Response In Schizophrenia Research Articles

Infectious agents and immune responses in schizophrenia: A case control study

Introduction: Exact causal mechanism of schizophrenia is still unknown; however, genetic and environmental factors are implicated in disease aetiology. The aim of the study is to determine the association of infectious agents cytomegalovirus and T.gondii along with immune cytokines IL-2, IL-6 and IFN-γ with schizophrenia. Methods: Ninety subjects participated in the study, 45 were patients diagnosed with schizophrenia, and the other 45 were a healthy control group. Qualitative and quantitative enzyme immunoassays were used for detection of antibodies and quantitation of cytokines respectively in subjects’ sera. Results: Both patients and control groups had similar CMV seroprevalence of 93.3% (42/45). Prevalence of anti T. gondii IgG antibodies were 53.3% and 64.4% among schizophrenic patients and controls respectively. No statistically significant difference was observed between patients and controls (p > 0.05). A significant difference (p<0.005) between mean serum Interleukin-2 levels in patients (14.7 pg/mL) and controls (33.5 pg/mL) was observed. No statistically significant difference (p>0.05) was found between the median IQR serum Interleukin-6 levels of patients (4.3 pg/mL) and controls (3.1 pg/mL). There was a significant difference (p< 0.001) in median IQR serum IFN – γ levels between patients (0.8 pg/mL) and the control group (4.9 pg/mL). Conclusions: No significant differences between schizophrenic patients and healthy controls with regard to previous infections with cytomegalovirus or T.gondii were observed. While significantly higher levels of proinflammatory cytokines IL-6 and IFN – γ among controls than patients might be an indication of weaker than normal immune responses in schizophrenic patients.

Increased regional homogeneity modulated by metacognitive training predicts therapeutic efficacy in patients with schizophrenia

Previous studies have demonstrated the efficacy of metacognitive training (MCT) in schizophrenia. However, the underlying mechanisms related to therapeutic effect of MCT remain unknown. The present study explored the treatment effects of MCT on brain regional neural activity using regional homogeneity (ReHo) and whether these regions’ activities could predict individual treatment response in schizophrenia. Forty-one patients with schizophrenia and 20 healthy controls were scanned using resting-state functional magnetic resonance imaging. Patients were randomly divided into drug therapy (DT) and drug plus psychotherapy (DPP) groups. The DT group received only olanzapine treatment, whereas the DPP group received olanzapine and MCT for 8 weeks. The results revealed that ReHo in the right precuneus, left superior medial prefrontal cortex (MPFC), right parahippocampal gyrus and left rectus was significantly increased in the DPP group after 8 weeks of treatment. Patients in the DT group showed significantly increased ReHo in the left ventral MPFC/anterior cingulate cortex (ACC), left superior MPFC/middle frontal gyrus (MFG), left precuneus, right rectus and left MFG, and significantly decreased ReHo in the bilateral cerebellum VIII and left inferior occipital gyrus (IOG) after treatment. Support vector regression analyses showed that high ReHo levels at baseline in the right precuneus and left superior MPFC could predict symptomatic improvement of Positive and Negative Syndrome Scale (PANSS) after 8 weeks of DPP treatment. Moreover, high ReHo levels at baseline and alterations of ReHo in the left ventral MPFC/ACC could predict symptomatic improvement of PANSS after 8 weeks of DT treatment. This study suggests that MCT is associated with the modulation of ReHo in schizophrenia. ReHo in the right precuneus and left superior MPFC may predict individual therapeutic response for MCT in patients with schizophrenia.

Editorial

Clozapine is considered to be a gold standard antipsychotic in treatment resistant schizophrenia. This study aims to investigate clozapine augmentation METHODS utilized in schizophrenia and compare the sociodemographic characteristics, clinical features and remission states of patients whose treatments are augmented and not. This study included 122 outpatients diagnosed with DSMIV schizophrenia. Patients were assessed with the Structured Clinical Interview for DSM-IV Axis I Disorders, Positive and Negative Syndrome Scale, Clinical Global Impression Scale, Global Assessment of Functioning, Calgary Depression Scale for Schizophrenia, Panic Agoraphobia Scale, Yale-Brown Obsessive Compulsive Scale and the World Health Organization Disability Assessment Schedule II. The remission state of the patients was assessed utilizing the Remission in Schizophrenia Working Group criteria for schizophrenia. Combined antipsychotic drug use was the most prevalent method utilized for clozapine augmentation. Patients on augmentation treatment were on higher daily clozapine doses and their remission rates were lower. In addition, the severity of psychopathology related with schizophrenia and comorbid symptoms, the level of functioning and disability were worse in this particular patient group. History of antipsychotic combination use prior to clozapine was found to predict the future use of clozapine augmentation. Adding a second antipsychotic seems to be the most common method of augmenting clozapine treatment in schizophrenia. The group of patients whose clozapine treatment is augmented appears to represent a "more difficult to treat" patient group before clozapine is initiated.

The Role of Cytokines in Predicting the Efficacy of Acute Stage Treatment in Patients with Schizophrenia.

PurposeInflammatory response in schizophrenia (SCz) is related to its underlying pathological mechanism and might be significant in deciding a patient’s prognosis. The current study aims to investigate the differences in the serum inflammation level between schizophrenic patients and healthy controls and identify inflammatory markers that can predict clinical therapeutic effects in early-stage SCz patients at the 6-month follow-up.Patients and MethodsIn total, 71 subjects were recruited in this study, including 35 patients with Scz and 36 healthy controls. The 35 Scz patients, who were in the first-episode or acute relapse state at admission, had completed the 6-month follow-up. The Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impression (CGI) assessment results, demographic details, and blood samples were collected at the baseline and at follow-up. Data were analyzed using the Spearman correlation and multiple linear regression.ResultsSerum interleukin (IL-1β, IL-4, IL-6, and IL-8) levels were significantly elevated in SCz patients at baseline compared with healthy controls, with a reduced IL-8 level at the follow-up. Furthermore, a higher IL-6 level and lower IL-8 level was found to predict better improvement in negative symptoms. The higher IL-6 level also predicted lesser improvement in depressive symptoms. Finally, a higher interferon (IFN)-γ level predicted a lower therapeutic effect for excitatory symptoms.ConclusionThe serum levels of inflammatory markers were higher in patients with SCz than in healthy controls. These markers can be considered accurate predictors of therapeutic effects in patients with SCz.

Pattern of expression of Toll like receptor (TLR)-3 and -4 genes in drug-naïve and antipsychotic treated patients diagnosed with schizophrenia

Toll like receptors (TLRs), a class of conserved immune molecules are crucially involved in initiating innate immune response to infection. TLR activation and subsequent inflammation are linked to pathogenesis of many brain disorders. Preliminary studies indicate a possible role of TLR-driven immuno-inflammatory responses in schizophrenia. However, gene expression data of TLRs in drug-naïve as well as antipsychotic treated patients diagnosed with schizophrenia are albeit limited. In this study, expression profile of TLR3 and TLR4 genes in peripheral blood mononuclear cells (PBMCs) was compared between drug-naïve patients diagnosed with schizophrenia (N = 31) and healthy controls (N = 30). In addition, the pattern of expression of TLR3 and TLR4 genes were also examined after three months of antipsychotic medication in patients. Compared to healthy controls, gene expression levels of only TLR4 (F = 3.87, p = 0.05, ηp2 = 0.06), not TLR3 (F = 0.17, p = 0.71, ηp2 = 0.003) was significantly up-regulated in drug-naïve patients. The changes in the levels of gene expression of TLR3 (t = 0.09, p = 0.93, d = 0.02) and TLR4 (t = 0.29, p = 0.77, d = 0.06) before and after antipsychotic medication were not found to be statistically significant. This finding suggests possible contribution of TLR4 in immunopathogenetic pathway of schizophrenia.

P.155 The efficacy and heterogeneity of antipsychotic response in schizophrenia: a meta-analysis

P.155 The efficacy and heterogeneity of antipsychotic response in schizophrenia: a meta-analysis

Reduced Brain Activity in the Right Putamen as an Early Predictor for Treatment Response in Drug-Naive, First-Episode Schizophrenia.

Antipsychotic medications can have a significant effect on brain function after only several days of treatment. It is unclear whether such an acute effect can serve as an early predictor for treatment response in schizophrenia. Thirty-two patients with drug-naive, first-episode schizophrenia and 32 healthy controls underwent resting-state functional magnetic resonance imaging. Patients were treated with olanzapine and were scanned at baseline and 1 week of treatment. Healthy controls were scanned once at baseline. Symptom severity was assessed within the patient group using the Positive and Negative Syndrome Scale (PANSS) at three time points (baseline, 1 week of treatment, and 8 weeks of treatment). The fractional amplitude of low frequency fluctuation (fALFF) and support vector regression (SVR) methods were used to analyze the data. Compared with the control group, the patient group showed increased levels of fALFF in the bilateral putamen at baseline. After 1week of olanzapine treatment, the patient group showed decreased levels of fALFF in the right putamen relative to those at baseline. The SVR analysis found a significantly positive relationship between the reduction in fALFF after 1 week of treatment and the improvement in positive symptoms after 8 weeks of treatment (r = 0.431, p = 0.014). The present study provides evidence that early reduction and normalization of fALFF in the right putamen may serve as a predictor for treatment response in patients with schizophrenia.

Anti-TSNARE1 IgG plasma levels differ by sex in patients with schizophrenia in a Chinese population.

It was recently reported that levels of plasma IgG antibodies against peptide antigens derived from proteins encoded by schizophrenia‐associated genes are altered in individuals with schizophrenia treated with antipsychotics. This study aimed to replicate the initial finding in antipsychotic‐naïve patients with first‐episode schizophrenia and to explore the possible mechanism by which immune tolerance of B cells may be altered in this disease. A total of 408 case–control plasma samples were collected for analysis of circulating IgG antibodies against fragments derived from TCF4, TSNARE1, ZNF804A, TRANK1, ERCC4, DPYD and CD25 using an in‐house ELISA. The Mann–Whitney U‐test revealed that patients with schizophrenia had a significant change in plasma anti‐TSNARE1 and anti‐CD25 IgG levels; male patients mainly contributed to the increased levels of anti‐TSNARE1 IgG and anti‐CD25 IgG. Receiver operating characteristic (ROC) curve analysis revealed that the anti‐TSNARE1 IgG assay had an area under the ROC curve of 0.625 with a sensitivity of 15.7% and a specificity of 95.2%. Work on a B‐cell model revealed that TRANK1‐derived antigen treatments could enhance the proportions of CD83+ cells and apoptotic B cells when compared with TSNARE1‐derived antigen and vehicle treatment. We conclude that there is a gender difference in autoimmune responses in schizophrenia and suggest that anti‐TSNARE1 IgG may be indicative of schizophrenia in a subgroup of male patients.

The efficacy and heterogeneity of antipsychotic response in schizophrenia: A meta-analysis.

SummaryThe response to antipsychotic treatment in schizophrenia appears to vary, and as such it has been proposed that different subtypes of schizophrenia exist, defined by treatment-response. This has not been formally examined using meta-analysis. Randomised controlled trials comparing placebo and antipsychotics in acute treatment of schizophrenia listed in PubMed, EMBASE and PsycINFO from inception until November 30, 2018 were examined. Relative variability of symptomatic improvement in antipsychotic-treated individuals compared to placebo-treated individuals was quantified using coefficient of variation ratio (CVR). Mean difference in symptom change was quantified using Hedges’ g. In addition, individual patient data from two clinical trials was examined in terms of both the distribution of total symptom change, and the variability of individual symptoms and symptom factors. 11,006 articles were identified. 66 met inclusion criteria, reporting on 17,202 patients. Compared with placebo, antipsychotic-treated patients demonstrated greater total symptom improvement (g=0.47, p<0.001) and reduced variability in symptomatic improvement for total (CVR=0.86, p<0.001), positive (CVR=0.89, p<0.001), and negative symptoms (CVR=0.86, p=0.001). Lower variability in antipsychotic-response was associated with studies published earlier (z=3.98, p<0.001), younger patients (z=3.07, p=0.002), higher dose treatments (z=-2.62, p=0.009), and greater mean-difference in symptom-change (z=-5.70, p<0.001). In the individual patient dataset (N=522 patients), antipsychotic treated patients did not show significantly increased variability for any individual symptom, and there was no evidence of a bimodal distribution of response. Compared to placebo, antipsychotic treatment shows greater improvement and lower variability of change in total, positive and negative symptoms. This is contrary to the hypothesis that there is a subtype of antipsychotic non-responsive schizophrenia. Instead our findings, provide evidence for a relatively homogeneous effect of antipsychotic treatment in improving symptoms of schizophrenia.

Association between Serum Lipids and Antipsychotic Response in Schizophrenia.

Metabolic abnormalities are serious health problems in individuals with schizophrenia. Paradoxically, studies have noted an association where individuals who gained body weight or who have increased their serum lipids demonstrated a better antipsychotic response. As serum lipids serve as more specific physiological markers than body weight, the objective of this study was to review studies that examined the association between changes in serum lipids and changes in symptoms during antipsychotic treatment in individuals with schizophrenia. A Medline® literature search was performed. Fourteen studies were included and analyzed. Evidence suggests that increases in serum lipids may be associated with decreases in symptoms during antipsychotic treatment. This inverse association may be independent of confounding variables, such as weight gain, and may be most evident during treatment with clozapine. Also, according to recent randomized controlled tri-als, lipid-lowering agents do not appear to worsen symptoms although this needs to be further investigated in clozapine-treated patients. Future studies should investigate the association in question in a larger population and identify underlying mechanisms.

Cingulum and abnormal psychological stress response in schizophrenia.

Stress is implicated in many aspects of schizophrenia, including heightened distress intolerance. We examined how affect and microstructure of major brain tracts involved in regulating affect may contribute to distress intolerance in schizophrenia. Patients with schizophrenia spectrum disorders (n = 78) and community controls (n = 95) completed diffusion weighted imaging and performed psychological stress tasks. Subjective affect was collected pre and post stressors. Individuals who did not persist during one or both stress tasks were considered distress intolerant (DI), and otherwise distress tolerant (DT). Fractional anisotropy (FA) of the dorsal cingulum showed a significant diagnosis x DT/DI phenotype interaction (p = 0.003). Post-hoc tests showed dorsal cingulum FA was significantly lower in DI patients compared with DI controls (p < 0.001), but not different between DT groups (p = 0.27). Regarding affect responses to stress, irritability showed the largest stress-related change (p < 0.001), but irritability changes were significantly reduced in DI patients compared to DI controls (p = 0.006). The relationship between irritability change and performance errors also differed among patients (ρ = -0.29, p = 0.011) and controls (ρ = 0.21, p = 0.042). Further modeling highlighted the explanatory power of dorsal cingulum for predicting DI even after performance and irritability were taken into account. Distress intolerance during psychological stress exposure is related to microstructural properties of the dorsal cingulum, a key structure for cognitive control and emotion regulation. In schizophrenia, the affective response to psychological stressors is abnormal, and distress intolerant patients had significantly reduced dorsal cingulum FA compared to distress intolerant controls. The findings provide new insight regarding distress intolerance in schizophrenia.

Schizophrenia, Not a Psychotic Disorder: Bleuler Revisited.

Current diagnostic criteria delineate schizophrenia as a discrete entity essentially defined by positive symptoms. However, the role of positive symptoms in psychiatry is being questioned. There is compelling evidence that psychotic manifestations are expressed in the population in a continuum of varying degrees of severity, ranging from normality to full-blown psychosis. In most cases, these phenomena do not persist, but they constitute risk factors for psychiatric disorders in general. Psychotic symptoms are also present in most non-psychotic psychiatric diagnoses, being a marker of severity. Research revealed that hallucinations and delusions appear to have distinct, independent biological underpinnings—in the general population, in psychotic, and in non-psychotic disorders as well. On the other hand, negative symptoms were seen to be far more restricted to schizophrenia, have other underlying pathophysiology than positive symptoms, predict outcome and treatment response in schizophrenia, and start before the first psychotic outbreak. The current work discusses the concept of schizophrenia, suggesting that a greater emphasis should be put on cases where psychotic symptoms emerge in a premorbid subtly increasing negative/cognitive symptoms background. In those cases, psychosis would have a different course and outcome while psychosis occurring in the absence of such background deterioration would be more benign—probably having no, or a milder, underlying degenerative process. This reformulation should better drive psychopathological classification, face positive symptoms as epiphenomenon of the schizophrenia process, and dishevel stigma from schizophrenia and from delusions and hallucinations.

F176. Dysregulation of the IRE1α Pathway of the Unfolded Protein Response in Schizophrenia

F176. Dysregulation of the IRE1α Pathway of the Unfolded Protein Response in Schizophrenia

Study on ceramide modulates EAAT-2 participation in the immunoinflammatory response in schizophrenia.

Abnormal immunoinflammatory responses play important roles in the pathogenesis of schizophrenia, but the underlying molecular mechanisms are still unclear. In this study, the ceramide agonist daunorubicin (DNR) was injected into the lateral ventricles to induce ceramide accumulation. The behavioral tests were used to observe schizophrenia-like behavioral changes. Changes in the mRNA levels of the proinflammatory cytokines and the protein levels of the glutamate transporter excitatory amino acid transporter-2 (EAAT-2) were detected. After inhibition of nuclear factor-κB (NF-κB), the above indices were detected again. Nissl staining was used to assess neuronal damage. After intracerebroventricular injection of DNR, ceramide significantly accumulated in the hippocampus, and behavioral tests revealed negative schizophrenia symptoms accompanied by induced learning and memory dysfunction. Furthermore, the hippocampus demonstrated increased mRNA levels of the proinflammatory cytokines including interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α) and significantly decreased EAAT-2 protein levels. Nissl staining revealed neuronal damage after ceramide accumulation. The NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC) reduced the behavioral abnormalities caused by ceramide accumulation, downregulated CONCLUSIONS: The experimental results suggest that ceramide reduces EAAT-2 expression through the NF-κB/TNF-α pathway and causes neuronal excitotoxicity in the pathogenesis of schizophrenia, leading to neuronal damage.

Emotional response in schizophrenia to the "36 questions that lead to love": Predicted and experienced emotions regarding a live social interaction.

Evidence suggests that individuals with schizophrenia (SZ) report anticipatory pleasure deficits compared to controls and that these deficits are linked to decreased motivation to engage socially. However, these deficits have been identified via self-report measures of hypothetical pleasant stimuli, leaving it unclear whether they exist in reference to actual social situations. To address this issue, we created a live social interaction that minimized the reliance of higher-order cognitive processes. SZ and control participants were told that they would be playing an "enjoyable sharing game" with another study participant (who was actually a confederate) that involved asking and answering questions (36 interpersonal closeness generation questions; Aron et al., 1997). Participants then reported their current mood and the emotions they anticipated experiencing during the pleasant social interaction. Immediately following the interaction, they reported their experienced emotions. We found that the SZ group anticipated more negative emotion (d = 1.0), but were less accurate in forecasting negative emotion (d = .81), than controls, and these effects were large. There were small, non-significant group differences in anticipation, experience, and accuracy in forecasting of positive emotion (all ds < .29). Also, social anhedonia was positively correlated with anticipated negative affect and negatively associated with experienced positive emotion. At the same time, controls reported finding the interaction to be a more positive emotional experience overall, d = 0.75. This is the first study to show that "anticipatory pleasure deficits" in SZ might actually be heightened anticipated negative emotion and that inaccurate forecasting could be linked to decreased social motivation.

Prediction of early response to overall treatment for schizophrenia: A functional magnetic resonance imaging study.

IntroductionTreatment response at an early stage of schizophrenia is of considerable value with regard to future management of the disorder; however, there are currently no biomarkers that can inform physicians about the likelihood of response.ObjectsWe aim to develop and validate regional brain activity derived from functional magnetic resonance imaging (fMRI) as a potential signature to predict early treatment response in schizophrenia.MethodsAmplitude of low‐frequency fluctuation (ALFF) was measured at the start of the first/single episode resulting in hospitalization. Inpatients were included in a principal dataset (n = 79) and a replication dataset (n = 44). Two groups of healthy controls (n = 87; n = 106) were also recruited for each dataset. The clinical response was assessed at discharge from the hospital. The predictive capacity of normalized ALFF in patients by healthy controls, ALFFratio, was evaluated based on diagnostic tests and clinical correlates.ResultsIn the principal dataset, responders exhibited increased baseline ALFF in the left postcentral gyrus/inferior parietal lobule relative to non‐responders. ALFFratio of responders before treatment was significantly higher than that of non‐responders (p < 0.001). The area under the receiver operating characteristic curve was 0.746 for baseline ALFFratio to distinguish responders from non‐responders, and the sensitivity, specificity, and accuracy were 72.7%, 68.6%, and 70.9%, respectively. Similar results were found in the independent replication dataset.ConclusionsBaseline regional activity of the brain seems to be predictive of early response to treatment for schizophrenia. This study shows that psycho‐neuroimaging holds promise for influencing the clinical treatment and management of schizophrenia.

Impact of baseline early auditory processing on response to cognitive remediation for schizophrenia

BackgroundEarly auditory processing (EAP) has increasingly become a focus of efforts to identify biomarkers of treatment response in schizophrenia. EAP deficits lead to poor functional outcome via impaired cognition, and treatments that target EAP may drive downstream cognitive improvements. Assessment of baseline need provides an opportunity for cognitive remediation (CR) programs that give EAP training to personalize treatment and optimize its impact. This initial efficacy study examined the differential benefit of EAP training for those with and without baseline EAP deficits as defined by performance on the Tone Matching Test. Methods103 outpatient adults diagnosed with schizophrenia or schizoaffective disorder were classified as having intact (48.5%) or impaired (51.5%) EAP and randomized to a CR program with restorative exercise plans that either included EAP training (N = 49) or did not (N = 54). Cognitive and functional outcomes were measured post-treatment and 3 months later. ResultsOnly in EAP impaired participants was there a significant benefit from EAP training on verbal learning. Treatment condition did not significantly impact global cognitive or functional outcomes for either EAP group. Cognitive gains partially mediated the relationship between gains in EAP and functional capacity. ConclusionThese findings support the importance of addressing basic auditory deficits when attempting to remediate higher order auditory impairments such as verbal learning. In addition, they highlight the need for routine assessment of EAP in cognitive remediation participants, as well as the need for more effective programs to reverse these impairments.

Enhanced Baseline Activity in the Left Ventromedial Putamen Predicts Individual Treatment Response in Drug-Naive, First-Episode Schizophrenia: Results from Two Independent Study Samples

Background: Antipsychotic medications are the common treatment for schizophrenia. However, reliable biomarkers that can predict individual treatment response are still lacking. The present study aimed to examine whether baseline putamen activity can predict individual treatment response in schizophrenia. Methods: Two independent samples of patients with drug-naive, first-episode schizophrenia (32 patients in sample 1 and 44 in sample 2) and matched healthy controls underwent resting-state functional magnetic resonance imaging (fMRI) at baseline. Patients were treated with olanzapine for 8 weeks; symptom severity was assessed using the Positive and Negative Syndrome Scale (PANSS) at baseline and week 8. Fractional amplitude of low frequency fluctuation (fALFF) and pattern classification techniques were used to analyze the data. Findings: Univariate analysis shows an elevated pre-treatment fALFF in the left ventromedial putamen in both patient samples compared to healthy controls (p's < 0.001). The support vector regression (SVR) analysis suggests a positive relationship between baseline pre-treatment fALFF in the left ventromedial putamen and improvement in positive symptom at week 8 in each patient group using a cross-validated method (r = 0.452, p = 0.002; r = 0.511, p = 0.003, respectively). Interpretation: Our study suggests that left ventromedial putamen activity may predict individual therapeutic response to olanzapine treatment in drug-naive, first-episode patients with schizophrenia. Future studies are needed to confirm whether this finding is generalizable to patients with schizophrenia treated with other antipsychotic medications. Funding Statement: This study was supported by grants from the National Key R&D Program of China (2016YFC1307100 and 2016YFC1306900) and the National Natural Science Foundation of China (Grant Nos. 81571310, 81771447, and 81630033). Declaration of Interests: Dr Fan reported receiving research support from the National Institute on Alcohol Abuse and Alcoholism, National Institute on Drug Abuse, the Stanley Medical Research Institute, the Baer Foundation, the Shine Foundation, the Vanguard Group, Janssen, Avanir Pharmaceuticals, Neurocrine, and Alkermes; and reported receiving honoraria for serving on an advisory board for Allergen. Other authors reported no disclosures. Ethics Approval Statement: The study was reviewed and approved by the ethics committees of the Second Xiangya Hospital of Central South University and the Second Affiliated Hospital of Guangxi Medical University. A written informed consent was obtained from each subject.

M71 - HIGH-THROUGHPUT ANTIBODY-BASED PROFILING OF SERUM IN SCHIZOPHRENIA AND BIPOLAR DISORDER PATIENTS: AN INTEGRATIVE GENOMICS-PROTEOMICS PILOT STUDY

Background The identification of biological markers in the peripheral blood for the prediction of the individual clinical outcome has an enormous potential in the frame of personalized medicine. Previous studies have already tried to create predictive models for major psychiatric disorders based on serum protein profiles though with inconclusive results. This study leverages the rich repertoire of biosamples available in the KFO241/PsyCourse cohort to perform a high-throughput antibody-based serum protein profiling. The aim of this pilot study is to establish the feasibility of such an analysis in the serum of these patients. This study also capitalizes on the availability of genomic data to carry out an integrative (genomics/proteomics) profiling. Methods Serum samples of 113 Schizophrenia (SCZ) and 125 Bipolar Disorder (BD) patients belonging to the German KFO241/PsyCourse cohort (www.kfo241.de; www.PsyCourse.de) were included in this study. All biomaterials in this cohort (blood, serum, plasma, DNA, RNA), available at different time points given its longitudinal design, are part of a high-end biobank. The expression of a selected panel of ~100 serum proteins was determined using a set of 155 antibodies in a high-throughput antibody-based assay. This suspension bead array technology enables a multiplexed protein profiling and it leverages the information generated by the Human Protein Atlas (www.proteinatlas.org). Median fluorescent intensities were log-transformed / standardized for downstream analyses. DNA samples were genotyped (Infinium PsychArray) and underwent genotype imputation (1000 Genomes Phase 3 ref. panel). Polygenic Risk Scores (PRS) were calculated by summing up the weighted effect of each SNP contributing to the PRS to obtain an individual estimate of SCZ genetic risk burden. Age, sex and ancestry principal components were used as covariates. Results Multivariate profiles based on the whole panel of quantified proteins did not significantly discriminate between both diagnoses (SCZ and BD). Single-protein ANCOVA analyses revealed, after Bonferroni correction, significant differences in C4B, CFB, VWF, NRG1, BACE1 and other proteins between SCZ and BD samples. High-risk versus Low-risk patients (according to PRS thresholds 5E-8, 5E-2 and 1) did not show a differential level of expression of these proteins. Likewise, polygenic risk did not correlate with the serum level of any of the proteins. Suggestive serum pQTL loci were identified. Discussion Our results confirm the feasibility and potential of this approach using serum samples of psychiatric patients. The observed differences in protein levels between diagnoses warrant replication in independent samples controlling the effect of medication. These results lay the groundwork for large-scale analyses for the discovery of predictive biomarkers of course, outcome and treatment response in SCZ and BD. Such an approach, joining the longitudinal phenotyping and biosample availability at four different time points in the KFO241/PsyCourse cohort with state-of-the-art biomarker quantification methodologies, holds promise for the generation of clinically-relevant predictive models in complex psychiatric disorders.

SU84 - THE GLUTAMATE RECEPTOR - GRM3 GENE AND ANTIPSYCHOTIC RESPONSE IN SCHIZOPHRENIA

Background Schizophrenia (SCZ) is a chronic, debilitating mental disorder characterized by positive, negative and cognitive symptoms. Currently, Antipsychotics (AP) are the best treatment for SCZ, but the clinical responses are highly variable across individuals. Many hypotheses have been proposed to explain the inter-individual difference in AP response. The glutamate system is a target for studying the pharmacogenetics of AP based on the research drug pomaglumetad (GRM2/3) that showed similar efficacy to olanzapine in clinical trials, as well as some evidence of genetic association from previous studies. Also, Bitopertin, a glycine reuptake inhibitor also showed promise in alleviating negative symptoms in SCZ. Glycine acts as co-agonist for the NMDA receptor thus influencing glutamate signaling in the brain. The glutamate genes that have been investigated for their roles in predicting AP response in SCZ include GRIN2A, GRM3 and GRIA1. We conducted an association study between variants in the GRM3 gene and AP using the CATIE sample (n=306). 23 SNPs were extracted from the sample. Methods We investigated 23 SNPs across the GRM3 gene using the CATIE sample. We selected 306 European ancestry patients that have been treated with one of 4 AP (olanzapine, risperidone, quetiapine, and ziprasidone). Treatment response was evaluated using the Positive and Negative Syndrome scale (PANSS). All SNPs with the GRM3 gene were selected from the UCSC genome browser (GRCh36/hg19) and extracted from the CATIE sample using PLINK 1.9. CATIE investigators arranged the genotyping at Perlegen Science using the Affymetrix 500 K two chip genotyping platform plus a custom 164 K fill-in chip. Linkage disequilibrium and Hardy-Weinberg equilibrium calculations were conducted using HaploView 4.2, and all statistical analyses were performed using IBM SPSS v24. Results Among the 23 SNPs obtained from the CATIE dataset, only rs274621 was significantly associated with AP response (p=0.02) under a recessive model. However, the results did not remain significant after correction for independent tests. Discussion Several association studies have investigated GRM3 polymorphisms versus clinical response to AP and yielded promising results in the past. We found a trend for rs274621 to be associated with AP response. The rs274621 marker is an upstream variant which may be located in the promoter region of GRM3 and may affect the transcription of the gene. Interestingly, rs274621 was also significantly associated with bipolar disorder in the University College London 1 (UCL1) subsample GWAS. Overall, the analyses of the European ancestry subsample of CATIE did not provide significant evidence for a role of GRM3 in AP responses. However, further studies of the glutamate system in AP response are required.