Poster #T27 ALTERED HIPPOCAMPAL GLUTAMATE FUNCTION IN PEOPLE AT ULTRA HIGH RISK FOR PSYCHOSIS

Poster #T27 ALTERED HIPPOCAMPAL GLUTAMATE FUNCTION IN PEOPLE AT ULTRA HIGH RISK FOR PSYCHOSIS

S298 Abstracts of the 4th Biennial Schizophrenia International Research Conference / Schizophrenia Research 153, Supplement 1 (2014) S1–S384 (psycho...

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S298

Abstracts of the 4th Biennial Schizophrenia International Research Conference / Schizophrenia Research 153, Supplement 1 (2014) S1–S384

(psychotic disorders). The association was in part correlated with age, since consanguinity was prevalent in older age groups. However the association was not modified by any mental disorder within the family. Any marriage between second or distant degree cousins was not associated with the outcome. Discussion: These results are consistent with claims that inbreeding can contribute to the risk of psychosis phenotype. The parental consanguinity and family history are one of the main risk factors for the development of psychosis.

Poster #T25 ANOMALIES IN THE FABRIC OF THE PERINEURONAL NET AND SCHIZOPHRENIA PATHOPHYSIOLOGY Byron K.Y. Bitanihirwe 1,2 , Charmaine Pietersen 3 , W. Tsung-Ung 4 World Health Organization; 2 Department of Mental Health and Substance Abuse; 3 McLean Hospital/Harvard Medical School; 4 Harvard Medical School 1

Background: Perineuronal nets (PNNs) represent key reticular structures consisting of components of the extracellular matrix (ECM) that coat a variety of cells in the mature mammalian brain. Until recently, the functions of the PNN had remained enigmatic, but are now considered to be important in development of the central nervous system, neuronal protection and synaptic plasticity, all elements which have been linked to schizophrenia. Recent studies have reported an alteration in PNNs and the constituent elements of these structures in the prefrontal and entorhinal cortex in addition to the amygdala and olfactory epithelium of patients with schizophrenia. We therefore sought to further extend these observations by investigating and characterizing which extracellular elements necessary for PNN structural integrity are preferentially affected in the superior temporal gyrus (STG) of patients with schizophrenia. Because the STG has been associated with developmental mechanisms of brain lateralization and the pathogenesis of language-related schizophrenic symptoms this struture lends itself to investigation of developmental deviance in the onset of schizophrenia. Methods: In this study we used single-cell gene expression profiling of laser-captured pyramidal neurons from layer 3 of the STG (Broadmann’s Area 42) from patients with schizophrenia and a corresponding set of normal controls. Microarray data were confirmed by quantitative RT-PCR. Results: Pyramidal neurons from patients with schizophrenia exhibited significant reductions in the expression of multiple components of the PNN including aggrecan (p=0.03, fold enrichment = −1.26), versican (p=0.04, fold enrichment = −1.13) and hyaluronan and proteoglycan link protein 1 (p=0.05, fold enrichment = −1.14). Significant changes in the expression levels of two families of endogenous extracellular metalloproteinases (viz. matrix metalloproteinase (MMPs), and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs)), which are enzymes involved in the breakdown and remodelling of the ECM were also detected. We specifically found the expression of MMP16 (p=0.02, fold enrichment = −1.17), MMP25 (p=0.02, fold enrichment = −1.14) and MMP24 (p=0.01, fold enrichment = 1.22) in addition to ADAMTS1 (p=0.03, fold enrichment = 2.56) and ADAMTS6 (p=0.05, fold enrichment = 1.15) to be significantly altered in schizophrenia. Discussion: The current data indicate deficits in constituents of the PNN in pyramidal neurons of the STG from patients with schizophrenia. In addition, these data suggest that a dysregulation in the remodelling of the ECM may represent a genuine mechanism underlying thepathophysiology of schizophrenia. Changes in the dynamics of the ECM under pathological conditions may affect and disrupt the structural integrity of PNNs triggering a cascade of molecular events culminating in the neuronal damage and synaptic dysfunction associated with schizophrenia.

Poster #T26 A CROSS-SECTIONAL AND LONGITUDINAL STUDY OF GLOBAL CORTICAL MORPHOLOGY IN THE EDINBURGH HIGH RISK STUDY OF SCHIZOPHRENIA Catherine L. Bois 1 , Liat Levita 2 , Lisa Ronan 3 , Stephen Lawrie 4 Department of Psychiatry, University of Edinburgh; 2 University of Sheffield; 3 University of Cambridge; 4 University of Edinburgh

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Background: Schizophrenia is associated with global brain abnormalities

that have been shown to be evident before disorder onset. Most structural studies of the cortex have restricted their analyses to gray matter volume, rather than its constituents of surface area and cortical thickness. This may obfuscate potentially unique contributions of these parameters in the pathophysiology of schizophrenia, as they have been shown to have distinct genetic underpinnings. At present it is also unclear whether generalized abnormalities that precede disorder onset are static, or become evident through aberrant development. Therefore, we investigated cortical thickness and surface area in a longitudinal study of individuals at high familial risk of schizophrenia, compared to healthy controls. Methods: Subjects were recruited from the Edinburgh High Risk Study of Schizophrenia. At baseline, there were 146 High Risk (HR) individuals, and 36 Healthy Controls (HC). We used subsequent clinical assessments to investigate baseline measures as well as longitudinal change in global cortical thickness and surface area across high risk individuals that remained well during the course of the study: HR[well] (n=72), individuals that had transient psychotic symptoms but did not develop schizophrenia: HR[symp] (n=57), and individuals that developed schizophrenia: HR[ill] (n=17). Individuals that became ill before the second time-point were not offered rescanning. Groups were also compared against HCs. Structural images were acquired at two time-points (mean scan interval = 1.87 years), and processed using the surface-based stream in Freesurfer v 5.0. Statistical analysis was conducted using mixed effects models implemented in R. Results: At baseline, there were no significant group differences in thickness. However, there were significant group differences in bilateral surface area, (F=2.80, df=165 p<0.05), which post-hoc tests showed were because HR[symp] and HR[ill] had significantly larger surface areas than HR[well], p<0.05. For the longitudinal comparisons in thickness, a significant group by time interaction emerged bilaterally (F=4.35, df=338, p<0.001). Post-hoc tests revealed that this was because HR[ill] group experienced significant thinning over the two scans, p<0.05, which no other groups did. A significant Group by time interaction emerged for surface area bilaterally, (F=4.6, df=329, p<0.05). Post-hoc tests revealed that the HC showed larger decreases in surface area, compared to all HR individuals, p<0.05. Discussion: At baseline, HR[symp] and HR[ill] had significantly larger surface areas compared to HR[well]. Longitudinally we found that all HR groups had a preservation of surface area compared to HC. Together these results suggest that relatively larger surface areas, either at baseline or developmentally may serve respectively as a state marker of psychosis or a trait marker for the disorder. The cortical thinning in HR[ill] suggests that an additional brain insult occurs near to the time of disorder onset. Our study indicates that static and progressive abnormalities in surface area confer vulnerability to the disorder, whilst further progressive changes in thickness may be on the causal pathway for schizophrenia. Our results reinforce the importance of investigating surface area and thickness separately.

Poster #T27 ALTERED HIPPOCAMPAL GLUTAMATE FUNCTION IN PEOPLE AT ULTRA HIGH RISK FOR PSYCHOSIS Matthijs G. Bossong 1 , Paul Allen 2 , Carly Samson 1 , Haleema Rasheed 2 , Beverly Quinn 3 , Ilaria Bonoldi 4,5 , Gemma Modinos 6 , James Stone 1 , Oliver Howes 7 , Philip McGuire 4 1 Department of Psychosis Studies, Institute of Psychiatry, King’s College London, London, UK; 2 Institute of Psychiatry, King’s College London; 3 CAMEO Early Intervention Services, Cambridgeshire and Peterborough NHS Foundation Trust, UK; 4 King’s College London; 5 OASIS prodromal clinic, SLaM NHS Foundation Trust, London, UK; 6 Department of Psychosis Studies, Institute of Psychiatry, King’s College London; 7 IOP Background: Altered glutamatergic neurotransmission is thought to play a key role in the pathophysiology of schizophrenia. Recent neuroimaging studies have shown that striatal and thalamic glutamatergic abnormalities are present before the onset of the disorder, thereby significantly contributing to the risk for psychosis. However, hippocampal glutamate function has been more difficult to study due to methodological constraints and, as such, it is unclear if hippocampal glutamate function is altered or if it is associated with symptomatology. Here we examined if subjects at Ultra High Risk (UHR) for psychosis show altered glutamate function in the hippocampus, and how this relates to symptomatology.

Abstracts of the 4th Biennial Schizophrenia International Research Conference / Schizophrenia Research 153, Supplement 1 (2014) S1–S384

Methods: Thirty-three individuals who met UHR criteria and 20 healthy volunteers participated in the study. Levels of glutamate (Glu) and the combined measure of glutamine and glutamate (Glx) were assessed in the left hippocampus using proton magnetic resonance spectroscopy at 3.0 Tesla (PRESS: Point-RESolved Spectroscopy; TE=30ms; TR=3000ms; 96 averages; voxel size 20×20×15). All spectra were analysed using LCModel version 6.3-0A, and water-scaled Glu and Glx values were corrected for CSF content. Symptomatology was determined using the Comprehensive Assessment of At-Risk Mental State (CAARMS). Group differences were determined using independent samples t-test (two groups) or one-way ANOVA (three groups). Relationships between hippocampal glutamate function and symptom severity were determined using Pearson’s correlation. Results: There were no significant group differences in hippocampal Glu (controls vs UHRs 6.96±0.90 and 7.29±1.13) or Glx levels (controls vs UHRs 9.36±2.05 and 9.97±2.11). However, subdivision of UHR subjects according to the level of positive symptoms at presentation (median CAARMS positive symptoms score ≤7 and >7) revealed a significant effect for hippocampal Glu concentrations (p=0.015) and a trend towards significant differences in hippocampal Glx levels (p=0.099) across all three groups. Post hoc tests revealed higher Glu levels and a tendency towards higher Glx levels in more symptomatic UHR subjects compared to both UHR subjects with minimal positive symptoms (p=0.013 and 0.062, respectively) and healthy controls (p=0.017 and 0.077). No changes in Glu and Glx concentrations were shown between UHR subjects with minimal symptoms and healthy volunteers. In addition, hippocampal Glu levels were positively correlated with positive symptoms (p=0.030), and showed a trend towards a negative relationship with negative symptoms (p=0.095). No correlations were demonstrated with cognitive symptoms or between hippocampal Glx levels and symptomatology. Discussion: These results indicate higher hippocampal glutamate function in subjects at UHR for psychosis, who exhibit higher levels of positive symptoms. These data are consistent with the theory that glutamatergic abnormalities are fundamental to the development of psychosis, and support the notion that glutamate dysfunction is involved in the vulnerability to psychosis.

Poster #T28 OBSESSIVE COMPULSIVE SYMPTOMS AND PREMORBID ADJUSTMENT AS PREDICTORS OF TRANSITION TO PSYCHOSIS IN ULTRA-HIGH RISK (UHR) SUBJECTS Julie Bourgin 1 , Emilie Magaud 2 , Anne Gut 3 , Mathilde Kazes 3 , Marie-Odile Krebs 3 1 SHU, Sainte Anne Hospital; 2 Mental Health Centre University of Calgary; 3 Sainte Anne Hospital Background: Identifying at-risk mental states of psychosis can reduce the duration of untreated psychosis and the rate of transition. Meanwhile, it may improve prevention strategies of suicide, substance abuse and anxiety disorders comorbidities. We aim to investigate the clinical symptomatology differences at baseline, especially in non-specific symptoms, between UHR patients who did or did not make a transition to psychosis. Sharpening UHR inclusion criteria may improve prediction of transition to psychosis. Methods: The study included 85 young help-seekers (mean age= 20 y.o.) meeting UHR CAARMS’ criteria. 46 were followed up over a period of 30 months and 27 of them were assessed in a comprehensive clinical interview. Out of 46 finally included UHR subjects, 11 (40%) made a transition to psychosis. Psychopathology was investigated with the Comprehensive Assessment of At-Risk Mental State (CAARMS), BPRS and GAF-score. To identify the most predictive variables of transition, we applied a stepwise logistic regression on CAARMS’ criteria plus other variables (premorbid adjustment scale, cannabis use, subjective experienced life events, treatment and suicide). Results: At baseline, premorbid adjustment and severity of CAARMS’ Obesssive-Compulsive Symptoms (OCS) were found to significantly influence the transition: poor premorbid adjustment, associated with moderate level of OCS increased the sensitivity (72.7%) and the specificity (92.8%) of the prediction. Discussion: Premorbid adjustment and level of OCS were predictive of transition in subjects at UHR. These characteristics could increase the level of prediction of psychosis.

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Poster #T29 HOW TO PREDICT AND MEASURE MEDICATION ADHERENCE IN SCHIZOPHRENIA: TWELVE MONTHS OF ELECTRONIC MONITORING (MEMS® ) IN THE SWEDISH COAST-STUDY Cecilia Brain 1,2 , Katarina Allerby 1 , Birgitta Sameby 1 , Patrick Quinlan 3 , Erik Joas 3 , Ulla Karilampi 4 , Eva Lindström 5 , Jonas Eberhard 6 , Tom Burns 7 , Margda Waern 3 1 Nå Ut-teamet, Psychosis Clinic, Sahlgrenska University Hospital, Gothenburg, Sweden; 2 Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry; 3 Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, Sahlgrenska Academy, University of Gothenburg, Sweden; 4 Psychosis Clinic, Sahlgrenska University Hospital, Gothenburg, Sweden; 5 Department of Neuroscience, Uppsala University Hospital, Uppsala, Sweden; 6 Department of Psychosis Studies, Institute of Psychiatry at the Maudsley, King’s College London, United Kingdom; 7 Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, United Kingdom Background: Non-adherence to antipsychotics increases the risk of relapse in schizophrenia. Non-adherence is most commonly measured through subjective clinician - and patient self-reports, but these measures may underestimate adherence. Most previous studies have been small and short. The aim was to compare objective and subjective measures of adherence and to investigate clinical predictors of adherence to antipsychotics in a larger naturalistic cohort of schizophrenia outpatients over 12 months between October 2008 and June 2011. Methods: Antipsychotic medication adherence was monitored in 117 outpatients diagnosed with schizophrenia or schizophrenia-like psychosis according to DSM-IV criteria in a naturalistic prospective study. Adherence was determined by the Medication Event Monitoring System (MEMS® ), pill count, plasma levels, and patient, staff, psychiatrist and close informant ratings. The plasma level adherence measure reflects adherence to medication and to lab visits. Relationships between MEMS® adherence and other measures were expressed as a concordance index and kappa (K). In 112 of the patients symptom burden, insight, psychosocial function (PSP) and side effects were rated at baseline. A comprehensive neuropsychological test battery was administered and a global composite score was calculated. The Drug Attitude Inventory (DAI-10) was filled in. A slightly modified DAI-10 version for informants was distributed as a postal questionnaire. Results: Non-adherence (MEMS® ≤0.80) was observed in 27% of the patients. MEMS® adherence was highly correlated with pill count (concordance= 89% and K=0.72, p<0.001). Concordance and K were lower for all other adherence measures and very low for the relationship between MEMS® adherence and plasma levels (concordance= 56% and K= 0.05, p=0.217). Adherence measures were also entered into a principal component analysis that yielded three components. MEMS® recordings, pill count and informant ratings had their highest loadings in the first component, plasma levels alone in the second, and patient, psychiatrist and staff ratings in the third. In univariate regression models low scores on DAI-10 and DAI10 informant, higher positive symptom burden, poor function, psychiatric side effects and lack of insight predicted non-adherence. No association was observed with global cognitive function. In multivariate regression models, low patient-rated DAI-10 and PSP scores emerged as predictors of non-adherence. A ROC analysis showed that DAI-10 had a moderate ability to correctly identify non-adherent patients (AUC = 0.73, p<0.001). At the most “optimal” cut-off of 4, one third of the adherent would falsely be identified as non-adherent. A somewhat larger AUC (0.78, p<0.001) was observed when the ROC procedure was applied to the final regression model including DAI-10 and PSP. For the subgroup with informant data, the AUC for the DAI-10 informant version was 0.68 (p=0.021). Discussion: The strong agreement between MEMS® and pill count suggests that structured pill count might be a useful tool to follow adherence in clinical practice. The large discrepancy between MEMS® and the adherence measure based on plasma levels needs further study in clinical settings. Non-adherence cannot be properly predicted in the clinical setting on the basis of the studied instruments alone. The DAI-10 informant questionnaire needs further testing.