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.

Behavioral Effects of Neuronal, Parent-specific Commd1 Knockout in Mice.

In this study we focused on gene expression and behavioral differences in mice with brain-specific Commd1 knockout. Commd1 is an imprinted gene with preferential maternal expression, residing within a larger genomic region previously found to affect sensorimotor gating. In this study, individuals harboring a conditional Commd1 mutant allele were bred with Syn1-Cre animals, paying special attention to the parent of origin of the Commd1 mutation. Analysis of mRNA levels of Commd1 and phenotypic tests, including the open field, sensorimotor gating, and the forced swim test, were conducted on offspring with either maternally or paternally derived Commd1 knockout. We found that measurable Commd1 mRNA knockout occurred only in the maternally derived line and affected stereotypy and depressive-like behavior without differences in total locomotion compared to controls. Interestingly, we found that maternal knockout animals exhibited decreased time swimming and increased time immobile when compared to maternal and paternal wild type, and paternal knockout animals. However, there were no differences in climbing behavior between genotypes. This study demonstrates an in vivo behavioral role for Commd1 for the first time and demonstrates the need for careful interpretation of experimental results involving Cre-based knockout systems.

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.

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.

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.

Long non-coding and endogenous retroviral RNA levels are associated with proinflammatory cytokine mRNA expression in peripheral blood cells: Implications for schizophrenia.

Recent research indicates that the expression of long non-coding and endogenous retroviral RNAs is coordinated with the activity of immune molecules often dysregulated in schizophrenia. We measured the expression of TMEVPG1, NRON, HERV-W env and HERV-W gag in blood cells from participants with schizophrenia and controls. We report that a) expression levels of these non-coding RNAs are correlated with proinflammatory cytokine mRNA expression in all participants, b) HERV-W transcripts are negatively correlated with atypical antipsychotic use in participants with schizophrenia, and c) that these RNAs are transcribed in response to proinflammatory stimuli in a THP-1 monocyte cell line.

Exploring the Intersections of Trauma, Structural Adversity, and Psychosis among a Primarily African-American Sample: A Mixed-Methods Analysis.

Traumatic life events (TLEs) have been associated with multiple psychiatric diagnoses, including anxiety disorders, major depression, PTSD, and psychosis. To advance our understanding of the complex interactions between forms of adversity as they manifest across the lifespan, psychosis, and symptom content, we undertook a mixed-methods investigation of TLEs and psychosis. Our research explored the association between cumulative exposures, type of TLE, and proximity to the traumatic event and psychosis; the association between TLEs and clinical symptomology including specific types of delusions and/or hallucinations; and how qualitative data further inform understanding of complex relationships and patterns of past trauma and symptoms as they unfold over time. There were a total of 97 participants in the quantitative study sample, 51 participants with present state psychosis and 46 non-clinical. There were a total of 34 qualitative study participants, all of whom were experiencing psychosis. The quantitative analysis showed that when comparing persons with psychosis to the non-clinical group, there were no group differences in the overall total score of TLEs. However, there was a significant difference in cumulative TLEs that "Happened," demonstrating that as the number of TLEs increased, the likelihood of clinical psychosis also increased. We also found a correlation between lifetime cumulative TLEs that "Happened" and PANSS five-factor analysis: positive, excitement, depression, thought disorder, activation, and paranoia scores. The qualitative analysis further built on these finding by providing rich narratives regarding the timing of trauma-related onset, relationships between trauma and both trauma-related and religious-spiritual content, and trauma and hallucinatory modality. Analysis of participant narratives suggests the central role of localized cultural and sociopolitical influences on onset, phenomenology, and coping and contributes to a growing literature calling for strengths-based, client-driven approaches to working with distressing voices and beliefs that centers the exploration of the personal and social meaning of such experiences including links to life narratives. Findings also underscore the clinical importance of trauma assessment and trauma-informed care.

Immersion in altered experience: An investigation of the relationship between absorption and psychopathology.

Understanding alterations in perceptual experiences as a component of the basic symptom structure of psychosis may improve early detection and the identification of subtle shifts that can precede symptom onset or exacerbation. We explored the phenomenological construct of absorption and psychotic experiences in both clinical (bipolar psychosis and schizophrenia spectrum) and non-clinical participants. Participants with psychosis endorsed significantly higher absorption compared to the non-clinical group. Absorption was positively correlated with all types of hallucinations and multiple types of delusions. The analysis yielded two distinct cluster groups that demarcated a distinction along the continuum of self-disturbance: on characterized by attenuated ego boundaries and the other stable ego boundaries. The study suggests that absorption is a potentially important but under-researched component of psychosis that overlaps with, but is not identical to the more heavily theorized constructs of aberrant salience and hyperreflexivity.

Activated Phosphorylated STAT1 Levels as a Biologically Relevant Immune Signal in Schizophrenia.

OBJECTIVE: Activation of STAT1 is directly downstream of the cytokine receptors that signal from specific proinflammatory cytokines known to be dysregulated in schizophrenia (SZ), such as IFNγ, IL6, IL2 and IL10, as well as hypoxia, viral/bacterial infections and peptide growth factors. If the increased cytokine protein levels repeatedly observed in SZ have biological consequences, then the measurement of pSTAT1 is a logical step forward. METHODS: Peripheral blood mononuclear cells (PBMCs) from controls (n = 13) and subjects with SZ (n = 22) were extracted using the Ficoll method. Participants with SZ were diagnosed using the SCID, clinical symptomatology was measured using the Positive and Negative Syndrome Scale (PANSS), and cognitive functioning was measured using the MATRICS Consensus Cognitive Battery. Levels of activated STAT1 (Y701), i.e. phosphorylated STAT1 (pSTAT1), were measured by a commercially available ELISA in nuclear extracts from PBMCs. RESULTS: There was a significant bimodal distribution in the sample, with an SZ subgroup expressing significantly greater levels of activated pSTAT1 than the remainder of the participants. In this subgroup, levels of pSTAT1 were significantly higher than in the control group, as well as significantly higher than in the remainder of the SZ subjects. Furthermore, this subsample of patients manifested significantly poorer cognitive performance on several measures of the MATRICS. DISCUSSION: pSTAT1 levels may provide a measure of the biological relevance of widely reported elevations in levels of cytokines in SZ over the past several decades. Activation of kinase cascades can be used to partition or disassemble the composite immune signal in patients living with SZ.

The intrasubjectivity of self, voices and delusions: A phenomenological analysis.

To advance the area of phenomenology of voices and their interrelatedness to forms of delusions this study investigated the prevalence and interrelatedness of co-occurring auditory verbal hallucinations (AVHs) and delusions. Additionally we explored the characterization of distinct sub-categories/clusters of AVHs and delusions. Ninety-two participants experiencing psychosis were administered standardized clinical measures. We found a significant diagnostic difference with increased prevalence of co-occurring AVHs and delusions within the schizophrenia group compared to the bipolar with psychosis group. Regardless of diagnosis, there was a significant positive correlation between AVHs and delusions of reference, persecution, control, thought insertion, thought withdrawal and thought broadcasting. However, no significant relationship was found between AVHs and grandiose, somatic, religious, guilty or jealousy-themed delusions. Cluster analysis yielded two distinct cluster groups. Cluster One: Voices and Thought Delusions, and Cluster Two: Voices and Thematic Delusions. Cluster One participants showed elevated disorganized, cognitive and depressive symptoms, but not negative symptoms or excitement. This study underscores the need for expanded clinical and phenomenological research into the intersection of AVHs and delusions, including work that seeks to deconstruct conventional divisions between ostensible symptoms of perception' (hallucinations) and belief' (delusions).

Characterization of peripheral cannabinoid receptor expression and clinical correlates in schizophrenia.

The relationship between cannabinoid receptor signaling and psychosis vulnerability requires further exploration. The endocannabinoid signaling system is extensive, with receptors exerting regulatory functions in both immune and central nervous systems. In the brain, cannabinoid receptors (CBR) directly modulate neurotransmitter systems. In the peripheral lymphocyte, CBRs mediate cytokine release, with dysregulated cytokine levels demonstrated in schizophrenia. mRNA levels of CBRs were measured in human peripheral blood mononuclear cells (PBMCs) obtained from 70 participants (35 non-clinical controls, 35 participants with schizophrenia), who were recruited for the absence of marijuana use/abuse by self-report. Changes in mRNA expression were measured using qRT-PCR. Clinical measurements collected included the MATRICS Cognitive Battery and the Positive and Negative Syndrome Scale. Levels of CB1R and CB2R mRNA in PBMCs were significantly higher in participants with schizophrenia compared to the non-clinical controls. Additionally, CB1R and CB2R mRNA levels correlated with impairments in cognitive processing and clinical symptom severity in multiple domains. These results continue to support dysregulation of particular aspects of the endocannabinoid signaling system in participants with schizophrenia selected for the self-reported absence of marijuana abuse/dependence.

Listening to Schneiderian Voices: A Novel Phenomenological Analysis.

BACKGROUND/AIMS: This paper reports on analyses designed to elucidate phenomenological characteristics, content and experience specifically targeting participants with Schneiderian voices conversing/commenting (VC) while exploring differences in clinical presentation and quality of life compared to those with voices not conversing (VNC). METHODS: This mixed-method investigation of Schneiderian voices included standardized clinical metrics and exploratory phenomenological interviews designed to elicit in-depth information about the characteristics, content, meaning, and personification of auditory verbal hallucinations. RESULTS: The subjective experience shows a striking pattern of VC, as they are experienced as internal at initial onset and during the longer-term course of illness when compared to VNC. Participants in the VC group were more likely to attribute the origin of their voices to an external source such as God, telepathic communication, or mediumistic sources. VC and VNC were described as characterological entities that were distinct from self (I/we vs. you). We also found an association between VC and the positive, cognitive, and depression symptom profile. However, we did not find a significant group difference in overall quality of life. CONCLUSIONS: The clinical portrait of VC is complex, multisensory, and distinct, and suggests a need for further research into the biopsychosocial interface between subjective experience, socioenvironmental constraints, individual psychology, and the biological architecture of intersecting symptoms.

The value of interleukin 6 as a peripheral diagnostic marker in schizophrenia.

BACKGROUND: Associations between a pro-inflammatory state and schizophrenia have been one of the more enduring findings of psychiatry, with various lines of evidence suggesting a compelling role for IL-6 in the underlying pathogenesis of schizophrenia. METHODS: In this study, we examined IL-6 mRNA levels by real-time RT-PCR from fresh extracted peripheral blood mononuclear cells (PBMC) in normal controls and participants with schizophrenia. RESULTS: We found that peripheral PBMC IL-6 mRNA levels, in the absence of any other information, reliably discriminated between a diagnosis of schizophrenia and normal controls. Furthermore, in participants with schizophrenia, we also found elevated levels of IL-6 mRNA with earlier ages of illness onset and worse positive symptom presentation, as measured by the Positive and Negative Syndrome Scale. CONCLUSIONS: These findings provide important and continued support for a pathophysiological role of inflammation in patients with schizophrenia. Future utilization of peripheral IL-6 mRNA levels could be clinically useful during an initial diagnosis and help tailor individualized treatment plans for patients with schizophrenia.