A Brief History of Immunological Research into Psychosis and Pathways for Immune Influence of the Brain.

Infection and inflammation resulting from a malfunctioning of the immune system have been discussed as pathological factors in psychosis for more than 130 years. The first immune-modulating therapeutic approaches for psychosis were developed more than 100 years ago, but the breakthrough of antipsychotic treatment in the 1950s shifted the emphasis of research to catecholaminergic neurotransmission. In the 1990s, however, the unsatisfactory therapeutic effects of antipsychotics, and the fact that the pathological mechanisms of psychosis were still unknown, reignited the scientific interest in other topics, including inflammation. In parallel, the further development of immunological methods enabled a more sophisticated examination of immunological and inflammatory mechanisms. Psychiatrists' interest in this interdisciplinary field increased as a consequence of encouraging results of psychoneuroimmunological research and broader funding of the field. In the meantime, the benefits of anti-inflammatory treatment in psychosis have been demonstrated in clinical studies and meta-analyses. Future studies are warranted to evaluate the exact immunological mechanisms in the pathophysiology of the disease, optimize the anti-inflammatory treatment approach and develop more targeted, personalized therapies in psychosis.

COX-2 Inhibitors, Aspirin, and Other Potential Anti-Inflammatory Treatments for Psychiatric Disorders.

Inflammatory processes associated with persistent (chronic) infection have long been discussed as etiological factors in psychiatric disorders. Studies have found that people with major depression have higher levels of pro-inflammatory cytokines, for example, IL-1, IL-6, and tumor necrosis factor-alpha, and C-reactive protein. In schizophrenia, many reports have described raised levels of cytokines, for example, IL-6; and meta-analyses have confirmed these findings. Microglia cells are important in inflammatory processes, and positron emission tomography studies have shown microglia activation in both depression and schizophrenia.As a consequence of the above findings, immunomodulation is widely discussed as a potential treatment approach in both major depression and schizophrenia. The COX-2 inhibitor celecoxib was found to have a significant positive effect on major depression, not only in single studies but also in meta-analyses. Celecoxib has also been studied in schizophrenia and has shown efficacy, in particular, in early disease stages. The mixed COX inhibitor aspirin (acetylsalicylic acid) seems to have both protective and therapeutic effects on schizophrenia.This paper discusses the hypothesized role of inflammation in major depression and schizophrenia, including markers of inflammation; pertinent studies on celecoxib and aspirin; and additional immunomodulatory therapeutic strategies.

Immunological aspects of the treatment of depression and schizophrenia.

Schizophrenia and major depression (MD) have been associated with immune system dysfunction. One example of this is the altered level of cytokines-important inflammatory mediators-in blood, and a proinflammatory immune state has been described in some subgroups of patients. A knock to the immune system in early life might trigger a life-long increased immune reactivity, and infections and autoimmune disorders are now known to be risk factors for development of schizophrenia and MD. Pro- and anti-inflammatory cytokines mediate indoleamine 2,3-dioxygenase activity; this enzyme drives metabolism of tryptophan and kynurenin in the central nervous system and degrades serotonin. Alterations of serotonergic, noradrenergic, and glutamatergic neurotransmission have been associated with low-level neuroinflammation, and anti-inflammatory compounds have a therapeutic benefit in MD and schizophrenia, as shown in meta-analyses. Moreover, antidepressants and antipsychotics have intrinsic immunomodulatory effects. With evidence pointing to the role inflammatory processes play in the pathogenesis of major psychiatric disorders, this review will look at various immunological aspects of treatment of such disorders.

La esquizofrenia y la depresión mayor (DM) se han asociado con una disfunción del sistema inmune, como lo demuestra la alteración en el nivel sanguíneo de citoquinas - importantes mediadores inflamatorios - y un estado inmune proinflamatorio descrito en algunos subgrupos de pacientes. Una agresión al sistema inmune en edades precoces puede gatillar un aumento de la reactividad inmune a lo largo de la vida. Hoy se sabe que las infecciones y los trastornos inmunes constituyen factores de riesgo para el desarrollo de la esquizofrenia y la DM. Las citoquinas pro y anti-inflamatorias median la actividad de la indolamina 2,3 dioxigenasa, enzima que estimula el metabolismo del triptófano y la quinurenina en el sistema nervioso central y que degrada la serotonina. Los resultados de meta-análisis han asociado la alteración de la neurotransmisión serotoninérgica, noradrenérgica y glutamatérgica con bajos niveles de neuroinflamación, y el beneficio terapéutico de los compuestos antiinflamatorios en la DM y en la esquizofrenia. Además, los antidepresivos y los antipsicóticos tienen efectos inmunomoduladores intrínsecos. Este artículo revisa varios aspectos inmunológicos del tratamiento de importantes trastornos psiquiátricos, de acuerdo con la evidencia que apunta al papel que juegan los procesos inflamatorios en la patogénesis de estos trastornos.

Schizophrénie et dépression caractérisée sont associées à une dysfonction du système immunitaire comme le montrent l'altération du taux de cytokines (médiateurs inflammatoires importants) dans le sang et l'état immunitaire pro-inflammatoire décrit chez certains sous-groupes de patients. Une atteinte précoce du système immunitaire peut déclencher une augmentation de la réactivité immunitaire tout au long de la vie, les infections et les troubles auto-immuns étant connus aujourd'hui pour être des facteurs de risque de développement de schizophrénie et de dépression caractérisée. Les cytokines pro- et anti-inflammatoires sont les médiateurs de l'activité de l'indoléamine 2,3-dioxygénase, enzyme qui stimule le métabolisme du tryptophane et de la kynurénine dans le système nerveux central et qui dégrade la sérotonine. Il existe une association entre des modifications de la neurotransmission sérotoninergique, noradrénergique et glutamatergique et une neuro-inflammation de faible niveau ; de plus, des méta-analyses montrent un bénéfice thérapeutique des anti-inflammatoires dans la schizophrénie et la dépression caractérisée. D'autre part, les antidépresseurs et les antipsychotiques ont des effets immunomodulateurs intrinsèques. Cet article s'intéresse aux différents aspects immunologiques du traitement des troubles psychiatriques caractérisés en soulignant les données en faveur du rôle joué par les processus inflammatoires dans leur pathogenèse.

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.

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.

Treatment of echinococcosis: albendazole and mebendazole--what else?

The search for novel therapeutic options to cure alveolar echinococcosis (AE), due to the metacestode of Echinococcus multilocularis, is ongoing, and these developments could also have a profound impact on the treatment of cystic echinococcosis (CE), caused by the closely related Echinococcus granulosus s.l. Several options are being explored. A viable strategy for the identification of novel chemotherapeutically valuable compounds includes whole-organism drug screening, employing large-scale in vitro metacestode cultures and, upon identification of promising compounds, verification of drug efficacy in small laboratory animals. Clearly, the current focus is targeted towards broad-spectrum anti-parasitic or anti-cancer drugs and compound classes that are already marketed, or that are in development for other applications. The availability of comprehensive Echinococcus genome information and gene expression data, as well as significant progress on the molecular level, has now opened the door for a more targeted drug discovery approach, which allows exploitation of defined pathways and enzymes that are essential for the parasite. In addition, current in vitro and in vivo models that are used to assess drug efficacy should be optimized and complemented by methods that give more detailed information on the host-parasite interactions that occur during drug treatments. The key to success is to identify, target and exploit those parasite molecules that orchestrate activities essential to parasite survival.

Schizophrenia genes, epigenetics and psychoneuroimmunology therapeutics: all make sense now?

Genetics, epigenetics, infection as an environmental factor, functional findings for the immune system, and a therapeutic approach with anti-inflammatory therapy provide evidence for a pivotal role of the immune system in schizophrenia. This field, therefore, should focus more on further schizophrenia research.

Stable expression of Escherichia coli beta-glucuronidase A (GusA) in Giardia lamblia: application to high-throughput drug susceptibility testing.

OBJECTIVES: In order to create a suitable model for high-throughput drug screening, a Giardia lamblia WB C6 strain expressing Escherichia coli glucuronidase A (GusA) was created and tested with respect to susceptibility to the anti-giardial drugs nitazoxanide and metronidazole. METHODS: GusA, a well-established reporter gene in other systems, was cloned into the vector pPacVInteg allowing stable expression in G. lamblia under control of the promoter from the glutamate dehydrogenase (gdh) gene. The resulting transgenic strain was compared with the wild-type strain in a vitality assay, characterized with respect to susceptibility to nitazoxanide, metronidazole and -- as assessed in a 96-well plate format -- to a panel of 15 other compounds to be tested for anti-giardial activity. RESULTS: GusA was stably expressed in G. lamblia. Using a simple glucuronidase assay protocol, drug efficacy tests yielded results similar to those from cell counting. CONCLUSIONS: G. lamblia WB C6 GusA is a suitable tool for high-throughput anti-giardial drug screening.

A psychoneuroimmunological perspective to Emil Kraepelins dichotomy: schizophrenia and major depression as inflammatory CNS disorders.

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.

Comparative study on the antioxidant and biological activities of carvacrol, thymol, and eugenol derivatives.

Four derivatives of thymol, carvacrol, and eugenol were synthesized: 4-(hydroxymethyl)-5-isopropyl-2-methylphenol, 4,4'-methylenebis(5-isopropyl-2-methyl)phenol, 4-allyl-6-(hydroxymethyl)-2-methoxyphenol, and 4-(hydroxymethyl)-2-isopropyl-5-methylphenol. The obtained derivatives showed remarkably better antioxidative properties according to 1,1-diphenyl-2-picrylhydrazyl assay (50% inhibitory concentrations = 4-156 microg/mL) and Rancimat assay (protection factors = 1.55-5.84) when compared with parent compounds and values similar to or better than those of butylated hydroxytoluene and vitamin C. At concentrations of 10 mM carvacrol derivatives had no toxic effect on viability of Escherichia coli K-12 (determined by minimum inhibitory concentrations). Other phenol derivatives showed reduced cytotoxic effect on E. coli K-12 at concentrations of 2-5 mM on the basis of 50% lethal dose measurements. In comparison with the parent compounds, phenol derivatives showed reduced cytotoxic effect for Saccharomyces cerevisiae cells (determined by yeast colony reduction). On the other hand, the majority of synthesized compounds had dose-dependent antiproliferative effects on human uterine carcinoma cells (HeLa), which makes them potentially interesting for the adjuvant experimental cancer treatments. The 4,4'-methylenebis(5-isopropyl-2-methyl)phenol derivative of carvacrol showed lower inhibiting capacity also for the HeLa cells, which makes this particular derivative attractive as an efficient antioxidant with negligible cytotoxic effects.

T- and B-lymphocytes in patients with schizophrenia in acute psychotic episode and the course of the treatment.

Schizophrenia is associated with alterations of the immune system. There are, however, only limited data dealing with immune parameters in unmedicated schizophrenic patients and the course of these parameters during treatment. In this study, we monitored CD19+ (B)- and CD3+ (T)-lymphocytes in the course of antipsychotic treatment. Forty patients diagnosed with an acute exacerbation of schizophrenia were tested before and after 3 days, 2 weeks, 4 weeks and 3 months of treatment with antipsychotics. The percentages of CD19+- and CD3+ -lymphocytes were analysed by flow cytometry using fluorescence conjugated anti-CD19 and anti-CD3 antibodies. Twenty healthy volunteers served as controls. In the acute state of psychosis, a significant reduction of the CD3+ -lymphocyte subpopulation was observed, while the percentage of CD19(+)-lymphocytes was increased. Both subpopulations levelled to those of the control group in the course of treatment. As expected, the levels of the immune parameters did not change in the healthy controls during the course of the study. The observed alterations of the CD19+ - and CD3+ -lymphocytes in the acute state of psychosis especially in patients with the paranoid subtype of schizophrenia, and the "normalization" during the observation period are discussed under the aspect of the immune hypothesis of schizophrenia, in particular of the type-1/type-2 imbalance hypothesis.

A questionnaire: will plateletpheresis donors accept multicomponent donation?

BACKGROUND AND OBJECTIVES: New technological developments make it possible to collect red blood cells (RBC) by apheresis which provides standardised products and has the potential for improved RBC quality. The purpose of this study was to evaluate the donors' opinion about the multicomponent donation procedure. MATERIAL AND METHODS: For evaluating the donors' opinion about this new apheresis technique we compiled a questionnaire. The questionnaire was given to all single needle actual plateletpheresis donors (n = 133) that donated platelets in our Institute during February-March 2001. The questionnaire contained 12 questions related to: (1) general information about previous donations of our donors and (2) donors' opinion about multicomponent donation. After implementation of multicomponent donation in December 2001 the data of the questionnaire were compared with the actual opinions of the donors about the procedure. RESULTS: The mean age of the donors was 38.1 +/- 9.1 years. The median number of previous platelets donations of the interviewed donors was 30. The majority of donors (92.4%) were willing for multicomponent donation. In the same time the majority of donors (74.8%) were willing to donate multicomponents four times per year. The different donation time was not an argument for the donors for the multicomponent donation, while the reduction of incidence of transfusion transmitted diseases was a motivation for them. The decrease of hemoglobin and the side effects caused by possible iron-supplementation therapy were found acceptable from most of our donors. Approximately 74% of the donors thought that the donation of a second component should result in better remuneration whereas 20% of them believed that the remuneration should be unchanged. Seventy-five RBC units were concurrently collected with platelets since December 15th, 2001. Six donors (7.4%) were unwilling to donate an additional RBC unit. CONCLUSION: Acceptance and disacceptance rates were almost equal after the implementation of multicomponent donation and at the time point when the interview was performed. The majority of donors was highly motivated to donate multicomponents, by these means we were able to increase our RBC supply and to improve standardization of our products.