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Increased cytokines and increased intercellular adhesion molecule-1 (ICAM1) found in the schizophrenia prefrontal cortex and in the blood may relate to cognitive deficits. Endothelial ICAM1 regulates immune cell trafficking into the brain by binding to integrins located on the surface of leukocytes. Whether the circulating levels of the main ICAM1 adhesion partners, lymphocyte-function associated antigen-1 (LFA1) and complement receptor 3 (CR3), both integrins, are altered in schizophrenia is unknown. Gene expressions of ICAM1, LFA1 and CR3 were measured in leukocytes from 86 schizophrenia patients and 77 controls. Participants were also administered cognitive testing to determine the extent to which cognitive ability was related to molecular measures of leukocyte adhesion. This cohort was previously stratified into inflammatory subgroups based on circulating cytokine mRNAs; thus, gene expressions were analysed by diagnosis and by inflammatory subgroups. Previously measured plasma ICAM1 protein was elevated in "high inflammation" schizophrenia compared to both "high" and "low inflammation" controls while ICAM1 mRNA was unchanged in leukocytes. LFA1 mRNA was decreased and CR3 mRNA was increased in leukocytes from people with schizophrenia compared to controls. LFA1 mRNA levels were positively correlated with working memory and elevated soluble ICAM1 was negatively correlated with verbal memory in schizophrenia. Altogether, some of the cognitive deficits in schizophrenia may be associated with altered expression of molecules that regulate immune cell trafficking.

Altered levels of stress-signalling transcripts have been identified in post-mortem brains of people with schizophrenia, and since stress effects may be expressed throughout the body, there should be similar changes in peripheral cells. However, the extent to which these markers are altered in peripheral white blood cells of people with schizophrenia is not known. Furthermore, how peripheral cortisol and stress-related mRNA are associated with negative symptom severity and emotional states in people with schizophrenia versus schizoaffective disorder has not been determined. Whole blood samples were collected from 86 patients with either schizophrenia or schizoaffective disorder (56 people with schizophrenia and 30 people with schizoaffective disorder), and 77 healthy controls. Total RNA was isolated, cDNA was synthesized, and stress-signalling mRNA levels (for NR3C1, FKBP5, FKBP4, PTGES3 and BAG1) were determined. Stress and symptom severity scores were measured by the Depression, Anxiety and Stress Scale, and the Positive and Negative Syndrome Scale, respectively. We found increased FKBP5 mRNA, Z(156) = 2.5, p = 0.01, decreased FKBP4 mRNA, t(155) = 3.5, p ≤ 0.001, and decreased PTGES3 mRNA, t(153) = 3.0, p ≤ 0.01, in schizophrenia and schizoaffective disorder cohorts combined compared to healthy controls. Stress-related peripheral mRNA levels were differentially correlated with negative emotional states and symptom severity in schizoaffective disorder (β's = –0.45–0.56, p's = 0.05–0.001) and schizophrenia (β's = −0.34–0.38, p's = 0.04–0.03), respectively. Therefore, molecules of the stress-signalling pathway appear to differentially contribute to clinical features of schizophrenia versus schizoaffective disorder.

Background There is growing evidence for complement system involvement in the pathophysiology of schizophrenia, although the extent and magnitude of complement factor disturbances has not been fully reported. It also remains unclear whether complement abnormalities are characteristic of all patients with schizophrenia or whether they are representative of a subgroup of patients who show signs of heightened inflammation. The aim of the present study was to quantify and compare the levels of a range of complement factors, receptors and regulators in healthy controls and people with schizophrenia and to determine the extent to which the levels of these peripheral molecules relate to measures of brain structure, particularly cortical thickness. Method Seventy-five healthy controls and 90 patients with schizophrenia or schizoaffective disorder were included in the study. Peripheral blood samples were collected from all participants and mRNA expression was quantified in 20 complement related genes, four complement proteins, as well as for four cytokines. T1-weighted structural MRI scans were acquired and analysed to determine cortical thickness measures. Results There were significant increases in peripheral mRNA encoding receptors (C5ar1, CR1, CR3a), regulators (CD55, C59) and protein concentrations (C3, C3b, C4) in people with schizophrenia relative to healthy controls. C4a expression was significantly increased in a subgroup of patients displaying elevated peripheral cytokine levels. A higher inflammation index score derived from mRNA expression patterns predicted reductions in cortical thickness in the temporal lobe (superior temporal gyrus, transverse temporal gyrus, fusiform gyrus, insula) in patients with schizophrenia and healthy controls. Conclusions Analysis of all three major complement pathways supports increased complement activity in schizophrenia and also shows for the first time that peripheral C4a up-regulation is related to increased peripheral pro-inflammatory cytokines in schizophrenia. Our region-specific, neuroimaging findings linked to an increased peripheral complement mRNA expression pattern suggests a role for complement in cortical thinning. Further studies are required to further clarify clinical and neurobiological consequences of aberrant complement levels in schizophrenia and related psychoses.

The kynurenine pathway (KP) of tryptophan (TRP) catabolism links immune system activation with neurotransmitter signaling. The KP metabolite kynurenic acid (KYNA) is increased in the brains of people with schizophrenia. We tested the extent to which: (1) brain KP enzyme mRNAs, (2) brain KP metabolites, and (3) plasma KP metabolites differed on the basis of elevated cytokines in schizophrenia vs. control groups and the extent to which plasma KP metabolites were associated with cognition and brain volume in patients displaying elevated peripheral cytokines. KP enzyme mRNAs and metabolites were assayed in two independent postmortem brain samples from a total of 71 patients with schizophrenia and 72 controls. Plasma KP metabolites, cognition, and brain volumes were measured in an independent cohort of 96 patients with schizophrenia and 81 healthy controls. Groups were stratified based on elevated vs. normal proinflammatory cytokine mRNA levels. In the prefrontal cortex (PFC), kynurenine (KYN)/TRP ratio, KYNA levels, and mRNA for enzymes, tryptophan dioxygenase (TDO) and kynurenine aminotransferases (KATI/II), were significantly increased in the high cytokine schizophrenia subgroup. KAT mRNAs significantly correlated with mRNA for glial fibrillary acidic protein in patients. In plasma, the high cytokine schizophrenia subgroup displayed an elevated KYN/TRP ratio, which correlated inversely with attention and dorsolateral prefrontal cortex (DLPFC) volume. This study provides further evidence for the role of inflammation in a subgroup of patients with schizophrenia and suggests a molecular mechanism through which inflammation could lead to schizophrenia. Proinflammatory cytokines may elicit conversion of TRP to KYN in the periphery and increase the N-methyl-d-aspartate receptor antagonist KYNA via increased KAT mRNA and possibly more enzyme synthesis activity in brain astrocytes, leading to DLPFC volume loss, and attention impairment in schizophrenia.

While high levels of glucocorticoids are generally neuro-damaging, a related adrenal steroid, dehydroepiandrosterone (DHEA), has anti-glucocorticoid and neuroprotective properties. Previous work has shown increased circulating levels of DHEA and abnormal cortisol/DHEA ratios in people with schizophrenia, however reports are limited and their relationship to neuropathology is unclear. We performed the largest study to date to compare levels of serum DHEA and cortisol/DHEA ratios in people with schizophrenia and healthy controls, and investigated the extent to which cortisol/DHEA ratios predict brain volume. Serum cortisol and DHEA were assayed in 94 people with schizophrenia and 81 healthy controls. T1-weighted high-resolution anatomical scans were obtained using a 3 T Achieva scanner on a subset of 59 people with schizophrenia and 60 healthy controls. Imaging data were preprocessed and analyzed using SPM12. People with schizophrenia had significantly increased serum DHEA levels (p = 0.002), decreased cortisol/DHEA ratios (p = 0.02) and no difference in cortisol levels compared to healthy controls. Cortisol/DHEA ratios were inversely correlated with hippocampal (r = -0.33 p = 0.01) and dorsolateral prefrontal cortex (r = -0.30, p = 0.02) volumes in patients. Our findings suggest that the cortisol/DHEA ratio may be a molecular blood signature of hippocampal and cortical damage. These results further implicate the role of DHEA and hypothalamic-pituitary-adrenal axis dysfunction in the pathophysiology of schizophrenia.

Elevated pro-inflammatory cytokines exist in both blood and brain of people with schizophrenia but how this affects molecular indices of the blood–brain barrier (BBB) is unclear. Eight mRNAs relating to BBB function, a microglia and three immune cell markers were measured by qPCR in the prefrontal cortex from 37 people with schizophrenia/schizoaffective disorder and 37 matched controls. This cohort was previously grouped into “high inflammation” and “low inflammation” subgroups based on cortical inflammatory-related transcripts. Soluble intercellular adhesion molecule-1 (sICAM1) was measured in the plasma of 78 patients with schizophrenia/schizoaffective disorder and 73 healthy controls. We found that sICAM1 was significantly elevated in schizophrenia. An efflux transporter, ABCG2, was lower, while mRNAs encoding VE-cadherin and ICAM1 were higher in schizophrenia brain. The “high inflammation” schizophrenia subgroup had lower ABCG2 and higher ICAM1, VE-cadherin, occludin and interferon-induced transmembrane protein mRNAs compared to both “low inflammation” schizophrenia and “low inflammation” control subgroups. ICAM1 immunohistochemistry showed enrichment in brain endothelium regardless of diagnosis and was localised to astrocytes in some brains. Microglia mRNA was not altered in schizophrenia nor did it correlate with ICAM1 expression. Immune cell mRNAs were elevated in “high inflammation” schizophrenia compared to both “low inflammation” schizophrenia and controls. CD163+ perivascular macrophages were identified by immunohistochemistry in brain parenchyma in over 40% of “high inflammation” schizophrenia brains. People with high levels of cytokine expression and schizophrenia display changes consistent with greater immune cell transmigration into brain via increased ICAM1, which could contribute to other neuropathological changes found in this subgroup of people.

BACKGROUND: Schizophrenia is characterized by positive and negative symptoms and cognitive deficits related to functional disability. Approved treatments targeting small molecule neurotransmitter receptors are limited in their effectiveness and often leave residual symptoms and debilitating side effects. Psychotic symptoms, cognitive deficits, and treatment response are variable in schizophrenia, highlighting heterogeneity in the etiology and presentation of the illness. There is a critical need for novel treatments targeting subgroups related to underlying biology that can be identified by biomarkers. A substantial subgroup (40%) of people with schizophrenia can be distinguished by cytokines in both peripheral blood and in brain. The cytokine interleukin 1-beta (IL-1β) mRNA and protein levels are significantly increased in serum, plasma, white blood cells, cerebrospinal fluid and brain in chronically ill patients and in first episode psychosis. Canakinumab is an approved human anti-IL-1β monoclonal antibody that interferes with the bioactivity of IL-1β and interrupts excessive immune response. However, the extent to which IL-1β blockade by canakinumab can reduce peripheral markers of an overactive immune system (e.g., high sensitivity C-reactive protein: hsCRP) and reduce psychotic symptom severity in schizophrenia is unknown. METHODS: We conducted a randomized, placebo-controlled, double-blind, parallel group trial of the monoclonal antibody canakinumab to block IL-1β in schizophrenia. Twenty-seven chronically ill patients with schizophrenia or schizoaffective disorder who had elevated peripheral inflammation markers (IL-1β, IL-6, hsCRP and/or neutrophil to lymphocyte ratio) at baseline were randomized to a one-time subcutaneous injection of canakinumab (150 mg) or placebo (normal saline) as an adjunctive treatment to antipsychotics. Peripheral hsCRP levels were measured at baseline (prior to injection) and at 1, 4- and 8-weeks post treatment. Positive and Negative Syndrome Scale scores were assessed at baseline and at 4- and 8-weeks post treatment. RESULTS: Separate t-tests comparing canakinumab or placebo at weeks 1, 4, and 8 to baseline showed significant reductions in peripheral hsCRP levels at all time points (all p’s < .02) for canakinumab only. Separate t-tests also showed a significant reduction in positive symptom severity scores at week 8 (p = 0.05) for canakinumab and at week 4 (p = 0.02) for placebo. There was a trend for low peripheral hsCRP levels to be strongly correlated with low positive symptom severity scores (r = .57, p = .07) only at week 8 in the canakinumab group. There were no significant reductions in negative or general psychopathology symptom severity scores in either group. DISCUSSION: Blockade of the cytokine IL-1β by the monoclonal antibody canakinumab significantly reduces peripheral hsCRP serum levels and these reductions may be related to a reduction in positive symptom severity in chronically ill patients with schizophrenia. Importantly, only those patients who initially displayed elevated peripheral markers of inflammation were recruited. The effects of canakinumab on the reduction of peripheral hsCRP is potentially beneficial to general health. The relatively strong relationship between the effects of canakinumab on the biological marker hsCRP and positive symptom severity after 8 weeks of treatment supports the effect of canakinumab on positive symptom severity. Given that treatment with a monoclonal antibody is a novel and substantial advance in the potential treatment of psychotic symptom severity in schizophrenia, future studies should consider increased or top-up doses with longer follow-up to confirm the benefit of adjunctive canakinumab treatment in schizophrenia.

Lower testosterone levels are associated with greater negative symptoms in men with schizophrenia. Testosterone signals via androgen receptor (AR). A functional variant in the AR gene (CAG trinucleotide repeat polymorphism) is associated with circulating testosterone and mood-related symptoms in healthy people. Raloxifene increases testosterone in healthy males and reduces symptom severity and improves cognition in schizophrenia; however, whether raloxifene increases testosterone in men with schizophrenia is unknown. We assessed the interaction of a functional AR gene variant and adjunctive raloxifene on peripheral testosterone and symptom severity in schizophrenia. Patients with schizophrenia (59 males and 38 females) participated in a randomized, double-blind, placebo-controlled, crossover trial of adjunctive raloxifene (120 mg/day). Healthy adults (46 males and 41 females) were used for baseline comparison. Baseline circulating testosterone was decreased in male patients compared to male controls and positively correlated with CAG repeat length in male controls and female patients. Male patients with short, compared to long, CAG repeat length had higher stress scores. Raloxifene treatment increased testosterone in male patients, but was unrelated to AR CAG repeat length, suggesting that raloxifene’s effects may not depend on AR activity. Sex-specific alterations of the relationship between AR CAG repeat length and testosterone suggest that altered AR activity may impact perceived stress in men with schizophrenia.

There is increasing clinical and molecular evidence for the role of hormones and specifically estrogen and its receptor in schizophrenia. A selective estrogen receptor modulator, raloxifene, stimulates estrogen-like activity in brain and can improve cognition in older adults. The present study tested the extent to which adjunctive raloxifene treatment improved cognition and reduced symptoms in young to middle-age men and women with schizophrenia. Ninety-eight patients with a diagnosis of schizophrenia or schizoaffective disorder were recruited into a dual-site, thirteen-week, randomized, double-blind, placebo-controlled, crossover trial of adjunctive raloxifene treatment in addition to their usual antipsychotic medications. Symptom severity and cognition in the domains of working memory, attention/processing speed, language and verbal memory were assessed at baseline, 6 and 13 weeks. Analyses of the initial 6-week phase of the study using a parallel groups design (with 39 patients receiving placebo and 40 receiving raloxifene) revealed that participants receiving adjunctive raloxifene treatment showed significant improvement relative to placebo in memory and attention/processing speed. There was no reduction in symptom severity with treatment compared with placebo. There were significant carryover effects, suggesting some cognitive benefits are sustained even after raloxifene withdrawal. Analysis of the 13-week crossover data revealed significant improvement with raloxifene only in attention/processing speed. This is the first study to show that daily, oral adjunctive raloxifene treatment at 120 mg per day has beneficial effects on attention/processing speed and memory for both men and women with schizophrenia. Thus, raloxifene may be useful as an adjunctive treatment for cognitive deficits associated with schizophrenia.

Background Increases in pro-inflammatory cytokines are found in the brain and blood of people with schizophrenia. However, increased cytokines are not evident in all people with schizophrenia, but are found in a subset. The cytokine changes that best define this subset, termed the “elevated inflammatory biotype”, are still being identified. Methods Using quantitative RT-PCR, we measured five cytokine mRNAs (IL-1β, IL-2 IL-6, IL-8 and IL-18) from peripheral blood of healthy controls and of people with schizophrenia or schizoaffective disorder (n = 165). We used a cluster analysis of the transcript levels to define those with low and those with elevated levels of cytokine expression. From the same cohort, eight cytokine proteins (IL-1β, IL-2, IL-6, IL-8, IL-10, IL-12, IFNγ and TNFα) were measured in serum and plasma using a Luminex Magpix-based assay. We compared peripheral mRNA and protein levels across diagnostic groups and between those with low and elevated levels of cytokine expression according to our transcription-based cluster analysis. Results We found an overall decrease in the anti-inflammatory IL-2 mRNA (p = 0.006) and an increase in three serum cytokines, IL-6 (p = 0.010), IL-8 (p = 0.024) and TNFα (p

Background: Cytokine messenger RNA (mRNA) transcripts derived from peripheral blood can be used to identify individuals with putative inflammation, and patients with schizophrenia increased proportions of those with elevated cytokines. However, the reliability of the TwoStep clustering algorithm, used to identify elevated cytokine subsets, has not been systematically examined. Here we use bootstrapping procedures to assess the reliability of this method.

Background: The kynurenine pathway (KP) of tryptophan (TRP) catabolism is considered to link the immune and neurotransmitter systems. The KP metabolite kynurenic acid (KYNA) shows increases in the brain of patients with schizophrenia. Here, we tested whether changes in brain KP enzyme mRNAs and plasma KP metabolites are related to cytokine levels in schizophrenia. We expected Kynurenine Aminotransferase II (KATII) mRNA to be increased in brains of people with schizophrenia, particularly in patients displaying elevated cytokines. Furthermore, we expected that the kynurenine (KYN)–TRP ratio in the plasma of chronically ill patients to be associated with cognitive and brain volume abnormalities in schizophrenia with high inflammation.

Background Schizophrenia is a disabling and often unremitting mental illness with an unknown cause that is characterized by heterogeneity in psychotic symptom presentation, cognitive deficits and treatment response. There is accumulating evidence for the role of inflammation in the etiology of schizophrenia. Inflammatory markers have been identified in the brains and peripheral blood of chronically ill patients with schizophrenia and in first episode patients and these markers have been associated with structural and functional brain abnormalities and cognitive deficits. Intercellular adhesion molecule 1 (ICAM-1) is a transmembrane protein expressed on endothelial cells which binds to leukocyte receptors that promotes transmigration of white blood cells into tissue. While peripheral inflammatory markers are altered in people with schizophrenia relative to controls, the extent to which ICAM-1 is elevated in the brains of people with schizophrenia and peripheral levels of soluble ICAM-1 (sICAM-1) is increased in relation to cognitive impairment in schizophrenia is unknown. Methods In a post-mortem cohort, 8 mRNAs relating to BBB function and 3 immune cell markers were measured by qPCR in the prefrontal cortex of 37 people with schizophrenia and 37 matched controls. In an independent living cohort, sICAM-1 was measured with a Luminex immunoassay from the plasma of 78 chronically ill patients with schizophrenia (all receiving antipsychotic medication) and 73 healthy controls. All participants from the living cohort received the following cognitive assessments: Wechsler Adult Intelligence Scale – 3rd edition to assess current IQ, Controlled Oral Word Association Test verbal fluency and Wechsler Memory Scale-Revised to assess verbal memory. Pearson’s or Spearman’s correlations were performed between cognitive measures and sICAM1 levels as appropriate in schizophrenia patients and healthy controls. Results ICAM-1 was elevated in the brains of people with schizophrenia relative to controls and CD163+ perivascular macrophages were found in the parenchyma. Peripheral sICAM1 was elevated by 29.2% in people with schizophrenia compared to healthy controls, t(140) = -3.988, p < 0.01. In people with schizophrenia, sICAM1 was inversely correlated with immediate verbal memory (r=-0.30, p=0.01), delayed verbal memory (rho=-0.29, p=0.01), verbal abstract reasoning (r=-0.23, p=0.05), and processing speed (rho=-0.28, p=0.02). In healthy controls, sICAM1 levels were inversely correlated with verbal fluency (r=-0.27, p=0.03) and processing speed (rho=-0.26, p=0.03). Discussion The brain endothelium of people with schizophrenia can attract more immune cells via increased ICAM-1. sICAM-1, a cleavage product of ICAM which enables white blood cell migration into tissue (including brain) is significantly elevated in peripheral blood of patients with schizophrenia. sICAM-1 is associated with poor verbal memory, reasoning and processing speed in people with schizophrenia and accounts for variation in cognition of healthy controls. This suggests that increased inflammatory processes, measured in blood, may reflect brain related cognitive deficits that are the hallmark of schizophrenia. Anti-inflammatory treatments may reverse cognitive impairment in schizophrenia.

Reward detection, surprise detection and prediction-error signaling have all been proposed as roles for the ventral striatum (vStr). Previous neuroimaging studies of striatal function in schizophrenia have found attenuated neural responses to reward-related prediction errors; however, as prediction errors represent a discrepancy in mesolimbic neural activity between expected and actual events, it is critical to examine responses to both expected and unexpected rewards (URs) in conjunction with expected and UR omissions in order to clarify the nature of ventral striatal dysfunction in schizophrenia. In the present study, healthy adults and people with schizophrenia were tested with a reward-related prediction-error task during functional magnetic resonance imaging to determine whether schizophrenia is associated with altered neural responses in the vStr to rewards, surprise prediction errors or all three factors. In healthy adults, we found neural responses in the vStr were correlated more specifically with prediction errors than to surprising events or reward stimuli alone. People with schizophrenia did not display the normal differential activation between expected and URs, which was partially due to exaggerated ventral striatal responses to expected rewards (right vStr) but also included blunted responses to unexpected outcomes (left vStr). This finding shows that neural responses, which typically are elicited by surprise, can also occur to well-predicted events in schizophrenia and identifies aberrant activity in the vStr as a key node of dysfunction in the neural circuitry used to differentiate expected and unexpected feedback in schizophrenia.

Social and occupational functioning difficulties are a characteristic feature of schizophrenia, and a growing body of evidence suggests that deficits in social cognition contribute significantly to these functional impairments. The present study sought to investigate whether the association between social cognition and social functioning in schizophrenia would be mediated by self-reported levels of empathy. Thirty outpatients with a diagnosis of schizophrenia or schizoaffective disorder, and twenty-five healthy controls completed a well-validated facial affect processing task (Ekman 60-faces facial task from the Facial Expressions of Emotion - Stimuli and Tests; FEEST), The Awareness of Social Inference Test (TASIT; to assess emotion perception and complex social cognitive skills such as the detection of sarcasm and deceit, from realistic social exchanges), and measures of self-reported empathy and social functioning. Participants with schizophrenia performed more poorly than controls in identifying emotional states from both FEEST and TASIT stimuli, and were impaired in their ability to comprehend counterfactual information in social exchanges, including sarcasm and lies, on the TASIT. Impairment in the comprehension of sarcasm was associated with higher empathic personal distress, and lower recreational functioning. Impairment in the identification of the emotions of others was found to be associated with lower satisfaction and lower empathic fantasy. However, empathy could not be explored as a mediator of associations between social cognition and functional outcome, due to lack of common associations with functional outcome measures. These findings have implications for the remediation of specific social cognitive deficits with respect to improving functional outcomes in schizophrenia.

A prominent emotional disturbance in schizophrenia is clinically evident in blunted affect, often observed as reduced emotional expressivity alongside the individual's report of normal or heightened emotional experience. It has been suggested that this disjunction between the experience and expression of emotion may reflect problems with the regulation of emotional expression. The present study thus set out to examine the capacity to engage in particular emotion regulatory strategies, and specifically, the ability to amplify the emotional expression of an experienced emotion ('amplification') or suppress the emotional expression of an experienced emotion ('suppression') whilst watching film clips selected to elicit amusement. Twenty nine participants with schizophrenia and 30 demographically matched non-clinical controls were asked to watch three different amusing film clips, whilst engaging in different regulatory strategies. The results indicate that participants with schizophrenia have difficulties with the amplification (but not suppression) of emotion expressive behavior. These difficulties are significantly correlated with total negative symptoms experienced, particularly emotional blunting.

Background: We undertook a twelve-month intervention study for community mental health patients using a number of measures administered at baseline and at twelve months. Overall improvement in that sample allowed for comparative analyses of the key measures in terms of their ability to measure and to predict outcome. Aims: To assess and compare the usefulness of each of the measures in predicting outcome status. Methods: A patient-rated quality of life (QOL) questionnaire, the DSM-III-R Global Assessment of Functioning (GAF), the Life Skills Profile (LSP) and the Health of the Nation Outcome Scales (HoNOS) were compared and evaluated in a sample of seventy-nine patients. Results: The LSP appeared to measure disability only, while the HoNOS and the GAF assessed composite symptoms and general functioning. The HoNOS was identified as the most distinctive predictor of outcome. Conclusions: The utility of the HoNOS as an overall service measure is supported, while properties and likely utility of other measures in outcome studies are detailed.

The immune system is implicated in the pathogenesis of schizophrenia, with elevated proinflammatory cytokine mRNAs found in the brains of ~40% of individuals with the disorder. However, it is not clear if antibodies (specifically immunoglobulin-γ (IgG)) can be found in the brain of people with schizophrenia and if their abundance relates to brain inflammatory cytokine mRNA levels. Therefore, we investigated the localization and abundance of IgG in the frontal cortex of people with schizophrenia and controls, and the impact of proinflammatory cytokine status on IgG abundance in these groups. Brain IgGs were detected surrounding blood vessels in the human and non-human primate frontal cortex by immunohistochemistry. IgG levels did not differ significantly between schizophrenia cases and controls, or between schizophrenia cases in ‘high’ and ‘low’ proinflammatory cytokine subgroups. Consistent with the existence of IgG in the parenchyma of human brain, mRNA and protein of the IgG transporter (FcGRT) were present in the brain, and did not differ according to diagnosis or inflammatory status. Finally, brain-reactive antibody presence and abundance was investigated in the blood of living people. The plasma of living schizophrenia patients and healthy controls contained antibodies that displayed positive binding to Rhesus macaque cerebellar tissue, and the abundance of these antibodies was significantly lower in patients than controls. These findings suggest that antibodies in the brain and brain-reactive antibodies in the blood are present under normal circumstances.

Summary Background Sex steroids such as oestrogen and testosterone are potent neurodevelopmental hormones that also play a role in neuromodulation and neuroprotection of the mature brain. Sex steroid hormones may also be involved in the pathophysiology of schizophrenia as reduced circulating sex steroid levels and changes in brain sex steroid receptors are found in people with schizophrenia compared to controls. In men with schizophrenia, recent studies have documented an inverse correlation between serum testosterone and negative symptoms. Our study sought to confirm whether men with schizophrenia had lower levels of testosterone relative to controls and to determine whether lower testosterone levels were related to higher symptom severity and impaired cognition. Method Circulating serum hormone levels (testosterone, oestrogen, and prolactin), cognitive function and symptoms were assessed in 29 chronically ill men with schizophrenia or schizoaffective disorder. Twenty healthy men were recruited as a comparison group. A series of regression analyses were performed to determine the extent to which circulating sex steroid hormone levels predict cognition and symptoms in men with schizophrenia. Results We did not find a significant difference in serum testosterone levels between groups. However, circulating testosterone levels significantly predicted performance on verbal memory, processing speed, and working memory in men with schizophrenia. With the exception of an effect of oestrogen on verbal memory, circulating sex steroid levels did not predict cognitive function in healthy men. Testosterone levels were not related to positive or negative symptom severity, but testosterone influenced excitement/hostility levels in our schizophrenia sample. Conclusions The results suggest that circulating sex steroids may modulate cognitive deficits associated with schizophrenia.

This study investigated immune activation, as measured by production of interleukin-2 (IL-2) and soluble interleukin-2 receptors (sIL-2R) from stimulated lymphocytes, in schizophrenia and schizophreniform disorder. The study included 13 neuroleptic-free patients, 13 medicated patients and 13 age- and sex-matched control subjects. Production of IL-2 and sIL-2R by peripheral blood mononuclear cells (PBMCs) was measured after in vitro stimulation with phytohaemagglutinin (PHA). Patients' symptoms were rated on the Scales for Assessment of Positive (SAPS) and Negative Symptoms (SANS) and the Brief Psychiatric Rating Scale (BPRS). IL-2 production by stimulated lymphocytes was significantly elevated in neuroleptic-free patients compared with both medicated patients and control subjects. IL-2 production was inversely correlated with the SAPS subscales of bizarre behaviour and formal thought disorder. The pattern of increased IL-2 production is in contrast to previous findings in patients with schizophrenia. Significant associations with clinical rating scores suggest that IL-2 production may vary in different biological subgroups of schizophrenia and schizophreniform disorder.

Early intervention into prodromal schizophrenia has shown promise, but controversy continues regarding the ethical acceptability of identifying a group of ‘ultra high risk’ individuals of whom only 30 to 50% will develop a psychotic disorder. With well developed early intervention services this group faces the possibility of being labelled as ‘pre-psychotic’, a condition for which the well known stigma associated with the diagnosis of schizophrenia or bipolar disorder is likely to be associated. In addition, the use of potent antipsychotic and other medications (albeit usually at lower doses than those used for those with manifest psychosis) mandates consideration of the risks associated with their use and neurological and metabolic side effects. The potential for iatrogenic morbidity in the ‘false positive’ group must be weighed against the need of the ‘true positives’ identified through screening and assessment. Current evidence for the concept of ‘at-risk mental state’ was reviewed within a neurodevelopmental framework, including emerging data on the effectiveness of early intervention for the purpose of providing recommendations for community mental health services. The review suggests that different treatment strategies may be appropriate depending on the clinical stage of the condition as long as the benefits of intervention outweigh its risk burden. It further suggests that the severity of psychoses and the evidence of its early onset in utero and its acceleration in adolescence positions ‘ultra high risk’ intervention as a core model for early intervention for young people by teasing apart the symptomatic components of the ‘prepsychotic state’ and ensuring the population is reaching targeted mental health services for screening. The model is not restricted to the delivery of intervention for ‘pre-psychotic’ young people but is applicable for targeted programmes for a number of clinical groups considered at ‘ultra high risk’. However, only further research in naturalistic populations embedded in clinical practice and ideally conducted in partnership of mental health services with academic research institutions will help clarify potential risks of early identification and intervention and assist in updating and making more explicit the clinical guidelines services will use in approaching those in the ‘ultra high risk’ group.

Individuals can exert considerable control over their experience and expression of emotion by applying different regulatory strategies such as reappraisal and suppression. However, although it has been suggested that blunted affect in schizophrenia, characterized by markedly reduced emotion expressivity alongside apparently normal emotion experience, may reflect overuse of suppression, no study to date has assessed self-reported use of these different emotion regulatory strategies in relation to this disorder. In the present study, 41 individuals with schizophrenia and 38 control participants completed a self-report measure that differentiated between use of suppression and reappraisal. Symptom severity and various aspects of cognitive and psychosocial functioning were also assessed. Relative to controls, individuals with schizophrenia did not differ with regard to their reported use of suppression and reappraisal, and reported use of both strategies was unrelated to clinical ratings of blunted affect. However, whereas (lower) use of reappraisal was associated with greater social function impairment for both groups, only for controls was (greater) use of suppression associated with reduced social functioning. Implications for understanding blunted affect and social dysfunction in schizophrenia are discussed.

Background. Previous studies have implicated emotional suppression, in particular suppression of anger, in the onset and progression of breast cancer. Many of these studies used non-standardized measures and failed to control for the effects of age and/or possible knowledge of diagnosis. The present study aimed to avoid these methodological errors in investigating the relationship of emotional suppression to a diagnosis of breast cancer in a large mammography screened population.Method. Data were collected from 1151 women with suspicious mammograms recalled to a breast screening programme. Prior to multidisciplinary assessment women were asked to complete the Courtauld Emotional Control Scale. Imaging assessment outcome data and biopsy results were collected.Results. Fifteen per cent of this population subsequently were diagnosed with breast cancer. There were no significant associations between a cancer outcome and emotional suppression before or after the highly significant effect of age was taken into account.Conclusions. These results suggest that suppression of emotion may not be relevant to the development of breast cancer. Its role in the progression of existing disease requires clarification.

Although there are a number of demonstration early psychosis intervention (EPI) programs, comprehensive procedures for implementing EPI in routine community service environments have not been published. The present study describes the introduction and evaluation of a specialized EPI program in a routine Australian urban mental health service. The program was supported by enhancement funding for 18 months (December 1995 to June 1997) and consisted of four full-time staff and two quarter-time consultant psychiatrists who worked in an Assertive Community Treatment team framework. Of 161 referrals, 149 were assessed and 70 clients were actively treated. Clients showed statistically significant short-term (3–6 months) improvements on all outcome instruments. Detection and retention rates for the specialized EPI program appeared to be better than those for an adjacent service that used a case-manager-implemented EPI protocol but without additional resources or dedicated staff. Preliminary results of a medium-term (3–4 years) follow-up indicated that the social, but not the vocational, function of clients was greatly improved. The authors concluded that the appropriate level of specialized treatment and evaluation required for early psychosis intervention is only possible if models of specialized case management are used and there is a long-term commitment by the mental health service to support early psychosis intervention as a specialized function. Recommendations for the successful introduction and evaluation of early psychosis intervention are discussed.

Objective: The study investigated the provision of client-focused services to community-based clients with schizophrenia and bipolar disorder. It hypothesised that the delivery of more client-focused services would improve client outcome in terms of functioning, disability and satisfaction with services. Client-focused services were developed using an empowerment model of case management and by the addition of consumer advocates. Method: Clients referred for case management were randomly allocated to one of three groups: standard case management (n = 35), client-focused case management (n = 39), or client-focused case management plus consumer advocacy (n = 45). Measures of functioning, disability, quality of life, burden of care and service satisfaction were measured at baseline and 12 months. Outcome data were collected concerning number and duration of hospital readmission, crisis intervention and compliance with treatment and services. Results: While there were no differences between the groups on quantitative measures of functioning, disability, quality of life, service satisfaction and burden of care, there were significant between-group differences on qualitative measures of satisfaction with services. Conclusions: Several methodological difficulties hampered interpretation of the findings. Although clients did not differ on outcome measures of functioning and disability, the group receiving client-focused case management reported greater satisfaction with service delivery.

Objective: The aim of the present paper was to describe the development of a consumer advocacy program within the Eastern Suburbs of Sydney (NSW, Australia). Methods: The program was developed within the context of a research project that investigated the effect on outcome of client-focused approaches to community case management for clients with schizophrenia and bipolar disorder. Results: While the development of the advocacy program was limited by the constraints imposed by the research methodology, the study provided the opportunity to delineate the process involved and identify key components that need to be incorporated into future advocacy programs. Conclusions: The main guidelines determined were that consumer participation in service delivery needs to be flexible, consumer driven, have broad-based support, ready access to supervision and debriefing, ongoing training and clear job descriptions. Given adequate support, autonomy and funding, consumer advocates can provide a much needed resource for their fellow consumers.

Schizophrenic patients reportedly have a deficit in the control of sensitivity to auditory stimuli as shown by the P50 auditory evoked potential wave in a conditioning-testing paradigm that measures suppression of response to a repeated stimulus. Although this finding has been replicated by several US laboratories, one European group has not found differences between schizophrenic patients and normal control subjects. In the present study, investigators in the Schizophrenia Research Center at the Prince of Wales Hospital in Sydney, Australia, selected 22 normal control subjects, 11 acutely ill schizophrenic inpatients, and 11 clinically stable schizophrenic outpatients. Both schizophrenic groups were treated with similar doses of classical neuroleptic medications. Evoked potentials were recorded by an investigator from the US laboratory that initially reported the difference; five averages, each the response to 32 stimulus pairs, were recorded from each subject. The normal control subjects demonstrated significantly more suppression of the P50 response to the repeated stimuli than the schizophrenic groups, as previously reported. There were no significant changes in the suppression measure over the five trials. The suppression of the P50 wave by schizophrenic outpatients was somewhat greater than that by schizophrenic inpatients, but both schizophrenic groups had decreased suppression, compared with the normal subjects. The mean P50 suppression for five averages was successfully used in a logistic regression to classify subjects as normal or schizophrenic. This method was more accurate than attempts to classify subjects with only one average. The mean amplitude of the initial conditioning response did not differ between groups. Schizophrenic patients had slightly shorter mean latencies. There was no direct relationship of P50 suppression to measures of clinical psychopathology.

Significant differences in fMRI related activity between healthy adults and people with schizophrenia during reward-related prediction-errors

We selectively review recent research findings in the field of psychoimmunology which test the hypotheses that immunological dysfunction may be aetiologically related to mental illnesses such as schizophrenia, and that certain morbid affective states such as depression and other forms of psychosocial distress may be the cause of immunosuppression and through this mechanism affect the outcome of illnesses such as cancer. Our examination of research implicating immunological or infective mechanisms in the aetiology of schizophrenia indicates that most studies have been unable to control for major methodological difficulties but the compatibility of these theories with the dopamine hypothesis suggests that further research attention is warranted. More clearly, there is growing evidence demonstrating a link between depression, other states of psychological distress and immunosuppression, but the clinical significance of these findings remains uncertain. The complex relationship between stress and the outcome of illnesses such as cancer is discussed and the possible implications of these findings for clinical psychiatry are suggested.

SummaryDiagnostic patterns for schizophrenia and affective psychosis were examined for all admissions to psychiatric facilities in New South Wales over a ten-year (1967–1977) period, before, during, and after lithium carbonate had been established as an accepted treatment. While the proportion of functional psychoses to total admissions remained relatively constant over the study, there was a relative decrease in schizophrenia, and a relative increase in the affective psychosis group. Analyses of sub-groups suggested, after controlling for the effects of time, that the introduction of lithium has been associated with an increase in diagnoses of mania and a decrease in diagnoses of paranoid schizophrenia, both for first admissions and for readmissions.