Immune and oxidative stress biomarkers in pediatric psychosis and psychosis-risk: Meta-analyses and systematic review.

OBJECTIVE: While genetic and cohort studies suggest immune and reduction/oxidation (redox) alterations occur in psychosis, less is known about potential alterations in children and adolescents. METHODS: We conducted a systematic review to identify immune and redox biomarker studies in children and adolescents (mean age ≤ 18 years old) across the psychosis spectrum: from psychotic like experiences, which are common in children, to threshold psychotic disorders like schizophrenia. We conducted meta-analyses when at least three studies measured the same biomarker. RESULTS: The systematic review includes 38 pediatric psychosis studies. The meta-analyses found that youth with threshold psychotic disorders had higher neutrophil/lymphocyte ratio (Hedge's g = 0.40, 95 % CI 0.17 - 0.64), tumor necrosis factor (Hedge's g = 0.38, 95 % CI 0.06 - 0.69), C-reactive protein (Hedge's g = 0.38, 95 % CI 0.05 - 0.70), interleukin-6 (Hedge's g = 0.35; 95 % CI 0.11 - 0.64), and total white blood cell count (Hedge's g = 0.29, 95 % CI 0.12 - 0.46) compared to youth without psychosis. Other immune and oxidative stress meta-analytic findings were very heterogeneous. CONCLUSION: Results from several studies are consistent with the hypothesis that signals often classified as "proinflammatory" are elevated in threshold pediatric psychotic disorders. Data are less clear for immune markers in subthreshold psychosis and redox markers across the subthreshold and threshold psychosis spectrum. Immune and redox biomarker intervention studies are lacking, and research investigating interventions targeting the immune system in threshold pediatric psychosis is especially warranted.

Aiding and Abetting Anhedonia: Impact of Inflammation on the Brain and Pharmacological Implications.

Exogenous administration of inflammatory stimuli to humans and laboratory animals and chronic endogenous inflammatory states lead to motivational deficits and ultimately anhedonia, a core and disabling symptom of depression present in multiple other psychiatric disorders. Inflammation impacts neurotransmitter systems and neurocircuits in subcortical brain regions including the ventral striatum, which serves as an integration point for reward processing and motivational decision-making. Many mechanisms contribute to these effects of inflammation, including decreased synthesis, release and reuptake of dopamine, increased synaptic and extrasynaptic glutamate, and activation of kynurenine pathway metabolites including quinolinic acid. Neuroimaging data indicate that these inflammation-induced neurotransmitter effects manifest as decreased activation of ventral striatum and decreased functional connectivity in reward circuitry involving ventral striatum and ventromedial prefrontal cortex. Neurocircuitry changes in turn mediate nuanced effects on motivation that include decreased willingness to expend effort for reward while maintaining the ability to experience reward. Taken together, the data reveal an inflammation-induced pathophysiologic phenotype that is agnostic to diagnosis. Given the many mechanisms involved, this phenotype represents an opportunity for development of novel and/or repurposed pharmacological strategies that target inflammation and associated cellular and systemic immunometabolic changes and their downstream effects on the brain. To date, clinical trials have failed to capitalize on the unique nature of this transdiagnostic phenotype, leaving the field bereft of interpretable data for meaningful clinical application. However, novel trial designs incorporating established targets in the brain and/or periphery using relevant outcome variables (e.g., anhedonia) are the future of targeted therapy in psychiatry. SIGNIFICANCE STATEMENT: Emerging understanding of mechanisms by which peripheral inflammation can affect the brain and behavior has created unprecedented opportunities for development of pharmacological strategies to treat deficits in motivation including anhedonia, a core and disabling symptom of depression well represented in multiple psychiatric disorders. Mechanisms include inflammation and cellular and systemic immunometabolism and alterations in dopamine, glutamate, and kynurenine metabolites, revealing a target-rich environment that nevertheless has yet to be fully exploited by current clinical trial designs and drugs employed.

First clinical evaluation of the safety and efficacy of tarumase for the debridement of venous leg ulcers.

We report the first clinical evaluation of a new enzymatic wound debridement product containing tarumase in venous leg ulcer patients. As a first-in-human study, this was a prospective, open-label, multi-centre, dose escalation study across five dose cohorts and involving a total of 43 patients treated three times weekly for up to 4 weeks (12 applications). The primary and secondary endpoints of the study were to assess the systemic safety, local tolerability, and early proof of concept both for wound debridement and healing. Results indicated that the tarumase enzyme was well tolerated when applied topically to wounds, with no indications of systemic absorption, no evidence of antibody generation, and no systemic effects on coagulation pathways. Locally, there was no evidence of pain on application, no local itching, no increases in erythema, oedema, exudate or bleeding and only a few treatment emergent adverse events were reported. As the concentration of tarumase was escalated, trends towards faster and improved effectiveness of wound debridement were observed, especially in patients with significant slough at baseline. Trends towards faster rates of healing were also noted based on observations of increased granulation tissue, increased linear healing and reduction in surface area over the 4-week treatment period.

Predictors of successful anti-inflammatory drug trials in patients with schizophrenia: A meta-regression and critical commentary.

Given evidence pointing toward a role for immune dysregulation in the pathogenesis of schizophrenia, anti-inflammatory agents are promising adjunctive treatments that have potential to support a causal relationship for inflammation and psychopathology and lead to novel treatments for individuals. Indeed, previous meta-analyses have demonstrated small-to-medium effect sizes (ES) in favor of various anti-inflammatory agents, though there is significant heterogeneity and challenges in the interpretation of this literature. Identifying predictors, including sociodemographic variables, trial duration, and/or symptoms themselves, of successful anti-inflammatory trials may help identify which patients who might benefit from these compounds. We performed a meta-regression analysis of 63 adjunctive anti-inflammatory trial arms (2232 patients randomized to adjunctive anti-inflammatory agents and 2207 patients randomized to placebo).Potential predictors of effect size estimates for changes in psychopathology scores from baseline to endpoint included geography, trial duration, sample size, age, sex, race, smoking, body mass index, illness duration, age of onset of psychosis, study quality score and psychopathology scores (total and subscale) at baseline. Geography (ß = 0.31, p = 0.011), smaller sample size (ß = 0.33, p = 0.009), and higher study quality score (ß = 0.44, p < 0.001) were significant predictors of larger ES estimates for change in total psychopathology in favor of anti-inflammatory agents. Smaller sample size (ß = 0.37, p = 0.034) and higher study quality score (ß = 0.55, p = 0.003) were significant predictors of larger ES estimates for change in negative psychopathology in favor of anti-inflammatory agents. Higher study quality score (ß = 0.46, p = 0.019) was a significant predictor of larger ES estimates for change in general psychopathology in favor of anti-inflammatory agents. These findings should be interpreted with caution given concerns of publication bias regarding the geographic differences and small study effects. The lack of an association with other demographic variables should be seen as a primary limitation of the literature that needs to be considered in future studies. The association with study quality score suggests that future anti-inflammatory trials must consider demographic variables known to be associated with inflammation (e.g., BMI and smoking) and evidence of increased baseline inflammation should be incorporated in study design. Moreover, evidence of target engagement and endpoints thoughts to be associated with increased inflammation should be considered as well.

The human lncRNA GOMAFU suppresses neuronal interferon response pathways affected in neuropsychiatric diseases.

Long noncoding RNAs (lncRNAs) play multifaceted roles in regulating brain gene networks. LncRNA abnormalities are thought to underlie the complex etiology of numerous neuropsychiatric disorders. One example is the human lncRNA gene GOMAFU, which is found dysregulated in schizophrenia (SCZ) postmortem brains and harbors genetic variants that contribute to the risk of SCZ. However, transcriptome-wide biological pathways regulated by GOMAFU have not been determined. How GOMAFU dysregulation contributes to SCZ pathogenesis remains elusive. Here we report that GOMAFU is a novel suppressor of human neuronal interferon (IFN) response pathways that are hyperactive in the postmortem SCZ brains. We analyzed recently released transcriptomic profiling datasets in clinically relevant brain areas derived from multiple SCZ cohorts and found brain region-specific dysregulation of GOMAFU. Using CRISPR-Cas9 to delete the GOMAFU promoter in a human neural progenitor cell model, we identified transcriptomic alterations caused by GOMAFU deficiency in pathways commonly affected in postmortem brains of SCZ and autism spectrum disorder (ASD), with the most striking effects on upregulation of numerous genes underlying IFN signaling. In addition, expression levels of GOMAFU target genes in the IFN pathway are differentially affected in SCZ brain regions and negatively associated with GOMAFU alterations. Furthermore, acute exposure to IFN-γ causes a rapid decline of GOMAFU and activation of a subclass of GOMAFU targets in stress and immune response pathways that are affected in SCZ brains, which form a highly interactive molecular network. Together, our studies unveiled the first evidence of lncRNA-governed neuronal response pathways to IFN challenge and suggest that GOMAFU dysregulation may mediate environmental risks and contribute to etiological neuroinflammatory responses by brain neurons of neuropsychiatric diseases.

Antipsychotics and Medical Comorbidity: A Retrospective Study in an Urban Outpatient Psychiatry Clinic.

Patients with psychotic disorders have increased rates of medical comorbidities. In this cross-sectional study, we investigated the relationship between antipsychotics and medical comorbidities among patients with psychotic disorders in an urban psychiatry clinic in Atlanta, Georgia (n = 860). Each antipsychotic group was compared to a group of patients from the same sample who were not on any antipsychotic, and logistic regression models were constructed for each comorbidity. Ziprasidone was associated with diabetes (aOR 2.56, 95% CI 1.03-6.38) and obesity (aOR 3.19, 95% CI 1.37-7.41). Aripiprazole was associated with obesity (aOR 2.39, 95% CI 1.27-4.51). Clozapine was associated with GERD (aOR 3.59, 95% CI 1.11-11.61), movement disorders (aOR 4.44, 95% CI 1.02-19.32), and arrythmias (4.89, 95% CI 1.44-16.64). Two antipsychotics that are considered weight neutral, ziprasidone and aripiprazole, were associated with cardiometabolic comorbidities. This study suggests that research is warranted to study the association between antipsychotics, medical comorbidity, and psychotic symptom burden.

Transcriptomic signatures of psychomotor slowing in peripheral blood of depressed patients: evidence for immunometabolic reprogramming.

Inflammation impacts basal ganglia motor circuitry in association with psychomotor retardation, a key symptom of major depression (MD). We previously reported associations between circulating protein inflammatory biomarkers and psychomotor slowing as measured by neuropsychological tests probing psychomotor speed in patients with MD. To discover novel transcriptional signatures in peripheral blood immune cells related to psychomotor slowing, microarray data were analyzed in a primary cohort of 88 medically-stable, unmedicated, ambulatory MD patients. Results were confirmed and extended in a second cohort of 57 patients with treatment resistant depression (TRD) before and after anti-inflammatory challenge with the tumor necrosis factor antagonist infliximab versus placebo. Composite scores reflecting pure motor and cognitive-motor processing speed were linearly associated with 403 and 266 gene transcripts in each cohort, respectively (|R| > 0.30, p < 0.01), that were enriched for cytokine signaling and glycolysis-related pathways (p < 0.05). Unsupervised clustering in the primary cohort revealed two psychomotor slowing-associated gene co-expression modules that were enriched for interferon, interleukin-6, aerobic glycolysis, and oxidative phosphorylation pathways (p < 0.05, q < 0.1). Transcripts were predominantly derived from monocytes, plasmacytoid dendritic cells, and natural killer cells (p's < 0.05). In infliximab-treated TRD patients with high plasma C-reactive protein concentrations (>5 mg/L), two differential co-expression modules enriched for oxidative stress and mitochondrial degradation were associated with improvements in psychomotor reaction time (p < 0.05). These results indicate that inflammatory signaling and associated metabolic reprogramming in peripheral blood immune cells are associated with systemic inflammation in depression and may affect relevant brain circuits to promote psychomotor slowing.

A Comparison of Attitudes, Comfort, and Knowledge of Clozapine Among Two Diverse Samples of US Psychiatrists.

Considerable variation in clozapine utilization exists across the United States, and little is known about the perspective of psychiatrists in states with low clozapine use. To better understand clozapine practices, attitudes, and barriers, a survey was administered to a group of southeastern state conference attendees (SSCA; N = 86). The same survey was administered to psychiatrists belonging to a national community psychiatry organization (AACP; N = 57), and differences were analyzed across the two samples. In comparison to the AACP, the SSCA group felt less comfortable, perceived clozapine as less safe and effective, had fewer patients on clozapine, and were more likely to prefer antipsychotic polypharmacy to clozapine use. Across the sample, use of a myocarditis screening protocol was rare (N = 14/76; 18%) and less than half used plasma antipsychotic levels to guide dosage (N = 60/129; 47%). Continuing professional education on clozapine are needed for psychiatrists who see individuals with psychotic disorders.

Four cases of myocarditis in US hospitals possibly associated with clozapine poor metabolism and a comparison with prior published cases.

Objectives: Clozapine-induced myocarditis may be a hypersensitivity reaction due to titration that was too rapid for a patient's clozapine metabolism. Obesity, infections, and inhibitors (e.g., valproate) may lead to clozapine poor metabolizer (PM) status. The hypothesis that 4 patients with clozapine-induced myocarditis from two United States hospitals were clozapine PMs was tested by studying their minimum therapeutic clozapine doses and titrations. Methods: Using methodology from a prior myocarditis case series of 9 Turkish patients, we studied: 1) the concentration-to-dose (C/D) ratio; 2) minimum therapeutic dose required to reach 350 ng/ml (a marker for PM status); and 3) titration speed. Results: All 4 patients were possible clozapine PMs (their respective minimum therapeutic doses were: 134, 84, 119 and 107 mg/day). The identified possible contributors to clozapine PM status were: 1) valproate in Cases 1, 2 and 4; 2) obesity and a urinary tract infection in Case 2; and 3) obesity and very rapid titration in Case 4. Case 3, who was given a normal US titration, appeared to be a genetic clozapine PM. He developed clozapineinduced drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome after rechallenge using 12.5 mg/day > 3 months later. The results were similar to 9 Turkish cases, all of which were PMs (6 on valproate, 4 with obesity, 1 with infection and 1 possibly genetic). Conclusions: Future studies using clozapine levels and considering the role of clozapine PM status should explore whether or not all cases of clozapine-induced myocarditis could be explained by lack of individualized titration. (Neuropsychopharmacol Hung 2022; 24(1): 29-41).

Prenatal exposure to viral infection and neuropsychiatric disorders in offspring: A review of the literature and recommendations for the COVID-19 pandemic.

The SARS-CoV-2 virus has emerged as a striking 21st century pandemic. Communities across the globe have experienced significant infection rates and widespread psychosocial stress and trauma, leading to calls for increased allocation of resources for mental health screening and treatment. In addition to the burden of psychosocial stress, there is increasing evidence of direct viral neuroinvasion of the central nervous system through physical contact with the nasal mucosa. In a parallel fashion, there is a significant body of ongoing research related to the risk of in utero viral transmission and the resulting neurodevelopmental impact in the fetus. Aberrant neurodevelopment secondary to viral transmission has previously been related to the later development of psychosis, schizophrenia, and schizophrenia spectrum disorders, generating the hypothesis that this population of individuals exposed to SARS-CoV-2 may see an increased incidence in future decades. We discuss the current understanding of the possible neurotropism and vertical transmission of SARS-CoV-2, and relate this to the history of viral pandemics to better understand the relationship of viral infection, aberrant immune response and neurodevelopment, and the risk for schizophrenia disorder.

What does plasma CRP tell us about peripheral and central inflammation in depression?

Peripheral blood C-reactive protein (CRP) is a biomarker used clinically to measure systemic inflammation and is reproducibly increased in a subset of patients with major depressive disorder (MDD). Furthermore, increased peripheral blood CRP in MDD has been associated with altered reward circuitry and increased brain glutamate in relation with symptoms of anhedonia. Nevertheless, the relationship between peripheral CRP and other peripheral and central markers of inflammation in depressed patients has not been established. Plasma (n = 89) and CSF (n = 73) was collected from medically stable, currently unmedicated adult outpatients with MDD. Associations among plasma and CSF CRP and plasma and CSF inflammatory cytokines (interleukin [IL]-6, tumor necrosis factor [TNF] and IL-1beta) and their soluble receptors/antagonists were examined. Relationships between plasma and CSF inflammatory markers and depressive symptoms including anhedonia and reduced motivation (RM) were also explored. Plasma CRP was correlated with multiple plasma inflammatory markers (all p < 0.05), and a strong correlation was found between plasma and CSF CRP (r = 0.855, p < 0.001). CSF CRP in turn correlated with CSF cytokine receptors/antagonists (all p < 0.05). Principal component analyses revealed clusters of CSF inflammatory markers that were associated with high plasma CRP (>3 mg/L) and correlated with depressive symptom severity. These findings were driven by CSF TNF, which correlated with RM (r = 0.236, p = 0.045), and CSF IL-6 soluble receptor, which correlated with anhedonia (r = 0.301, p = 0.010) in the sample as a whole and particularly females. CRP appears to be a peripheral biomarker that reflects peripheral and central inflammation and seems well-suited for guiding immunotherapies targeting TNF and IL-6 in patients with MDD.

Protein and gene markers of metabolic dysfunction and inflammation together associate with functional connectivity in reward and motor circuits in depression.

Bidirectional relationships between inflammation and metabolic dysfunction may contribute to the pathophysiology of psychiatric illnesses like depression. Metabolic disturbances drive inflammation, which in turn exacerbate metabolic outcomes including insulin resistance. Both inflammatory (e.g. endotoxin, vaccination) and metabolic challenges (e.g. glucose ingestion) have been shown to affect activity and functional connectivity (FC) in brain regions that subserve reward and motor processing. We previously reported relationships between elevated concentrations of endogenous inflammatory markers including C-reactive protein (CRP) and low corticostriatal FC, which correlated with symptoms of anhedonia and motor slowing in major depression (MD). Herein, we examined whether similar relationships were observed between plasma markers related to glucose metabolism (non-fasting concentrations of glucose, insulin, leptin, adiponectin and resistin) in 42 medically-stable, unmedicated MD outpatients who underwent fMRI. A targeted, hypothesis-driven approach was used to assess FC between seeds in subdivisions of the ventral and dorsal striatum and a region in ventromedial prefrontal cortex (VS-vmPFC), which was previously found to correlate with both inflammation and symptoms of anhedonia and motor slowing. Associations between FC and gene expression signatures were also explored. A composite score of all 5 glucose-related markers (with increasing values reflecting higher concentrations) was negatively correlated with both ventral striatum (VS)-vmPFC (r = -0.33, p < 0.05) and dorsal caudal putamen (dcP)-vmPFC (r = -0.51, p < 0.01) FC, and remained significant after adjusting for covariates including body mass index (p < 0.05). Moreover, an interaction between the glucose-related composite score and CRP was observed for these relationships (F[2,33] = 4.3, p < 0.05) whereby significant correlations between the glucose-related metabolic markers and FC was found only in patients with high plasma CRP (>3 mg/L; r = -0.61 to -0.81, p < 0.05). Insulin and resistin were the individual markers most predictive of VS-vmPFC and dcP-mPFC FC, respectively, and insulin, resistin and CRP clustered together and in association with both LV-vmPFC and dcP-vmPFC in principal component analyses. Exploratory whole blood gene expression analyses also confirmed that gene probes negatively associated with FC were enriched for both inflammatory and metabolic pathways (FDR p < 0.05). These results provide preliminary evidence that inflammation and metabolic dysfunction contribute jointly to deficits in reward and motor circuits in MD. Future studies using fasting samples and longitudinal and interventional approaches are required to further elucidate the respective contributions of inflammation and metabolic dysfunction to circuits and symptoms relevant to motivation and motor activity, which may have treatment implications for patients with psychiatric illnesses like depression.

Gene signatures in peripheral blood immune cells related to insulin resistance and low tyrosine metabolism define a sub-type of depression with high CRP and anhedonia.

Inflammation and altered glucose metabolism are two pathways implicated in the pathophysiology of major depressive disorder (MDD). We have previously shown that high inflammation as measured by C-reactive protein (CRP) in MDD patients is associated with symptoms of anhedonia, a core symptom of MDD, along with deficits in dopaminergic reward circuitry. Increased inflammation can shift metabolic demand and reprogram cellular energy sources, which may collectively impact the brain and reward processing to contribute to symptoms of anhedonia. To determine whether immunometabolic gene signatures were enriched in immune cells of depressed patients with increased inflammation and anhedonia, we examined whole-blood gene expression microarray (Illumina HumanHT-12) data from unmedicated, medically-stable patients with MDD (n = 93). Patients were considered to have increased inflammation based on High (>3mg/L) versus Low (≤3mg/L) plasma CRP, and further classified as having a self-reported phenotype of High (n = 30, 33rd percentile) versus Low (n = 32, 67th percentile) Anhedonia. Functional enrichment of gene pathways was assessed by Gene Set Enrichment Analysis (GSEA) using the KEGG pathway database. Pathways related to glucose metabolism (insulin signaling, insulin resistance, HIF-1, PI3K/AKT signaling), cancer (e.g., genes related to insulin and PI3K/AKT signaling), and inflammation (B cell, T cell and Fc receptor signaling) were specifically enriched in patients with both High CRP and High Anhedonia (all FDR q < 0.25). Within patients with High CRP in GSEA, the insulin signaling pathway was the top enriched pathway in patients with High versus Low Anhedonia (n = 10 and 9 respectively), which was driven by genes expressed predominantly in monocytes (z = 2.95, p < 0.01). Conversely, within patients with High Anhedonia, in addition to enrichment of immunometabolic pathways, the tyrosine metabolism pathway was also reduced in patients with High versus Low CRP (n = 20 and 10 respectively). Of note, enrichment of immunometabolic pathways was confirmed in complementary linear regression analyses examining pathways associated with a CRP-by-Anhedonia interaction term while controlling for clinical covariates in all patients (n = 93). These results indicate that increased glucose and low tyrosine metabolism define a subset of depressed patients with high inflammation and anhedonia. Enrichment of cancer-related pathways driven by metabolic genes also suggests a shift in immune cell metabolism from oxidative phosphorylation to glycolysis. Together these data suggest that anhedonia in MDD with high CRP involves both immunometabolic shifts and reduced dopamine precursor availability.

Historic psychedelic drug trials and the treatment of anxiety disorders.

INTRODUCTION: In this paper, we systematically review literature from 1940 to 2000 relating to the combined use of psychological therapies and psychedelic drugs in the treatment of ICD-10 anxiety disorders. METHODS: The databases Ovid MEDLINE(R), PsycINFO, and Multidisciplinary Association for Psychedelic Studies (MAPS) were searched for case reports and trials involving humans in the treatment of ICD-10 anxiety and related disorders. Twenty-four studies are described; four describe anxiety symptoms in diverse patient groups, 14 studies describe historic diagnoses that usefully correspond with ICD-10 anxiety disorders, six studies pooled results or failed to detail results specific to contemporary ICD-10 anxiety disorders. Two of the 24 studies reported are individual case reports while two of them were inadequate in terms of the reporting of outcome measures. Thus 20 studies were ultimately included in the summary analysis. RESULTS: Three of the 20 studies reviewed described improvements in anxiety by standardized measures (p < .05) and two studies found that this effect was dose related. Of the 20 studies included in the final analysis, 94 of 145 (65%) cases of "psychoneurotic anxiety reaction" as defined by Diagnostic and Statistical Manual of Mental Disorders-I showed improvement that ranged from moderate improvement to full recovery. Despite methodological inadequacies, the results from previous studies are encouraging and should be used to guide and inform further investigation. CONCLUSION: The majority of studies indicate that a combination of psychedelic drug administration and psychological therapy was most beneficial. We found no study suggesting that the pharmacological action of psychedelic drugs in isolation is sufficient.

Psychosis as an adverse effect of monoclonal antibody immunotherapy.

Immunotherapy is a "hot" area in schizophrenia research. Monoclonal antibodies (mAbs) target specific immune molecules, and therefore offer an unparalleled opportunity to directly test the hypothesis that immune dysfunction plays a causal role in psychopathology in schizophrenia. Cytokine-based immunotherapy for other disorders has been associated with a range of neuropsychiatric adverse effects, including psychosis. The purpose of the present study was to investigate the prevalence of spontaneously-reported adverse drug reactions of psychotic symptoms for mAbs, and to calculate odds of psychosis for individual mAbs, compared to bevacizumab, which does not directly target the immune system. We searched the publicly available VigiBase, a World Health Organization global individual case safety report database from inception through February 2019 for which a mAb was the suspected agent of an adverse drug reaction (ADR). We investigated 43 different mAbs, comprising 1,298,185 case reports and 2025 psychosis ADRs. For individual mAbs, the prevalence of psychosis ADRs ranged from 0.1 to 0.4%. Seven mAbs were associated with a significantly increased odds of psychosis (OR = 1.42-2.22), including two agents that target CD25. Eight mAbs were associated with a significantly decreased odds of psychosis (OR = 0.28-0.75), including 4 anti-TNF-α agents. Our results suggest that psychosis is a relatively rare adverse effect of mAb treatment, but risks vary by specific agents. Findings indicate that modulating the immune system may sometimes lead to the development of psychosis. Ongoing clinical trials of adjunctive mAb immunotherapy in schizophrenia will provide valuable insights into the role of the immune system in psychosis.

Association of baseline inflammatory markers and the development of negative symptoms in individuals at clinical high risk for psychosis.

Negative symptoms are common in individuals at clinical high-risk (CHR) for psychosis and are associated with worse functional outcomes. Inflammation may be one mechanism underlying negative symptoms. Inflammatory markers are altered in individuals at CHR and are associated with negative symptoms in patients with schizophrenia. We thus hypothesized that baseline inflammatory markers would predict the development of negative symptoms in individuals at CHR for psychosis. Thirty seven individuals from the North American Prodromal Longitudinal Study who met CHR criteria were included in the study. Inflammatory cytokines, including interferon (IFN)-λ, Interleukin (IL)-1ß, IL-1 receptor antagonist (IL-1RA), IL-4, IL-6, IL-8, IL-10, and tumor necrosis factor (TNF) were measured at baseline. Negative symptoms as measured by the Scale of Prodromal Symptoms, were measured at baseline and six and twelve months. Associations between inflammatory markers and the trajectory of negative symptoms (slope) over the first year of follow-up, were assessed using linear regression models controlling for age, sex, race and depressive symptom severity (as assessed by the Calgary Depression Scale for Schizophrenia). Baseline TNF (beta = 0.361, p = 0.007) and IL-6 (beta = -0.306, p = 0.026) predicted negative symptoms slopes, along with depressive symptom severity at baseline (beta = -0.596, p = 0.000). These findings demonstrate that inflammatory cytokines may underlie the development of negative symptoms in some individuals at CHR for psychosis. TNF predicted the development of negative symptoms independent of baseline depression. Given the heterogeneity of the CHR population, the comorbidity of negative symptoms and depression in this population, and the particular challenges in treating negative symptoms, immune markers could represent potential biomarkers that underlie the development of negative symptoms, representing a potential treatment target.

Fibroblast growth factor 23 is associated with fractional excretion of sodium in patients with chronic kidney disease.

BACKGROUND: Recent studies suggest that the phosphaturic hormone fibroblast growth factor 23 (FGF23) is involved in regulation of renal sodium excretion and blood pressure. There is evidence of both direct effects via regulation of the sodium-chloride symporter (NCC) in the distal tubule, and indirect effects through interactions with the renin-angiotensin-aldosterone system. However, clinical data on the association between FGF23 and renal sodium regulation is lacking. Herein, we investigated the associations of FGF23 with renal sodium handling and blood pressure in non-dialysis CKD patients. METHODS: This was a cross-sectional study encompassing 180 CKD patients Stage 1-5, undergoing renal biopsy. Plasma intact FGF23, 24-h urinary sodium excretion, fractional excretion of sodium (FENa) and blood pressure were measured at baseline. The association between FGF23 and renal sodium handling was explored by multivariate regression analysis. RESULTS: The median age was 52.8 years, 60.6% were men and the median estimated glomerular filtration rate (eGFR) was 50.6 mL/min/1.73 m2. In univariate analysis, FGF23 was positively associated with FENa (Spearman's rho = 0.47; P < 0.001) and systolic blood pressure (rho = 0.17, P < 0.05), but not with plasma sodium, 24-h urinary sodium excretion or mean arterial blood pressure. The association between FGF23 and FENa remained significant after adjustment for potential confounders (multivariable adjusted ß coefficient 0.60, P < 0.001). This association was stronger among the 107 individuals with eGFR <60 mL/min/1.73 m2 (ß = 0.47, P = 0.04) and in the 73 individuals on any diuretics (ß = 0.88, P < 0.001). Adjustment for measured GFR instead of eGFR did not alter the relationship. CONCLUSIONS: FGF23 is independently associated with increased FENa in non-dialysis CKD patients. These data do not support the notion that FGF23 causes clinically significant sodium retention. Further studies are warranted to explore the mechanism underlying this association.

Potential life-years gained over a 5-year period by correcting DOPPS-identified modifiable practices in haemodialysis: results from the European MONITOR-CKD5 study.

BACKGROUND: DOPPS reported that thousands of life-years could be gained in the US and Europe over 5 years by correcting six modifiable haemodialysis practices. We estimated potential life-years gained across 10 European countries using MONITOR-CKD5 study data. METHODS: The DOPPS-based target ranges were used, except for haemoglobin due to label changes, as well as DOPPS-derived relative mortality risks. Percentages of MONITOR-CKD5 patients outside targets were calculated. Consistent with the DOPPS-based analyses, we extrapolated life-years gained for the MONITOR-CKD5 population over 5 years if all patients were within targets. RESULTS: Bringing the 10 MONITOR-CKD5 countries' dialysis populations into compliance on the six practices results in a 5-year gain of 97,428 patient-years. In descending order, survival impact was the highest for albumin levels, followed by phosphate levels, vascular access, haemoglobin, dialysis adequacy, and interdialytic weight gain. CONCLUSIONS: Optimal management of the six modifiable haemodialysis practices may achieve 6.2% increase in 5-year survival. TRIAL REGISTRATION: NCT01121237 . Clinicaltrials.gov registration May 12, 2010 (retrospectively registered).