Abstracts of the 4th Biennial Schizophrenia International Research Conference / Schizophrenia Research 153, Supplement 1 (2014) S1–S384 S153 events. It is possible that changes in cortisol and pituitary gland volume normalize after transition to psychosis since there was no difference be- tween healthy controls and FES patients. The lack of difference in pituitary volume between the subgroups could reflect that many factors affect the pituitary volume, e.g. hormones and age. The findings of changes in stress response in UHR patients compared to healthy controls and an inverse cor- relation between cortisol morning response and recent life events support that further studies should investigate the stress levels in patients at UHR of developing psychosis. Poster #S175 THE ERYTHROCYTE MEMBRANE LIPIDABNORMALITIES OBSERVED IN SCHIZOPHRENIA PATIENTS SUPPORT THEOXIDATIVE STRESS HYPOTHESIS IN SCHIZOPHRENIA Philippe Nuss 1,2 ,Cédric Tessier 2 , Haifa Bergaoui 3 , Ariel Fragerman 3 , Antonin Lamaziere 4 , Marc De Hert 5 1 AP-HP, Saint-Antoine Hospital, Paris, France; 2 Sorbonne Universités, UPMC Univ. Paris, UMR 7203, Bioactive Molecules Laboratory; 3 AP-HP, Saint-Antoine Hospital, Department of Psychiatry, Paris France; 5 Laboratory of Mass Spectrometry-APLIPID, ER7-UPMC, Paris, France; 6 University Psychiatric Centre campus Kortenberg KU Leuven, Kortenberg, Belgium Background: Markers of oxidative stress have been postulated as soon as in early brain development phases in patients with schizophrenia (SCZ) potentially leading to excitatory/inhibitory imbalance in particular for glu- tamate and GABA neurotransmission. Furthermore, a decrease in the total antioxidant status is also described in SCZ patients. In the present work dedicated to a thorough analysis of the composition and distribution of lipid in the erythrocyte membrane (EM) in SCZ patients, we examined to what extend some of the observed lipid abnormalities support the hypothesis of an increased oxidant status in SCZ patients. Methods: The oxidative status of the EM lipids was examined in a popu- lation of chronic medicated patients with SCZ (n=75) and healthy control (HC, n=40). EM phospholipids (PL) as well as their constitutive fatty-acids (FA) were analysed using LC-MS/MS method. The distribution between the inner and outer membrane leaflet of lysophosphatidyl ethanolamine (LPE) was measured using trinitrobenzene sulfonic acid labelling. The antioxidant status was examined through the percentage of membrane plasmalogens (PLG), a group of PL with a vinyl ether bond in the sn-1 position, considered to be preventative biomolecules against oxidative stress. The oxidant status was assessed via the degree of unsaturation of phospholipids FA. Results: The plasmalogen (alkenyl) percentage was calculated for the membrane LPE. A significant decreased percentage of PLG (p=0.001) was observed in the EM of SCZ patients (5.9±1.1) vs HC (6.6±1.3). PLG decrease was observed in 59% of the SCZ patients population versus only 27.5% for the HC population. The percentages of LPE fatty-acid species were calcu- lated as well as their distribution on both sides of the membrane leaflet. A significant decrease of both n-3 and n-6 species percentage was found for the externally located LPE between patients and control (n-3 p=0.038; n-6 p=0.036). Discussion: Among the several membrane PL abnormalities identified in the EM of patients with SCZ, we could identify 2 abnormalities compatible with the increased oxidative stress hypothesis in SCZ. This work could not determine whether these abnormalities are a cause or consequence of the general reduced antioxidant status in SCZ. Confounding factors such as antipsychotic drugs, duration of disease and age of onset were examined and could not account for the results. Poster #S176 UNIQUELY TARGETED MOLECULAR THERAPEUTIC FOR SCHIZOPHRENIA: CHARACTERIZATION OF ITI-007INVITRO AND INVIVO ANIMAL MODELS Lawrence P. Wennogle 1 , Gretchen L. Snyder 1 , Robert E. Davis 1,2 , Kimberly Vanover 1 , Joseph Hendrick 1 , Peng Li 1 1 Intra-Cellular Therapies, Inc; 2 3D Pharma Background: ITI-007 is a unique therapeutic designed to target molecular systems capable of beneficially impacting the multiple symptom domains of schizophrenia, while not affecting systems known to cause undesirable side effects such as cognitive dysfunction, cardiovascular abnormalities and metabolic consequences. Here we describe a combination of novel target mechanisms impacted by ITI-007 as defined by in vitro and in vivo characterization using animal models. The predicted spectrum of effects on positive, negative and cognitive symptoms is distinct from other therapeu- tic agents for schizophrenia. ITI-007 has been shown effective in human phase II clinical trials. Methods: In vitro binding studies were performed using isolated mem- branes from cloned human receptor systems expressed in CHO or HEK cells. Affinity constants were expressed as Ki values after correction for radioligand Km affinity and represent 6-8 point curves. Animal models of conditioned avoidance response, catalepsy, quipazine-induced head twitch, in vivo microdialysis and dopamine turnover experiments were performed using standard methods (Snyder et al. 2014, in preparation). Results: ITI-007 is a 0.54nM inhibitor of serotonin 5HT2A receptors, has a 32nM affinity against dopamine D2 receptors, is a 33nM inhibitor of serotonin transport systems (SERT), and displays a 52nM affinity versus dopamine D1 receptors. It has little or no activity versus systems that may contribute to weight gain and cognitive dysfunction, namely histamine H1 receptors and muscarinic cholinergic receptors. It has low affinity for sero- tonin 5HT2B, 5HT2c, and alpha adrenergic receptors and minimal activity versus a panel of off-target receptor/enzyme/channel systems. ITI-007 dis- plays mesolimbic specificity resulting in the phosphorylation of the NMDA receptor NR2B subunit at Tyrosine-1472 in nucleus accumbens, but not in the striatum. This activity is known to enhance glutamate transmission resulting from agonist activity at dopamine D1 receptors. ITI-007 displays dopamine D2 activity in vivo that is consistent with pre-synaptic partial agonist and post-synaptic antagonist action. Pre-synaptic partial agonist activity leads to an absence of enhanced dopamine presynaptic synthesis and a resulting lack of extra-pyramidal side effects (EPS) liability. Using our platform technology, CNSProfileTM we determined that striatal tyrosine hydroxylase (the rate determining step in dopamine synthesis) Serine-40, essential for enzyme activity, was not phosphorylated in mice treated with ITI-007. In contrast, a panel of approved antipsychotic drugs, known to produce EPS, significantly increased Serine-40 phosphorylation. Dopamine metabolism and microdialysis experiments have confirmed the predictions of pre-synaptic D2 partial agonist activity. In the quipazine head-twitch model, ITI-007 was effective at an ED50 of 0.2 mg/kg and in the conditioned avoidance response model ITI-007 has an ED50 of 1.5 mg/kg. These results are consistent with the ∼60-fold ratio of D2/5HT2A Ki affinity values, a ratio unlike any current antipsychotic agent. ITI-007 is bio-available after oral administration and rapidly enters the brain. Discussion: The effects of ITI-007 in pre-clinical in vitro and in vivo models indicate that this agent is a unique therapeutic targeting receptors known to be beneficial for the multiple symptom domains of schizophrenia illness, namely negative symptoms, positive symptoms and associated depression. Furthermore, ITI-007 enhances glutamatergic transmission in brain areas involved in cognitive function. Due to a lack of interaction with undesirable receptor systems, side effects are predicted to be minimal. Poster #S177 PROTEOMIC AND GENOMIC ANALYSES IMPLICATE THE POSTSYNAPTIC DENSITYIN SCHIZOPHRENIA Melanie Foecking 1,2 , Lorna M. Lopez 3 , Jane English 2 , Patrick Dicker 2 , Gerard Cagney 3 , David Cotter 2 1 Department of Psychiatry; 2 Royal College of Surgeons in Ireland; 3 University College Dublin Background: The PostSynaptic Density (PSD) is a highly organized structure, attached to the postsynaptic neuronal terminal, comprised of a complex network of cytoskeletal scaffolding and signalling proteins that facilitate the movement of receptor and signalling complexes. Candidate genes and signalling mechanisms, that converge on and act through it, include NMDA, AMPA and mGLU receptors. NMDA receptor hypo function contributes to the pathophysiology of schizophrenia and it has been proposed that the PSD may contribute to this by dysregulation of NMDA receptor recycling. We enriched for the PSD and conducted proteomic analysis of this fraction in order to test the hypothesis of altered clathrin-mediated endocytosis (CME) within the PSD in schizophrenia. Methods: Sucrose density gradient centrifugation was employed to en-