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Among numerous impediments to further advancement between the fifth and sixth symposia on Search for the Causes of Schizophrenia, several uncertainties endure: (i) What are the boundaries of psychotic illness? (ii) Where do we position what we currently conceptualise and diagnose as schizophrenia within the much broader reality of psychotic disorder among those with serious mental illness and, indeed, of psychotic phenomena among the general population? (iii) To what extent are those components of psychotic illness that we resolve into separate diagnostic categories actually distinct in any fundamental way in terms of their epidemiological, clinical and pathobiological ‘signature’?

Irritable bowel syndrome (IBS) has been linked with abnormal serotonin functioning and immune activation. Tryptophan forms the substrate for serotonin biosynthesis, but it can alternatively be catabolized to kynurenine (Kyn) by the enzyme indoleamine 2,3-dioxygenase (IDO), the main inducer of which is interferon-gamma. The primary aim of this study was to test the hypothesis that IBS is associated with increased tryptophan (Trp) catabolism along the Kyn pathway due to increased IFN-gamma levels. Plasma Kyn, Trp and IFN-gamma levels were measured in 41 female IBS subjects and 33 controls. Indoleamine 2,3-dioxygenase activity was assessed using the Kyn to Trp ratio. Psychiatric co-morbidity was assessed using the Patient Health Questionnaire, and severity of IBS assessed using self-report ordinal scales. Irritable bowel syndrome subjects had increased Kyn concentrations compared with controls (P = 0.039) and there was a trend for Kyn:Trp to be increased in the IBS group (P = 0.09). There was a positive correlation between IBS severity and Kyn:Trp (r = 0.57, P < 0.001). Those with severe IBS symptoms had increased Kyn:Trp (P < 0.005) compared to those with less severe symptoms and controls, and were over twice as likely to have depression or anxiety compared to those with less severe IBS (RR = 2.2, 95% CI 1.2-3.9). No difference in IFN-gamma levels was observed between groups; however, IFN-gamma was positively correlated with Kyn:Trp in IBS (r = 0.58, P = 0.005) but not controls (r = 0.12, P = 0.5). Females with IBS have abnormal Trp catabolism. The Kyn:Trp is related to symptom severity, and those with severe IBS symptoms have increased shunting of Trp along the Kyn pathway which contributes to the abnormal serotonergic functioning in this syndrome.

Host defence against infection requires a range of innate and adaptive immune responses that may lead to tissue damage. Such immune-mediated pathologies can be controlled with appropriate T regulatory (Treg) activity. The aim of the present study was to determine the influence of gut microbiota composition on Treg cellular activity and NF-κB activation associated with infection. Mice consumed the commensal microbe Bifidobacterium infantis 35624 followed by infection with Salmonella typhimurium or injection with LPS. In vivo NF-κB activation was quantified using biophotonic imaging. CD4+CD25+Foxp3+ T cell phenotypes and cytokine levels were assessed using flow cytometry while CD4+ T cells were isolated using magnetic beads for adoptive transfer to naïve animals. In vivo imaging revealed profound inhibition of infection and LPS induced NF-κB activity that preceded a reduction in S. typhimurium numbers and murine sickness behaviour scores in B. infantis–fed mice. In addition, pro-inflammatory cytokine secretion, T cell proliferation, and dendritic cell co-stimulatory molecule expression were significantly reduced. In contrast, CD4+CD25+Foxp3+ T cell numbers were significantly increased in the mucosa and spleen of mice fed B. infantis. Adoptive transfer of CD4+CD25+ T cells transferred the NF-κB inhibitory activity. Consumption of a single commensal micro-organism drives the generation and function of Treg cells which control excessive NF-κB activation in vivo. These cellular interactions provide the basis for a more complete understanding of the commensal-host-pathogen trilogue that contribute to host homeostatic mechanisms underpinning protection against aberrant activation of the innate immune system in response to a translocating pathogen or systemic LPS., Author Summary The normal response to infection is rapid and effective clearance of pathogenic microbes. However, this immune response may occasionally cause collateral inflammatory damage to host tissue and in severe cases, such as systemic sepsis, results in organ failure. Various cellular mechanisms, including regulatory T cells, protect against aggressive immune responses. However, environmental agents which promote regulatory T cells are not well understood. We and others have previously shown that non-pathogenic or commensal micro-organisms can protect the host from aberrant pro-inflammatory activity within the gut, but the influence of these microbes on regulatory T cells in the context of systemic infection has not been examined. In this study, we demonstrate that consumption of a single commensal bacterium induces regulatory T cells in vivo which protect the host from pathogen-induced inflammatory responses by limiting activation of the pro-inflammatory transcription factor NF-κB via the toll-like receptor 4 (TLR-4) pathway. This report conclusively demonstrates a cellular and molecular basis for the commensal-host-pathogen trilogue resulting in enhanced protection from systemic infection whilst limiting pro-inflammatory damage mediated by activation of the innate immune system.

There is evidence that increased inflammatory activity contributes to treatment non-response in depression and studies suggest that omega-3 fatty acid supplementation is effective in antidepressant non-responders. We tested the hypotheses that in major depression (1) the plasma omega-6:omega-3 fatty acid ratio is greater in antidepressant non-responders than responders and (2) higher omega-6:omega-3 ratios are associated with a pro-inflammatory cytokine profile. Twenty DSM-IV major depressives who had failed a six week course of an SSRI, 14 subjects who responded to a six week course of an SSRI and were currently euthymic and 24 healthy comparison subjects took part in the study. Six millilitres of whole blood was collected in ethylenediaminetetraacetic acid (EDTA) tubes for determination of fatty acids together with IL-6 and TNF-alpha. Arachidonic acid (AA) levels were elevated in both the responders and the non-responders. IL-6 was elevated in a similar manner but differences in TNF-alpha did not reach statistical significance. The eicosapentaenoic acid (EPA):AA ratio in the three groups was as follows: controls 0.08+/-0.01; responders 0.08+/-0.01; non-responders 0.04+/-0.01. These differences are significant (p0.001). AA and IL-6 were highly correlated in both responders and non-responders but not in healthy volunteers. The findings of this study provide further support for the view that major depression is associated with a pro-inflammatory phenotype which at least partially persists when patients become normothymic.

The D-amino acid oxidase (DAO) signaling pathway has been implicated in schizophrenia pathogenesis. This may be mediated through modulation of NMDA function by DAO, which is in turn activated by DAO activator (DAOA, formerly G72). Chumakov et al. (2002); PNAS 99: 13675–13680, identifying the novel schizophrenia susceptibility gene DAOA/G30 and a number of independent studies have since reported evidence of association between the DAOA and DAO genes and schizophrenia. However, at least two studies have failed to replicate the epistatic interaction between these loci described in the original report and there have been differences in the associated alleles/haplotypes reported at each locus. In this study, we performed association and epistasis analyses of the DAOA/G30 and DAO loci in a sample of 373 cases with DSM-IV schizophrenia/schizoaffective disorder and 812 controls from the Republic of Ireland. Corrected for the number of tests performed, we found evidence for association between markers at both genes and schizophrenia: DAOA/G30 (P = 0.005, OR = 1.34 (1.09, 1.65)) and DAO (P = 0.003, OR = 1.43 (1.12, 1.84). The data suggest that evidence for association at DAO (marker rs2111902) is more consistent than previously realized, particularly in Caucasian schizophrenia populations. We identified evidence for epistatic interaction between the associated SNPs at DAOA and DAO genes in contributing to schizophrenia risk (OR = 9.3 (1.4, 60.5). Based on these data, more systematic investigation of genes involved in DAO signaling is required. © 2007 Wiley-Liss, Inc.

Several studies have indicated that cytokines may be involved in the pathophysiology of schizophrenia. Previous studies, however, have yielded contradictory results; in this study we assess the plasma levels of both T-helper-1 (Th1) and T-helper-2 (Th2) cytokines in patients with acute exacerbations of schizophrenia. Plasma concentrations of interleukin-4 (IL-4), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-alpha) and soluble receptor of interleukin-6 (sIL-6R) were measured with high sensitivity, enzyme-linked immunosorbent assays (ELISA) in patients with acute exacerbations of schizophrenia as compared with healthy controls. Patients with an acute exacerbation of schizophrenia had significantly increased production of TNF-alpha and significantly reduced production of IL-4 as compared with healthy subjects. No significant difference was observed in IL-6, sIL-6R, IL-8 and IL-10. Acute exacerbations of schizophrenia are associated with increased TNF-alpha concentrations (Th1) with concomitantly reduced concentrations of IL-4 (Th2) and a resulting increased TNF-alpha/IL-4 ratio.

Objective: The lifetime prevalence of major depression is twice as high in females as in males. Depression is known to increase at periods where there are changes in gonadal hormones. We examined pro- and anti-inflammatory cytokine levels during the normal menstrual cycle of healthy females compared to similar time points in healthy males. Methods: Plasma concentrations of interleukin (IL)-4, IL-6, IL-8, IL-10, tumour necrosis factor-α (TNF-α) and soluble IL-6 receptor (sIL-6R) were measured with enzyme-linked immunosorbent assays in healthy females during the normal ovulatory menstrual cycle and also in males at similar time points. Results: The luteal phase of the menstrual cycle is associated with increased production of sIL-6R, IL-4 and TNF-α compared to the early follicular phase. No change was observed in IL-6, IL-8 and IL-10 concentration throughout the menstrual cycle. We found IL-4 positively correlated with oestrogen while TNF-α positively correlated with progesterone. Females were found to have significantly higher concentrations of TNF-α and sIL-6R across all phases of the menstrual cycle, compared to males across similar time points. Conclusion: The normal menstrual cycle is associated with increased production of sIL-6R, IL-4 and TNF-α in the luteal phase compared to the early follicular phase. Females have significantly higher concentrations of sIL-6R and TNF-α at all time points across the menstrual cycle than males.

Background The DTNBP1 gene, encoding dysbindin, has been strongly implicated in schizophrenia (SZ) susceptibility by a series of independent genetic association and gene expression studies. Among its known functions, dysbindin is part of a protein complex, termed the biogenesis of lysosome-related organelles complex 1 (BLOC-1), the molecular components of which might be involved in the regulation of vesicular trafficking and dendrite branching. Methods A systematic investigation of the other seven BLOC-1 genes (MUTED, PLDN, CNO, SNAPAP, BLOC1S1, BLOC1S2, and BLOC1S3) for evidence of association with SZ was undertaken in a sample of 373 SZ cases and 812 control subjects. Possible epistasis between combinations of BLOC-1 genes, including DTNBP1, was tested with a novel method of investigating for gene–gene interaction. Quality control measures were incorporated into genotyping strategy, and all results were corrected for multiple testing to prevent false positive results. Results We identified significant evidence of association between BLOC1S3 and SZ (odds ratio=1.45, confidence interval=1.13–1.86, p = .0028, corrected p = .0389). We also report evidence for epistatic interaction between DTNBP1 and MUTED contributing to SZ in the absence of a significant main effect at MUTED ( p = .0009, corrected p = .0252). Single marker and epistasis results remained significant after correction for multiple testing. Conclusions Together these data provide evidence for the involvement of the BLOC-1 protein complex in SZ pathogenesis

Background. There is evidence to indicate that peripheral glucocorticoid receptor (GR) function is reduced in major depression, and a possible molecular explanation for this is the impact of raised pro-inflammatory cytokines. The topical steroid vasoconstriction assay provides a convenient probe of peripheral GR function. The present study sought to assess the sensitivity of peripheral GRs in antidepressant-resistant major depressives and investigate the association between GR sensitivity and circulating plasma cytokines.Method. Nineteen antidepressant-resistant depressives together with age- and sex-matched healthy controls underwent the steroid vasoconstriction assay using three commercial preparations of corticosteroids containing clobetasol propionate 0·05%, betamethasone valerate 0·1%, and clobetasone butyrate 0·05%, corresponding to very potent, potent, and moderately potent steroid creams respectively. The pro-inflammatory cytokines, tumour necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) were measured using enzyme-linked immunosorbent assays. The severity of the depressive episode was assessed using the Hamilton Depression Scale (HAMD).Results. Depressed subjects had a significantly reduced vasoconstriction response across all three strengths of steroid. They also had significantly higher concentrations of TNF-α and IL-6. There was a significant inverse correlation between TNF-α concentration and vasoconstriction response and also between the HAMD score and vasoconstriction response.Conclusions. These findings suggest that cutaneous GR function is abnormal in antidepressant-resistant depression, that circulating TNF-α may play a significant role in this abnormality and that the efficacy of topical steroids in antidepressant-resistant depressives is reduced.

The authors first review current evidence concerning abnormalities of brain structure and function in schizophrenia and interpret them within a "network" pathophysiological model of the disorder. This information is then placed within a contemporary neurodevelopmental framework that "roots" the illness in adverse events during early pregnancy, which result in a developmentally compromised nervous system. They then consider the controversy as to whether the subsequent expression of psychosis reflects an active morbid process and, in a more general sense, whether the disorder is characterized by subsequent progression and clinical deterioration. The authors argue that the developmental and progressive models should not be considered in an either-or manner, since this perspective is not logical and favors nihilistic approaches to intervention and treatment, but rather should be integrated within a lifetime trajectory model. Finally, implications for current psychiatric practice are considered.

Background & Aims: Irritable bowel syndrome (IBS) is a functional disorder with an etiology that has been linked to both psychological stress and infection. The primary aim of this study was to examine the hypothalamic-pituitary-adrenal axis in patients with IBS and to relate such response to plasma cytokine profiles. Methods: A total of 151 subjects, 76 patients and 75 controls, were recruited. The patients with IBS were diagnosed according to Rome II criteria. Forty-nine patients and 48 matched controls had cytokine levels measured, and a subset of 21 patients and 21 controls also underwent a corticotropin-releasing hormone (CRH) stimulation test with plasma levels of adrenocorticotropic hormone (ACTH) and cortisol measured. The remaining 27 patients and 27 controls underwent a dexamethasone (1 mg) challenge. Results: Cortisol and the proinflammatory cytokines interleukin (IL)-6 (together with its soluble receptor) and IL-8 were elevated in all IBS subgroups (diarrhea predominant, constipated, and alternators), although the elevation was most marked in the constipated subgroup. There was no alteration in the anti-inflammatory cytokine IL-10. Following CRH infusion, an exaggerated release of both ACTH and cortisol was observed in patients with IBS. There was a significant correlation between the ACTH response (δACTH) and the IL-6 levels. A similar relationship existed between the δACTH/δcortisol ratio and the IL-6 levels. Dexamethasone suppression of cortisol was similar in patients and controls. Conclusions: IBS is characterized by an overactivation of the hypothalamic-pituitary-adrenal axis and a proinflammatory cytokine increase.

We performed an extensive genetic association study of the six known apolipoprotein-L (APOL) genes and schizophrenia (SZ) using a novel DNA pooling strategy. The APOL genes are both positional and functional candidate genes for SZ. This gene family maps to chromosome 22q12.3, a region implicated by SZ linkage studies as likely to contain one or more SZ susceptibility genes. A recent gene expression study demonstrated up-regulation of APOL1, 2, and 4 in post-mortem brain samples from SZ patients compared to controls in two independent samples. To test for genetic association with SZ, we analyzed 143 SNPs from dbSNP from across the APOL genes in an Irish sample of 219 cases and 231 controls. Of these 143 SNPs, 51 (36%) were polymorphic in our Irish sample and were genotyped using a novel three-stage DNA pooling strategy. This strategy does not require the identification of a heterozygous individual for DNA pooling association analysis and is therefore very efficient when using public database SNPs. We found no evidence to support the hypothesis that genetic variation at the APOL genes contributes to SZ susceptibility in our sample.

It is now generally accepted that the use of second-generation, or atypical, antipsychotics for schizophrenia represents an advance over conventional antipsychotic agents. However, adherence continues to be a problem, as with other medications for chronic disorders. Long-acting formulations of conventional antipsychotics partly address adherence problems, but their use is limited by tolerability issues. This article provides practical advice to physicians on the characteristics of patients who would benefit from treatment with long-acting atypical antipsychotic agents and offers suggestions on how to initiate treatment.A literature search for studies published between 1980 and 2003 that evaluated the treatment of patients with schizophrenia with long-acting atypical agents was conducted by using MEDLINE and EMBASE. The primary search parameters were "schizophrenia," "atypical," "antipsychotic," and "long-acting." As expected, long-acting risperidone was the only long-acting atypical agent identified; thus this article focuses on practical advice and suggestions on how to initiate therapy with long-acting risperidone.From the results of the literature search and the discussion of a panel of experts at a meeting held in Dublin in 2003 and supported by JohnsonJohnson, it is possible to conclude that long-acting risperidone has demonstrated efficacy and tolerability, even among patients who are considered clinically stable on other antipsychotics. Most patients can switch safely and effectively to long-acting risperidone if appropriate strategies are applied. Long-acting risperidone provides a new and promising therapeutic option for the treatment of schizophrenia.

Two recent association studies have implicated the neuregulin-1 gene (NRG1) at chromosome 8p21-22 as a susceptibility gene for schizophrenia. Stefansson et al identified three 'at-risk' haplotypes (HapA, B and C) which spanned the NRG1 locus and shared a common core haplotype. Subsequently, they demonstrated evidence that the core haplotype was associated with schizophrenia in an independent Scottish sample. To confirm and refine this haplotype we investigated the NRG1 locus in an independent Irish case-control sample. We did not find the core haplotype to be associated in our sample. However, we identified a refined 2-marker haplotype (HapB(IRE)) that shared common alleles with one of the Icelandic 'at-risk' haplotypes and is in significant excess in the Irish cases (19.4%) vs controls (12.3%) (P=0.013). This refined 'at-risk' haplotype is also in significant excess in the Scottish case sample (17.0% vs 13.5%; P=0.036). Interestingly, this refined 'at-risk' haplotype is positioned close to an EST cluster of unknown function (Hs.97362) within intron 1 of NRG1.

A recent study identified a putative association between variants in the regulator of G-protein signalling 4 (RGS4) and schizophrenia, Chowdari et al. [2002: Hum Mol Genet 11: 1373-1380]. RGS4 is both a positional and functional candidate gene for schizophrenia. Chowdari and colleagues identified association at this locus in a number of distinct and ethnically diverse samples, although the pattern of association was not the same in all the samples. Our study attempted to replicate this association in an independent Irish sample of schizophrenia cases and controls. We succeeded in detecting evidence of association at the RGS4 locus. The signal comes from a four-marker haplotype that is in significant excess in our case sample. The same haplotype is in excess in the Caucasian schizophrenia sample used by Chowdari et al. [2002: Hum Mol Genet 11: 1373-1380]. This study provides further support for the contribution of RGS4 to schizophrenia susceptibility.

In reviewing the extent to which our understanding has advanced between the 4thand 5thsymposia on Search for the Causes of Schizophrenia, the conclusion is salutary: a committed and expanding research community, able to apply an increasing armamentarium of molecular genetic, neuropathological, neuroimaging and additional techniques, has made only modest gains over this five-year period. In the face of such a slow (though not negligible) rate of progress, it is necessary to give further consideration to some of the premises which guide current thinking, as they may be impeding rather than facilitating these endeavours.

While premature death in schizophrenia is well recognised, mortality risk has received little longitudinal study in relation to population representativeness and patient engagement with health services. Within a rural Irish catchment area of socioeconomic, ethnic and geographical homogeneity and low residential mobility, an epidemiologically complete population of 72 patients with schizophrenia was followed up over 7.5 years in order to quantify mortality prospectively. Information was obtained in relation to 99% of the cohort, with 94% of those surviving retained in engagement with psychiatric care. There were 25 deaths (35% of cohort). A relative risk of 2.06 (95% CI, 1.40– 2.80; P-0.001) among this epidemiologically complete population may constitute an estimate of risk for mortality inherent to schizophrenia when disengagement from health services, residential mobility and socioeconomic, ethnic and geographical diversity are minimised. On long-term prospective evaluation, risk for death in schizophrenia was doubled on a background of enduring engagement in psychiatric care with increasing provision of community-based services and introduction of second-generation antipsychotics. 2003 Elsevier Science Ireland Ltd. All rights reserved.

A recent family-based association study identified a putative association between variants in the dystrobrevin binding protein 1 (dysbindin) gene (DTNBP1) and schizophrenia. This study used a sample of 270 Irish pedigrees multiply affected with schizophrenia. We attempted to replicate these findings in an independent Irish sample of 219 schizophrenia cases and 231 controls. No evidence was found to suggest an association between the DTNBP1 gene and schizophrenia in our sample. Possible reasons for these findings are discussed.

While a controversy has endured as to whether schizophrenia evidences the geographical variations in rate that characterise essentially all medical conditions, even less is known of such fundamental aspects of the epidemiology of schizoaffective and bipolar disorder. Within an ethnically and socioeconomically homogeneous region of rural Ireland, population 29,542, several methodological refinements were adopted to seek an epidemiologically complete population of 'all' cases of these disorders, with each potential case interviewed and diagnosed. Prevalence and morbid risk were calculated over the region as a whole and for each of the 39 constituent District Electoral Divisions [DEDs], by place at birth and by place at onset. Using multiple sources of information, 115 cases of schizophrenia, 33 of schizoaffective disorder and 77 of bipolar disorder were identified. Unremarkable overall prevalence and morbid risk values obscured marked variation between District Electoral Divisions for schizophrenia. No such variation was observed for bipolar disorder. These data indicate, using improved methodology, that what is often interpreted as an invariant overall rate of schizophrenia across countries and cultures may not apply to spatial microstructure; macroscopic rates can obscure small area variations when ethnic and socioeconomic diversity are minimised and effects of urbanicity are absent. Under these conditions, small area variations in bipolar disorder may be limited.

Baldwin PA, Scully PJ, Quinn JF, Morgan MG, Kinsella A, O'Callaghan E, Owens JM, Waddington JL. First episode bipolar disorder: systematic comparison of incidence with other affective and non-affective psychoses among an epidemiologically complete, rural population. Bipolar Disord 2002: 4(Suppl. 1): 39–40. © Blackwell Munksgaard, 2002

BackgroundThe potential of first-episode studies in schizophrenia is maximised through systematic epidemiological, clinical and biological comparisons between homogeneous populations of the psychoses.AimsTo conduct prolonged accrual of ‘all’ cases of non-affective and affective psychotic illness on an epidemiologically complete basis.MethodWithin the region covered by Cavan–Monaghan psychiatric service (population 102 810), all putative cases of first-episode psychosis were diagnosed using DSM–IV.ResultsFrom 1995 to 2000, 69 cases of psychosis were ascertained, the incidence being 2.3-fold lower in females than in males. On resolving the ‘core’ diagnoses of schizophrenia and bipolar disorder, incidence of schizophrenia among women was 7.5-fold lower than among men whereas incidence of bipolar disorder among women was 6.6-fold lower than among men.ConclusionsThis homogeneous population, which eliminates factors associated with urbanicity and minimises confounding factors such as socioeconomic, ethnic and geographical diversity, shows a markedly reduced incidence among females both of schizophrenia and of bipolar disorder.

Understanding the temporal origin(s) of schizophrenia, through specifying the earliest identifiable pathology, might indicate when to look for etiological factor(s), what their nature might be, and how course of illness might evolve from these origins. From this premise, earlier formulations are elaborated to offer a rigorously data-driven model that roots schizophrenia in cerebro-craniofacial dysmorphogenesis, particularly along the mid-line but involving other structures, over weeks 9/10 through 14/15 of gestation. However, a brain that has been compromised very early in fetal life is still subject to the normal endogenous programme of developmental, maturational and involutional processes on which a variety of exogenous biological insults and psychosocial stressors can impact adversely over later pregnancy, through infancy and childhood, to maturation and into old age, to sculpt brain structure and function; it should be emphasised that the effects of such endogenous programmes and exogenous insults on such an already developmentally-compromised brain may be different from their effects on a brain whose early fetal origins were unremarkable. From these early origins, a lifetime trajectory model for schizophrenia from developmental basis to 'neuroprogressive' process is constructed. Thereafter, consideration is given to what the model can explain, including cerebral asymmetry and homogeneity, what it cannot explain, what empirical findings would challenge or disprove the model, what cellular and molecular mechanisms might underpin the model, and what are its implications.

This study examined geographical variation in rate of occurrence of schizophrenia by place at birth vs place at onset, among a rural Irish catchment area population of unusual stability and socioeconomic homogeneity. Within a catchment area of 21 520 persons, all cases of schizophrenia were sought using current inpatient and outpatient records and key informants active in the community. Suspected cases were interviewed personally and diagnosed using DSM-III-R criteria. Place at birth and place at onset of psychosis were specified among the 32 District Electoral Divisions constituting the study region. For the 72 cases ascertained, an unremarkable overall prevalence rate/morbid risk obscured substantial and significant geographical variations therein between District Electoral Divisions. Particularly after controlling for high-density families, men demonstrated prominent geographical variation both by place at birth and by place at onset, with most men remaining unmarried and becoming ill at their place of birth; conversely, women demonstrated prominent variation by place at birth but more limited variation by place at onset, despite more frequent transitions from the parental home to the marital home before onset. Even when cases changed their location before the onset of psychosis, geographical variation in rate of occurrence of schizophrenia remained associated more strongly with factors related to the place of their birth.

It is argued that schizophrenia has origins in events occurring during the first or early second trimester that are reflected in minor physical anomalies and which may at least in part predispose to later obstetric complications. This neurodevelopmental basis underlies certain neuromotor and psychosocial abnormalities of infancy and childhood, which are the early manifestations of what will be reconceptualised later as negative symptoms and (particularly frontal) cognitive dysfunction, but gives rise to positive symptoms only on the maturation of other systems necessary for their expression. This later emergence of psychosis reflects an active morbid process that is associated with increased accrual of negative symptoms and of general (but not frontal) cognitive impairment that may be ameliorated by effective antipsychotic treatment. The psychological or biological basis of this heuristic process is poorly understood. Contemporary re-appraisal of any impact of antipsychotics on the long-term course of schizophrenia must take into account what is known of the origins of the disease process with which such drugs might interact. Much recent work continues to indicate that very early events, during the embryonic\fetal period, are important in, if not fundamental to, the genesis of schizophrenia; i.e. that there is a neurodevelopmental basis to the disorder. The present article seeks to establish a time-line relating early intrauterine adversity and dysmorphogenesis, through the onset of psychosis, to the chronic phase of the illness over adulthood; from this time-line, a schema is elaborated for a beneficial impact of antipsychotics on the course of psychopathology, cognition and, less clearly, neurobiological abnormality.

Over almost four decades, few fundamentally different antipsychotic drugs evolved to challenge classical neuroleptics as the mainstay of the pharmacotherapy of schizophrenia. However, the recent re-emergence of clozapine, together with the emergence of risperidone, portends an increasing number of new antipsychotics which are now either traversing the stages of regulatory approval or else well-advanced in clinical development. This article first evaluates the significance of clozapine and risperidone; it then reviews some of the new antipsychotics and how they might be classified vis-a-vis potential advantages for patients, outlines putative mechanisms and new therapeutic targets, and considers whether such agents may act on any disease process inherent to schizophrenia. One fundamental issue is the extent to which the new antipsychotics might shift materially the risk-benefit balance towards intervention, not just at the earliest possible stage following the onset of psychosis but at a yet earlier, ‘prodromal’ phase of the disorder where there is a considerably greater likelihood of ‘treating’ behavioural disturbances that prove not to be the harbingers of psychotic illness.

Background. It has been suggested that the expression of psychosis may reflect an active morbid process that is associated with increasingly poor outcome unless ameliorated by antipsychotic drugs. Methods. The subjects of this study were 48 in-patients with schizophrenia, many of whom had been admitted before the introduction of antipsychotic drugs to rural Irish psychiatric hospitals in the late 1950s. Each patient was assessed for positive and negative symptoms, and for general and executive (frontal) cognitive function. Results. After controlling for age and for duration and continuity of subsequent antipsychotic treatment, current severity both of negative symptoms and of general cognitive impairment was predicted strongly by increasing duration of initially untreated psychosis; duration of illness following initiation of antipsychotic medication failed to predict the severity thereof. Neither of these indices of illness duration predicted the severity of positive symptoms or of executive dyscontrol. Conclusions. Increasing duration of initially untreated psychosis was associated specifically with heightened accrual of prominent negative symptoms and general cognitive impairment. Executive dyscontrol, though also prominent in these patients, may be 'locked-in' at an earlier phase of the illness.

The reaction catalyzed by Candida albicans phosphomannose isomerase (PMI) (EC 5.3.1.8) has a bell-shaped pH dependence, with pKa's at 5.6 and 8.7. The enzyme can be inhibited in a time-dependent manner using the arginine-specific modification reagent phenylglyoxal. This modification takes place with a rate constant of 0.022 +/- 0.002 min-1 mM-1 at 37 degrees C in 50 mM Hepes buffer, pH 8.5. The enzyme can be protected from this inactivation by the addition of the substrate mannose 6-phosphate at concentrations close to its Km value. The pH dependence of the inactivation reaction shows a single pKa at 9.1 +/- 0.1, which is close to one of the values for the pH dependence of the enzyme-catalyzed reaction. Using [7-14C]phenylglyoxal, it is shown that a single molecule is incorporated into the enzyme in the absence of substrate and that this inactivates the enzyme. This incorporation of radioactivity is prevented by the coincubation with substrate. The modified protein has then been reduced with sodium borohydride to fix the modification and then cleaved with Asp-N protease. The resultant peptides were separated by HPLC, and the radioactivity was counted. Sequencing of the peptide with the highest incorporation level identified it as DNVVRAGFTPKFK, which corresponds to amino acids 300-312 of phosphomannose isomerase. Radioactive counting of the phenylthiohydantoin amino acid derivatives confirmed that the modified amino acid was arginine 304. The role of this residue in the catalytic reaction of phosphomannose isomerase is discussed.

Scully PJ, Owens JM, Kinsella A, Waddington JL. Dimensions of psychopathology in bipolar disorder versus other affective and non-affective psychoses among an epidemiologically complete population. Bipolar Disord 2002: 4(Suppl. 1): 43–44. © Blackwell Munksgaard, 2002

G A A b st ra ct s correlations were noted between abdominal pain and right colon transit time (r=-0.18; p

Background Bifidobacteria and lactobacilli are among the early and important colonizers of the gastrointestinal tract and are generally considered to be part of a normal, healthy microbiota. It is believed that specific strains within the microbiota can influence host immune-reactivity and may play a role in protection from infection and aberrant inflammatory activity. One such strain, Bifidobacterium animalis AHC7, has been previously shown to protect against Salmonella typhimurium infection in mice and helps resolve acute idiopathic diarrhea in dogs. The aim of this study was to investigate the potential molecular and cellular mechanisms underpinning the Bifidobacterium animalis AHC7 protective effect. Results Following 4 hours of infection with Salmonella typhimurium, NF-κB activation was significantly elevated in vivo in placebo and Enterococcus faecium-fed animals while Bifidobacterium animalis AHC7 consumption significantly attenuated the NF-κB response. In vitro anti-CD3/CD28 stimulated Peyer's patch cells secreted significantly less TNF-α and IFN-γ following Bifidobacterium animalis AHC7 consumption. Stimulated cells released more IL-12p70 but this difference did not reach statistical significance. No alteration in mucosal IL-6, IL-10 or MCP-1 levels were observed. No statistically significant change in the cytokine profile of mesenteric lymph node cells was noted. In vitro, Bifidobacterium animalis AHC7 was bound by dendritic cells and induced secretion of both IL-10 and IL-12p70. In addition, co-culture of CD4+ T cells with Bifidobacterium animalis AHC7-stimulated dendritic cells resulted in a significant increase in CD25+Foxp3+ T cell numbers. Conclusion Bifidobacterium animalis AHC7 exerts an anti-inflammatory effect via the attenuation of pro-inflammatory transcription factor activation in response to an infectious insult associated with modulation of pro-inflammatory cytokine production within the mucosa. The cellular mechanism underpinning Bifidobacterium animalis AHC7 mediated attenuation of NF-κB activation may include recognition of the bacterium by dendritic cells and induction of CD25+Foxp3+ T cells.

Background: Experimental and clinical studies suggest an association between SIBO and NASH. Liver injury and fibrosis could be related to exposure to a bacterial burden, notably endotoxins, of intestinal origin. Moreover, the gut microbiota and endotoxemia have been described to play a contributory role in metabolic dysfunction, particularly insulin resistance, which is a key factor in NASH development. The extracellular receptor molecules for LPS are Lipopolysaccharide Binding Protein (LBP), CD14, toll-like receptor-4 (TLR-4) and myeloid differentiation-2 (MD-2). Endotoxaemia also induces proinflammatory cytokine release from immune cells. Aim: To investigate the prevalence of small intestinal bacterial overgrowth (SIBO) and relationships to LPS receptors and systemic cytokines in NASH. Methods: 18 NASH patients (8 males and 10 females) and 16 ageand gender-matched healthy volunteers were studied. SIBO was assessed by the lactulose breath hydrogen test (LHBT), plasma LBP levels were measured by ELISA and expression (as a %) of TLR-2 and 4 on CD14 positive cells determined by flow cytometry. Proinflammatory mediators (IL-1β, IL-6, IL-8 and TNFα) were measured in plasma by MSD (Meso Scale Discovery). Results: SIBO was more common in NASH patients (71%) than in control subjects (35.7%). This was mainly due to H2 production which was significantly greater in NASH than control at time points 45, 60, 75 and 90minutes during the LHBT (p=0.0241, 0.0476, 0.0470 and 0.0139 respectively). On the other hand, CH4 production was similar in NASH and control groups. No significant differences were detected between NASH and controls for LBP levels, p=0.5448. TLR-4/ MD-2 expression on CD14 positive was significantly higher among NASH patients than in control subjects: % expression, mean ± SEM, NASH vs control: 20.95± 2.91% vs 12.73 ± 2.29%, p=0.048 while TLR-2 expression was not significantly different. Among the cytokines studied, IL-8 levels were significantly higher in patients than control (p=0.0413) and correlated positively with TLR-4 (r=0.5123, p=0.0355) expression but not with TLR-2 expression. Conclusion: Small intestinal bacterial overgrowth is common in NASH, largely related to excess production of H2 and is associated with increased circulating levels of IL-8 and upregulation of TLR-4/MD2.

Introduction: Irritable bowel syndrome (IBS) is a functional disorder which has been linked with abnormal serotonin functioning. It has a high psychiatric co-morbidity with depressive and anxiety disorders, conditions which result from a central serotonergic deficit. Tryptophan (TRP) forms the substrate for serotonin biosynthesis, but alternatively TRP can also be catabolised to kynurenine (KYN). Tryptophan catabolism along the kynurenine pathway is regulated by the enzyme indoleamine 2,3-dioxygenase (IDO), and therefore the ratio of kynurenine to tryptophan provides a measurement of IDO activity. The main inducer of IDO is the pro-inflammatory cytokine, interferon-gamma (IFN-γ). Aims: The primary aim of this study was to investigate tryptophan catabolism in IBS, and to relate such catabolism to immune activation and psychiatric co-morbidity. We hypothesised that there would be increased IFN-γ levels in IBS, and consequently, increased shunting of tryptophan along the kynurenine pathway at the expense of serotonin biosynthesis. Method: 42 female IBS subjects and 22 female healthy controls had plasma kynurenine and tryptophan concentrations measured using an HPLC method. Interferon-γ was assayed using an electro-chemiluminescence multiplex system imager. Co-morbid depressive and anxiety disorders were identified using a valid and reliable self-report tool, the Patient Health Questionnaire (PHQ), and the severity of IBS was assessed using a summary score of 4-point ordinal scales in accordance with a previously published method. Results: Of the 42 IBS subjects, 17 had severe IBS, 16 reported moderate symptoms and 9 reported mild IBS symptomatology. There was a significant positive correlation between IBS severity and Kyn/Trp ratio(r = 0.47, p=0.002). Those with severe IBS symptoms demonstrated increased tryptophan catabolism along the kynurenine pathway (i.e. increased Kyn/Trp ratio)compared to those with mildto-moderate IBS and healthy controls(p = 0.004); and those with severe IBS were over twice as likely to have depression or anxiety compared to those with less severe symptoms (RR = 2.2;95% C.I 1.2-3.9). No difference in IFN-γ levels was observed between the IBS patients and controls; however IFN-γ was positively correlated with Kyn:Trp ratio in the IBS group (r = 0.58, p = 0.005) and this was not seen in the controls (r = 0.05, p = 0.8). Conclusion: Our results indicate an increased sensitivity to IFN-γ in the regulation of tryptophan catabolism in IBS. This may predispose to the increased rate of Kyn production observed in severe IBS cases and to the high co-morbidity with depressive and anxiety disorders in this group.