Abstracts of the 4th Biennial Schizophrenia International Research Conference / Schizophrenia Research 153, Supplement 1 (2014) S1–S384 S59 5:45 PM THE NEUROBIOLOGY OF NEGATIVE SYMPTOMS AND THE EFFECT OF GLYCINE REUPTAKE INHIBITORS Daniela Alberati F. Hoffmann-La Roche AG, pRED, Pharma Research & Early Development, DTA Neuroscience Background: Negative symptoms can affect up to 60% of patients with schizophrenia. Their severity is predictive of poor outcomes. Avolition (reduced motivation to initiate or persist in goal-directed behaviour) is a critical component of negative symptoms in schizophrenia and has been hypothesised to drive clinical features of apathy, asociality, and alogia. Re- cently, four major components have been identified that transform reward information into behavioural responses: 1) hedonics; 2) reward predic- tion and wanting combined with reinforcement learning; 3) cost-benefit analysis; and 4) ability to generate and execute goal-directed action plans necessary to achieve the valued outcome. Methods: Animal models were used to investigate the in vitro and in vivo effects of bitopertin (a glycine reuptake inhibitor [GRI] under phase 3 investigation for the treatment of predominantly negative and suboptimally controlled positive symptoms of schizophrenia) and a close analogue of bitopertin on different components of motivation typically dysfunctional in schizophrenia, particularly in patients with negative symptoms. Results: Bitopertin modulated rat ventral tegmental area dopaminergic neuronal firing (a crucial process for reward prediction and reinforcement learning) and attenuated deficit in motivated behaviour induced by de- creased dopaminergic neurotransmission in rats. In non-human primates, bitopertin enhanced accuracy in the delayed match-to-sample task, a dor- solateral prefrontal cortex paradigm, implying a positive effect on working memory (a crucial component of executive function). Furthermore, GRIs alleviated deficits in attentional-set shifting (an index of cognitive flexi- bility) in rats induced by subchronic phencyclidine (PCP) treatment. GRIs also alleviated social interaction deficits in rats induced by subchronic PCP treatment or by isolation rearing in combination with early post-natal PCP treatment. Discussion: These results support the hypothesis that improved NMDA receptor function may be a valuable strategy for the treatment of avolition in patients with negative symptoms. 6:00 PM THE ROLE OF OLIGOPEPTIDASES IN SCHIZOPHRENIA – TRANSLATIONAL EVIDENCE FROMHUMAN TO ANIMAL RESEARCH Ary Gadelha 1 , Camila Yonamine 2 , Ana Vendramine 2 , Mauricio Machado 3 , Marcela Nering 2 , Vitor Oliveira 3 , Robson Lopes 4 , Vanessa Abilio 2 , Rodrigo Bressan 5 , Mirian Hayashi 2 1 Universidade Federal de São Paulo; 2 Departamento de Farmacologia, Universidade Federal de São Paulo (UNIFESP), Brazil; 3 Departamento de Biofísica, Universidade Federal de Sao Paulo (UNIFESP), Brazil; 4 Centro de Toxinologia Aplicada (CAT-CEPID), Instituto Butantan, São Paulo, Brazil; 5 Schizophrenia Program (PROESQ), Department of Psychiatry, Universidade Federal de São Paulo (UNIFESP), Brazil Background: Oligopeptidases are a class of enzymes that cleaves peptides but not proteins. The first two oligopeptidases described were Nuclear- Distribution protein nudE-like 1 (Ndel1) and Prolyl-oligopeptidase (POP), besides the Angiotensin-I Converting Enzyme (ACE). Later, Ndel1 was showed to be the binding partner of DISC1, a gene associated to schizophre- nia (SCZ) susceptibility. In the first study to evaluate the Ndel1 enzyme activity in human, we found a significantly lower Ndel1 activity in SCZ patients compared to healthy controls (HC) plasma (Gadelha et al., J Psych Res 2013). To extend the investigation of oligopeptidases in SCZ, we also examined the POP and ACE activities in human plasma, as these enzymes also share the same natural substrates with Ndel1. Cognitive enhancing properties of POP inhibitors and the ACE involvement in cognition and behavior were demonstrated by others using animal models. Few studies have suggested altered ACE levels in cerebrospinal fluid of SCZ patients. However, we are the first to validate the correlation of the enzymatic activity with SCZ in both human patients and animal models. Methods: 92 SCZ patients were compared to 105 HC. POP and ACE activity in human plasma samples were measured by fluorimetric assays, using FRET specific peptide substrate. ACE transgenic mice were evaluated in cognitive tasks. Results: POP activity in human plasma was null for all samples. The ACE enzymatic activity was significantly higher in SCZ patients compared to HCs (F=0.16, p<0.001) and, among patients, this higher activity was correlated with the PANSS disorganized/cognitive dimension (Spearman’s rho=-0.224 p=0.037). No correlation of ACE enzymatic activity to gender and age in the whole sample, and of duration of illness and dose of antipsychotics among SCZ patients were observed. Titration of ACE gene using transgenic mice allowed demonstrating a significant cognitive impairment due to higher ACE activity. Discussion: Our results show convergent evidence suggesting that higher ACE enzymatic activity levels could be associated to cognitive/disorgani- zation symptoms in SCZ. Furthermore, ACE inhibitors have been showed to improve cognitive measures in animal models and to delay demen- tia progression in humans. Previous results with Ndel1 showed a lower enzymatic activity levels among hebephrenic and treatment-resistant SCZ patients, which usually present more prominent cognitive disturbances and disorganization symptoms, pointing towards the same direction of ACE results. Final validation of the full range of behavioral characteristics of ACE transgenic mice and genetic and cognitive evaluation of our patients and controls samples is being conducted. Overall, these results support a potential involvement of oligopeptidases in SCZ. Oral Presentations GENETICS AND EPIDEMIOLOGY Chairperson: Dan Rujescu Tuesday, 8 April 2014 4:15 PM – 6:15 PM 4:15 PM A POPULATION-BASED LONGITDUNAL STUDY OF SERUMINTERLEUKIN-6 AND C-REACTIVE PROTEIN INCHILDHOOD AS PREDICTORS OF PSYCHOSIS AND DEPRESSION IN YOUNG ADULT LIFE Golam Khandaker 1 , Rebecca Pearson 2 , Stanley Zammit 3 , Glyn Lewis 4 , Peter B. Jones 1 1 University of Cambridge; 2 University of Bristol; 3 University of Cardiff; 4 University College, London Background: A potential role of early-life infection and inflammation in the aetiology of schizophrenia is supported by clinical epidemiological, experimental healthy volunteer and animal model research. Recently, cy- tokine mediated communication between the immune system and the brain has been implicated in the pathophysiology of both schizophrenia and depression. This is supported by meta-analyses reporting increased serum interleukin (IL) 6 and C-reactive protein (CRP) in first episode psychosis, acute psychotic relapse and depression. However, due to their cross-sectional design these studies cannot ascertain whether increased IL-6/CRP is a cause or consequence of illness. Longitudinal studies of sys- temic inflammatory markers and subsequent risk of psychosis are lacking, and those of depression are limited in number with inconsistent results. In a longitudinal design we predicted that higher levels of systemic inflam- matory markers (IL-6 and CRP) in childhood would increase the risks of developing psychosis and depression in the future. Methods: We used data from approximately 4500 individuals from the general population-based Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort. IL-6 and CRP was measured in non-fasting serum samples obtained at age 9 years. The outcomes of psychotic experiences and psychotic disorder were measured by the face-to-face semi-structured psychotic-like symptoms interview (PLIKSi) at age 18 years. Depression was measured in two ways: a clinical interview and a questionnaire so as to allow internal replication. The sample was divided into thirds ac- cording to tertiles of the IL-6 and CRP distributions in all individuals with these measures at age 9 years (irrespective of their status at the end of follow-up). We used logistic regression to calculate the odds ratios (ORs) and 95% confidence intervals (CI) for developing psychiatric outcomes at age 18 years among individuals in the middle and top, compared with the bottom third of inflammatory marker distribution at age 9 years. Linearity