Natural Science Foundation of Shanghai (20ZR1426700); and Startup Fund for Youngman Research at SJTU (19 × 100040033).

Schizophrenia is a neuropsychiatric illness with no single definitive aetiology, making its treatment difficult. Antipsychotics are not fully effective because they treat psychosis rather than the cognitive or negative symptoms. Antipsychotics fail to alleviate symptoms when patients enter the chronic stage of illness. Topical application of niacin showed diminished skin flush in the majority of patients with schizophrenia compared to the general population who showed flushing. The niacin skin flush test is useful for identifying patients with schizophrenia at their ultra-high-risk stage, and understanding this pathology may introduce an effective treatment. This review aims to understand the pathology behind the diminished skin flush response, while linking it back to neurons and microglia. First, it suggests that there are altered proteins in the GPR109A-COX-prostaglandin pathway, inflammatory imbalance, and kinase signalling pathway, c-Jun N-terminal kinase (JNK), which are associated with diminished flush. Second, genes from the GPR109A-COX-prostaglandin pathway were matched against the 128-loci genome wide association study (GWAS) for schizophrenia using GeneCards, suggesting that G-coupled receptor-109A (GPR109A) may have a genetic mutation, resulting in diminished flush. This review also suggests that there may be increased pro-inflammatory mediators in the GPR109A-COX-prostaglandin pathway, which contributes to the diminished flush pathology. Increased levels of pro-inflammatory markers may induce microglial-activated neuronal death. Lastly, this review explores the role of JNK on pro-inflammatory mediators, proteins in the GPR109A-COX-prostaglandin pathway, microglial activation, and neuronal death. Inhibiting JNK may reverse the changes observed in the diminished flush response, which might make it a good therapeutic target.

Many hypotheses have been proposed for the development of schizophrenia, including the one proposing that exogenous and endogenous factors are linked to inflammatory processes. There is strong evidence about the immunological and inflammatory dysfunction in schizophrenia. In this study, we aimed to measure serum 15-deoxy-delta(12,14)-prostaglandin J (15d-PGJ), peroxisome proliferator-activated receptor gamma(PPARγ), prostaglandin E2 (PGE2) and C-reactive protein (CRP) levels. Forty-four patients and 39 healthy volunteers were included in the study. Serum PGE2, 15d-PGJ, PPARγ and CRP levels were measured in both the groups. Demographic data forms were filled out for the patient group, and the Positive and Negative Syndrome Scale, Clinical Global Impression-Severity scale and Calgary Depression scale were used to assess patients' clinical status. Serum PGE2, 15d-PGJ and PPARγ levels were found to be significantly lower in patients with schizophrenia than in healthy controls. There was no significant relationship between the serum PGE2, 15d-PGJ and PPARγ levels and CRP levels.In this study, the evidence of systemic inflammatory conditions in patients with schizophrenia was found. The duration of the disease has been found to be the only variable that independently affects all three biomarker levels in the patients with schizophrenia.

Schizophrenia is a serious mental illness of unclear aetiology. The reduced ability of methylnicotinate to induce a topical vasodilatory response in patients with the disorder is well established. Methylnicotinate causes vasodilation via stimulating the release of prostaglandins (including prostaglandin D₂) in the skin which in turn leads to relaxation of vascular smooth muscle. To determine whether the abnormality is likely to be due to decreased prostaglandin production, or a decreased effect of prostaglandins upon the vessels, topical methylnicotinate was applied to the forearms of patients with schizophrenia or healthy controls, followed by rating of the resulting erythema. The concentration of prostaglandin D₂ and its metabolite 11β-prostaglandin F_2α in the blood draining the arm was also measured. Although erythema was reduced in the patient group, this was not correlated with plasma prostaglandin concentrations. This data suggests the abnormality underlying the reduced potency of methylnicotinate to produce vasodilation in the disorder occurs downstream of prostaglandin synthesis possibly within the vasculature itself.

Schizophrenia (SCZ) is a multifactorial psychiatric disorder. Currently, its molecular pathogenesis remains largely unknown, and no reliable test for diagnosis and therapy monitoring is available. Polyunsaturated fatty acids (PUFAs) and their derived eicosanoid signaling abnormalities are relevant to the pathophysiology of schizophrenia. However, comprehensive analysis of eicosanoids and related mediators for schizophrenia is very rare. In this study, we applied a targeted liquid chromatography-mass spectrometry based method to monitor 158 PUFAs, eicosanoids and related mediators from enzyme-dependent or independent pathways, in the serum samples of 109 healthy controls, and 115 schizophrenia patients at baseline and after an 8-week period of antipsychotic therapy. Twenty-three metabolites were identified to be significantly altered in SCZ patients at baseline compared to healthy controls, especially arachidonic acid (AA) derived eicosanoids. These disturbances may be related to altered immunological reactions and neurotransmitter signaling. After 8-week antipsychotic treatment, there were 22 metabolites, especially AA and linoleic acid derived eicosanoids, significantly altered in posttreatment patients. Some metabolites, such as several AA derived prostaglandins, thromboxanes, and di-hydroxy-eicosatrienoic acids were reversed toward normal levels after treatment. Based on univariate analysis and orthogonal partial least-squares discriminant analysis, anandamide, oleoylethanolamine, and AA were selected as a panel of potential biomarkers for differentiating baseline SCZ patients from controls, which showed a high sensitivity (0.907), good specificity (0.843) and excellent area under the receiver operating characteristic curve (0.940). This study provided a new perspective to understand the pathophysiological mechanism and identify potential biomarkers of SCZ.

Nesfatin-1 and ghrelin are two hormones which has opposite effects and play role in food intake. This study was planned on the idea that both metabolic syndrome and psychiatric disorders are associated with nesfatin-1 and ghrelin. In this study, it was aimed to investigate the levels of ghrelin and nesfatin-1 in patients with schizophrenia, by taking confounding factor as the metabolic syndrome (MS). 55 patients with schizophrenia and 33 healthy controls were included in the study.11 out of the 55 patients (%20) has MS. Serum ghrelin and nesfatin-1 levels of schizophrenia patients with MS have been compared with both healthy controls and schizophrenia patients without MS. Patients with schizophrenia had significantly higher serum nesfatin-1 levels compared to healthy controls. But serum ghrelin levels was not different in both groups. Serum nesfatin-1 concentrations were significantly higher in the schizophrenia patients with MS (10.51-350.8pg/ml) with respect to the healthy control group (4.86-68.91pg/ml). There was no significant statistical difference between the three groups in terms of ghrelin levels. Our findings suggests that, MS presence also contributed to significantly high levels of nesfatin-1 level. Nesfatin-1 may have a part in a novel studies regarding the treatment of schizophrenia and its metabolic effects.

Objectives Platelets, the smallest anucleated blood cells, play an essential role in the first step of complex haemostatic process. This review presents the haemostatic function of blood platelets related to their activation in psychiatric disorders (schizophrenia, depression), the role of antipsychotic and antidepressant medication, and introduces the mechanisms by which activated platelets may be involved in the pathophysiology of these disorders. Methods Platelets are interesting and easily accessible blood cells to study biochemical pathways related to schizophrenia and other psychiatric disorders, and their complex activation process might be useful as a diagnostic peripheral marker for studying psychiatric disorders and haemostatic complications. Results The excessive activation of platelets observed in patients with depression and schizophrenia is involved in cardiovascular diseases, stroke and increased risk of thrombotic complications that may be major causes of morbidity and mortality of patients. The use of antidepressants or antipsychotic drugs in depression and schizophrenia treatment is often associated with haematological side effects such as bleeding, venous thromboembolism and impaired platelet function. Conclusions Understanding the role of platelet activation in psychiatric disorders such as schizophrenia or depression and medication may improve therapies in the future.

The search for biomarkers in cognition has been the focus of a large part of the research on patients suffering from schizophrenia. The scientific literature is heterogeneous, and few studies establishing an integrative model of pathogenesis and therapeutic response are available in this field. In this review, we aimed to summarize three essential aspects correlated with cognitive performance: 1) the relationship between inflammation and cognition in schizophrenia, 2) the role of prolactin in cognition, and 3) the association between cognition and neurotrophic factors, particularly brain-derived neurotrophic factor (BDNF). Several studies support the association of inflammatory markers with cognitive status in schizophrenia. In recent decades, the development of effective therapies for cognitive impairment in schizophrenia has focused on the search for anti-inflammatory and immunomodulatory medications. Conversely, the implications of prolactin and its functions in cognition, the transition to psychosis and the diagnosis and prognosis of schizophrenia have been established independent of antipsychotic treatment. With regard to neurotrophic factors, a recent study has correlated BDNF levels with cognitive recovery in schizophrenic patients treated with cognitive remediation. We conclude that although there is a diversity of biomarkers focused on cognitive function in schizophrenia, BDNF is the biomarker that has accumulated the vast majority of evidence in the current literature.

In the past decade, there has been renewed interest in immune/inflammatory changes and their associated oxidative/nitrosative consequences as key pathophysiological mechanisms in schizophrenia and related disorders. Both brain cell components (microglia, astrocytes, and neurons) and peripheral immune cells have been implicated in inflammation and the resulting oxidative/nitrosative stress (O&NS) in schizophrenia. Furthermore, down-regulation of endogenous antioxidant and anti-inflammatory mechanisms has been identified in biological samples from patients, although the degree and progression of the inflammatory process and the nature of its self-regulatory mechanisms vary from early onset to full-blown disease. This review focuses on the interactions between inflammation and O&NS, their damaging consequences for brain cells in schizophrenia, the possible origins of inflammation and increased O&NS in the disorder, and current pharmacological strategies to deal with these processes (mainly treatments with anti-inflammatory or antioxidant drugs as add-ons to antipsychotics).

Extensive research implicates disturbed immune function and development in the etiology and pathology of schizophrenia. In addition to reviewing evidence for immunological factors in schizophrenia, this paper discusses how an emerging model of atypical immune function and development helps explain a wide variety of well-established - but puzzling - findings about schizophrenia. A number of theorists have presented hypotheses that early immune system programming, disrupted by pre- and perinatal adversity, often combines with abnormal brain development to produce schizophrenia. The present paper focuses on the hypothesis that disruption of early immune system development produces a latent immune vulnerability that manifests more fully after puberty, when changes in immune function and the thymus leave individuals more susceptible to infections and immune dysfunctions that contribute to schizophrenia. Complementing neurodevelopmental models, this hypothesis integrates findings on many contributing factors to schizophrenia, including prenatal adversity, genes, climate, migration, infections, and stress, among others. It helps explain, for example, why (a) schizophrenia onset is typically delayed until years after prenatal adversity, (b) individual risk factors alone often do not lead to schizophrenia, and (c) schizophrenia prevalence rates actually tend to be higher in economically advantaged countries. Here we discuss how the hypothesis explains 10 key findings, and suggests new, potentially highly cost-effective, strategies for treatment and prevention of schizophrenia. Moreover, while most human research linking immune factors to schizophrenia has been correlational, these strategies provide ethical ways to experimentally test in humans theories about immune function and schizophrenia. This article is part of a Special Issue entitled SI: Neuroimmunology in Health And Disease.

Platelets, known for their role in primary haemostasis, prevent excessive bleeding after injury. The study of platelets has, therefore, traditionally focused on bleeding disorders. It has recently become evident, however, that platelet research can contribute to unravelling the disease mechanisms that underlie neuropathological disorders that have a subtle subclinical platelet phenotype. Platelets and neurosecretory cells have common gene expression profiles and share several biological features. This review provides a literature update on the use of platelets as easily accessible cells to study neurological disorders. We provide examples of the use of different platelet-based tests to understand the underlying pathophysiological mechanisms for both complex and monogenetic neuropathological disorders. In addition to the well-studied regulated granule secretion and serotonin metabolism, more recent studies have shown that defects in transcription factors, membrane transporters, G-protein signal transduction, and cytoskeletal proteins can be investigated using platelets to gain information on their role in neuropathology.

Schizophrenia is a chronic syndrome of unknown etiology, predominantly defined by signs of psychosis. The onset of the disorder occurs typically in late adolescence or early adulthood. Efforts to study pathophysiological mechanisms in early stages of the disease are crucial in order to prompt intervention.

Case-control study of first-episode psychotic (FEP) patients and matched controls. We recruited 117 patients during the first year after their FEP according to the DSM-IV criteria and recruited 106 gender-, race-, and age-matched controls between September 2010 and June 2011.

Biochemical studies carried out in peripheral mononuclear blood cells (PMBC) and plasma evidence a significant increase in intracellular components of a main proinflammatory pathway, along with a significant decrease in the anti-inflammatory ones. Multivariate logistic regression analyses identified the expression of inducible isoforms of nitric oxide synthase and cyclooxygenase in PMBC and homocysteine plasma levels as the most reliable potential risk factors and the inhibitor of the inflammatory transcription factor NFκB, IκBα, and the anti-inflammatory prostaglandin 15d-PGJ2 as potential protection factors.

Taken as a whole, the results of this study indicate robust phenotypical differences at the cellular machinery level in PMBC of patients with FEP. Although more scientific evidence is needed, the determination of multiple components of pro- and anti-inflammatory cellular pathways including the activity of nuclear receptors has interesting potential as biological markers and potential risk/protective factors for FEP. Due to its soluble nature, a notable finding in this study is that the anti-inflammatory mediator 15d-PGJ2 might be used as plasmatic biomarker for first episodes of psychosis.

Inflammation, caused by both external and endogenous factors, has been implicated as a main pathophysiological feature of chronic mental illnesses, including schizophrenia. An increase in pro-inflammatory cytokines has been described both in experimental models and in schizophrenia patients. However, not much is known about the effects that antipsychotic drugs have on intra- and intercellular mechanisms controlling inflammation. The aim of the present study was to investigate the possible anti-inflammatory effect of a standard schizophrenia treatment not only at the level of soluble mediators, but also at intra- and intercellular inflammatory pathways. The present study was conducted in a model of mild neuroinflammation using a lipopolysaccharide (LPS) challenge that was not an endotoxaemic dose (0.5 mg/kg i.p.) in young adult rats.

single doses of risperidone (0.3-3.0 mg/kg i.p.) prevented increased inflammatory parameters induced by LPS in brain cortex [expression of inflammatory cytokines, interleukin (IL)-1β and tumour necrosis factor (TNF)-α, activity of the inducible inflammatory enzymes nitric oxide synthase and cyclooxygenase, p38 mitogen-activated protein kinase (MAPK) and inflammatory nuclear transcription factor κB] and restored anti-inflammatory pathways decreased by LPS challenge (deoxyprostaglandins and peroxisome proliferator activated receptor γ). This is the first study demonstrating that risperidone elicits a preventive effect on the anti-inflammatory arm of the homeostatic mechanism controlling inflammation in a model of mild encephalitis in rats. Our findings suggest a possible protective effect of risperidone on brain cells.

Emerging evidence indicates that schizophrenia is associated with activated peripheral and central inflammatory responses. Such inflammatory processes seem to be influenced by a number of environmental and genetic predisposition factors, and they may critically depend on and contribute to the progressive nature of schizophrenic disease. There is also appreciable evidence to suggest that activated inflammatory responses can undermine disease-relevant affective, emotional, social, and cognitive functions, so that inflammatory processes may be particularly relevant for the precipitation of negative and cognitive symptoms of schizophrenia. Recent clinical trials of anti-inflammatory pharmacotherapy in this disorder provide promising results by showing superior beneficial treatment effects when standard antipsychotic drugs are co-administered with anti-inflammatory compounds, as compared with treatment outcomes using antipsychotic drugs alone. Given the limited efficacy of currently available antipsychotic drugs to ameliorate negative and cognitive symptoms, the further exploration of inflammatory mechanisms and anti-inflammatory strategies may open fruitful new avenues for improved treatment of symptoms undermining affective, emotional, social and cognitive functions pertinent to schizophrenic disease.

A number of findings suggest that inflammation plays a role in the pathophysiology of schizophrenia. Taking into account a physiological balance between pro- and anti-inflammatory mediators, we measured the plasma levels of cyclooxygenase-derived mediators and other key pro- and anti-inflammatory transcription factors in peripheral blood mononuclear cells (PBMC). Forty healthy subjects and 46 treated chronic schizophrenic patients with an acutely exacerbated condition who met DSM-IV criteria were included. COX by-products prostaglandin E2 (PGE2) and 15d-prostaglandin J2 (15d-PGJ2) plasma levels were measured by EIA. Peroxisome proliferator-activated receptor gamma (PPARγ) as well as nuclear factor kappaB (NFκB) activity in nuclear extracts from PBMC and expression of its inhibitory subunit IκBα in cytosolic extracts were determined using ELISA-based kits. Schizophrenic patients showed higher plasma levels of pro-inflammatory PGE2 than age-matched controls (p=0.043). On the contrary, levels of anti-inflammatory 15-d-PGJ2 were lower (p=0.004), correlating with a lower expression of its nuclear target, PPARγ in nuclear extracts from PBMC (p=0.001). Although no changes in NFκB activity were observed between patients and healthy controls, the expression of its inhibitory protein IκBα was lower in the patients compared to the controls (p=0.027). These findings suggest that schizophrenia is associated with a systemic imbalance in the plasma levels of pro-inflammatory/anti-inflammatory prostaglandins in favor of the former. Furthermore, the expression and activity of anti-inflammatory PPARγ are diminished in PBMC, which indicates a state of inflammation and blunted anti-inflammatory counterbalancing mechanisms at systemic level in these patients.

This chapter has carried out a review of the literature and combined this with the results of in-house studies to identify candidate blood-based biomarkers for schizophrenia and antipsychotic drug response. Literature searches retrieved 185 publications describing a total of 273 schizophrenia biomarkers identified in serum and/or plasma. Examination of seven in-house multicenter studies resulted in the identification of 137 serum/plasma biomarkers. Taken together, the findings suggested an ongoing immunological and inflammatory process in schizophrenia. This was accompanied by altered cortisol levels which suggested activated stress response and altered hypothalamic-pituitary-adrenal axis function in these patients. The authors conclude that such biomarkers may prove useful as additional parameters for characterizing specific immune and/or metabolic or hormonal subsystems in schizophrenia and might, therefore, facilitate the development of future patient stratification and personalized medicine strategies.

The aetiology of psychiatric diseases such as depression or schizophrenia remains largely unknown, even though multiple theories have been proposed. Although monoamine theory is the cornerstone of available pharmacological therapies, relapses, incomplete control of symptoms or failure in treatment occur frequently. From an inflammatory/immune point of view, both entities share several common hallmarks in their pathophysiology, e.g. neuroendocrine/immune alterations, structural/functional abnormalities in particular brain areas, and cognitive deficits, suggesting a dysregulated inflammatory-related component of these diseases that better explains the myriad of symptoms presented by affected individuals. In this review we aimed to explore the role and relevance of inflammatory related lipids (prostanoids) derived from arachidonic acid metabolism by identification of new inflammatory markers and possible pharmacological/dietary modulation of these compounds, with the aim of improving some of the symptoms developed by individuals affected with psychiatric diseases (a critical review of basic and clinical studies about inflammatory-related arachidonic acid metabolism on neuropsychiatric diseases is included). As a specific candidate, one of these immunoregulatory lipids, the anti-inflammatory prostaglandin 15d-PGJ₂ and its nuclear receptor peroxisome proliferator-activated nuclear receptor (PPARγ) could be used as a biological marker for psychiatric diseases. In addition, its pharmacological activation can be considered as a multi-faceted therapeutic target due to its anti-inflammatory/antioxidant/anti-excitotoxic/pro-energetic profile, reported in some inflammatory-related scenarios (neurological and stress-related diseases). PPARs are activated by a great variety of compounds, the most relevant being the currently prescribed group of anti-diabetic drugs thiazolidinediones, and some cannabinoids (both endocannabinoids, phytocannabinoids or synthetic), as possible novel therapeutical strategy.

Schizophrenia is associated with a blunted flush response to niacin. Since niacin-induced skin flushing is mediated by vasodilators derived from arachidonic acid (AA), we tested whether the blunted flush response to niacin is a marker of AA deficiency.

Eight concentrations of methylnicotinate were applied to the forearms of 20 adults with schizophrenia and 20 controls. Laser Doppler measurement of blood flow responses was used to derive values for niacin sensitivity (defined as the concentration eliciting half-maximal response, i.e., EC(50) value) and efficacy (defined as the maximal evoked blood flow response). RBC membrane fatty acids were analyzed by gas chromatography.

Niacin sensitivity and efficacy were reduced in schizophrenia. In the control group, there was significant correlation between AA levels and niacin sensitivity as well as a trend toward correlation between AA levels and niacin efficacy. In contrast, neither sensitivity nor efficacy of niacin correlated with AA levels in schizophrenia. An expected correlation between the levels of AA and its elongation product (adrenic acid) was absent in schizophrenia. Adrenic acid levels correlated with niacin efficacy in schizophrenia.

The schizophrenia-associated niacin response abnormality involves both diminished sensitivity and reduced efficacy. The lack of expected correlation between levels of AA and adrenic acid suggests homeostatic imbalance within the n-6 polyunsaturated fatty acid (PUFA) pathway in schizophrenia. Though AA levels were unrelated to measures of niacin response in schizophrenia, the correlation between adrenic acid and niacin efficacy in schizophrenia suggests relevance of the n-6 PUFA pathway to the blunted niacin response.

We propose a unifying hypothesis of schizophrenia to help reconcile findings from many different disciplines. This hypothesis proposes that schizophrenia often involves pre- or perinatal exposure to adverse factors that produce a latent immune vulnerability. When this vulnerability is manifested, beginning around puberty with changes in immune function and involution of the thymus, individuals become more susceptible to infections and immune dysfunctions that contribute to schizophrenia. Our hypothesis suggests theoretical bridges between different lines of evidence on schizophrenia and offers explanations for many puzzling findings about schizophrenia. For example, the hypothesis helps account for why schizophrenia patients tend to have had increased exposure to neurotropic infections, but most individuals with such exposure do not develop schizophrenia, and why prenatal hardships increase risk for schizophrenia, but the onset of symptoms typically does not occur until after puberty. The hypothesis also explains another paradox: lower socioeconomic status and poor prenatal care increase risk for schizophrenia at the same geographic site, but international comparisons indicate that countries with higher per capita incomes and better prenatal care actually tend to have higher schizophrenia prevalences. As the hypothesis predicts, (1) prenatal adversity, which increases risk for schizophrenia, also impairs post-pubertal immune competence, (2) schizophrenia patients experience elevated morbidity from infectious and auto-immune diseases, (3) genetic and environmental risk factors for schizophrenia increase vulnerability to these diseases, (4) factors that exacerbate schizophrenic symptoms also tend to impair immune function, (5) many anti-psychotic medications combat infection, (6) effects of early infections may not appear until after puberty, when they can produce neurologic and psychiatric symptoms, and (7) immune dysfunctions, such as imbalances of pro- and anti-inflammatory cytokines, may contribute to the onset of psychotic symptoms and the progressive loss of brain tissue in schizophrenia. The disruptive effects of prenatal adversity on the development of the immune system may often combine with adverse effects on prenatal brain development to produce schizophrenia. This paper focuses on the adverse immune system effects, because effects on the brain have been extensively discussed in neurodevelopmental theories of schizophrenia. We propose new tests of scientific predictions. We also point out potential clinical implications of the hypothesis; for example, individuals with schizophrenia may often have underlying infections or immune dysfunctions, such as imbalances in inflammatory cytokines, that contribute to the illness. This possibility could be tested experimentally--e.g., by clinical trials in which patients' exposure to infection is reduced or immune function is normalized.

Oxidative stress in schizophrenia may be responsible for the changes of platelet function and reactivity. Therefore, the aim of our present study was to evaluate the response of platelets from patients with schizophrenia to platelet agonists such as ADP and collagen.

Platelet aggregation of schizophrenic patients and healthy subjects stimulated by collagen or ADP showed significant differences. Aggregation of platelets stimulated by collagen was significantly lower in schizophrenic patients (about 86%) than in healthy subjects (P=0.022), but when this process was induced by ADP, aggregation of platelets was significantly higher in schizophrenic patients (increase to about 112%) than in healthy subjects (P=0.018). We also observed that antipsychotic drugs (clozapine, risperidone, olanzapine, haloperidol) reduce aggregation of platelets of schizophrenic patients and healthy group in vitro.

The obtained results indicate that the response of platelets from schizophrenic patients to ADP and collagen is different than in healthy subjects.

Although emerging evidence suggests that schizophrenia (SZ) is associated with peripheral and central polyunsaturated fatty acid (PUFA) deficits, there is currently nothing known about the expression of genes that mediate PUFA biosynthesis in SZ patients. Here we determined Delta5 desaturase (FADS1), Delta6 desaturase (FADS2), elongase (HELO1 [ELOVL5]), peroxisomal (PEX19), and Delta9 desaturase (stearoyl-CoA desaturase, SCD) mRNA expression, and relevant fatty acid product:precursor ratios as estimates of enzyme activities, in the postmortem prefrontal cortex (PFC) of patients with SZ (n=20) and non-psychiatric controls (n=20). After correction for multiple comparisons, FADS2 mRNA expression was significantly greater in SZ patients relative to controls (+36%, p=0.002), and there was a positive trend found for FADS1 (+26%, p=0.15). No differences were found for HELO1 (+10%, p=0.44), PEX19 (+12%, p=0.44), or SCD (-6%, p=0.85). Both male (+34%, p=0.02) and female (+42%, p=0.02) SZ patients exhibited greater FADS2 mRNA expression relative to same-gender controls. Drug-free SZ patients (+37%, p=0.02), and SZ patients treated with typical (+40%, p=0.002) or atypical (+31%, p=0.04) antipsychotics, exhibited greater FADS2 mRNA expression relative to controls. Consistent with increased Delta6 desaturase activity, SZ patients exhibited a greater 20:3/18:2 ratio (+20%, p=0.03) and a positive trend was found for 20:4/18:2 (+13%, p=0.07). These data demonstrate abnormal, potentially compensatory, elevations in Delta6 desaturase (FADS2) expression in the PFC of SZ patients that are independent of gender and antipsychotic medications. Greater Delta6 desaturase expression and activity could have implications for central prostaglandin synthesis and proinflammatory signaling.

The Kraepelinian classification of psychiatric disorders, in particular the dichotomy of dementia praecox and manic-depressive psychosis is under discussion since a long time. In recent years, not only new research in the fields of psychopathology and clinical outcome, but also findings of biological markers in the areas of neurophysiology, neuroendocrinology, psychoneuroimmunology, genetics, or psychopharmacology show a big overlap between both groups of disorders. This overlap of symptoms and markers of both disorders intensified the discussion and the proposals for new criteria for the classification of psychiatric disorders. By means of findings from the field of psychoneuroimmunology and inflammation it will be shown that different pathological mechanisms in depression and schizophrenia may lead to the same final common pathway of inflammation. These mechanisms include the immunological balance between type-1 and type-2 immune activation which influences the tryptophan-degradating enzyme indoleamine 2,3-dioxygenase (IDO) in the CNS in opposite ways, leading to an altered availability of tryptophan and serotonin, and a disturbance of the kynurenine metabolism with an imbalance in favor of the production of the NMDA-receptor agonist quinolinic acid in depression and of the NMDA-receptor antagonist kynurenic acid in schizophrenia. In both disorders, however, an increased production of prostaglandin E2 and increased expression of cyclo-oxygenase-2 reflect a slight inflammatory process taking place probably in different regions of the CNS. Albeit this common inflammatory pathway--inflammation is a general pathway of the body as answer to a lot of different noxae and pathogens--the Kraepelinian dichotomy is important with respect to pathological mechanisms and therapeutic approaches, not only for further research in understanding the exact pathological mechanisms but also for the development of preventive strategies in high risk individuals and in patients. Opposite pathways regarding the immune activation, the neurotoxic versus neuroprotective kynurenine metabolites and the agonistic versus antagonistic effects on the NMDA receptor and the glutamatergic neurotransmission show despite a possible therapeutic advantage of anti-inflammatory therapy in both disorders that the Kraepelinian dichotomy still has a significant value from a biologic-psychiatric point of view.

This overview presents a hypothesis to bridge the gap between psychoneuroimmunological findings and recent results from pharmacological, neurochemical and genetic studies in schizophrenia. In schizophrenia, a glutamatergic hypofunction is discussed to be crucially involved in dopaminergic dysfunction. This view is supported by findings of the neuregulin- and dysbindin genes, which have functional impact on the glutamatergic system. Glutamatergic hypofunction is mediated by NMDA (N-methyl-D-aspartate) receptor antagonism. The only endogenous NMDA receptor antagonist identified up to now is kynurenic acid (KYN-A). KYN-A also blocks the nicotinergic acetycholine receptor, i.e. increased KYN-A levels can explain psychotic symptoms and cognitive deterioration. KYN-A levels are described to be higher in the CSF and in critical CNS regions of schizophrenics. Another line of evidence suggests that of the immune system in schizophrenic patients is characterized by an imbalance between the type-1 and the type-2 immune responses with a partial inhibition of the type-1 response, while the type-2 response is relatively over-activated. This immune constellation is associated with the inhibition of the enzyme indoleamine 2,3-dioxygenase (IDO), because type-2 cytokines are potent inhibitors of IDO. Due to the inhibition of IDO, tryptophan is predominantly metabolized by tryptophan 2,3-dioxygenase (TDO), which is located in astrocytes, but not in microglia cells. As indicated by increased levels of S100B, astrocytes are activated in schizophrenia. On the other hand, the kynurenine metabolism in astrocytes is restricted to the dead-end arm of KYN-A production. Accordingly, an increased TDO activity and an accumulation of KYN-A in the CNS of schizophrenics have been described. Thus, the immune-mediated glutamatergic-dopaminergic dysregulation may lead to the clinical symptoms of schizophrenia. Therapeutic consequences, e.g. the use of antiinflammatory cyclooxygenase-2 inhibitors, which also are able to directly decrease KYN-A, are discussed.

This manuscript deals with whether immune-mediated mechanisms of inflammation contribute to the pathogenesis of schizophrenia. A model is presented which integrates psychoneuroimmunologic findings and actual results from pharmacological, neurochemical, and genetic studies in schizophrenia. A pivotal role in the neurobiology of schizophrenia is played by dopaminergic neurotransmission, which is modulated by influences of the glutamatergic system. The decreased function of the glutamate system described in schizophrenia seems primarily mediated by N-methyl-D-aspartate (NMDA) receptor antagonism. Kynurenine acid is the only known endogenous NMDA receptor antagonist. In higher concentrations it blocks the NMDA receptor, but in lower concentrations it blocks the nicotinergic acetylcholin receptor, which has a prominent role in cognitive functions. Therefore, higher levels of kynurenine acid may explain psychotic symptoms and cognitive dysfunction. Several findings point out that prenatal infection, associated with an early sensitisation of the immune system, may result in an imbalance of the immune response (type 1 vs type 2) in schizophrenia. This immune constellation leads to inhibition of the enzyme indoleamin dioxigenase (IDO). It and tryptophane 2,3-dioxygenase (TDO) both catalyse the degradation from tryptophan to kynurenine. Due to the inhibition of IDO, tryptophan is metabolised to kynurenine primarily by TDO. In the CNS, TDO is located only in astrocytes, which are in particular activated in schizophrenia and in which kynurenine acid is the final product and can not be further metabolised. Therefore kynurenine acid accumulates in the CNS of schizophrenics and - due to its NMDA-antagonistic properties - leads to cognitive dysfunction and psychotic symptoms. This model describes the pathway of immune-mediated glutamatergic-dopaminergic dysregulation, which may lead to the clinical symptoms of schizophrenia. Therapeutic consequences (e.g. cyclo-oxygenase-2 inhibitors) are discussed.

Consistent with the hypothesis that neuroinflammatory processes contribute to the neuropathology of schizophrenia, the protein levels of epidermal growth factor (EGF) and its receptor ErbB1 are abnormal in patients with schizophrenia. To evaluate neuropathological significance of this abnormality, we established an animal model for behavioral deficits by administering EGF into the striatum and evaluated the effects of cyclooxygenase-2 (Cox-2) inhibitor celecoxib. Intracranial infusion of EGF into the striatum of adult male rats activated ErbB1 and induced neurobehavioral impairments observed in several schizophrenia models. Unilateral EGF infusion to the striatum lowered prepulse inhibition (PPI) in a dose-dependent manner and impaired latent learning of active shock avoidance without affecting basal learning ability. Bilateral EGF infusion similarly affected PPI. In contrast, EGF infusion to the nucleus accumbens did not induce a behavioral deficit. Intrastriatal EGF infusion also increased Cox-2 expression, elevated tyrosine hydroxylase activity, and upregulated the levels of dopamine and its metabolites. Subchronic administration of celecoxib (10 mg/kg, p.o.) ameliorated the abnormalities in PPI and latent learning as well as normalized dopamine metabolism. We conclude that this EGF-triggered neuroinflammatory process is mediated in part by Cox-2 activity and perturbs dopamine metabolism to generate neurobehavioral abnormalities.

The objective of the current research was to examine the relation between non-steroidal anti-inflammatory drugs (NSAID) use and risk of psychosis. To this end we performed a longitudinal case-control study using prescription data from a Dutch health insurance company. Men aged 25 years or over and women aged 30 years or over were excluded to prevent inclusion of non-incident cases. This resulted in eighty-two cases and 359 randomly selected controls from the same population. The overall relative risk of incident antipsychotic use for NSAID users, adjusted for age and prescription frequency, was 0.80 (95% CI: 0.48-1.33). After stratification for gender the risk of psychosis was significantly lower (59%) in male NSAID users only. The relative risks for male and female subjects were 0.41 (95% CI: 0.17-0.97) and 1.31 (95% CI: 0.65-2.64), respectively. These results suggest that in men NSAIDs may lower the risk of psychosis.

This review focuses on possible causes and the impact of different immune states in schizophrenia and major depression. It discusses the fact that, in schizophrenia, an over-activation of the type 2 immune response may dominate, while the type 1 and the pro-inflammatory immune responses are over-activated in major depression. The consequence of these diverse immune states is the activation and, respectively, inhibition of different enzymes in tryptophan/kynurenine metabolism, which may lead to an overemphasis of N-methyl-D-aspartate (NMDA) receptor antagonism in schizophrenia and of NMDA-receptor agonism in depression, resulting in glutamatergic hypofunction in schizophrenia and glutamatergic hyperfunction in major depression. In addition, the activation of the type 1 and the pro-inflammatory immune responses in major depression result in increased serotonin degradation and a serotonergic deficit. While antipsychotics and antidepressants today mainly act on the dopaminergic-glutamatergic and the noradrenergic-serotonergic neurotransmission, anti-inflammatory and immune-modulating therapies might act more basically at the pathophysiological mechanism. The limitations of this concept, however, are critically discussed.

This overview tries to bridge the gap between psychoneuroimmunological findings and recent results from pharmacological, neurochemical and genetic studies in schizophrenia. Schizophrenia is a disorder of dopaminergic neurotransmission, but modulation of the dopaminergic system by glutamatergic neurotransmission seems to play a key role. This view is supported by genetic findings of the neuregulin- and dysbindin genes, which have functional impact on the glutamatergic system. Glutamatergic hypofunction, however, is mediated by the N-methyl-D-aspartate (NMDA)-receptor antagonism. The only endogenous NMDA receptor antagonist identified up to now is kynurenic acid (KYNA). Despite the NMDA receptor antagonism, KYNA also blocks, in lower doses, the nicotinergic acetycholine receptor, i.e., increased KYNA levels can explain psychotic symptoms and cognitive deterioration. KYNA levels are described to be higher in the cerebrospinal fluid (CSF) and in critical central nervous system (CNS) regions of schizophrenics as compared to controls. Another line of evidence suggests that a (prenatal) infection is involved in the pathogenesis of schizophrenia. Due to an early sensitization process of the immune system or to a (chronic) infection, which is not cleared through the immune response, an immune imbalance between the type-1 and the type-2 immune responses takes place in schizophrenia. The type-1 response is partially inhibited, while the type-2 response is over-activated. This immune constellation is associated with inhibition of the enzyme indoleamine dioxygenase (IDO), because IDO - located in astrocytes and microglial cells - is inhibited by type-2 cytokines. IDO catalyzes the first step in tryptophan metabolism, the degradation from tryptophan to kynurenine, as does tryptophan 2,3-dioxygenase (TDO). Due to the inhibition of IDO, tryptophan-kynurenine is predominantly metabolized by TDO, which is located in astrocytes, not in microglial or other CNS cells. In schizophrenia, astrocytes in particular are activated, as increased levels of S100B appear. Additionally, they do not have the enzymatic equipment for the normal metabolism-route of tryptophan. Due to the lack of kynurenine hydroxylase (KYN-OHase) in astrocytes, KYNA accumulates in the CNS, while the metabolic pathway in microglial cells is blocked. Accordingly, an increase of TDO activity has been observed in critical CNS regions of schizophrenics. These mechanisms result in an accumulation of KYNA in critical CNS regions. Thus, the immune-mediated glutamatergic-dopaminergic dysregulation may lead to the clinical symptoms of schizophrenia. Therapeutic consequences, e.g., the use of anti-inflammatory cyclo-oxygenase-2 inhibitors, which can also decrease KYNA directly, are discussed.

A better understanding of the human immune system and its complex interactions has resulted in new insights into the pathoaetiological mechanisms of psychiatric disorders. As a result, new treatment options are being explored. Several findings suggest that an imbalanced immune response is involved in the pathophysiology of schizophrenia. COX-2 inhibitors are known to influence the immune system in a way that may redirect this imbalance. Based on these suggestions, the COX-2 inhibitor celecoxib has been tested as a possible adjunctive therapeutic approach in the treatment of schizophrenia. While the first trial using celecoxib as add-on therapy to an atypical antipsychotic showed a significant beneficial effect, recent studies demonstrated that this effect may be limited to patients with recent-onset schizophrenia.

Cyclooxygenase-2 (COX-2) is constitutively expressed in the central nervous system, and is thought to have an important functional role therein. COX-2 interacts with neurotransmitters such as acetylcholine, 5-hydroxytryptamine and glutamate but is also involved in the regulation of the central nervous system immune system and in inflammation via the effects of prostaglandins, in particular prostaglandin E2. A general therapeutic effect of the COX-2 inhibitor celecoxib on symptoms of schizophrenia was observed during a prospective, randomised, double-blind study of celecoxib add-on treatment to the atypical antipsychotic risperidone. The results from this trial of adjunctive therapy with a COX-2 inhibitor in schizophrenia are encouraging, and the findings support the view that an immunological/inflammatory process is involved in the pathogenesis of the disease. The add-on to an antipsychotic design of the study was chosen due to ethical reasons; in less acute schizophrenic states a monotherapy with COX-2 inhibitors would be interesting. From a theoretical point of view, other psychiatric indications for selective COX-2 inhibitors are discussed. COX-2 inhibitors have failed to show therapeutic effects in Alzheimer's disease but studies from basic research and a clinical perspective suggest it has an effect on disturbed cognition. In depression, however, signs of inflammation have been described for many years. Although results of clinical studies with COX-2 inhibitors in depression are still lacking, clinical improvement of a depressive syndrome has been observed in patients who have been treated with the COX-2 inhibitor rofecoxib due to other indications. These preliminary clinical data are encouraging for clinical therapeutic effects of the selective COX-2 inhibitors in psychiatric disorders, although these effects have to be confirmed in larger clinical studies.

Patients with schizophrenia have an increased risk over the general public of developing cardiovascular illness. It is unknown if there are functional changes in platelet surface receptors in schizophrenia. We therefore analyzed the surface expression of glycoprotein (GP)Ib, the integrin receptor alpha(IIb)beta(IIIa), CD62 (P-selectin), and CD63, and investigated platelet function in schizophrenic patients compared with healthy volunteers.

Nineteen drug-naive, first-episode patients with a DSM IV diagnosis of paranoid schizophrenia were compared with matched healthy controls. Flow cytometry was used to assess platelet surface expression levels of GPIb, alpha(IIb)beta(IIIa), CD62, and CD63. Adenosine diphosphate-induced platelet aggregation was assayed.

The schizophrenic patients had a significantly (p < .0001) increased number of 68,145 +/- 8,260.1 alpha(IIb)beta(IIIa) receptors, platelet compared with 56,235 +/- 8,079.4 receptors, platelet in healthy controls.

Patients with schizophrenia have increased platelet expression of alpha(IIb)beta(IIIa), which may contribute to their increased risk of cardiovascular illness compared with the general population.

We have earlier demonstrated that dopamine stimulates the liberation of the prostaglandin E(2) (PGE(2)) precursor, arachidonic acid, in Chinese hamster ovary cells transfected with the rat dopamine D(2) receptor (long isoform), also without concomitant administration of a Ca(2+)-releasing agent [Nilsson et al., Br J Pharmacol 1998;124:1651-8]. In the present report, we show that dopamine, under the same conditions, also induces a concentration-dependent increase in the production of PGE(2), with a maximal effect of 235% at approximately 100 microM, and with an EC(50) of 794 nM. The effect was counteracted by the D(2) antagonist eticlopride, pertussis toxin, the inhibitor of intracellular Ca(2+) release TMB-8, incubation in Ca(2+)-free experimental medium, and PKC desensitization obtained by chronic pretreatment with the phorbol ester TPA. It was also antagonized by the non-specific cyclooxygenase (COX) inhibitor, indomethacin, and by the selective COX-2 inhibitor, NS-398, but not by the specific COX-1 inhibitor, valeryl salicylate. Both the non-specific phospholipase A(2) inhibitor, quinacrine, and an inhibitor of cPLA(2) and iPLA(2), AACOF3, counteracted the effect; in contrast, a selective iPLA(2) inhibitor, BEL, and a selective sPLA(2) inhibitor, TAPC, were ineffective. No effects of dopamine were obtained in control cells mock-transfected with the p3C vector only. The results reinforce previous assumptions that dopamine may interact with eicosanoid metabolism by means of D(2) receptor activation, and implicate an involvement of cPLA(2) and COX-2 in this effect. It is suggested that measurement of dopamine-induced PGE(2) production may serve as a convenient way to study D(2) receptor function in vitro.

The discovery of blood platelet's ability to release 2-arachidonoyl-glycerol (2-AG), a highly lipophilic cannabinoid molecule may usher in a radical change in our understanding of how the vascular system interacts with the brain. This paper primarily extends Kayai's second messenger imbalance theory of schizophrenia, suggesting that 2-AG is the unidentified second messenger system that Kayai theorized was unbalanced in schizophrenia; furthermore, that a chronic over-release of 2-AG by platelets may be a causal factor in the cognitive deficits associated with negative symptom schizophrenia. Finally, platelet release of 2-AG may also be the causal agent in the cognitive deficits associated with states of high arousal, shock and in other conditions that feature heightened platelet activation. As such, heightened platelet activation may be a profoundly important vector for changing endogenous cannabinoid levels in the brain.