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Approximately one-third of people with schizophrenia have elevated levels of antigliadin antibodies of the immunoglobulin G type (AGA IgG) — a higher rate than seen in healthy controls. We performed the first double-blind clinical trial of gluten-free versus gluten-containing diets in a subset of patients with schizophrenia who were positive for AGA IgG. In this pilot feasibility study, 16 participants with schizophrenia or schizoaffective disorder who had elevated AGA IgG (≥ 20 U) but were negative for celiac disease were admitted to an inpatient unit for a 5-week trial. All participants received standardized gluten-free meals and were randomized in a double-blind fashion to receive a shake containing 10 g of gluten flour or 10 g of rice flour each day. Participants were rated for psychiatric, cognitive and gastrointestinal symptoms at baseline and end point. Of the 16 participants, 14 completed the 5-week trial (2 discontinued early for administrative reasons). Compared with participants on the gluten-containing diet, participants on the gluten-free diet showed improvement on the Clinical Global Impressions scale (Cohen d = −0.75) and in negative symptoms (Cohen d = −0.53). We noted no improvement in positive or global cognitive symptoms, but did observe an improvement in attention favouring the gluten-free diet (Cohen d = 0.60). Robust improvements in gastrointestinal adverse effects occurred in the gluten-free group relative to the gluten-containing group. Adverse effects were similar between groups. This study was limited by its small sample size; larger studies are needed. This feasibility study suggests that removal of gluten from the diet is associated with improvement in psychiatric and gastrointestinal symptoms in people with schizophrenia or schizoaffective disorder.

Background Evidence is conflicting about a causal role of inflammation in psychosis and, specifically, regarding antibodies binding to neuronal membrane targets, especially N-methyl-D-aspartate receptors. NMDAR, LGI1 and GABA-A antibodies were found more prevalent in people with psychosis than in healthy controls. We aim to test whether these antibodies are pathogenic and may cause isolated psychosis. The SINAPPS2 phase IIa double-blinded randomised controlled trial will test the efficacy and safety of immunoglobulin and rituximab treatment versus placebo for patients with acute psychosis symptoms as added to psychiatric standard of care. Methods We will screen approximately 2500 adult patients with acute psychosis to identify 160 with antibody-positive psychosis without co-existing neurological disease and recruit about 80 eligible participants to the trial in the period from September 2017 to September 2021 across the UK. Eligible patients will be randomised 1:1 either to intravenous immunoglobulin (IVIG) followed by rituximab or to placebo infusions of 1% albumin followed by 0.9% sodium chloride, respectively. To detect a time-to-symptomatic-recovery hazard ratio of 0.322 with a power of 80%, 56 participants are needed to complete the trial, allowing for up to 12 participants to drop out of each group. Eligible patients will be randomised and assessed at baseline within 4 weeks of their eligibility confirmation. The treatment will start with IVIG or 1% albumin placebo infusions over 2–4 consecutive days no later than 7 days from baseline. It will continue 4–5 weeks later with a rituximab or sodium chloride placebo infusion and will end 2–3 weeks after this with another rituximab or placebo infusion. The primary outcome is the time to symptomatic recovery defined as symptomatic remission sustained for at least 6 months on the following Positive and Negative Syndrome Scale items: P1, P2, P3, N1, N4, N6, G5 and G9. Participants will be followed for 12 months from the first day of treatment or, where sustained remission begins after the first 6 months, for an additional minimum of 6 months to assess later response. Discussion The SINAPPS2 trial aims to test whether immunotherapy is efficacious and safe in psychosis associated with anti-neuronal membrane antibodies. Trial registration ISRCTN, 11177045. Registered on 2 May 2017. EudraCT, 2016-000118-31. Registered on 22 November 2016. ClinicalTrials.gov, NCT03194815. Registered on 21 June 2017.

Rationale Psychosocial stressors are a well-documented risk factor for mental illness. Neuroinflammation, in particular elevated microglial activity, has been proposed to mediate this association. A number of preclinical studies have investigated the effect of stress on microglial activity. However, these have not been systematically reviewed before. Objectives This study aims to systematically review the effects of stress on microglia, as indexed by the histological microglial marker ionised calcium binding adaptor molecule 1 (Iba-1), and consider the implications of these for the role of stress in the development of mental disorders. Methods A systematic review was undertaken using pre-defined search criteria on PubMed and EMBASE. Inclusion and data extraction was agreed by two independent researchers after review of abstracts and full text. Results Eighteen studies met the inclusion criteria. These used seven different psychosocial stressors, including chronic restraint, social isolation and repeated social defeat in gerbils, mice and/or rats. The hippocampus (11/18 studies) and prefrontal cortex (13/18 studies) were the most frequently studied areas. Within the hippocampus, increased Iba-1 levels of between 20 and 200 % were reported by all 11 studies; however, one study found this to be a duration-dependent effect. Of those examining the prefrontal cortex, ∼75 % found psychosocial stress resulted in elevated Iba-1 activity. Elevations were also consistently seen in the nucleus accumbens, and under some stress conditions in the amygdala and paraventricular nucleus. Conclusions There is consistent evidence that a range of psychosocial stressors lead to elevated microglial activity in the hippocampus and good evidence that this is also the case in other brain regions. These effects were seen with early-life/prenatal stress, as well as stressors in adulthood. We consider these findings in terms of the two-hit hypothesis, which proposes that early-life stress primes microglia, leading to a potentiated response to subsequent stress. The implications for understanding the pathoaetiology of mental disorders and the development of new treatments are also considered.

Abstract Innate immunity has been linked to initiation of Alzheimer’s disease and multiple sclerosis. Moreover, risk of first-episode psychosis (FEP) and schizophrenia (Sz) is increased after various infections in predisposed individuals. Thus, we hypothesized an analogous role of innate immunity with increased C-reactive protein (CRP) in non-affective psychosis. Differential blood count, CRP, neutrophil and monocyte–macrophage activation markers, cortisol and psychotic symptoms (Positive and Negative Syndrome Scale [PANSS]) were assessed in controls (n = 294) and acutely ill unmedicated FEP (n = 129) and Sz (n = 124) patients at baseline and after 6 weeks treatment. Neutrophils, monocytes, and CRP were increased in patients vs controls at baseline (P < .001), and neutrophil and monocyte counts correlated positively with activation markers. Eosinophils were lower at baseline in FEP (P < .001) and Sz (P = .021) vs controls. Differences in neutrophils (P = .023), eosinophils (P < .001), and CRP (P < .001) were also present when controlling for smoking and cortisol, and partially remitted after antipsychotic treatment. FEP patients with high neutrophils (P = .048) or monocytes (P = .021) had higher PANSS-P scores at baseline but similar disease course. CRP correlated with PANSS-P at baseline (ρ = 0.204, P = .012). Improvement of positive symptoms after treatment correlated with declining neutrophils (ρ = 0.186, P = .015) or CRP (ρ = 0.237, P = .002) and rising eosinophils (ρ = −0.161, P = .036). In FEP, normalization of neutrophils (ρ = −0.231, P = .029) and eosinophils (ρ = 0.209, P = .048) correlated with drug dosage. In conclusion, innate immune system activation correlated with PANSS-P, supporting the immune hypothesis of psychosis. Neutrophil and monocyte counts and CRP levels may be useful markers of disease acuity, severity, and treatment response.

Immune parameters are elevated in psychosis, but it is unclear whether alterations are homogenous across patients or heterogeneity exists, consistent with the hypothesis that immune alterations are specific to a subgroup of patients. To address this, we examine whether antipsychotic-naïve first-episode psychosis patients exhibit greater variability in blood cytokines, C-reactive protein, and white cell counts compared with controls, and if group mean differences persist after adjusting for skewed data and potential confounds. Databases were searched for studies reporting levels of peripheral immune parameters. Means and variances were extracted and analyzed using multivariate meta-analysis of mean and variability of differences. Outcomes were (1) variability in patients relative to controls, indexed by variability ratio (VR) and coefficient of variation ratio (CVR); (2) mean differences indexed by Hedges g; (3) Modal distribution of raw immune parameter data using Hartigan’s unimodality dip test. Thirty-five studies reporting on 1263 patients and 1470 controls were included. Variability of interleukin-6 (IL6) (VR = 0.19), tumor necrosis factor-α (TNFα) (VR = 0.36), interleukin-1β (VR = 0.35), interleukin-4 (VR = 0.55), and interleukin-8 (VR = 0.28) was reduced in patients. Results persisted for IL6 and IL8 after mean-scaling. Ninety-four percent and one hundred percent of raw data were unimodally distributed in psychosis and controls, respectively. Mean levels of IL6 (g = 0.62), TNFα (g = 0.56), interferon-γ (IFNγ) (g = 0.32), transforming growth factor-β (g = 0.53), and interleukin-17 (IL17) (g = 0.48) were elevated in psychosis. Sensitivity analyses indicated this is unlikely explained by confounders for IL6, IFNγ, and IL17. These findings show elevated cytokines in psychosis after accounting for confounds, and that the hypothesis of an immune subgroup is not supported by the variability or modal distribution.

Despite mixed findings, increasing evidence suggests that people with first-episode psychosis (FEP) show increased pro-inflammatory and pro-oxidative status. We used the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines to conduct a systematic literature search of cross-sectional studies comparing in vivo inflammatory and oxidative blood markers between FEP patients and healthy controls. We analyzed 61 independent samples from 59 publications, including 3002 patients with FEP (ie, patients with FEP, early psychosis, first-episode schizophrenia or early schizophrenia) and 2806 controls. After controlling for multiple comparisons, our meta-analysis showed that total antioxidant status and docosahexaenoic acid levels were significantly lower in FEP patients than in controls, whereas levels of homocysteine, interleukin-6 and tumor necrosis factor alpha were significantly higher in FEP patients than in controls. This suggests that FEP patients had reduced antioxidant status and a pro-inflammatory imbalance, and that these biological processes may be targets for managing FEP.

Schizophrenia is associated with increased physical morbidity and early mortality, suggesting that the aging process may be accelerated in schizophrenia. However, the biological underpinnings of these alterations in aging in schizophrenia are unclear. We conducted a detailed search of peer-reviewed empirical studies to evaluate evidence for accelerated biological aging in schizophrenia based on systemic, age-related biomarkers. We included studies that investigated differences between persons with schizophrenia and healthy comparison subjects in levels of biomarkers known to be associated with aging and examined the relationship of these biomarkers to age in the 2 groups. Forty-two articles that met our selection criteria were reviewed. Nearly 75% reported abnormal biomarker levels among individuals with schizophrenia, including indices of inflammation, cytotoxicity, oxidative stress, metabolic health, gene expression, and receptor/synaptic function, with medium to large effect sizes reported in many studies. Twenty-nine percent of the studies observed differential age-related decline in schizophrenia. Markers of receptor/synaptic function and gene expression were most frequently differentially related to age in schizophrenia. Schizophrenia patients with greater disease severity and longer illness duration exhibited higher levels of inflammatory and oxidative stress biomarkers and shorter telomere length. Most studies show biomarker abnormalities in schizophrenia, and there is some suggestion for accelerated aging. Although definitive interpretation is limited by cross-sectional design of the published reports, findings in the area of gene expression and synaptic function are promising and pave the way for future longitudinal studies needed to fully test this hypothesis.

People with psychotic disorders show abnormalities in several organ systems in addition to the central nervous system (CNS); and this contributes to excess mortality. However, it is unclear how strong the evidence is for alterations in non-CNS systems at the onset of psychosis, how the alterations in non-CNS systems compare to those in the CNS, or how they relate to symptoms. Here, we consider these questions, and suggest potential models to account for findings. We conducted a systematic meta-review to summarize effect sizes for both CNS (focusing on brain structural, neurophysiological, and neurochemical parameters) and non-CNS dysfunction (focusing on immune, cardiometabolic, and hypothalamic–pituitary–adrenal (HPA) systems) in first-episode psychosis (FEP). Relevant meta-analyses were identified in a systematic search of Pubmed and the methodological quality of these was assessed using the AMSTAR checklist (A Measurement Tool to Assess Systematic Reviews). Case–control data were extracted from studies included in these meta-analyses. Random effects meta-analyses were re-run and effect size magnitudes for individual parameters were calculated, as were summary effect sizes for each CNS and non-CNS system. We also grouped studies to obtain overall effect sizes for non-CNS and CNS alterations. Robustness of data for non-CNS and CNS parameters was assessed using Rosenthal’s fail-safe N. We next statistically compared summary effect size for overall CNSand overall non-CNS alterations, as well as for each organ system separately. We also examined how non-CNS alterations correlate CNS alterations, and with psychopathological symptoms. Case-control data were extracted for 165 studies comprising a total sample size of 13,440. For people with first episode psychosis compared with healthy controls, we observed alterations in immune parameters (summary effect size: g = 1.19), cardiometabolic parameters (g = 0.23); HPA parameters (g = 0.68); brain structure (g = 0.40); neurophysiology (g = 0.80); and neurochemistry (g = 0.43). Grouping non-CNS organ systems together provided an effect size for overall non-CNS alterations in patients compared with controls (g = 0.58), which was not significantly different from the overall CNS alterations effect size (g = 0.50). However, the summary effect size for immune alterations was significantly greater than that for brain structural (P < 0.001) and neurochemical alterations (P < 0.001), while the summary effect size for cardiometabolic alterations was significantly lower than neurochemical (P = 0.04), neurophysiological (P < 0.001), and brain structural alterations (P = 0.001). The summary effect size for HPA alterations was not significantly different from brain structural (P = 0.14), neurophysiological (P = 0.54), or neurochemical alterations (P = 0.22). These outcomes remained similar in antipsychotic naive sensitivity analyses. We found some, but limited and inconsistent, evidence that non-CNS alterations were associated with CNS changes and symptoms in first episode psychosis. Our findings indicate that there are robust alterations in non-CNS systems in psychosis, and that these are broadly similar in magnitude to a range of CNS alterations. We consider models that could account for these findings and discuss implications for future research and treatment.

Abstract Blood-based biomarker discovery for psychotic disorders has yet to impact upon routine clinical practice. In physical disorders antibodies have established roles as diagnostic, prognostic and predictive (theranostic) biomarkers, particularly in disorders thought to have a substantial autoimmune or infective aetiology. Two approaches to antibody biomarker identification are distinguished: a “top-down” approach, in which antibodies to specific antigens are sought based on the known function of the antigen and its putative role in the disorder, and emerging “bottom-up” or “omics” approaches that are agnostic as to the significance of any one antigen, using high-throughput arrays to identify distinctive components of the antibody repertoire. Here we review the evidence for antibodies (to self-antigens as well as infectious organism and dietary antigens) as biomarkers of diagnosis, prognosis, and treatment response in psychotic disorders. Neuronal autoantibodies have current, and increasing, clinical utility in the diagnosis of organic or atypical psychosis syndromes. Antibodies to selected infectious agents show some promise in predicting cognitive impairment and possibly other symptom domains (eg, suicidality) within psychotic disorders. Finally, infectious antibodies and neuronal and other autoantibodies have recently emerged as potential biomarkers of response to anti-infective therapies, immunotherapies, or other novel therapeutic strategies in psychotic disorders, and have a clear role in stratifying patients for future clinical trials. As in nonpsychiatric disorders, combining biomarkers and large-scale use of “bottom-up” approaches to biomarker identification are likely to maximize the eventual clinical utility of antibody biomarkers in psychotic disorders.