Using latent class analysis to investigate enduring effects of intersectional social disadvantage on long-term vocational and financial outcomes in the 20-year prospective Chicago Longitudinal Study.

BACKGROUND: Class and social disadvantage have long been identified as significant factors in the etiology and epidemiology of psychosis. Few studies have explicitly examined the impact of intersecting social disadvantage on long-term employment and financial independence. METHODS: We applied latent class analysis (LCA) to 20-year longitudinal data from participants with affective and non-affective psychosis (n = 256) within the Chicago Longitudinal Research. LCA groups were modeled using multiple indicators of pre-morbid disadvantage (parental social class, educational attainment, race, gender, and work and social functioning prior to psychosis onset). The comparative longitudinal work and financial functioning of LCA groups were then examined. RESULTS: We identified three distinct latent classes: one comprised entirely of White participants, with the highest parental class and highest levels of educational attainment; a second predominantly working-class group, with equal numbers of Black and White participants; and a third with the lowest parental social class, lowest levels of education and a mix of Black and White participants. The latter, our highest social disadvantage group experienced significantly poorer employment and financial outcomes at all time-points, controlling for diagnosis, symptoms, and hospitalizations prior to baseline. Contrary to our hypotheses, on most measures, the two less disadvantaged groups did not significantly differ from each other. CONCLUSIONS: Our analyses add to a growing literature on the impact of multiple forms of social disadvantage on long-term functional trajectories, underscoring the importance of proactive attention to sociostructural disadvantage early in treatment, and the development and evaluation of interventions designed to mitigate ongoing social stratification.

Ethanol- and PARP-Mediated Regulation of Ribosome-Associated Long Non-Coding RNA (lncRNA) in Pyramidal Neurons.

Although, by definition, long noncoding RNAs (lncRNAs) are not translated, they are sometimes associated with ribosomes. In fact, some estimates suggest the existence of more than 50 K lncRNA molecules that could encode for small peptides. We examined the effects of an ethanol and Poly-ADP Ribose Polymerase (PARP) inhibitor (ABT-888) on ribosome-bound lncRNAs. Mice were administered via intraperitoneal injection (i.p.) either normal saline (CTL) or ethanol (EtOH) twice a day for four consecutive days. On the fourth day, a sub-group of mice administered with ethanol also received ABT-888 (EtOH+ABT). Ribosome-bound lncRNAs in CaMKIIα-expressing pyramidal neurons were measured using the Translating Ribosome Affinity Purification (TRAP) technique. Our findings show that EtOH altered the attachment of 107 lncRNA transcripts, while EtOH+ABT altered 60 lncRNAs. Among these 60 lncRNAs, 49 were altered by both conditions, while EtOH+ABT uniquely altered the attachment of 11 lncRNA transcripts that EtOH alone did not affect. To validate these results, we selected eight lncRNAs (Mir124-2hg, 5430416N02Rik, Snhg17, Snhg12, Snhg1, Mir9-3hg, Gas5, and 1110038B12Rik) for qRT-PCR analysis. The current study demonstrates that ethanol-induced changes in lncRNA attachment to ribosomes can be mitigated by the addition of the PARP inhibitor ABT-888.

Effects of alcohol and PARP inhibition on RNA ribosomal engagement in cortical excitatory neurons.

We report on the effects of ethanol (EtOH) and Poly (ADP-ribose) polymerase (PARP) inhibition on RNA ribosomal engagement, as a proxy for protein translation, in prefrontal cortical (PFC) pyramidal neurons. We hypothesized that EtOH induces a shift in RNA ribosomal-engagement (RE) in PFC pyramidal neurons, and that many of these changes can be reversed using a PARP inhibitor. We utilized the translating ribosome affinity purification (TRAP) technique to isolate cell type-specific RNA. Transgenic mice with EGFP-tagged Rpl10a ribosomal protein expressed only in CaMKIIα-expressing pyramidal cells were administered EtOH or normal saline (CTL) i.p. twice a day, for four consecutive days. On the fourth day, a sub-group of mice that received EtOH in the previous three days received a combination of EtOH and the PARP inhibitor ABT-888 (EtOH + ABT-888). PFC tissue was processed to isolate both, CaMKIIα pyramidal cell-type specific ribosomal-engaged RNA (TRAP-RNA), as well as genomically expressed total-RNA from whole tissue, which were submitted for RNA-seq. We observed EtOH effects on RE transcripts in pyramidal cells and furthermore treatment with a PARP inhibitor "reversed" these effects. The PARP inhibitor ABT-888 reversed 82% of the EtOH-induced changes in RE (TRAP-RNA), and similarly 83% in the total-RNA transcripts. We identified Insulin Receptor Signaling as highly enriched in the ethanol-regulated and PARP-reverted RE pool and validated five participating genes from this pathway. To our knowledge, this is the first description of the effects of EtOH on excitatory neuron RE transcripts from total-RNA and provides insights into PARP-mediated regulation of EtOH effects.

Differential H3K9me2 heterochromatin levels and concordant mRNA expression in postmortem brain tissue of individuals with schizophrenia, bipolar, and controls.

The existence of repressive and durable chromatin assemblies along gene promoters or networks, especially in the brain, is of theoretical and therapeutic relevance in a subset of individuals diagnosed with schizophrenia who experience a chronic, persistent, and treatment-resistant trajectory. We used chromatin immunoprecipitation followed by deep sequencing (ChIP-Seq) to generate an epigenomic map that includes differential sites occupied by di-methylated lysine 9 of histone 3 (H3K9me2), a repressive modification that is yet unexplored in human postmortem brain tissue. We have discovered over 150 significantly differential promoter sites in the postmortem prefrontal cortex tissue of individuals diagnosed with schizophrenia (n = 15) when compared to controls (n = 15). Potentially dysregulated gene categories include postsynaptic proteins, processing enzymes (for proproteins, lipids, and oxidative stress), cadherin family genes, the complement system, and peptide hormones. Ten genes with significantly increased or decreased H3K9me2 promoter occupation were selected through statistical analysis, function, or previous GWAS association, and Quantitative RT-PCR (qRT-PCR) was performed on an extended sample of postmortem brain tissue, adding an additional 17 controls, 7 individuals with schizophrenia, and 19 individuals with bipolar samples (n = 32 control, 22 schizophrenia, 19 bipolar). This approach revealed that mRNA expression levels correlated with chromatin modification levels in eight of 10 selected genes, and mRNA expression in the total sample could be predicted by the occupancy of H3K9me2. Utilization of this method and replication in a larger sample open a pathway to durable and restrictive epigenomic assemblies whose accumulation across the lifespan of individuals diagnosed with schizophrenia may explain treatment resistance, and advance therapeutic options.

The Sensory and Perceptual Scaffolding of Absorption, Inner Speech, and Self in Psychosis.

This study examines the interconnectedness between absorption, inner speech, self, and psychopathology. Absorption involves an intense focus and immersion in mental imagery, sensory/perceptual stimuli, or vivid imagination that involves decreased self-awareness and alterations in consciousness. In psychosis, the dissolution and permeability in the demarcation between self and one's sensory experiences and perceptions, and also between self-other and/or inter-object boundaries alter one's sense of self. Thus, as the individual integrates these changes new "meaning making" or understanding evolves as part of an ongoing inner dialogue and dialogue with others. This study consisted of 117 participants: 81 participants with psychosis and 36 controls. We first conducted a bivariate correlation to elucidate the relationship between absorption and inner speech. We next conducted hierarchical multiple regressions to examine the effect of absorption and inner speech to predict psychopathology. Lastly, we conducted a network analysis and applied extended Bayesian Information Criterion to select the best model. We showed that in both the control and psychosis group dialogic and emotional/motivational types of inner speech were strongly associated with absorption subscales, apart from the aesthetic subscale in the control group which was not significant, while in psychosis, condensed inner speech was uniquely associated with increased imaginative involvement. In psychosis, we also demonstrated that altered consciousness, dialogic, and emotional/motivational inner speech all predicted positive symptoms. In terms of network associations, imaginative involvement was the most central, influential, and most highly predictive node in the model from which all other nodes related to inner speech and psychopathology are connected. This study shows a strong interrelatedness between absorption, inner speech and psychosis thus identifying potentially fertile ground for future research and directions, particularly in the exploration into the underlying construct of imaginative involvement in psychotic symptoms.

Monocyte Transcriptional Profiling Highlights a Shift in Immune Signatures Over the Course of Illness in Schizophrenia.

With advanced understanding of the intricate interplay between the immune and central nervous systems in neurological and neuropsychiatric illness, there is renewed interest in the potential contribution of immune dysregulation to the development and progression of schizophrenia. To inform this line of inquiry requires a more nuanced understanding of specific immune changes throughout the course of illness. Here, we utilized a genome-wide sequencing approach to transcriptionally profile circulating monocytes in participants with chronic schizophrenia. These myeloid cells, isolated from whole blood samples, are highly plastic with potentially important disease-modifying functions. Differential gene expression and gene set enrichment analyses, focusing on established monocyte phenotypic signatures, including those related to proinflammatory ("M1-like") and protective or tissue remodeling ("M2-like") functions, were carried out. We demonstrate an overall enrichment of both "M1-like" (interferon-alpha, interferon-gamma, lipopolysaccharide acute) and "M2-like" (endotoxin tolerance, glucocorticoid acute) monocyte signatures in the participants with schizophrenia compared to non-psychiatric controls. There was no enrichment of the "M1-like" chronic stress signature or the "M2-like" interleukin-4 signature. Using the Molecular Signatures Database Hallmark gene sets list, the "interferon response" was most strongly enriched in schizophrenia compared to controls. Additionally, an exploratory subgroup analysis based on illness duration suggests a shift in monocyte phenotype with illness progression. Specifically, the "M1-like" interferon-gamma signature shows decreased enrichment accompanied by increased enrichment of opposing "M2-like" signatures in participants with a medium illness duration shifting to a strong enrichment of interferon response signatures only in participants with a long illness duration. These findings related to circulating immune cell phenotype have potentially important implications for understanding the role of immune dysregulation in schizophrenia and are a critical consideration for future study design and immune-targeting treatment strategies.

Modulation of Poly ADP Ribose Polymerase (PARP) Levels and Activity by Alcohol Binge-Like Drinking in Male Mice.

Binge drinking is a frequent pattern of ethanol consumption within Alcohol Use Disorders (AUDs). Binge-like ethanol exposure increases Poly(ADP-ribose) polymerase (PARP) expression and activity. PARP enzymes have been implicated in addiction and serve multiple roles in the cell, including gene expression regulation. In this study, we examined the effects of binge-like alcohol consumption in the prefrontal cortex (PFC) of adult C57BL/6J male mice via a 4-day Drinking-in-the-Dark (DID) paradigm. The role of PARP in associated gene expression and behavioral changes was assessed by administering the PARP inhibitor ABT-888 on the last DID day. We then conducted an RNA-seq analysis of the PFC gene expression changes associated with DID-consumed ethanol or ABT-888 treatment. A separate cohort of mice was inoculated with an HSV-PARP1 vector in the PFC and subject to a DID experiment to verify whether overexpressed PARP1 increased ethanol drinking. We confirmed that alcohol increases Parp1 gene expression and PARP activity in the PFC. RNA-seq showed significantly altered expression of 41 genes by DID-consumed ethanol, and of 48 genes by ABT-888. These results were confirmed by qPCR in 7 of the 10 genes validated, 4 of which have been previously associated with addiction. ABT-888 reduced, and overexpression of PFC PARP1 increased DID ethanol consumption. In our model, alcohol binge drinking induced specific alterations in the PFC expression of genes potentially involved in addiction. Pharmacological PARP inhibition proved effective in reversing these changes and preventing further alcohol consumption. Our results suggest an involvement of ethanol-induced PARP1 in reinforcing binge-like addictive behavior.

The role of inner speech on the association between childhood adversity and 'hearing voices'.

Adverse childhood experiences are associated with later development of psychosis, particularly auditory verbal hallucinations and delusions. Although auditory hallucinations have been proposed to be misattributed inner speech, the relation between childhood adversity and inner speech has not been previously investigated. The first aim was to test whether childhood adversity is associated with inner speech in persons with psychosis. The second aim was to test for the influence of inner speech on the association between childhood adversity and auditory hallucinations. Our final aim was to test for evidence that would falsify the null hypothesis that inner speech does not impact the relationship between childhood adversity and delusions. In persons with psychosis, we found a positive association between childhood adversity and dialogic inner speech. There was a significant total effect of childhood adversity on auditory hallucinations, including an indirect effect of childhood adversity on auditory hallucinations via dialogic inner speech. There was also a significant total effect of childhood adversity on delusions, but no evidence of any indirect effect via inner speech. These findings suggest that childhood adversities are associated with inner speech and psychosis. The relation between childhood adversity and auditory hallucination severity could be partially influenced by dialogic inner speech.

Treatment with the antipsychotic risperidone is associated with increased M1-like JAK-STAT1 signature gene expression in PBMCs from participants with psychosis and THP-1 monocytes and macrophages.

Clinical studies demonstrate alterations to immune measures in psychosis that can vary with illness stage and severity. For example, recent data show that changes to the JAK-STAT1 transcriptional signature, characteristic of an "M1" proinflammatory monocyte and macrophages phenotype, are related to illness duration. While antipsychotics have demonstrated immunomodulatory properties, their effects on this important immune signaling pathway are unknown. The primary aims of this study were to determine the effects of risperidone, a commonly prescribed antipsychotic drug, on the JAK-STAT1 transcriptional signature. Selected measures of JAK-STAT1 signature gene expression in peripheral blood mononuclear cells (PBMCs) from a clinical sample with psychosis were compared to examine differences induced by risperidone treatment. Additionally, the direct effects of risperidone on the JAK-STAT1 signature were investigated using a THP-1 human monocyte and macrophage cell model. Comparisons within the clinical sample demonstrated that the JAK-STAT1 signature was elevated in PBMCs from participants treated with risperidone who had a longer illness duration compared to untreated participants and those who were risperidone treated but had a shorter illness duration. Results of the in-vitro experiments showed a consistent potentiating effect of risperidone on expression of JAK-STAT1 signature genes in activated monocytes and monocyte-derived macrophages. Collectively these data indicate that risperidone may skew myeloid cells to a more proinflammatory phenotype, potentially contributing to increases in expression of JAK-STAT1 signature genes in participants with a longer illness duration.

The multidimensional construct of resilience across the psychosis spectrum: Evidence of alterations in people with early and prolonged psychosis.

OBJECTIVE: Research has demonstrated that resilience impacts functional outcomes and is often reduced among those with prolonged psychosis. However, little work has examined when during the course of psychosis resilience declines and whether resilience impacts symptoms and functioning similarly in different illness phases. This study examined whether overall resilience (a) differed between those with early compared to relatively prolonged psychosis, (b) differed between the psychosis groups and nonclinical controls, and (c) differentially related to symptoms and functioning in the psychosis groups. METHOD: Participants with early (n = 30) and prolonged psychosis (n = 64) and nonclinical controls (n = 58) completed the Resilience Scale. Psychosis participants also completed clinician-rated functioning and symptom measures. Analyses of Variance were used to compare group resilience levels. Pearson's correlations identified relationships between resilience, symptoms, and functioning. RESULTS: Overall resilience levels did not significantly differ between the psychosis groups, but both psychosis groups had lower resilience than nonclinical controls. Higher overall resilience was significantly associated with lower negative symptoms in the early psychosis group and lower mood symptoms in the prolonged psychosis group; greater resilience was significantly associated with higher functioning in both psychosis groups. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Resilience may be reduced throughout the course of psychosis but may differentially impact symptom domains in different illness phases. Targeting resilience with psychosocial interventions may be important throughout the course of psychosis and may lead to improvements in functioning as well as negative symptoms and mood symptoms (in early and prolonged psychosis, respectively). (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Examining the effects of the histone methyltransferase inhibitor BIX-01294 on histone modifications and gene expression in both a clinical population and mouse models.

Schizophrenia has been consistently characterized by abnormal patterns of gene down-regulation, increased restrictive chromatin assemblies, and reduced transcriptional activity. Histone methyltransferase (HMT) mRNA and H3K9me2 levels are elevated in postmortem brain and peripheral blood cells of persons with schizophrenia. Moreover, this epigenomic state likely contributes to the disease, as HMT levels correlate with clinical symptomatology. This manuscript sought to establish the potential therapeutic value of the HMT inhibitor BIX-01294 (BIX). Human peripheral mononuclear cells (PBMC) from 24 individuals with schizophrenia and 24 healthy individuals were cultured in the presence of BIX (5uM or 10uM). Mice were given once daily intraperitoneal injections of BIX (0.5 or 1mg/kg) for one week. Cultured cells, mouse cortex, or striatum was harvested, RNA extracted and RT-PCR conducted for several schizophrenia candidate genes: IL-6, Gad1, Nanog, KLF4, Reln, and Bdnf9a. Total H3K9me2 levels were measured using western blot while H3K9me2 binding to selected genes of interest was conducted using chromatin immunoprecipitation (ChIP). Neuronal subtype-specific BDNF conditional knockdown was conducted using the cre/lox system of mutant animals. Treatment with BIX decreased H3K9me2 and increased selected mRNA levels in cultured PBMCs from both normal controls and participants with schizophrenia. In mice, peripheral administration of BIX decreased cortical H3K9me2 levels and increased schizophrenia candidate gene expression. In BDNF conditional knockdown animals, BIX administration was able to significantly rescue Bdnf9a mRNA levels in ChAT and D1 Bdnf conditional knockdown mice. The results presented in this manuscript demonstrate a potential for further research into the clinical effectiveness of histone modifying pharmacology in the treatment of schizophrenia.

Traumagenics: At the intersect of childhood trauma, immunity and psychosis.

Early childhood trauma, including physical, sexual or emotional abuse, neglect, harm or threat of harm, is associated with adulthood dysregulation of the immune system. Trauma can induce chronic immune system activation. Associations between a chronic pro-inflammatory state and schizophrenia are an enduring finding of psychiatry, with elevated cytokine concentrations correlated with psychotic symptom severity. Most importantly, persons with schizophrenia and a history of childhood trauma demonstrate increased cytokine levels. Specific types of childhood trauma can also differentially impact the expression of unique immune markers. This study tested the hypotheses that levels of adverse childhood experiences (ACEs) would be associated with levels of peripheral immune activity assessed by IL6, IFNG, CXCL10, IRF1, STAT1 and TLR4 mRNA expression, and that there would be an association between ACEs and psychosis along a continuum from non-clinical controls (NCC) to psychotic disorders such as schizophrenia. These hypotheses were tested in 20 schizophrenia, 20 NCC. We found correlations between ACEs scores and immune markers, specifically IL6. We also found a positive association between ACEs and positive symptoms. Childhood trauma, through its effects on IL6, may be a risk factor for schizophrenia.

Visual memory uniquely predicts anhedonia in schizophrenia but not bipolar disorder.

OBJECTIVE: Deficits in memory have been suggested as an influential mechanism of anhedonia, because while pleasant experiences may be enjoyed in-the-moment, the cognitive processes involved in reporting anticipated or remembered enjoyable experiences is thought to be impaired. This study will determine whether any aspects of memory, including visual memory, verbal memory or working memory, are significantly predictive of anhedonia in a sample of schizophrenia, psychotic bipolar disorder and healthy controls. METHODS: The study included 38 individuals with schizophrenia, 19 individuals with bipolar disorder with psychosis, and 43 age-matched healthy controls. All participants completed a self-report social and physical anhedonia questionnaire along with a cognitive screening battery, which assessed the domains of attention/vigilance, working memory, verbal learning, visual learning, and reasoning and problem-solving. RESULTS: Anhedonia scores were regressed onto domain scores to determine which areas of cognition uniquely predicted level of anhedonia in each group. For the schizophrenia group, physical anhedonia was significantly predicted by worse visual memory performance. The regression models did not find significant cognitive predictors of physical or social anhedonia in the bipolar disorder or control groups. CONCLUSIONS: This study found a significant relationship between visual memory and physical anhedonia in schizophrenia patients that was not present in a sample of psychotic bipolar patients or healthy controls, adding to an accumulating body of evidence that visual memory is related to anhedonia in schizophrenia. This relationship may be explained by underlying abnormalities in the orbitofrontal cortex in schizophrenia.

The JAK-STAT1 transcriptional signature in peripheral immune cells reveals alterations related to illness duration and acuity in psychosis.

Multiple lines of inquiry demonstrate alterations to immune function in psychosis. Clinically, this is reflected by elevated proinflammatory cytokines in serum, indicating activation of circulating immune cells. Data from isolated cells in clinical populations support the presence of altered activity of pertinent intracellular signaling pathways. Here, we focus on the well-characterized IFN-γ mediated JAK-STAT1 signaling pathway, which is involved in multiple aspects of immunity, including activation of circulating immune cells to a proinflammatory phenotype. By measuring a transcriptional signature characteristic of activation of this pathway, we demonstrate that JAK-STAT1 signature gene expression is suppressed in participants with psychosis who are early in illness and in participants who are hospitalized with an acute exacerbation of psychosis. Furthermore, we find that this expression signature normalizes in participants who have a longer illness duration and chronic, but not acute, psychopathology. This relationship of JAK-STAT1 signature gene expression with clinical characteristics highlights the temporal and contextual complexity of alterations to immune activity in psychosis and provides important insight into the functional state of circulating immune cells. These findings are of particular interest given recent research illustrating the importance of peripherally derived immune cells and the effectors they secrete in mediating neurophysiological processes of relevance for psychiatric illness.

Long Non-Coding RNAs Associated with Heterochromatin Function in Immune Cells in Psychosis.

Psychosis is associated with chronic immune dysregulation. Many long non-coding RNAs (lncRNAs) display abnormal expression during activation of immune responses, and play a role in heterochromatic regulation of gene promoters. We have measured lncRNAs MEG3, PINT and GAS5, selected for their previously described association with heterochromatin. Peripheral blood mononuclear cells (PBMCs) were isolated from blood samples collected from 86 participants with a diagnosis of psychosis and 44 control participants. Expression was assessed in relation to diagnosis, illness acuity status, and treatment with antipsychotic medication. We observed diagnostic differences with MEG3, PINT and GAS5, and symptom acuity effect with MEG3 and GAS5. Medication effects were evident in those currently on treatment with antipsychotics when compared to drug-naïve participants. We observed that clinical diagnosis and symptom acuity predict selected lncRNA expression. Particular noteworthy is the differential expression of MEG3 in drug naïve participants compared to those treated with risperidone. Additionally, an in vitro cell model using M2tol macrophages was used to test the effects of the antipsychotic drug risperidone on the expression of these lncRNAs using quantitative real-time PCR (qRT-PCR). Significant but differential effects of risperidone were observed in M2tol macrophages indicating a clear ability of antipsychotic medications to modify lncRNA expression.

The tangled roots of inner speech, voices and delusions.

The role of inner speech in the experience of auditory verbal hallucinations (AVH) and delusions remains unclear. This exploratory study tested for differences in inner speech (assessed via self-report questionnaire) between 89 participants with psychosis and 37 non-clinical controls. We also tested for associations of inner speech with, i) state/trait AVH, ii) AVH-severity; iii) patients' relations with their voices, and; iv) delusion-severity. Persons with psychosis had greater levels of dialogic inner speech, other people in inner speech, and evaluative/motivational inner speech than non-clinical controls. Those with state, but not trait AVH had greater levels of dialogic and evaluative/motivational inner speech than non-clinical controls. After controlling for delusions, there was a positive relation between AVH-severity and both evaluative/motivational inner speech and other people in inner speech. Participants with greater levels of dialogic inner speech reported better relations both with and between their voices. There was no association between delusion-severity and inner speech. These results highlight the importance of better understanding relations between inner speech and AVH, provide avenues for future research, and underscore the need for research into the interrelatedness of inner speech, voices and delusions, and the complexities involved in disentangling these experiences.

Negative voice-content as a full mediator of a relation between childhood adversity and distress ensuing from hearing voices.

A key predictor of whether or not an individual who hears voices (auditory verbal hallucinations; AVH) meets criteria for a psychiatric diagnosis is the level of negative content of the voices (e.g., threats, criticism, abuse). Yet the factors that contribute to negative voice-content are still not well understood. This study aimed to test the hypotheses that levels of childhood adversity would predict levels of negative voice-content, and that negative voice-content would partially mediate a relation between childhood adversity and voice-related distress. These hypotheses were tested in a clinical sample of 61 patients with formally diagnosed psychotic disorders (48 schizophrenia, 13 bipolar). We found evidence consistent with negative voice-content fully (not partially) mediating the relation between childhood adversity and voice-related distress. Although bivariate analyses found depression to be associated with both negative voice-content and voice-related distress, we found no evidence of an indirect effect of childhood adversity on either negative voice-content or voice-related distress via depression. Alternative study designs are now needed to test if our findings are replicable and causal. Should they be, it will be necessary for psychological therapies to devise ways to reduce negative voice-content itself, rather than just changing beliefs about voices. A number of techniques are discussed (Avatar Therapy, Compassion Focused Therapy, voice-dialogue) that already show promise for this.

C4A mRNA expression in PBMCs predicts the presence and severity of delusions in schizophrenia and bipolar disorder with psychosis.

Altered immune function is an established finding in psychotic disorders such as schizophrenia and bipolar disorder with psychosis, though its role in their development and progression remains to be understood. Evidence suggests altered JAK-STAT1 pathway activity in peripheral blood cells from participants with schizophrenia compared to controls. Activation of this pathway leads to increased expression of complement component 4A (C4A), which has recently been implicated in schizophrenia. Here, we examine mRNA expression of C4A in peripheral blood cells from participants with schizophrenia, bipolar disorder and controls. STAT1 and IRF-1 mRNA expression are included as measures of JAK-STAT1 pathway activation in the same participants. Further, we examine the association of each genes mRNA expression with clinical symptom measures using the Positive and Negative Syndrome Scale (PANSS) and the Psychotic Symptom Rating Scale (PSYRATS). We demonstrate that C4A, STAT1 and IRF-1 mRNA expression levels are correlated across the entire sample, indicating shared transcriptional regulatory mechanisms. Further, we show that C4A mRNA expression alone is positively associated with psychotic symptomatology, specifically the presence and severity of delusions. These findings are noteworthy given recent findings that demonstrate a critical role for complement proteins in synaptic pruning, alterations of which are proposed to contribute to psychopathology in psychosis.

Working memory predicts presence of auditory verbal hallucinations in schizophrenia and bipolar disorder with psychosis.

OBJECTIVE: The recent dramatic increase in research investigating auditory verbal hallucinations (AVHs) has broadened the former narrow focus on schizophrenia to incorporate additional populations that experience these symptoms. However, an understanding of potential shared mechanisms remains elusive. Based on theories suggesting a failure of top-down cognitive control, we aimed to compare the relationship between AVHs and cognition in two categorical diagnoses of psychosis, schizophrenia and psychotic bipolar disorder. METHOD: A total of 124 adults aged 21-60 participated, of whom 76 had present-state psychosis (schizophrenia, n = 53; bipolar disorder with psychosis, n = 23), and 48 were non-clinical controls. Diagnosis and hallucination presence was determined using the Structured Clinical Diagnostic Interview for DSM-IV TR. AVHs severity was assessed using the Positive and Negative Syndrome Scale. Participants also completed the MATRICS cognitive battery. RESULTS: The bipolar disorder with psychosis group performed better than the schizophrenia group for cognitive domains of Processing speed, Attention, Working memory (WM), and Visual memory. Hierarchical binary logistic regression found that WM significantly predicted presence of AVHs in both psychotic groups, but diagnosis did not significantly increase the predictive value of the model. A hierarchical multiple linear regression found that schizophrenia diagnosis was the only significant predictor of hallucination severity. CONCLUSIONS: The findings of this study-the first, to our knowledge, to compare the relationship between AVHs and MATRICS domains across schizophrenia and bipolar disorder with psychosis-support theories that deficits in WM underly the genesis of AVHs. WM potentially represents a shared mechanism of AVHs across diagnoses, supporting dimensional classifications of these psychotic disorders. However, non-cognitive factors predictive of hallucination severity may be specific to schizophrenia.