These Papers Were Presented at the Summer Meeting of the BRITISH ASSOCIATION for PSYCHOPHARMACOLOGY

Home , Hadyn Ellis, Henry Wellcome, Hypoactivity, Psychopharmacology

SUPPLEMENT TO ISSUE 32, NUMBER 8, AUGUST 2018

These papers were presented at the Summer Meeting of the BRITISH ASSOCIATION FOR PSYCHOPHARMACOLOGY

22 – 25 July, London, UK

Indemnity The scientific material presented at this meeting reflects the opinions of the contributing authors and speakers. The British Association for Psychopharmacology accepts no responsibility for the contents of the verbal or any published proceedings of this meeting.

All contributors completed a Declaration of Interests form when submitting their abstract

BAP Office 36 Cambridge Place Hills Road Cambridge CB2 1NS

www.bap.org.uk Aii CONTENTS

Abstract Book 2018 Abstracts begin on page:

APPLIED CLINICAL SCIENCE STREAM Recent developments in treatment resistant schizophrenia (ACSS01–ACSS04) A1

SYMPOSIUM 1 Early intervention for the next generation: therapeutic challenges in youth mental health (S01–S04) A2

SYMPOSIUM 2 Mineralocorticoid/glucocorticoid receptor imbalance and early life stress as risk factors for affective disorders (S05–S08) A4

SYMPOSIUM 3 Microglia role in neuropsychiatric disease and its potential as a treatment target (S09–S12) A6

PLENARY SESSION Metabolic disturbance and inflammation in schizophrenia: comorbidity or therapeutic opportunity? (S13–S16) A8

SYMPOSIUM 4 PTSD: exposure to traumatic events, brain changes and current and novel treatments (S17–S20) A10

SYMPOSIUM 5 New concepts in the co-morbidity of psychiatric disorders, eating disorders and obesity (S21–S24) A12

SYMPOSIUM 6 Risk factors for autism and schizophrenia: Convergence or divergence? (S25–S28) A14

SYMPOSIUM 7 The opiate system in addiction: latest findings from substance and behavioural addictions (S29–S32) A16

SYMPOSIUM 8 Bridging the translational gap in psychiatry: a role for neuronal oscillations? (S33–S36) A18

SYMPOSIUM 9 Towards a mechanistic understanding of anxiety disorders: translational, pharmacological, neural and computational perspectives (S37–S40) A20 CONTENTS Aiii

POSTERS

Group A: Compulsive Disorders (A01–A09) A22

Group B: Schizophrenia (B01–B15) A28

Group C: Developmental Disorders (C01–C07) A39

Group D: Applied Clinical Research (D01–D14) A44

Group E: Drug Dependence (E01–E16) A54

Group F: Cognition (F01–F25) A66

Group G: Immune Dysfunction (G01–G23) A84

Group H: Neuroimaging (H01–H23) A101

Group I: Affective Disorders (I01–I27) A118

Group J: Other (J01–J06) A137

GUEST LECTURE Genomic insights about the neurodevelopmental origins of schizophrenia A141

POSTDOCTORAL SYMPOSIUM 1 What can animal behaviours really tell us about human cognitive and emotional processes? (PD01–PD04) A142

POSTDOCTORAL SYMPOSIUM 2 Cutting-edge translational therapeutics in mental health: a focus on cognition (PD05–PD08) A144

SHORT ORAL PRESENTATIONS

Short Orals 1: Targeted approaches to understand and alter cognition See abstracts F03, I15, F11, A08

Short Orals 2: New insights into the effects of ketamine See abstracts B07, H02, I07, I04

Short Orals 3: Understanding psychopathology and treatment mechanisms using neuroimaging See abstracts H13, H23, F08, C05

2018 PSYCHOPHARMACOLOGY AWARDS (PW01–PW03) A146

ABSTRACTS A1

ACSS01 WHEN META-ANALYSIS GOES WRONG: LESSONS FOR TREATMENT RESISTANT SCHIZOPHRENIA Howes O, King’s Coll & MRC LMS Imperial Coll, Box 67, IoPPN, Camberwell, SE5 8AF oliver.howes@lms. mrc.ac.uk McCutcheon R(1), Mizuno Y(1) (1) King’s Coll London Treatment resistant schizophrenia is common, and a major cause of unmet need, with substantially higher hospitalisation rates, and healthcare costs than schizophrenia in general. This talk will discuss a recent global effort to review treatment resistant schizophrenia, including up-dated criteria for assessment and diagnosis. This identifies the core and desirable components of assessment and diagnosis. It will go on to consider the implications of applying these to clinical trials of treatments for TRS, highlighting the issues affecting the translation of trial results to clinical practice. It will also consider the implications for meta- analyses of antipsychotic treatment strategies, and exemplar augmentation strategies. It will then present the results from a novel meta-analysis of variability approach that tests the unique role of clozapine in treatment resistance, as well as meta-analytic data on comparisons with other antipsychotics. This shows clozapine’s superiority, but variability was the same in comparison with other antipsychotics. These implications of these findings for the hypothesis the clozapine has unique efficacy in treatment resistance will be considered.

ACSS02 CAN TRS BE DIFFERENTIATED FROM TREATMENT RESPONSIVE SCHIZOPHRENIA? Pepper FS, Department of Neuroimaging, IoPPN, King’s College London, PO 089, De Crespigny Park, London, SE5 8AF [email protected] Cognitive impairment is apparent in patients with schizophrenia and associated disorders from the first episode, in cognitive tasks including working memory. Antipsychotic medications have been shown to improve positive symptoms but are not effective for negative or cognitive symptoms or have modest effects and are difficult to separate from other drug effects. Whilst several neural systems have been implicated, the neural mechanisms underlying cognitive impairments and negative symptoms remain unclear. This talk will give a brief introduction to positive and negative symptoms. It will go on to discuss how the dopamine system has been linked with psychotic symptoms. It is not clear what underlies negative symptoms. Our recent work demonstrated no relationship with negative symptoms and brain regions, leading to the conclusion that there are different neural mechanisms for positive and negative symptoms. Understanding these mechanisms is important to help identify new treatment approaches.

ACSS03 CBT IN PEOPLE WITH TREATMENT RESISTANT PSYCHOSIS Turkington D, Neuroscience, Newcastle University, Wolfson Unit, CAV, Westgate Road, Newcastle-upon- Tyne, NE4 6BE [email protected] Introduction: This presentation will report on the relative efficacy of TCB for those patients with schizophrenia spectrum disorder who are resistant to treatment. This may relate to complete refusal of antipsychotic medication, not responding to or partial response to typical/ atypical antipsychotics or to Clozapine. Methods: Randomised trials of CBT were conducted in the above three groups of treatment resistant patients. Results: CBT proved to be safe and effective in those who refuse antipsychotic medication (Morrison, A.P. et al, 2014. Cognitive therapy for people with schizophrenia spectrum disorders not taking antipsychotic drugs: a single-blind randomised controlled trial. Lancet, 383, 1395-1403) and with a smaller effect size for those resistant to standard typical and atypical antipsychotics (Aguilar, E.J. et al, 2017. Emotional fMRI auditory paradigm demonstrates normalisation of limbic hyperactivity after cognitive behaviour therapy for auditory hallucinations. Schizophrenia Research, 193, 304-312). The use of CBT in patients who are Clozapine resistant patients will be discussed (Pyle, M. et al, 2016. Design and protocol for the Focussing on Clozapine unresponsive symptoms (FOCUS) trial: a randomised controlled A2 ABSTRACTS trial. BMC Psychiatry, 16, 280). The characteristics of those most likely to respond to an expert CBT intervention will be described. The possible mechanism of CBT action in the treatment of schizophrenia will be discussed in relation to fMRI findings. Conclusions: CBT is now finding it’s place within the treatment of schizophrenia spectrum disorders with the emergence of clearer indications and a possible mechanism of action.

ACSS04 PREDICTIVE CODING AND HALLUCINATIONS: A COMPUTATIONALLY INFORMED TMS TREATMENT Corlett P, Department of Psychiatry, Yale University, Ribicoff Research Facilities Connecticut Mental Health Center 34 Park Street New Haven, 06519 [email protected] Psychotic symptoms represent a profound departure from consensual reality. They must involve the brain’s mechanisms for perception and belief. Under predictive coding theory, the brain contains an internal model of the world, organized hierarchically, with top-down predictions and bottom-up prediction errors. Depending on their relative precision, prior beliefs dominate and errors are ignored; or prediction errors prevail, leading to new learning. In this framework, hallucinations arise from overly precise prior beliefs. Using a conditioned-hallucinations paradigm we found evidence in favor of this hypothesis. Learned expectations generate hallucinations in human volunteers and people who hear voices are significantly more susceptible to this effect. Using computational modeling we demonstrated that the effect was driven by string prior beliefs (weighting ones’ past experiences over current sensory data). The effect engaged a circuit incorporating superior temporal sulcus (STS) and the insula. In patients with intractable voices, daily transcranial magnetic stimulation, bilaterally, over STS, significantly attenuates voices. The magnitude of this effect correlates with changes in functional connectivity between the STS and the insula. Thus, taking a computational psychiatry approach we can understand hallucinations at the levels of circuits and psychological mechanisms and perhaps better treat them.

S01 THE AT RISK MENTAL STATE, ATTENUATED PSYCHOTIC SYMPTOMS AND THEIR SIGNIFICANCE Yung AR, University of Manchester, Oxford Rd Manchester, M13 9PL [email protected] It is now possible to identify individuals at high and imminent risk of developing a first episode of psychosis through using the At Risk Mental State” (ARMS) criteria (also known as the “Ultra High Risk” (UHR) or Clinical High Risk (CHR) criteria). Most individuals meeting these criteria will have attenuated or subthreshold positive psychotic symptoms. About 15 - 22% of ARMS individuals develop a full psychotic disorder such as schizophrenia within 12 months. ARMS individuals are also at risk for chronic poor functioning and non-psychotic disorders. Recently the ARMS criteria were used as the basis for a new condition included in the DSM5, the “Attenuated Psychosis Syndrome” and identification of ARMS is included in the NHS England Access and Waiting Time Standard for Early Psychosis. However the idea of preventive treatment for this group is not straightforward. Most individuals meeting ARMS criteria do not develop a psychotic disorder. Further, many individuals in the general population, particularly adolescents, experience attenuated psychotic symptoms without progressing to develop an ARMS or psychotic illness. One problem is that psychotic symptoms, including their subthreshold forms, are thought of as a unitary phenomenon. We lack understanding of the factors associated with these symptoms that predict these outcomes, including underlying biological mechanisms. This presentation will summarise current knowledge and examine future directions for research. ABSTRACTS A3

S02 FIRST EPISODE PSYCHOSIS: PRESCRIBING PRACTICE, CHALLENGES AND OPPORTUNITIES Upthegrove RA, Institute for Mental Health, University of Birmingham, 52 Prichatts Road Edgbaston, B15 2TT [email protected] Background: First Episode Psychosis (FEP) has presented both diagnostic and therapeutic challenge for over 15 years. FEP is now the first mental disorder to have a waiting time target in the NHS, and this extenuates the challenge. Whilst the majority of FEP patients may meet diagnostic criteria for schizophrenia, considerable numbers do not present with such clarity. FEP challenges include provision across the adult-child divide, usually within the 14-30 age range, working with diagnostic uncertainty, understanding the role of early adversity and a staged model for treating psychosis. Co-morbidity with mood symptoms, emotional instability and substance misuse is the norm rather than exception. Aim: To present recent and summary data on the clinical profile and prescribing practices in UK EIP services, with reference to national prescribing guidelines. Method: Large data from EIP services will be used together with case examples to explore the complexity of presentation and potential pharmacological treatments therein. Review of national prescribing guidance relevant to the clinical profile of young people presenting to EIP services. Results: 63% of young people presenting to EIP services have comorbid mood disorder, 45% anxiety disorder, at least 50% substance misuse and 30% emotional instability. 40% history of traumatic brain injury. Thus, multiple co morbidity is frequent. However, symptomatic recovery also the norm, rather than exception. There may be a lack of guidance on prescribing in the face of co-morbidity, safe tailoring of treatments and when, and how, timing of trials off antipsychotic medication should be managed. Conclusion: Current national guidance, including NICE, continue to focus on categorical diagnoses which may increase the challenge of safe and effective prescribing in young people with multiple comorbidity and diagnostic uncertainty. Psychological interventions have been given significant weight in some guidance- this may leave practicing EIP psychiatrists without a script to follow in uncharted territory.

S03 MOOD INSTABILITY AS A TRANSDIAGNOSTIC CONSTRUCT AND THE CHALLENGES OF EARLY INTERVENTION FOR BIPOLAR DISORDER Broome M, Institute for Mental Health, School of Psychology, College of Life and Environmental Sciences, University of Birmingham, Birmingham, UK, B15 2TT [email protected] Marwaha S(1) (1) Unit of Mental Health and Wellbeing, Warwick Medical School, University of Warwick, Coventry, UK Literature offers a variety of definitions and conceptualisations of mood instability, and in turn, many tools to measure it. Our initial research was to conduct a systematic review synthesising conceptions and measures of mood instability in clinical populations, and reviewing the neuroscientific studies. In parallel, we began examining prevalence and clinical correlates of mood instability in a UK household morbidity survey, to determine whether mood instability had a clinical impact over and above the psychiatric diagnoses also present in the population. We also carried out a cross-sectional study examining dimensions of mood instability in a clinical population. The systematic review found three core attributes of mood instability. We propose that mood instability is defined as “rapid oscillations of intense affect, with a difficulty in regulating these oscillations or their behavioural consequences”. In our epidemiological work (n=7403) we found a prevalence of mood instability of 13.9%, and that it was associated with health service use and suicidal ideation. Longitudinally, mood instability may mediate some of the risk of childhood trauma causing psychosis. Neuroimaging data on mood instability focuses on those with borderline personality disorders but highlights the role of the amygdala, the cingulate, the limbic system and the relationship between the salience and central executive networks. Our data on clinical populations suggests that those with a variety of psychiatric diagnoses experience degrees of affect oscillation greater than healthy controls, however, affect intensity is the same. However, control of affect differs between diagnoses. Our work offers a definition of mood instability synthesising conceptions from the literature, and suggesting measures that can be used in research to capture the three attributes of the construct. A4 ABSTRACTS

Further, we discuss how mood instability may meet criteria as a transdiagnostic construct, to be examined at different levels for RDoC. The epidemiological project demonstrates that mood instability is prevalent and cuts across psychiatric diagnoses. Further, it is clinically important as indexes outcomes such as health service use and suicidal ideation, beyond that associated with any psychiatric diagnoses present. Lastly, mood instability may also have an important role in the aetiology of mental disorders and may serve as a target for future intervention strategies. The talk will conclude with some reflections as to how this work in mood instability may relate to the development of Early Intervention services and approaches for bipolar disorder.

S04 YOUTH, THE ULTRA HIGH RISK PARADIGM AND REAL WORLD CLINICAL PRACTICE van Amelsvoort T, Head of Division Mental Health, School of Mental Health and Neuroscience, Maastricht University PO box 616 6200 MD Maastricht, The netherlands [email protected] Findings from epidemiological studies show that 75% of major psychiatric disorders emerge before the age of 24. Moreover, the health burden, as expressed in years lost due to disability, is larger during the period between 15 and 24 years, than during any other phase of life. Transitional changes in the adolescent brain may explain part of the increased vulnerability during this period. Dynamic processes like pruning and myelination take place during adolescence and young people are particularly sensitive for immediate reward, whereas impulse control is then still incomplete. In addition, young people are less likely to ask for help when facing mental health problems, which is hampered by the traditional divide between Child and Adolescent Mental Health Services and Adult mental Health Services at the age of 18. New, youth friendly services, technologies and interventions are needed to help young people deal with the psychological distress they are facing and prevent the emergence of major psychiatric illness. Overall, there is an increasing awareness of continuity of care around the age of 18, and youth mental health care programs are starting to be developed. Moreover our own imaging and intervention studies focus particularly at the vulnerable period between the ages15-24 years. In this presentation an overview will be given on new recent Youth Mental Health care initiatives. In addition, results will be presented of our work on the ultra- high risk paradigm and neurobiological correlates of youth at increased risk for mental illness.

S05 LASTING EFFECTS OF MR/GR IMBALANCE ON BRAIN FUNCTION Joels M, Translational Neuroscience, University Medical Center Utrecht, Universiteitsweg 100, Utrecht, 3584 CG [email protected] Introduction: Rodent models for early life stress (ELS) have demonstrated strong and lasting effects of ELS on brain function in adulthood. Most studies have shown that the hypothalamo-pituitary-adrenal axis is quickly and lastingly affected by ELS and may be one of the mediators of changes in brain function. More specifically, a change in the MR/GR balance may occur over the course of the lifespan and predispose organisms to develop changes in brain function that eventually in humans contribute to affective disorders. We tested the hypothesis that a reduced MR/GR balance, particularly during critical developmental periods such as puberty, contributes to electrical dysfunction of the hippocampus and the behavioral functions in which this area is involved. The hippocampus is of interest as it is important for mood and mood disorders. Methods: ELS was induced in rats by 24h maternal deprivation on postnatal (PND) 3 or in mice by exposing the dam to limited bedding and nesting material between PND 2 and 9. MR/GR balance was experimentally manipulated by i) increasing MR expression after ELS; or ii) by pharmacologically blocking GR function for 3 days early in puberty. Results: In the mouse ELS model, hippocampal MR and GR expression changes in a region-, age- and sex-dependent manner, as do stress-induced levels of corticosterone. In the rat ELS model, the changes were more modest. In both models ELS caused impairments in contextual learning, which depends on the hippocampus, whereas behavioral function depending on the prefrontal cortex was less affected. The changes in contextual learning were accompanied by reductions in excitatory transmission, in the absence of significant changes in morphology, both at the macroscopic and microscopic level. Forebrain-specific MR overexpression ABSTRACTS A5

(starting around PND 15) in mice fully rescued the electrical and behavioral phenotype. Similarly, rats or mice treated with the GR-antagonist mifepristone for 3 days early in puberty showed electrical activity and behavioral responses that were comparable to those of animals not exposed to ELS. Conclusions: Increasing MR relative to GR activation may counteract some of the effects of ELS, especially when applied during critical developmental windows. This may offer opportunities for intervention of neuronal dysfunction after individuals have experienced early life adversity.

S06 EARLY LIFE STRESS IN ADULT AFFECTIVE DISORDERS: HPA AXIS RESPONSE TO GR/ MR AGONISTS AND ANTAGONISTS. Juruena MF, Psychological Medicine, Centre for Affective Disorders, Psychiatry, Psychology and Neuroscience-KCL, Institute of Psychiatry, Psychology and Neuroscience King’s College London PO72, De Crespigny Park Denmark Hill, London Room M3.24, SE5 8AF [email protected] Reported evidence shows that during early childhood and adolescence, enduring changes in brain structure and function occur, explaining why the negative consequences of traumatic events are lasting and can remain over the person’s life. Studies indicate that Early Life Stress (ELS) aggravates the clinical course of depression, bipolar and predicts poorer treatment outcome. We will present data and impact of ELS on the HPA axis in affective disorders patients, specifically by investigating responses to MR and GR agonists and antagonists in these patients. MR in the HPA axis is involved in the regulation of stress hormone secretion and complex behaviours, such as emotion, memory, and sleep. Potential novel clinical interventions based on HPA axis alterations and GR/MR abnormalities will be discussed. Our data indicated that from the sample studied, more than 70 % of patients in depressive episode experienced a severe subtype of ELS, compared to less than 30% without history of ELS. Furthermore, significant correlations were observed between the severity of ELS and severity of depressive symptoms, anxiety and suicidal ideation in the group with a history of ELS. Bipolar Depressed patients presented a positive correlation with hopelessness in subjects exposed to emotional and physical abuse. Unipolar depressed patients showed a significantly lower salivary cortisol awakening responses (CAR) after fludrocortisone (MR Agonist) and after spironolactone (MR Antagonist) compared with healthy controls. We found in a Linear Regression model that depressive patients with ELS showed CAR differences between placebo vs MR agonist; but not in patients without a history of ELS. These data indicate that MR activity is impaired in patients with depressive episodes compared with controls. Moreover, in depressed patients with ELS, there was suppression by MR agonist, indicating that patients with ELS are sensitive to MR agonists, in contrast with depressed patients without ELS. Our data indicated that in patients with ELS in a depressive episode exists an imbalance between HPA axis receptors and a significant MR dysfunction. Therefore, stress in early phases of development can induce persistent changes in the response of the HPA axis to stress in adulthood, leading to a raised susceptibility to more severe affective disorders. These abnormalities appear to be related to the HPA axis deregulation in ELS, partially due to MR. Consequently, recent research findings promise possibilities for new pharmacotherapy via modulation of MR function.

S07 MR FUNCTION IN BIPOLAR AFFECTIVE DISORDERS Watson S, ION, Newcastle University, WRC, CAV, NE4 5PL [email protected] Clark,J (2), Russam,G (3), Rushton,S (4), Gallagher,P (1), McAllister-Williams (1) (1) As presenting author; (2) Medical School, Newcastle; (3) Medical School, Newcastle; (4) School of Biology, Newcastle University In this presentation I will explore the differential long term impact of early adversity on the mineralocorticoid and glucocorticoid receptors and the implications of this for the pathophysiology of bipolar disorder and will consider the way that cognitive processes are impacted- and consider also the potential utility of cognitive measures as markers of MR and GR function. I will also describe our petri-net model of HPA axis function which gives a dynamic prediction of how the HPA axis will respond to stress and to pharmacological manipulation. A6 ABSTRACTS

S08 CLINICAL RELEVANCE OF HPA AXIS FUNCTION IN AFFECTIVE DISORDERS: ATYPICAL FEATURES, BIPOLARITY AND TREATMENT RESISTANCE Cleare AJ, Centre for Affective Disorders, IoPPN, Kings College London, De Crespigny Park London, N1 4DX [email protected] This talk will outline the clinical relevance of HPA axis changes in affective disorders. I will start by discussing a series of studies in patients with major depressive episodes in which we used novel methods of assessing long term cortisol levels, using fingernail and hair specimens. Short term measures such as saliva specimens were also obtained in the same patients. Overall, there is support for a differentiation between atypical and non-atypical forms of depression in terms of HPA axis changes and the relationship with environmental stress. However, results using long term cortisol measures do not always correspond to those seen with short term measures, suggesting that both are needed for a full understanding of HPA axis functioning. Altered HPA axis activity is also relevant to treatment outcomes. In a series of meta- analyses, we have shown that raised cortisol levels in depression are a predictor of poor subsequent treatment response, especially to psychological therapy. Preliminary results also suggest that specific polymorphisms in genes encoding the corticotropin-releasing hormone and melanocortin system are significantly associated with antidepressant response In treatment resistant depression (TRD), patients usually fail to suppress to dexamethasone, a measure of glucocorticoid receptor function, but show a normal suppression to prednisolone, a mixed glucocorticoid and mineralocorticoid receptor probe. This suggests that an intact mineralocorticoid receptor can compensate for the impaired glucocorticoid receptor function. The importance of this mechanism is that we have found that an intact mineralocorticoid receptor is predictive of whether TRD patients respond to optimised therapy. Thus, in prospective study, we showed that patients with TRD who showed non-suppression to the prednisolone test on admission (i.e. showed mineralocorticoid resistance as well as glucocorticoid resistance) did not subsequently respond to intensive multimodal inpatient treatment. Future trials of drugs modulating mineralocorticoid receptors in TRD may be warranted. We have also found that there is a contrasting pattern of HPA axis changes in patients with treatment resistant unipolar depression (TRUD) versus treatment resistant bipolar depression (TRBD), the latter showing a blunted cortisol awakening response compared to the heightened response seen in the former. This attests to neurobiological differences between the two types of TRD and may suggest alternative treatment approaches in the two conditions. Funding: This research was part- funded by the NIHR Biomedical Research Centre at South London and Maudsley NHS Trust and King’s College London.

S09 PERIPHERAL AND CENTRAL INFLAMMATION IN PATIENTS WITH PSYCHIATRIC DISORDERS: WHAT IS RELEVANT FOR FUTURE TREATMENT STRATEGIES Mondelli V, IoPPN, King’s College London, The Maurice Wohl Clinical Neuroscience Institute, Cutcombe Road, SE5 9RT [email protected] Background: Increased levels of peripheral immune markers have been widely acknowledged in patients with psychiatric disorders and few studies have suggested the relevance of this increased inflammation for clinical outcome of these patients. It remains still unclear whether peripheral inflammation is linked to central inflammation and whether peripheral or central inflammation could be used to guide future treatment strategies. Methods: The lecture will include data from recently published studies looking at peripheral immune markers such as high sensitive C reactive protein (hsCRP) in patients with depression divided in patients who are treatment resistant, treatment responders or drug naïve; and cytokines (e.g. interleukin-6) in patients with first episode psychosis divided again for treatment response. The lecture will also include unpublished data on meta-analysis of markers of neuroinflammation in patients with major depression. Results: Data from the recent published paper show increased inflammatory markers in both patients with depression (increased hsCRP) and patients with first episode psychosis (increased IL-6) who are not responding to conventional antidepressant or antipsychotic treatment. Our unpublished meta- analysis data confirm the presence of increased neuroinflammation in patients with major depression. ABSTRACTS A7

Conclusions: Our findings suggest that peripheral immune markers may be useful for identifying patients less likely to respond to conventional psychotropic medication and to guide the use of anti-inflammatory treatment. Increased neuroinflammation is also present in patients with major depression. Future studies would need to further clarify the link between peripheral and central inflammation and its relevance for new therapeutic strategies. Acknowledgments: The research presented received funding support from the National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London; the Wellcome Trust; V. Mondelli has also been supported by an ECNP Young Scientist Award and a Starter Grant for Clinical Lecturers from the Academy of Medical Sciences.

S10 INNATE IMMUNITY AS A TREATMENT TARGET IN NEUROPSYCHIATRIC DISEASES Priller J, Centre for Clinical Brain Sciences, Univ of Edinburgh, Chancellor’s Building, 49 Little France Crescent, City, Edinburgh, EH16 4SB [email protected] Microglia are the resident innate immune cells of the central nervous system (CNS). They are critical effectors and regulators of changes in brain homeostasis. Originating from primitive erythromyeloid precursors in the yolk sac, microglia are long-lived tissue macrophages that are susceptible to developmental disturbances and ageing. Maternal immune activation, e.g. as a result of infection, leads to the activation of microglia and increased susceptibility to psychosis in the offspring. Several lines of evidence suggest that microglia are activated in psychiatric disorders. First, positron-emission tomography (PET) studies indicate neuroinflammation in schizophrenia, autism spectrum disorder, major depression and bipolar disorder. Second, microglial activation and elevated levels of proinflammatory cytokines can be detected in post-mortem brain tissue from patients with psychosis. Third, many of the risk genes for psychosis that were identified in recent genome-wide association studies are expressed yb immune cells. Last, neuropsychiatric disorders can be caused by autoimmune encephalopathy. The emerging evidence on the role of the immune system in neuropsychiatric disorders opens new therapeutic avenues. Microglial activation may be modulated by anti-inflammatory drugs or minocycline as add-on treatments. Moreover, the complement system represents a novel target for therapeutic interventions.

S11 TARGETING NEUROINFLAMMATION IN SCHIZOPHRENIA USING MONOCLONAL ANTIBODIES ReisMarques T, Clinical Sciences Centre, Faculty of Medicine, Imperial College, Hammersmith Hospital, Du Cane Road, London, W12 0NN [email protected] Schizophrenia affects 1 in 100 people and is a chronic and disabling psychiatric illness. Antipsychotic drugs have been the cornerstone and first-line treatment for schizophrenia over the last 60 years. However, they have limited efficacy, are ineffective or not tolerated in three-quarters of patients and are not disease modifying. Given these limitations of existing treatments, there is an urgent need and huge potential for alternative, better treatments for schizophrenia, particularly those that may be disease modifying. A number of brain changes are seen in schizophrenia but recent evidence suggests a key role for alterations in the inflammatory system that could underlie the illness. Multiple lines of evidence have shown that there is an increase in inflammation in schizophrenia, with post-mortem studies showing an increase in microglial density and morphological changes indicating microglial activation. Positron emission tomography (PET) in-vivo studies have also reported an increase in microglia activity, in total grey matter and hippocampus of patients with schizophrenia. Furthermore, microglial markers are also elevated in subjects at risk of developing psychosis, and greater microglial activation is associated with greater symptom severity. Taken together this evidence, particularly the association with symptom severity and the elevation in the early phase of schizophrenia, implicates microglial activation in the pathophysiology of schizophrenia, and indicates that targeting microglia could be a new approach to treatment. However, it is still unknown if activated microglia play a primary role in the symptoms and other brain changes seen in schizophrenia or whether microglia changes are a secondary phenomenon. The key test is to reverse microglial activation and determine the effect on symptoms and brain measures. Natalizumab is A8 ABSTRACTS a monoclonal antibody shown to reduce the activation of microglia by >200% compared to comparator treatment in preclinical models, with reductions being directly related to reductions in disease severity scores. In this trial, patients with schizophrenia will receive either a monthly infusion of natalizumab or saline for a total period of 3 months. We are using [18F]-DPA714 PET imaging in conjunction with other brain imaging methods, peripheral and central inflammatory markers and clinical assessment, in order to assess if treatment with natalizumab will lead to a reduction in microglia activity when compared to placebo, to determine if a reduction in microglial activity is associated with a reduction in psychotic symptoms and to determine if changes in microglial activity are directly associated with changes in pro- inflammatory and structural brain changes.

S12 DOES INNATE IMMUNE ACTIVATION CONTRIBUTE TO THE PATHOGENESIS OF ALZHEIMER DISEASE? Heneka MTH, Neurodegenerative Diseases and Geriatric Psychiatry, University of Bonn, Sigmund-Freud Str. 25, 53127 Bonn, Germany, 53127 [email protected] Accumulation of neurotoxic amyloid-β peptides along with neurofibrillary tangle formation represent the key pathological hallmarks in Alzheimer’s disease (AD). Despite the brain has been viewed as an immune privileged organ, increasing evidence from translational, genetic and pathological studies suggests that activation of distinct innate immune pathways represents a third important component, which, once initiated, actively contributes to disease progression and chronicity. Microglia play a pivotal role in this immune response and are activated by binding of aggregated proteins or aberrant nucleic acids to pattern recognition receptors. This immune activation leads to the release of inflammatory mediators but also distracts microglia cells from their physiological functions and tasks. NLRP3 inflammasome activation and release of ASC specks contribute to spreading of pathology and impairs microglia clearance mechanisms together contributing to neuronal degeneration and spatial memory deficits. In keeping with this, inhibition of this immune pathways shows protection in cellular and murine models of AD. Modulation of the microglia driven innate immune response at key signalling steps may therefore provide protection and may alter progression of disease. Therefore, antiinflammatory treatment strategies should be considered. Data on microglial activation in AD along with suggestions to modify and alter the pro- into an antiinflammatory phenotype will be discussed.

S13 RELATIONSHIPS BETWEEN DYSGLYCAEMIA, IMMUNE ACTIVATION AND PSYCHOTIC EXPERIENCES: FINDINGS FROM A UK BIRTH COHORT Perry B, Dept of Psychiatry, Univ of Warwick, Coventry, CV4 7AL [email protected] Recent meta-analyses have found that sensitive measures of glucose dysregulation (insulin resistance [IR], impaired glucose tolerance [IGT] and fasting insulin [FI]) are associated with first-episode psychosis (FEP), independent of antipsychotic use and sociological/anthropomorphic factors, suggesting that the association between dysglycaemia and psychosis extends beyond the effects of antipsychotic medication, reduced access to healthcare and lifestyle factors. A pathophysiological link between glucose dysregulation and psychosis may exist via abnormal immune processes; raised interleukin-6 (IL-6) has been found to occur antecedent to both psychotic disorder and glucose dysregulation separately. We used data from the UK Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort to examine, both cross-sectionally and longitudinally, whether measures of glucose dysregulation (IR, IGT, FI, and fasting plasma glucose (FPG)) were associated with psychotic experiences (PEs), before the onset of FEP. We used logistic and linear regression analyses with detailed adjustments for potential confounders. Through statistical testing, we examined whether any associations were part of either a mediating or moderating relationship by antecedent low-grade systemic inflammation. Based on 2627 participants, at age 18 years, IR was associated with PEs (adjusted OR = 2.32; 95% CI, 1.37–3.97). IR was associated with IL-6 both cross-sectionally and longitudinally. Interaction analyses under a multiplicative model showed that IR moderated the association between IL-6 at age 9 years and PEs at age 18 years (adjusted OR for ABSTRACTS A9 interaction term = 2.18; 95% C.I., 1.06–4.49). Mediation analysis did not support a model of IR mediating the relationship between IL-6 and PEs. Our results provide evidence that even before the onset of clinical psychosis, some patients may have an active process involving IR and inflammation, which may predispose to further metabolic dysfunction. It is possible that inflammation and metabolic risk factors interact to increase risk of psychosis in some people. That IR is associated with PE’s even after controlling for potential confounding factors is important and may provide evidence for clinicians and those involved in clinical guideline formation, to the potential need for more sensitive examination of baseline metabolic function at FEP. As some second-generation antipsychotics are diabetogenic, careful selection of medication accounting for sensitive metabolic dysfunction may reduce the risk of iatrogenic “toppling” into clinical type-2 diabetes.

S14 CHILDHOOD BLOOD BIOMARKERS OF INFLAMMATION AND METABOLISM AS PREDICTOR OF PSYCHOSIS AND DEPRESSION IN YOUNG ADULTS: CAUSAL INVESTIGATIONS IN A UK BIRTH COHORT Khandaker G, Dept of Psychiatry, Univ of Cambridge, Herchel Smith Building, Cambridge Biomedical Campus, Cambridge, CB2 0SZ [email protected] There is evidence of low-grade systemic inflammation and metabolic dysfunction in patients with psychosis or depression, but causality has not been established. Concentrations of acute phase proteins (e.g. CRP) and inflammatory cytokines (e.g. IL-6) are elevated in acutely unwell patients with psychosis or depression, but it is unclear whether this increase is a result of illness-associated stress (i.e. reverse causality) or due to confounding by life style and other factors. To address the issue of reverse causality, we have examined association of 10 inflammatory and metabolic blood biomarkers, assessed in healthy 9 year old participants from the UK ALSPAC birth cohort, with risks of depression and psychosis at age 18 years. Blood markers included IL-6, CRP, leptin, adiponectin, Apo A, Apo B, HDL, LDL, triglyceride and total cholesterol. Higher levels of IL-6 and leptin in childhood were associated with increased risk of psychotic experiences (PEs) subsequently in early adulthood. The adjusted ORs for PEs for participants in the top compared with bottom thirds of IL-6 and leptin were, respectively, 1.81 (95% CI, 1.01-3.28), and 1.54 (95% CI, 1.04-1.29). To address the issue of confounding, we have carried out genetic association analyses informed by Mendelian randomisation. We found that a common functional variant in the IL6R gene (IL6R Asp358Ala; rs2228145 A>C), which is known to dampen down inflammation yb impairing IL6R signalling, is protective for psychosis and/or severe depression. Together these findings suggest that reverse causality and confounding are unlikely explanations for previously observed associations between inflammatory and metabolic markers and psychosis and depression. The association between IL-6 and these disorders is likely to be causal. Time permitting, I will discuss potential therapeutic implications for these findings.

S15 MANAGEMENT OF METABOLIC DISTURBANCE Cooper SJ, School of Medicine, Queen’s University Belfast, 36 Bristow Park, Belfast, BT9 6TH sjcooper@ btinternet.com Weight gain and the development of related metabolic disturbances are a significant problem for many patients with schizophrenia. Though staff on mental health teams are aware of these problems, monitoring and intervention to reverse these problems are frequently inadequate, as is demonstrated by data from sequential national clinical audits. Intervention for excess weight gain is not always straightforward. Lifestyle and illness related factors can play a part as well as factors related to antipsychotic medications. While switching antipsychotic medication can be a worthwhile strategy, this is not always feasible and direct evidence for its benefit is limited. The BAP guidelines on the management of weight gain, metabolic disturbances and cardiovascular risk associated with psychosis and antipsychotic drug treatment (Cooper et al, 2016. Journal of Psychopharmacology 30, 717-748) were an attempt to develop practical guidance from available clinical trial data, and meta analyses of these data, and relevant NICE guidelines. Four approaches with a worthwhile evidence base were identified: lifestyle interventions, antipsychotic switching, adjunctive aripiprazole and adjunctive metformin. Some approaches may only be appropriate A10 ABSTRACTS in specific circumstances and often a combination of lifestyle modification with another intervention yma be necessary. Lifestyle interventions will be discussed, and the evidence found for patients with psychosis compared with that found for people with overweight in the general population. The use of metformin will be discussed, with reference to current NICE guidelines for people with obesity in the general population. No sponsorship was received for the development of these guidelines. The Guideline Development Meeting was supported from BAP funds.

S16 NEUROINFLAMMATION IN FIRST EPISODE PSYCHOSIS - NEW EVIDENCE FROM PET IMAGING AND CLINICAL TRIALS OF MINOCYCLINE AND METHOTREXATE Deakin B, Neuroscience and Psychiatry Unit, University of Manchester, G907 Stopford Bldg, Oxford Rd, M13 9PT [email protected] Introduction: Three unpublished experimental medicine studies in schizophrenia funded by the UKMRC and Stanley Medical Research Institute will be discussed. They tested the predictions that if neuroinflammation occurs in schizophrenia, there should be a) evidence of cellular inflammation in the CNS and of neuronal damage, and b) anti-inflammatory drugs that access the CNS should be therapeutic. We focussed on microglia, the brain’s resident macrophages that mediate inflammatory responses. In their inflamed ‘M1’ form microglia express increased quantities of a translocator protein (TSPO). Radioligand binding to the TSPO can be quantified in-vivo using positron emission tomography (PET). Minocycline is widely used to block activation of microglia in laboratory experiments. It is effective in the clinic in autoimmune disorders such as psoriasis. Methods and Results: The BeneMin study (PMID:25886254) determined whether minocycline added to treatment as usual (TAU) for 12 months would prevent continued inflammation and neurotoxicity and so lessen the occurrence of negative symptoms compared to placebo. 207 people with schizophrenia of less than 5 years duration were randomised to trial treatment. Treatment had no effect on any outcome including negative symptoms, cytokine levels, medial prefrontal grey matter volume and cognitive function measured at baseline and through the study. There was no evidence of a persisting inflammatory or neurotoxic process on which minocycline could have exerted an effect. In contrast to the minocycline result, a feasibility study of methotrexate 7.5mg vs placebo, weekly for 12 weeks (PMID:25563714) found beneficial effects on positive symptoms in a randomisation sample of 92 participants. Initial studies with PET TSPO binding reported increases in schizophrenia and provided a strong impetus to the minocycline study. However, the first study in drug- free patients vs age matched controls in Manchester found no increase in [11C](R)-PK11195 binding potential (PMID:27698434). In our recent study, 6 drug-free patients had significantly lower TSPO binding than 9 age-matched controls. Indeed a recent meta-analysis of 5 studies using newer radioligands reported a significant decrease in patients compared with controls irrespective of drug treatment (PMID:29653835) Conclusions: The results suggest that microglial activation may not occur in schizophrenia which may account for the lack of effect of minocycline. Indeed the results suggest that schizophrenia may involve impaired microglial function or development. It is possible that excessive activity in the ‘M2’ synaptic pruning mode would reduce overall TSPO expression. The efficacy of methotrexate, if replicated could point to aberrant acquired immunity without secondary microglial activation in schizophrenia.

S17 SHAKY TIMES - THE CHRISTCHURCH, NEW ZEALAND EARTHQUAKES AND ALL THAT FOLLOWED Bell C, Dept of Psychological Medicine, Univ of Otago, PO Box 4345 Christchurch, Otago, New Zealand [email protected] Over an 18 month period between 2010 and 2011 there were 4 major earthquakes and over 12,000 aftershocks in Christchurch, New Zealand. This resulted in 185 deaths and huge damage to the city. There were also widespread secondary stressors including complex economic and practical consequences which compounded the difficulties of many. As a result some people developed mental health disorders, some reported subsyndromal problems, some post-traumatic growth but most just soldiered on. This highlights the enigma of understanding why some people develop PTSD after exposure to a traumatic life event while ABSTRACTS A11 others, exposed to the same experiences, do not. From her experience as a psychiatrist dealing with the spectrum of responses over this period, Dr Bell will discuss the psychological impact of the Christchurch earthquakes. This includes how people were affected, the phases of what was seen, what was helpful and the challenges of working in a chaotic, post-disaster environment.

S18 THE NEURAL BASIS OF POST-TRAUMATIC FLASHBACKS Brewin CR, Research Department of Clinical, Educational and Health Psychology, University College London, 1-19 Torrington Place, London, WC1E 7HB [email protected] A substantial number of structural and functional neuroimaging studies have been conducted with individuals suffering from PTSD. Many of them, however, have produced strikingly similar sets of findings to studies of depression and schizophrenia, for example involving reduced hippocampal volume and deficits in prefrontal control over limbic structures, particularly the amygdala. Investigations typically include only one psychiatric diagnosis and overlook the considerable symptom overlap between disorders. Hence previous research has not succeeded in distinguishing the correlates of generic aetiological or psychopathological factors from the specific processes that differentiate one disorder from another. This is essential if viable and well-targeted neurobiological models are to be developed that have clinical applications. Most imaging research has drawn on a limited set of basic science models such as fear conditioning. Despite its important contribution, the fear conditioning model of PTSD and paradigms such as script-driven imagery do not address important features such as the conscious reexperiencing of trauma and the distinction between voluntary and involuntary memory. The revised dual representation theory of PTSD (DRT) focusses on the difference between voluntary trauma memories and involuntary flashbacks, vivid images that are experienced in the present. Flashbacks differentiate PTSD from other disorders, are an important treatment target, and are addressed in trauma-focussed cognitive-behaviour therapy. According to DRT, flashbacks are primarily supported by sensation-based representations created by activity in the dorsal visual stream, insula, and amygdala that have become disconnected from corresponding contextualised representations created by activity in the ventral visual stream and medial temporal lobe. Preliminary structural and functional studies will be described that focus on flashbacks. Understanding the underlying processes and neural basis of these therapeutic target symptoms promises to generate more precise treatments, whether psychological or biological.

S19 EVIDENCE-BASED PHARMACOLOGICAL TREATMENT FOR PTSD Bisson JI, Div of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ [email protected] Post traumatic stress disorder (PTSD) is common with a point prevalence of around 3%. It causes significant suffering to the individual and those around them, is associated with substantial psychiatric and physical comorbidity, increased risk of suicide, and considerable economic burden. The development and routine use of effective treatments for PTSD should be a major health priority. It is widely accepted that, despite evidence for the efficacy of some pharmacological treatments for PTSD, the evidence for trauma focused psychological treatments, such as trauma focused cognitive behavioural therapy and eye movement desensitization and reprocessing, is currently stronger. This has resulted in several treatment guidelines, including those from the National Institute for Health and Care Excellence and World Health Organization, recommending pharmacological treatment as second line. In reality, drugs are commonly prescribed for PTSD and factors including current medical practice, limitations in access to appropriately trained therapists, co-morbidity, lack of stability to enter into psychological treatment and patient preference result in pharmacological treatment often being used first line. The most recent systematic reviews provide statistically significant evidence (when at least two andomizedr controlled trials (RCTs) were available) for four drugs (fluoxetine, paroxetine, sertraline, and venlafaxine) versus placebo. In single RCTs, amitriptyline, mirtazapine, and phenelzine have also shown superiority over placebo in reducing the symptoms of PTSD. Augmentation RCTs have provided evidence that prazosin A12 ABSTRACTS and risperidone can accentuate the effects of other drugs when resistance to treatment is encountered. Evidence to support the use of pharmacotherapy combined with psychological therapy over either treatment method separately is insufficient although promising RCT evidence is emerging for MDMA- assisted psychotherapy. An overview of the current evidence base will be presented along with evidence- based recommendations with respect to the pharmacological treatment of PTSD, including more complex presentations of PTSD and treatment resistant PTSD.

S20 POTENTIAL MECHANISMS FOR MDMA TREATMENT EFFICACY IN PTSD Nutt DJ, Neuropsychopharmacology Unit, Imperial College, Burlington Danes Building, Hammersmith Hospital, Du Cane Road, London, W12 0NN [email protected] MDMA [aka ecstasy] was being used in couples therapy before opposition to recreational use resulted in it being made illegal in the 1980s. since then there has been little research but one promising line of development is in the treatment of resistant PTSD where several trials have now shown efficacy as part of a therapeutic programme [Sessa B and Nutt D (2015) Making a medicine out of MDMA. Brit J Psychiatry 206, 4–6. doi: 10.1192/bjp.bp.114.152751]. The mechanisms of its effects are less well understood but at the psychological level include increased empathy with the therapists and an ability to engage with the trauma memories without becoming overwhelmed by their emotional content [Carhart-Harris RL et al. (2013) The effect of MDMA on recollecting autobiographical memories: an fMRI study with implications for MDMA-assisted psychotherapy. Int J Neuropsychopharmacology: Online: http://www.ncbi.nlm.nih.gov/ pubmed/24345398]. These effects are probably mediated by the release of 5-HT in the brain in humans [as has been well demonstrated in rodents] acting to enhance top-down cortical control of amygdala and hippocampal responsiveness as a recent fMRI study or ours in humans has shown [Carhart-Harris RL et al (2014) The effects of acutely administered MDMA on spontaneous brain function in healthy volunteers measured with arterial spin labelling and BOLD resting-state functional connectivity. Biological Psychiatry http://dx.doi.org/10.1016/j.biopsych.2013.12.015].

S21 EATING DISORDERS AS DEVELOPMENTAL, PSYCHOSOMATIC DISORDERS: BUILDING NEW MODELS WITH EVIDENCE FROM GENETICS AND EPIDEMIOLOGY Treasure J, Eating Disorders Research Unit, King’s College London, 103 Denmark Hill, London, SE5 8AZ [email protected] Recent GWAS studies in eating disorders suggest a shared genetic profile to both psychiatric disorders and metabolic traits. Moreover the epidemiology of eating disorders (high risk in type 1 diabetes, obesity, ADHD, ASD) etc. means that we may need to adjust our conceptual models to encapsulate the degree of overlap between other medical, neurodevelopmental and psychiatric disorders. In the case of disorders with loss of control of eating (bulimia nervosa, BED and diabulimia) it is possible that neuroadaptation produces a form of addiction. The transdiagnostic model within eating disorders needs to be adjusted to include both a wider trans diagnostic profile but also trait differences.

S22 A CLINICAL PERSPECTIVE ON THE ASSOCIATION BETWEEN SCHIZOPHRENIA AND OBESITY: RISK FACTORS AND INTERVENTIONS. Cooper SJ, School of Medicine, Queen’s University Belfast, 36 Bristow Park, Belfast, BT9 6TH sjcooper@ btinternet.com Patients with schizophrenia have reduced life expectancy. This is largely due to physical illness and particularly cardiovascular disease. Obesity is an important factor in this and represents a serious co- morbidity for many patients with psychotic illness. Treatment with antipsychotic medications is an important driver of this, though not the only one. Some evidence suggests there may be an inherent risk associated with schizophrenia itself, though this is not supported by all data. A number of mechanisms have been proposed to explain how antipsychotic drugs influence weight gain but there is no agreement ABSTRACTS A13 regarding any particular mechanism having precedence over others. While meta-analyses of the effects of different antipsychotics on weight gain suggest a hierarchy of magnitude of effects, it is difficult to make real practical use of this knowledge in clinical practice. It is also clear from national audits of clinical practice that adequate standards are not met regarding monitoring for physical health problems and intervention when these are discovered. However, when obesity is recognised do we have effective interventions to counter this? Approaches with a reasonable evidence base were reviewed in the BAP guidelines on the management of weight gain and metabolic disturbances and cardiovascular risk associated with psychosis and antipsychotic drug treatment (Cooper eta l, 2016. Journal of Psychopharmacology 30, 717-748). Key aspects of these guidelines will be discussed. The BAP guidelines referred to were supported by funding from BAP and did not receive any external funding. The National Clinical Audit of Psychosis was supported by funding from the Health Quality Improvement Partnership (funded in turn by NHS England).

S23 WHAT CAN BRAIN RESPONSES TO FOOD TELL US ABOUT DEPRESSION AND EATING DISORDERS? McCabe C, Psychology, Univ of Reading, Reading, Berks, RG6 6AL [email protected] Reward function has been found dysfunctional across many psychiatric disorders such as depression and eating disorders. However how different facets of reward processing in the brain might be related to specific symptoms is as yet not fully elucidated. Furthermore current pharmacological treatments such as antidepressants are used to treat both depression and eating disorders therefore it is important to understand how these medications interact with the human reward system. Using a functional MRI task that examines reward during an anticipatory phase (pleasant or unpleasant cue), an effort phase (button presses to achieve a pleasant taste or to avoid an unpleasant taste) and a consummatory phase (pleasant or unpleasant tastes) our work examines how reward is related to both symptoms of depression and anhedonia in young people and also in those at risk of eating disorders. We also examine how current antidepressant medications affect these reward responses in healthy controls. Using a dimensional approach we show that regions such as the pregenual anterior cingulate cortex and the insula track reduced anticipatory and motivational aspects of reward processing in a large sample of adolescents with a range of depressions scores. Further we report how drugs like bupropion a norepinephrine-dopamine reuptake inhibitor and agomelatine a 5-HT2c antagonist enhance aspects of reward processing in the brain in healthy volunteers. Taken together we discuss how the neural responses to reward might help explain the neurobiological underpinnings of symptoms like anhedonia and how we might use this type of work to differentiate dysfunctional reward responses in depression and eating disorders. This work was supported by the MRC.

S24 NEW DEVELOPMENTS IN OUR UNDERSTANDING OF THE RELATIONSHIP BETWEEN SPECIFIC SYMPTOMS OF ADHD AND BINGE EATING BEHAVIOUR. Higgs S, Psychology, Unversity of Birmingham, Edgbaston, Birmingham, B15 2TT [email protected] Kaisari P(2), Rotshtein P(2), Dourish CT(1) (1) P1vital, Wallingford, Oxfordshire; (2) School of Psychology, University of Birmingham Introduction: A diagnosis of Attention Deficit Hyperactivity Disorder (ADHD) is associated with an increased risk of developing disordered eating, in particular binge eating behaviour. However, whether specific ADHD symptoms are differentially associated with disordered eating behaviour remains unclear and little is known about the mediating mechanisms. Methods: The aim of this presentation is to provide an overview of recent research on the link between ADHD symptoms and binge eating behaviour in adults. The implications for the development of more effective treatments for ADHD and binge eating disorder and our understanding of the co-morbidities between disordered eating and psychiatric conditions will also be assessed. Results: Recent evidence from both online and laboratory based studies suggests a relationship between both inattentive and impulsive symptoms of ADHD and binge/disinhibited eating and identifies negative mood as a mediating mechanism. A novel finding is that reliance on interoceptive A14 ABSTRACTS hunger/satiety signs also mediates the relationship between inattentive symptoms of ADHD and binge eating. Furthermore, evidence from microstructural studies of eating in the absence of hunger conducted in our laboratory suggests that ADHD symptoms are associated with reduced responsiveness to the satiating effects of palatable foods. Conclusions: These data suggest that reduced attention to interoceptive signals may mediate binge eating associated with ADHD and that further investigation of the role of inattentive symptoms in disordered eating may be helpful in developing novel treatments for both ADHD and binge eating disorder. Lisdexamphetamine (Vyvanse®) has been marketed for a number of years for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) and has recently been approved by the FDA to treat binge eating disorder. It is unclear how lisdexamphetamine reduces binge eating but one potential mechanism worthy of investigation relates to its effects on attentional processes. Since many psychiatric conditions including depression, anxiety, ADHD and schizophrenia are associated with disordered eating and obesity it is possible that cognitive symptoms such as attentional problems and cognitive control, which cut across traditional categories of psychiatric disorders, may help to explain such comorbidities. This research was conducted as part of a Ph.D. studentship funded in the UK by the Biotechnology and Biological Sciences Research Council (BBSRC) in collaboration with P1vital.

S25 COPY NUMBER VARIANTS (CNVS) IN SCHIZOPHRENIA AND AUTISM Kirov G, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Hadyn Ellis Building, Cardiff, CF24 4HQ [email protected] Copy number variants (CNVs) are deletions and duplications of large stretches of chromosomes, ranging from 1000 to several million base pairs (Mb). At least 12 CNVs have been shown convincingly to increase risk of developing schizophrenia: deletions at 1q21.1, NRXN1, 3q29, 15q11.2, 15q13.3, 16p12.1 and 22q11.2, and duplications at 1q21.1, 7q11.23, 15q11.2-q13.1, 16p13.1 and proximal 16p11.2. They are large (up to several Mb) and affect multiple genes (apart from NRXN1). They cause substantial increases in risk to develop schizophrenia and autism. They are very rare, found cumulatively in 0.6% of population controls, in 2.6% of patients with schizophrenia and in 3.4% of people with developmental delay and autism spectrum disorders. Their penetrance is higher for the early-onset disorders, than for schizophrenia. The penetrance for any neurodevelopmental disorder is high, ranging from ~10% to nearly 100%. Carriers of these CNVs have increased rates of common medical disorders, such a diabetes and hypertension, and have an increased mortality. Adult carriers display cognitive deficits, even when free of neuropsychiatric disorders.

S26 STRUCTURAL AND FUNCTIONAL IMAGING IN BRAIN NETWORKS: BIOMARKERS FOR AUTISM? Murphy D, Forensic and Neurodevelopmental Sciences, King’s College London, P50 2nd Floor Inst. of Psychiatry Denmark Hill, London, SE5 8AF [email protected] Autism Spectrum Disorders (ASD) affect over 5 million people in the European Union (EU); and up to 70% of individuals have psychiatric and/or medical comorbidities (e.g. epilepsy) that are associated with a significant reduction in lifespan. Currently, however, there are no effective drug treatments for the core symptoms of ASD. Also there is limited understanding of the reason(s) for the high rates of co-morbidity or their most effective treatments. This is most likely due to limitations in the; 1) understanding of the biology of ASD and its comorbidities, 2) testing of drugs with specific actions in biologically heterogeneous populations; 3) availability of expert centres to run large scale clinical trials; 4) trial designs (e.g. placebo effects); and 5) alignment of findings from basic cellular and rodent models to humans. Our vision, therefore, is to improve patient outcomes by creating a pipeline for developing and testing new treatments for ASD. To do this we have established an EU wide network of 48 partners through funding from the EU Innovative Medicines Initiative (IMI). Our aim is to develop precision medicine approaches that are tailored to the biological profiles of patients. Our efforts will build on the achievements of 5 other IMI initiatives, 4 Horizon 2020 networks, EFPIA, Associated Charities (the Simons Foundation Autism Research Initiative (SFARI), Autism Speaks, and Autistica), other international groups (e.g. POND network) and ABSTRACTS A15

5 SMEs to; 1) mobilise stakeholders (including regulators) in Europe and beyond and involve them at each stage; 2) bring together global resources to help validate and qualify stratification biomarkers and objective outcome measures that can be used in trials; 3) develop a European-wide clinical trials network that is trained to good clinical practice (GCP) standards; 4) carry out better targeted clinical trials linked to other international efforts – including quick wins or “fast fails” of ineffective agents; 5) translate molecular mechanisms and drug effects between preclinical models and particular subtypes of ASD from infancy to adulthood; and 6) for the first time provide objective tools to measure outcomes from foetal life to adulthood. Together we hope to bring Europe to the forefront of clinical research in ASD and its comorbidities, provide a sustainable legacy that can be accessed by others across the world, attract industry into ASD, and help transform healthcare. Our first clinical trial will launch in April 2018 – and this links the EU, Canada (POND network), and the USA (SFARI). I will present initial results from our work providing proof of concept that brain functional abnormalities can be ‘normalised’ – and even in adults.

S27 BRAIN IMAGING AND NETWORK CONNECTIVITY IN GENETIC MOUSE MODELS RELEVANT TO SCHIZOPHRENIA AND AUTISM: OVERLAPPING AND DIVERGENT ENDOPHENOTYPES Dawson N, Div. Biomed. & Life Sciences, Lancaster University, Bailrigg, Lancaster, LA1 4YQ n.dawson1@ lancaster.ac.uk Hughes RB(1), Whittingham-Dowd JK(1), Bristow G(1) (1) As presenting author Introduction: Characteristic alterations in brain function and functional brain network connectivity have been identified in schizophrenia and autism. Human brain imaging studies have also identified the impact of risk gene variants for these disorders on brain function and network connectivity. We are only now beginning to reverse translate these observations into rodent genetic risk factor models. Methods: Rodent models offer the opportunity to elucidate the systems-level mechanisms by which these genes increase the risk of developing these disorders; including impacts on brain function, network connectivity and neurotransmitter systems. Given the highly polygenic nature and the functional diversity of the genetic risk factors identified for these disorders, establishing common pathways across a range of genetic rodent models is an essential step in elucidating the key systems-level mechanisms that mediate the increased risk of developing these disorders. Results: I will give a brief overview of the common, and some of the divergent, systems-level alterations that we have identified across a range of rodent models of genetic risk, including data gained in models of DISC1, NRXN1α, CACNA1C and 16p11.2 dysfunction. The data highlight the prefrontal cortex and reticular thalamus as key hubs of regional dysfunction that contribute towards altered functional brain network connectivity in these models. In addition, our data identify glutamate system dysfunction as a key common pathway contributing to brain dysfunction in these models. Conclusions: These data offer new insight into the mechanisms by which multiple genetic risk factors for schizophrenia and autism impact on the brain. These findings offer new hope for the development of targeted interventions to restore brain function and provide tractable endophenotypes against which the efficacy of novel therapeutics can be tested. In addition, these findings inform novel and emerging avenues of research into the primary nature of brain dysfunction in patients and at risk populations. Financial sponsorship: This work was supported by funding from The Royal Society (RG140134) and the Medical Research Council (MR/N012704/1). A16 ABSTRACTS

S28 RODENT MODELS FOR SOCIAL BEHAVIOURS AND SOCIAL COGNITION: TRANSLATIONAL CHALLENGES AND PROSPECTS FOR TREATMENTS Pratt JA, SIPBS, University of Strathclyde, 161 Cathedral St, Glasgow, G4 0RE [email protected] Mitchell EJ(1), Morris BJ(2) (1) As presenting author; (2) Institute of Neuroscience and Psychology, University of Glasgow G128QQ Neurodevelopmental disorders such as schizophrenia and autism share the phenotypic characteristic of a deficit in social cognition that is strongly associated with poor functional outcome and remains inadequately addressed by current pharmacotherapy. The CNTRICS initiative for improving animal models of cognitive impairment in schizophrenia, recognising the complexity and multidimensionality of social cognition in humans, recommended animal paradigms that focused on emotional dimension components (Millan and Bales 2013: Neuroscience and Neurobehavioural Rev 36; 2166-2180). I will give an overview of the paradigms that are currently employed in rodent models for the social cognition component of schizophrenia and autism, highlighting strengths and weaknesses for translation and for drug discovery. These include paradigms of social approach (sociability), preference for social novelty and reciprocal social interactions. Notably, CNTRICS recommended the development of new animal paradigms in this field. Recent technological advances are enabling home cage monitoring of multiple animals in the same cage. This provides an alternative approach for examining social behaviours and enables the better assessment of how social interactions change during neurodevelopment. Social interactions and play behaviour in juveniles/early adolescence are considered to play an important role in social and cognitive development. Hence rodent models that interrogate these behaviours allow insight into how risk factors for these disorders impact on the social cognition domain. I will discuss findings from our recent ‘home cage monitoring’ work on genetic risk factors for schizophrenia and autism (16p11.2 Dup and 16p11.2 Del mice) and on NMDA receptor antagonists and the challenges and opportunities for evaluating pharmacotherapies. Funded by MRC grant MR/N012704/1

S29 NEUROIMAGING OF THE OPIATE SYSTEM IN ALCOHOLISM AND IMPLICATIONS FOR TREATMENT Lingford-Hughes AR, Neuropsychopharmacology Unit, Imperial College London, Centre for Psychiatry Division of Brain Sciences, Dept of Medicine, Imperial College London, Burlington Danes Building, Hammersmith campus, 160 Du Cane Road, London, W12 0NN. [email protected] The opiate system plays an important role in a range of processes implicated in addiction. Opiate antagonist medications have shown clinical efficacy in treating addiction, largely predicated on modulating the reward system. However they do not help everyone. The presentation will present our programme of work using PET and fMRI to characterize the opiate system in alcoholism to improve treatment. Using 11C-carfentanil PET with an oral dexamphetamine (0.5 mg/kg) challenge to assess endogenous opioid release and mu opioid receptor (MOR) availability, we have shown blunted dexamphetamine-induced opioid release in abstinent alcohol dependent individuals though no differences in MOR availability (Turton, Molecular Psychiatry, in press). Blunted opioid release is consistent with an ‘opioid deficient’ state associated with reward deficiency theories of addiction.e W and others had previously reported higher MOR availability in recently abstinent alcohol or drug dependent individuals that was associated with craving. Our finding in this study likely reflects that the participants were stably abstinent for months with low craving. We established an fMRI platform (ICCAM) to characterize brain responses during tasks involving reward, impulsivity, emotional processing in abstinent addicts (Paterson et al J Psychopharmacology, 2015 29:943). The monetary incentive delay task was used to assess reward processes and blunted response to anticipation of reward was seen in abstinent alcohol dependent and polydrug (> alcohol, opiate, cocaine) dependent individuals compared with controls. However a single dose (50mg) of the opiate antagonist, naltrexone, failed to modulate this dysregulation (Nestor et al Addiction Biology, 2017 22:1576). By contrast, a single dose of another opiate antagonist used in the treatment of alcoholism, nalmefene, did blunt brain responses during anticipation of reward (Quelch et al Biological Psychiatry, 2017 81:941). In this study, however, since nalmefene is licensed for use to help stop drinking, ABSTRACTS A17 the alcohol dependent individuals were not abstinent and received an alcohol infusion during the task. These studies and those showing naltrexone modulates brain responses to alcohol cues suggest that a salient stimulus e.g alcohol is required for opiate antagonists to modulate reward processes. Our studies provide evidence for a dysregulated opioid system in alcohol dependence and particularly in reward processes involving a salient stimulus. However our demonstration of a blunted opioid system with control levels of MOR availability and lack of modulation of reward processes in longer-term abstinent addicts, suggests that other mechanisms such as modulation of impulsivity may contribute to the efficacy of opiate antagonists in treating addiction. Funding: MRC: G1002226 & G1000018

S30 NEUROIMAGING OF THE OPIATE SYSTEM IN GAMBLING DISORDER Clark L, Dept Psychology, Univ British Columbia, 2136 West Mall, Vancouver, B.C., Canada, V6T 1Z4 luke. [email protected] One of the key pillars that supported the DSM-5 reclassification of gambling disorder alongside the substance use disorders (set to be ratified in the ICD-11) was the overlap in effective treatments: several trials reported that the opioid receptor antagonists naltrexone and nalmefene were effective in reducing gambling symptomatology. The mechanisms underlying these benefits, in relation to the pathophysiology of gambling disorder, remain unclear. This talk will present functional MRI data in participants with gambling disorder following subchronic naltrexone treatment, and contextualize these data in relation to PET imaging data using the [11C]carfentanil tracer (Mick et al 2016 Neuropsychopharmacology 41: 1742-1750). Methods: Twelve males with gambling disorder, attending the National Problem Gambling Clinic in London, U.K., received 4 day naltrexone treatment (50mg) that culminated in an fMRI scan, in a placebo-controlled, double-blind, cross-over design. Brain responses to gambling cue reactivity and a slot machine task were assessed. In the PET study, 14 males with gambling disorder and 15 healthy participants underwent two [11C]carfentanil PET scans, before and after oral administration of 0.5 mg/kg of d-amphetamine. We assessed baseline [11C]carfentanil binding as an index of mu-opioid receptor levels, and the change in binding potential post-amphetamine as an index of opioid release. Results: In the fMRI study, we observed robust neural signals to gambling cues (minus neutral cues) and unexpected monetary wins (minus non-wins) across the naltrexone and placebo conditions, in line with our prior studies. While naltrexone was generally associated with reduced neural signals, few statistically significant differences were observed in the primary contrasts, and naltrexone did not affect in-scan craving ratings. In the PET study, the groups did not differ in baseline [11C]carfentanil binding, but opioid release (change in binding potential) was significantly blunted in the gambling disorder group across several regions of interest including frontal cortex, insula and putamen. Discussion: Subchronic naltrexone treatment was not associated with significant attenuation of gambling cue reactivity or the neural response to monetary wins. PET findings of blunted opioid release in gambling disorder are difficult to reconcile with naltrexone’s clinical efficacy, as a medication that would be expected to reduce opioid signalling. Analagous PET studies of dopamine transmission suggest altered dopamine-opioid interactions in gambling disorder. Comparisons with PET data in substance use disorders increasingly highlight divergent profiles across substance- and behavioural- addictions, with implications for understanding addiction vulnerability. Funding: Medical Research Council- MRC G1100554 (Clark) and G1002226 (Nutt).

S31 NEUROBIOLOGY OF OPIATE VS STIMULANT ADDICTION – DIFFERENCES MATTER Badiani A, School of Psychology, University of Sussex, Pevensey I, Room 2B19, University of Sussex, Brighton, BN1 9RH [email protected] DePirro S(1) (1) School of Psychology, University of Sussex, Brighton BN1 9RH; Self-administration experiments in rats have shown that the rewarding effects of heroin and cocaine are modulated in opposite directions by the setting. Rats that self-administer drugs at home tend to prefer heroin to cocaine; vice versa rats that self-administer drugs outside the home tend to prefer cocaine to A18 ABSTRACTS heroin (Caprioli et al. 2007, 2008, 2009). Translational studies in individuals with heroin and cocaine addiction have shown that the same phenomenon occurs in humans. Indeed, we found that individuals with heroin and cocaine addiction prefer to use these drugs in distinct settings: mostly at home in the case of heroin and mostly outside the home in the case of cocaine (Caprioli et al. 2009; Badiani and Spagnolo 2013). We investigated whether the context would modulate the affective and neural responses to to heroin and cocaine in a similar way. We used a novel emotional task to assess the affective state produced by heroin or cocaine in different settings, based on the recollections of drug users. Then we used fMRI in combination with emotional drug imagery (re-creating the setting of drug use) to investigate the. Consistent with our working hypothesis, the majority of participants reported a shift in the affective valence of heroin from mostly pleasant at home to mostly unpleasant outside the home. The opposite shift was observed for cocaine; that is, most participants who found cocaine pleasant outside the home found it unpleasant when taken at home. Furthermore, we found a double dissociation, as a function of drug and setting imagery, in BOLD signal changes in the left pre-frontal cortex and left caudate, as well as bilaterally in the cerebellum, suggesting that the fronto-striatal-cerebellar network is implicated in the contextualization of drug-induced affect. These findings are consistent with a theoretical model of drug- setting interaction (Badiani 2013) and indicate that, contrary to prevailing notions, the effects of opiates and psychostimulants depend on dissociable psychological and neural substrates. Most important our findings suggest that therapeutic approaches to addiction should take into account the peculiarities of different drug classes and the settings of drug use.

S32 DOPAMINE AND OPIOID SYSTEMS ADAPTATION IN ALCOHOLISM REVISITED: CONVERGENT EVIDENCE FROM POSITRON EMISSION TOMOGRAPHY AND POSTMORTEM STUDIES Sommer WH, Institute of Psychopharmacology, Central Institute for Mental Health, University of Heidelberg, Square J5, 68159 Mannheim, Germany [email protected] A major hypothesis in the addiction field suggests deficits in dopamine signaling during abstinence as a driving mechanism for the relapsing course of the disorder. At the same time, blockade of mu-opioid receptors (MORs) intended to suppress dopamine release and alcohol reward is a widely used treatment for preventing relapse in alcohol use disorder (AUD). To elucidate this apparent discrepancy, a systematic survey was performed of the literature on experimental studies in AUD subjects and animal models that assessed striatal dopamine levels and D1, D2-like receptor, dopamine transporter and MOR via positron emission tomography (PET) and ex vivo receptor binding assays. The reported evidence indicates a changing dopaminergic signaling over time which is associated with concomitant alterations in MOR, thus suggesting a highly dynamic regulation of the reward system during abstinence. Such a view can reconcile the various evidences from in vivo and postmortem studies, but makes developing a pharmacological intervention that targets either dopamine receptors or the transporter system with a good clinical outcome a daunting task.

S33 TRANSLATIONAL NEUROPHYSIOLOGICAL BIOMARKERS IN MOUSE MODELS OF PSYCHIATRIC DISEASE Bastlund JF, Director of Translational Biology, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark JFB@ lundbeck.com Drug discovery in psychiatry has been challenged by lack of solid neurobiological understand. The usefulness of electrophysiology in translational biological psychiatry has provided new tools for investigating biological mechanisms and treatment hypothesis across species. Studies with electroencephalography (EEG) and event-related potentials and oscillations have identified several characteristic phenotypes associated with psychiatric diseases like schizophrenia. More specifically, reduced amplitudes in event-related potentials (ERPs) like P300, reduced mismatch negativity (MMN) and reduced auditory steady-state responses (ASSR) at 40 Hz has been repeatedly reported in patients with schizophrenia. The talk will focus on current knowledge and efforts to back translate electrophysiological ABSTRACTS A19 phenotypes such as ERPs and ASSR into rodent assays. Rodent validation of such back translational electrophysiology phenotypes require careful attention to difference in behavioural states between species. Characterisation of pharmacological sensitivity and genetic models such as 22q11 microdeletion mice reveal that EEG and ERP processing deficits in the auditory domain can be captured in rodents. The results demonstrate that these electrophysiological based markers hold promise for future translational biological psychiatry research.

S34 ABNORMALITIES IN HIPPOCAMPAL OSCILLATIONS IN RODENT MODELS OF COGNITIVE DISORDERS Colgin LL, Neuroscience, University of Texas at Austin, The Center for Learning & Memory The University of Texas at Austin 1 University Station Stop C7000 Austin, TX USA, 78712-0805 [email protected] Mably AJ(1) (1) As presenting author Aberrant gamma oscillations (~25-100 Hz) have been observed in several cognitive disorders, including Alzheimer’s disease and Fragile X syndrome. In this talk, I will present recent results showing abnormal gamma rhythms in rodent models of Alzheimer’s disease and Fragile X syndrome and discuss how such results may help reveal links between cellular disturbances and memory impairments. I will also discuss how gamma results from rodent models of Alzheimer’s disease and Fragile X syndrome may provide insights about unique functions of distinct slow (~25-50 Hz) and fast gamma (~55-100 Hz) subtypes.

S35 EXPERIMENTAL MODELS OF CORTICAL RHYTHMS IN LIVE HUMAN BRAIN TISSUE: TRANSLATIONAL BIOMARKERS FOR CNS DRUG DEVELOPMENT Cunningham MO, Institute of Neuroscience, University of Newcastle upon Tyne, The Medical School, Framlington Place, Newcastle upon Tyne, NE2 4HH [email protected] Disorders of the human brain place a significant burden on society and economies on a global scale. In particular, psychiatric conditions such as schizophrenia pose a worldwide healthcare need. There is a major unmet need for effective treatments despite increased knowledge about the potential mechanisms that underlie the condition. Moreover, recent high profile failures of new drugs in clinical trials for the treatment of schizophrenia has discouraged the pharmaceutical industry sector and resulted in withdrawal of investment and research in this complex and challenging arena. The failure of translation of biological effects from preclinical animal models to humans remains a major barrier to the development of new and effective medicines for CNS disorders, particularly in psychiatry. One reason for this failure may be that human cortical microcircuits are likely to be more complex and exhibit different physiology and pharmacology to rodent neuronal circuits. As such, performing research in rodent systems has significant limitations and to reduce the risk of failure in the clinic it would be highly preferable to perform basic research in adult human brain tissue to eliminate species difference confounds and validate the efficacy of medicines in assays that are directly derived from the target organ that they are intended to treat. In this context, I will present data that demonstrates our use of live human neocortical tissue to examine a dynamic signature of human cortical function – the gamma rhythm. In vitro human brain slice preparations can be used to reproduce this translational spatiotemporal pattern and allow sufficient access and manipulation to probe its network, cellular and synaptic origins. Using this platform, we have assessed the the impact of a novel pharmacological treatment for schizophrenia. A20 ABSTRACTS

S36 HIGH-FREQUENCY OSCILLATIONS IN MEG-DATA ACROSS ILLNESS-STAGES IN SCHIZOPHRENIA Uhlhaas P, Institute of Neuroscience and Psychology, Univ. of Glasgow, 58 Hillhead Street, Glasgow, G12 8QB [email protected] A considerable body of work over the last 10 years combining non-invasive electrophysiology (electroencephalography/magnetoencephalography) in patient populations with preclinical research has contributed to the conceptualization of schizophrenia as a disorder associated with aberrant neural dynamics and disturbances in excitation/inhibition (E/I) balance parameters. Specifically, I will propose that recent technological and analytic advances in MEG provide novel opportunities to address these fundamental questions as well as establish important links with translational research. We have carried out several studies which have tested the importance of neural oscillations in the pathophysiology of schizophrenia through a combination of MEG-measurements in ScZ-patients and pharmacological manipulations in healthy volunteers which target the NMDA-receptor. These results highlight a pronounced impairment in high-frequency activity in both chronic and unmedicated patients which could provide novel insights into basic circuit mechanisms underlying cognitive and perceptual dysfunctions. Our recent work has employed MEG to understand the developmental trajectory of neural oscillations during adolescence and the possibility to develop a biomarker for early detection and diagnosis of ScZ. We found marked changes in the amplitude of high-frequency oscillations and synchrony that were particularly pronounced during the transition from adolescence to adulthood. Moreover, data from participants meeting ultra-high risk criteria for psychosis suggest that signatures of aberrant neuronal dynamics are already present prior to the onset of psychosis, highlighting the importance of advancing biomarkers for early intervention and diagnosis.

S37 TOWARDS A NEUROCOMPUTATIONAL ACCOUNT OF ANXIETY ACROSS ADAPTIVE AND PATHOLOGICAL STATES Robinson OJ, ICN, UCL, Alexandra House, Queen Square, WC1N 3AZ [email protected] Introduction: Serious and debilitating symptoms of anxiety are the most common mental health problem worldwide but our understanding of their underlying neurobiology is still limited. This impedes our ability to develop new treatments as well as target current treatments to responders. Methods: In this talk I will present two lines of research that attempt to build a more neurobiologically grounded understanding of anxiety symptoms. Results: Firstly, I will present neuroimaging data implicating coupling between the amygdala and the medial wall of the cingulate and prefrontal cortex in maintaining adaptive and pathological anxiety and treatment response. Secondly I will present work using computational models of behaviour that attempt to bridge the gap between observable brain activity and behaviour. Specifically, I will provide evidence that biophysically plausible models can generate behaviour that mimics pathological symptoms of anxiety. Conclusions: Together, this work may eventually enable a full mechanistic understanding of key symptoms of anxiety disorders and hence ultimately enable us to target treatments at specific underlying mechanisms rather than non-specific symptoms. Sponsorship: MRC CDA (MR/ K024280/1)

S38 No abstract available for this presentation. ABSTRACTS A21

S39 THE CONTRIBUTION OF DISTINCT PREFRONTAL AND ANTERIOR CINGULATE CORTICAL REGIONS TO THE MODULATION OF ANXIETY IN PRIMATES Roberts AC, Physiology, Development and Neuroscience, University of Cambridge, Downing street, Cambridge, CB2 3DY [email protected] Anxiety is an adaptive state, but if engaged chronically can become pathological and maladaptive. Pathological anxiety is associated with dysregulation in prefrontal (PFC) and anterior cingulate (dACC/ sgACC) cortices. Functional neuroimaging studies have identified hyper- and hypo-activity in a range of prefrontal and cingulate sub-regions not only in patients with anxiety disorders but also individuals with a high anxious disposition. Our work is addressing the causal involvement of these higher-order cortical regions in regulating negative emotion in a primate, the common marmoset, determining their interaction not only with each other but also with downstream subcortical and brainstem structures. We employ a combination of techniques that allow us to manipulate specific brain regions temporarily (intracerebral cannulation and more recently DREADDS), and identify their causal effects both on the regulation of cardiovascular and behavioural correlates of negative emotion (tests of conditioned discriminative fear, fear extinction and uncertainty) and activity across neural circuits (fluorodeoxyglucose PET imaging). In this presentation I will describe how temporary and/or permanent inactivation of primate ventrolateral prefrontal or anterior orbitofrontal cortex leads to increased amygdala activity and an associated high anxious phenotype, including rigid, inflexible conditioned fear learning. Their distinct cognitive contributions to emotion regulation will then be discussed along with the implication these findings have for treatment strategies. Comparisons will be made with recent unpublished findings that highlight the apparently opposing role of sgACC, overactivation of which heightens anxiety, retards fear extinction and slows cardiovascular recovery from negative arousal. This study was supported by an MRC Programme Grant (MR/M023990/1) and Wellcome Trust Investigator award (108089/Z/15/Z) to ACR and performed within The Behavioural and Clinical Neuroscience Institute, jointly funded by the MRC and Wellcome Trust.

S40 FROM NEUROSCIENCE TO ULTRA-BRIEF TREATMENTS FOR ANXIETY DISORDERS? Reinecke A, Department of Psychiatry, University of Oxford, Warneford Hospital, Warneford Lane, Oxford, OX3 7JX [email protected] One in five people suffer from a disabling anxiety disorder at some point in their life, being overly insecure in social situations, worrying excessively, or having unexpected panic attacks. Cognitive-behaviour therapy (CBT) can improve life-quality drastically by training new behaviour and thinking, but courses are long and expensive, often unavailable, and ineffective for some patients. Identifying the exact mechanisms of action of CBT is crucial to improve psychological treatments for anxiety disorders. Using neuroscience and pharmacological challenge approaches, our research aims to detect brain mechanisms that drive clinical recovery during CBT, and to establish potential pharmacological add-on treatments that may boost these effects logically and synergistically. Our work has shown that a carefully-designed single session of CBT already lifts anxiety dramatically, with one in three patients even being symptom free. Interestingly, this decrease in anxiety occurred with a 1-month delay, and it was stronger in patients showing a stronger reduction in amygdala activity and threat processing on the day after treatment. These findings suggest that treatment doses required for recovery from anxiety may be much lower than previously thought, and that the effects of this minimal CBT intervention might be further optimized by targeting and augmenting amygdala changes occurring very early during treatment. This talk will discuss studies looking at the effects of different pharmacological compounds on threat processing in the amygdala in healthy volunteers, to identify synergistic overlaps with CBT action. It will also highlight a clinical study where the combination of single-session CBT with a cognitive enhancer lead to recovery in ¾ of patients, comparable to rates seen after standard longer-term courses. Our findings show that by using a pharmacological- psychological combination approach, ultra-brief CBT may be developed into a highly effective stand-alone treatment, with response rates equivalent to currently available interventions. Such economic treatment A22 ABSTRACTS formats may lead to a rapid paradigm shift in mental health care by allowing easy-to-deliver standardised treatment of a higher number of patients with anxiety in a timely manner. Funders: MQ: Transforming Mental Health, Medical Research Council, University of Oxford John Fell Fund

A01 DEVELOPMENTAL TRAJECTORIES OF GOAL-DIRECTED AND HABITUAL LEARNING AND THEIR RELEVANCE FOR COMPULSIVITY Vaghi MM, Institute of Neurology – Department of Imaging Neuroscience, University College London, Wellcome Trust Centre for Neuroimaging 12 Queen Square London, United Kingdom, WC1N 3AR m.vaghi@ ucl.ac.uk Hauser TU(3), Kievit RA(3), Moutoussis M(1), Shahar N(1), NSPN Consortium, Jones PB(2), Goodyer IM(2), Bullmore ET(2), Dolan RJ(4) (1) As presenting author; (2) Department of Psychiatry, University of Cambridge; (3) Max Planck Centre for Computational Psychiatry and Ageing Research, UCL; (4) Max Planck Centre for Computational Psychiatry and Ageing Research and Institute of Neurology, UCL Introduction. Disorders of compulsivity are associated with diminished goal-directed behaviour (Voon et al., 2015). While most studies focus on adult patients, when symptoms tend to be already chronic and severe, compulsive disorders emerge early, with peaks of onset during adolescence and early adulthood (Paus et al., 2008). Here, we investigated normative longitudinal development of goal-directed behaviour in a large sample of adolescents. We also tested the hypothesis of mutual interactions between goal- directed behaviour and compulsivity traits during development. Methods. The NSPN Consortium recruited 2135 healthy young people (age range 14-25 years). Of this sample, 571 subjects were tested twice longitudinally on the two-step task (Daw et al., 2011). Compulsivity traits were measured on both occasions with questionnaires. For the two-step task, we analysed choices with a generalized linear mixed effects regression model. For each time-point, choices were modelled by the independent predictor of previous reward and previous transition type together with two-way interaction as fixed effects as well as random intercept and random slope. The two-way interaction between previous reward and previous transition type indexes goal-directed behaviour by detecting if choices take into account not only obtained reward but also an internal model of the task’s transition structure that evaluates action prospectively. To identify changes in goal-directed behaviour over measurements, the per-subject values of the two-way interaction were entered in a univariate latent change score model (LCSM) (Kievit et al., 2017). A separate univariate LCSM was implemented for the compulsivity values. A bivariate LCSM allowing for the investigation of cross-domain coupling was used to assess interactions between goal-directed behaviour and compulsivity traits during development. Results. Goal-directed behaviour increased (mean of the latent change factor, Z=14.164, p<0.001) and compulsivity scores decreased (mean of the latent change factor, Z=4.601, P<0.001) during development. In the bivariate LCSM, higher compulsivity was associated with reduced goal-directed behaviour at baseline (Z=-3.457, p=0.001). Goal-directed behaviour at baseline did not predict degree of change in compulsivity symptoms over development (Z=-0.295, p=0.768). In contrast, compulsivity traits at baseline predicted rate degree of change in goal-directed behaviour over development (Z=-3.068, p=0.002) such that high compulsivity was associated with diminished increase of goal-directed behaviour over time. This effect was not found for impulsivity suggesting specificity of the results. Conclusions. eW showed that typical development is characterized by improvement in goal-directed learning signature during development. In addition, compulsivity traits decelerate transition to goal-directed behaviour and impede typical development by either delaying or halting its trajectory. This study was supported by the Neuroscience in Psychiatry Network, a strategic award by the Wellcome Trust to the University of Cambridge and University College London (095844/Z/11/Z). RJD holds a Wellcome Trust Senior Investigator Award (098362/Z/12/Z). ABSTRACTS A23

A02 CHARACTERIZATION OF 8-OH-DPAT-DISRUPTED SPONTANEOUS ALTERNATION BEHAVIOUR AS AN INDUCED MODEL OF COMPULSIVE-LIKE RESPONSES Fitzpatrick CM, Drug Design and Pharmacology, University of Copenhagen, Universitetparken 2, Jagtvej 160, Copenhagen Ø, 2100 [email protected] Ulitiko A(1), Jessen L(1), Andreasen JT(1) (1) As presenting author Introduction: 5-hydroxytrypamine (5-HT) has long been of interest in the treatment of compulsive disorders (Bandelow et al., 2017, World J Biol Psychiatry, 18, 162-214). Pharmacological treatments elevating 5-HT levels are first-line treatments for obsessive-compulsive disorder (Kellner, 2010, Dialogues Clin Neurosci, 12, 187-97). Rodents exhibit natural exploratory behaviours when faced with novel environments. The spontaneous alternation behaviour (SAB) test can measure such behaviours, and perseverance in this test induced by the 5-HT1A receptor agonist, 8-OH-DPAT, resembles compulsive behaviours observed in humans (Yadin et al., 1991, Pharmacol Biochem Behav, 40, 311-5). This study characterized whether the mechanism of action of 8-OH-DPAT in reducing SAB in mice is mediated by the 5-HT1A receptor. It was also investigated whether the 5-HT reuptake inhibitor, citalopram, and releasing agent, 3,4-methylenedioxymethamphetamine (MDMA), attenuated the effects of 8-OH-DPAT in order to deepen understanding of 5-HT-related mechanisms. Methods: Perseverance was induced by administration of 8-OH-DPAT using a three armed Y-maze (L x W: 40 x 7 cm) in a red-lit room. Animals were considered to have performed a correct alternation when they visited three consecutive different arms. Alternation rate was calculated based on the number of correct alternations out of the maximum possible amount of correct alternations during a 10 min testing period and served as a measure of SAB. 8-OH-DPAT and WAY100635 were administered 15 min before start of the tests, while citalopram and MDMA were administrated 30 min pre-testing. All drugs were given i.p. with at least 7 days washout between each test. Animals that performed less than 12 arm visits in the SAB test (including the arm they were placed in) were excluded from the dataset because it was not possible to calculate a reliable alternation rate. Alternation rate and total number of arm visits in the SAB test were analysed by single measures analysis of variance (ANOVA) with drug treatments as independent factors. Results: Reduction in SAB in was induced by administration of 1 mg/kg 8-OH-DPAT (F3,25 = 48.01; p<0.001 ), and its 5-HT1A receptor mechanism was confirmed by co-administration of the 5-HT1A receptor antagonist 2 mg/kg WAY100635 (drug-by-drug internation main effect: F1,43 = 2.96; p = 0.09; p<0.05). Citalopram or MDMA failed to attenuate the robust 5-HT1AR-mediated effects of 8-OH-DPAT on SAB. Conclusions: These findings confirm the importance of 5-HT in regulating perseverative behaviour. Future investigations are required to determine the validity of the 8-OH-DPAT-disrupted SAB as a simple model of compulsive-like behaviours. Financial support: Lundbeckfonden, University of Copenhagen.

A03 ACTIVATION OF ANGIOTENSIN TYPE 2 RECEPTOR (AT2R) CONTRIBUTES TO FEAR MEMORY Marvar PJ, Pharmacology and Physiology, George Washington University, 2300 Eye St., NW, Ross Hall 457 Washington DC USA, 20037 [email protected] Yu Z(2), Swiercz AP(2), Hopkins L(2), Krause EG(3), Park J(1) (1) 1639 Pierce Drive Atlanta Georgia USA; (2) As presenting author; (3) Department of Pharmacodynamics College of Pharmacy University of Florida Gainesville, FL 32610 Introduction: Previous clinical studies have identified the renin-angiotensin system (RAS) as a potential therapeutic target in post-traumatic stress disorder (PTSD), however the mechanism(s) are unknown. We propose that brain angiotensin receptors contribute to modulating inhibitory and excitatory fear circuits important for the consolidation and extinction of fear memory in PTSD. Methods: Using brain angiotensin type 2-receptor (AT2R) eGFP-BAC reporter male mice (10-12 week old) combined with pharmacological and behavioral approaches the aim of the study was to examine the role of the brain AT2R in fear memory. Statistical Analysis: Data were analyzed with GraphPad Prism 5.0 using a t-test, one- or two- way ANOVA, or a repeated-measures ANOVA. Post hoc ANOVA comparisons were made using Bonferroni A24 ABSTRACTS test. Data in are presented as mean ± standard error from the mean and p values <.05 were considered statistically significant. Results: AT2R-eGFP+ immunoreactive cell types in the mouse brain were co- localized with the neuronal specific marker NeuN, while there were no detectable levels of co-localization in astrocytes (GFAP marker) or microglia (Iba-1 marker). The level of AT2R-eGFP+ expressing neurons in the major subnuclei of the amygdala, an important structure in the consolidation and extinction of fear memory, were then quantified. Within the amygdala subnuclei, AT2R-eGFP+ neurons were found to be predominately expressed in medial amygdala (203.8 ± 39.4 cells/mm2) and the medial division of central amygdala (CeM) (221.2 ± 15.3 cells/mm2), while the basolateral amygdala (11.7 ± 1.8 cells/mm2) contained very few AT2R-eGFP+ neurons. Moreover, within the CeM, 96% of the AT2R-eGFP+ neurons expressed the GABAergic marker GAD1, while approximately 40% GABAergic cells expressed interneuron markers (parvalbumin, calrentinin and somatostatin). To examine the behavioral role of AT2R in fear memory, we used classic Pavlovian fear conditioning, pairing auditory tones with footshocks. Following the acquisition of fear, AT2R mRNA expression was significantly elevated (t(22) = 2.5; p<0.05) within the CeA. In separate studies, a bilateral intra-CeA injection of C21 (0.06ug/ul) was administered prior to fear acquisition testing and freezing behavior quantified. Compared to vehicle control, mice receiving C21 into the CeA displayed a significant reduction in fear expression and enhanced extinction as measured yb percent time spent freezing (61.7% ± 5.4 vehicle v.s. 42.1% ± 5.7 C21 group, p<0.05, n=10-12) to the conditioned stimulus (auditory tones). Conclusions: These data provide anatomical, functional and behavioral evidence for brain AT2R in the consolidation and extinction of conditioned fear. Further studies are required to determine the neurobiological mechanism(s), which may involve changes in cerebral vascular blood flow and/or modulation of neuronal excitability and plasticity. Funding: American Heart Association - 15CSA24340001

A04 EFFECTS OF MANIPULATING GONADAL HORMONES DURING ADOLESCENCE ON ANXIETY-LIKE, NOVELTY-SEEKING AND SOCIAL BEHAVIOUR IN LABORATORY RATS Hodgson AR, School of Psychology & Neuroscience, University of St Andrews, St Mary’s Quad, South Street, St Andrews, KY16 9JP [email protected] Brown GR(1), Kulbarsh K(1) (1) As presenting author Introduction: In human beings, adolescence is characterised by physical changes, such as sexual maturation, and by behavioural changes, such as an increase in social behaviour. A number of mental health disorders also become more prevalent during this stage of life, including anxiety and mood disorders. Our research has investigated the link between adolescent exposure to gonadal hormones and the development of anxiety-like and social behaviour in female laboratory rats (Rattus norvegicus), using surgical and pharmacological techniques. Methods: Study 1: female Lister-hooded rats were ovariectomised either before puberty (postnatal, pnd, 32/33; N=10) or in late adolescence (pnd 58/59), then tested in three novel environments, elevated-plus maze (EMP), light-dark box (LDB) and open field (OF), during adulthood (pnd 101-108). Study 2: female rats were either treated with a gonadotropin-releasing hormone (GnRH) antagonist (Antide), which suppresses gonadal hormone production, during adolescence (pnd 28-60; N=14), or with a vehicle solution (N=14); the social behaviour of these females and a group of vehicle-treated males (N=14),was tested during adolescence (pnd 40-44). All subjects were weighed weekly. Results: In Study 1, females that were ovariectomised after puberty, and were thus exposed to normal ovarian hormone levels during the adolescence, spent less time on the open arms of the EPM in adulthood (F(1,18)=7.70, p<0.05), and entered the open arms less frequently (F(1,18)=4.52, p<0.05), than females that were ovariectomised before puberty. No differences were found in the LDB or OF. In Study 2, Antide-treated females gained significantly more weight than control females across the adolescent period (F(4,104)=3.09, p=.02). Preliminary analysis indicates that Antide-treated adolescent females do not spend a significantly different amount of time in the same area as a novel partner compared to control females (t(54)= .06, p=.95), though it is expected that groups will differ on measures of play behaviour. Conclusion: As the open arms of the EPM are considered as more aversive than the closed arms, the results of Study 1 suggest that exposure to ovarian hormones during adolescence increases levels of anxiety-like behaviour in later life, although no effects were found in other novel environments. Our research is consistent ABSTRACTS A25 with the hypothesis that adolescence is a sensitive period of development, when gonadal hormones may have long-term, ‘organisational’ effects on behaviour. This research was funded by the British Society for Neuroendocrinology and Wellcome Trust ISSF.

A05 BACLOFEN AND ANXIETY SYMPTOMS IN PATIENTS WITH ALCOHOL USE DISORDERS: STRUCTURED REVIEW Amaro H, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of Southampton, 4-12 Terminus Terrace, Southampton, SO14 3DT [email protected] Sinclair JS(1), Baldwin DS(1) (1) As presenting author Background: Baclofen is a GABAB receptor agonist (with some α2δ subunit-containing voltage-gated calcium channel blocking effects) which may reduce withdrawal symptoms and facilitate abstinence from alcohol in patients with alcohol use disorders. As the possible impact of baclofen on anxiety symptoms during alcohol withdrawal and abstinence is not fully understood, we reviewed current evidence. Method: Systematic search of available literature, accessing Cochrane Central Register of Controlled Trials, PUBMED, MEDLINE and PSYCINFO, using the terms ‘anxiety’ AND ‘alcohol dependence’ AND ‘baclofen’. All publications with an English language abstract were included in the initial search. Results: The initial search generated 100 publications: after screening, 44 were selected for appraisal (32 were found not to meet inclusion criteria and 24 represented duplications). In experimental (pre-clinical) investigations, all studies found that baclofen attenuated anxiety-like features (and decreased alcohol intake). Sixteen randomised controlled trials generated inconsistent findings (in 10, baclofen reduced anxiety symptoms and facilitated abstinence, there being no significant differences from placebo in the remaining 6 studies). One open-label randomized placebo-controlled trial found that anxiety (and craving for alcohol) decreased significantly more in the baclofen-treated group, compared with placebo. In one double-blind, double- dummy study baclofen had no significant effects in reducing anxiety. Baclofen treatment reduced anxiety overall in only one of three case series. Retrospective, open-label, observational and cohort studies all found beneficial effects on anxiety during periods of baclofen administration. In six of seven literature reviews, baclofen was found to be beneficial in reducing anxiety (three reviews also found that baclofen reduced the intensity of other alcohol withdrawal symptoms). In one meta-analysis, baclofen treatment was associated with higher rates of abstinence from alcohol with intention to treat analysis but had no effect on increasing the number of abstinent days, or measures of craving, anxiety or depression. In one single-bind study, baclofen showed no differences for reducing alcohol withdrawn compared to placebo. Discussion: Findings for the effect of baclofen on anxiety symptoms are variable, and the study design has often been sub-optimal, doses variable, and reported findings inconsistent. The relative contributions of its GABAB receptor agonist and α2δ subunit-containing voltage-gated calcium channel blocking activity at different doses to reducing anxiety have not been explored. Funding: HJA is an NIHR Academic Clinical Fellow. No funding was sought for this study.

A06 BNC210 EFFECTS ON CBF IN ANXIETY-RELATED CORTICAL REGIONS Macare CJ, Psych Med., CfAD, KCL-IoPPN, De Crespigny Park, London, Se5 8AF [email protected] O’Connor S(1), Williams SCR(2), O’Daly O(2), Perkins AM(2), Young AH(2) (1) Bionomics Ltd, 31 Dalgleish Street, Thebarton SA 5031 Australia; (2) KCL-IoPPN, De Crespigny Park, SE5 8AF London Introduction: Increasing evidence suggests an implication of cholinergic systems in behaviours related to anxiety. Animal work has shown effects of alpha-7 nicotinic acetylcholine receptor (nAChR) antagonist infusion at decreasing anxiety-like behaviour (Mineur, et al., 2016, Neuropsychopharmacology 41, 1579–1587). Little research focusses on the modulation of anxiety via the a7nAchR in clinical anxiety however. Methods: Here, we assessed the effects of a novel nAChR-acting compound, BNC210, on brain A26 ABSTRACTS metabolism as assessed by arterial spin labelling (ASL) in 24 patients with untreated Generalised Anxiety Disorder (GAD) in a randomized, double-blinded, placebo-controlled, multi-dose study. Results: Results of resting-state ASL imaging indicated that global cerebral blood flow (CBF) was significantly elevated by BNC210 (F(3,69)=2.93, p=0.040), post-hoc tests revealed that the this increase was driven by the high BNC210 dose. Whole brain analyses further showed significant differences in regional CBF in middle and superior temporal regions (Brodmann area, BA, 39: peak at MNI -40/-50/14, p(FWE-corrected)<0.001, cluster size=1758 voxels) in response to BNC210 compared to placebo. Increased regional CBF was also observed in the precentral gyrus (BA44: peak at MNI 42/6/8, p(FWE-corrected)=0.047, cluster size=356 voxels) in response to the low dose of BNC210 compared to placebo. Conclusions: We examined CBF alterations in response to the modulation of anxiety via the a7nAchR in unmedicated GAD patients. We found increased CBF in middle and superior temporal (BA39) and in the precentral gyri (BA44) in response to BNC210 as compared to placebo. These findings demonstrate that BNC210 affects CBF in a range of anxiety-related cortical regions, thereby possibly altering engagement in emotion regulation in these regions. Funding: Bionomics Ltd. 31 Dalgleish Street, Thebarton SA 5031 AUSTRALIA

A07 INFLAMMATORY CYTOKINES IN OBSESSIVE-COMPULSIVE DISORDER: A SYSTEMATIC REVIEW Tofani T, Psychiatric Unit, Department Health Science, AOUC, UNIFI, Viale della Maternità, Padiglione 8b AOUC, Florence, Italy, 50123 [email protected] Pallanti S(1), Hou R(2), Baldwin DS(2) (1) As presenting author; (2) University of Southampton, Department of Psychiatry, Academic Centre, College Keep, 4-12 Terminus Terrace, SO14 3DT, Southampton, UK Introduction: An increase in pro-inflammatory cytokines is reported in different psychiatric conditions including major depressive disorder and anxiety disorders, but the profile of inflammatory markers in obsessive-compulsive disorder (OCD) is not established. Methods: Systematic review of MEDLINE, EMBASE and WEB OF SCIENCE databases (1950-2017), identifying investigations of cytokines, chemokines or interleukins in blood or cerebrospinal fluid of childhood, adolescent and adult patients with OCD, defined by ICD or DSM criteria. Screening, data extraction and quality assessment were conducted. Studies were excluded if they represented pre-clinical studies or review articles, or were investigations in which OCD was not the primary mental disorder. Results: The search generated 1285 abstracts: after review, 16 studies (including 431 participants, comprising 13 studies in adults, and 3 in children and adolescents) were included. These studies generated inconsistent findings. TNFα is the most investigated pro- inflammatory cytokine: in adult patients Konuk et al. found an increase in plasma levels (13.7±10.61pg/ ml in OCD patients vs. 7.2±3.4pg/ml in healthy controls, p<0.000). These findings were supported by an investigation by Rao et al. where TNFα levels were 1.31±0.82pg/ml in OCD vs. 0.47±0.76pg/ml in healthy controls (p=0.005). In a study in children and adolescent patients, Simsek showed increased TNFα levels: 22.7 ± 32.1 pg/ml in OCD group vs. 4.9 ± 5.6 pg/ml (p=0.01) in healthy controls. Nevertheless, in four other investigations TNFα levels were reduced. Similar inconsistencies characterised studies with other pro-inflammatory cytokines, including IL-1β, IL-2, IL-6 and IFNγ. Levels of anti-inflammatory cytokines appear substantially unchanged, although one study found increased levels of IL-4 and IL-10, and another investigation found increased levels of IL-8. There were considerable differences in methodology between different investigations. Conclusions: No consistent pattern of pro-inflammatory or anti-inflammatory markers could be identified. Variations between study findings may relate to differences in study design (e.g. comorbidity, treatment, smoking, exercise, timing of sample collection, use of lipopolysaccharide stimulation techniques). Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. ABSTRACTS A27

A08 COMPUTATIONS UNDERLYING ATTENTIONAL BIAS TOWARD THREAT Wise T, Max-Planck UCL Centre for Computational Psychiatry and Ageing Research, University College London, 10-12 Russell Square, London, WC1B 5EH [email protected] Michely J(1), Dayan P(2), Dolan RJ(1) (1) As presenting author; (2) Gatsby Computational Neuroscience Unit, University College London, London, UK Introduction: Threat-related attentional bias is a robust finding in anxiety disorders and is thought to play an important role in the development of symptoms. However, the origin of this bias remains unclear. Here, we examine the influence of computations related to learning on visual attention, using a computational model of learning to identify components of the learning process whose abnormal operation may lead to a pathological attentional bias towards threat. Methods: Subjects performed a reinforcement learning task that involved learning to predict the occurrence of mild electric shocks. Eye tracking was used to monitor gaze during the task to assess visual attention. Computational models of learning were fit to behavioural responses and individual parameter estimates derived from these models were used to predict gaze position. Results: Subjects exhibited biased attention towards stimuli currently perceived as having a high threat likelihood. Importantly, individual differences in parameters governing updates in response to shock and no-shock outcomes were associated with subjective estimates of shock probability, suggesting that an attentional bias towards threat may be rooted in a learning style that leads to a distorted estimation of the likelihood of negative outcomes. Conclusions: This study demonstrates the importance of different learning processes underlying the allocation of visual attention, and indicates that the attentional bias seen in anxiety disorders could result from dysfunctional learning about threats in the environment. Future work will apply this computational framework to the study of clinical populations. This research was funded by a Wellcome Trust Sir Henry Wellcome Fellowship to T Wise

A09 INDUCED ANXIETY MAKES TIME PASS QUICKER Sarigiannidis I, UCL - Institute of Cognitive Neuroscience, UCL, Alexandra House, 17-19 Queen Square, Bloomsbury, London, UK, WC1N 3AZ [email protected] Grillon C(2), Ernst M(2), Roiser JP(1), Robinson OJ(1) (1) As presenting author; (2) NIMH Building 15K, Room 203 BETHESDA, MD 20814 Introduction: Anecdotal and experimental evidence suggest that time slows down during many unpleasant events, such as during a car crash. However, this might not be universally true: time seems to “fly” (i.e. speed up) when one is in the anxiogenic state of having to work to a deadline just hours away. One possibility is that time slows down when an individual is in a state of fear (an acute aversive state elicited by immediate and certain threat; e.g. car crash), but speeds up when an individual is in a state of anxiety (a more prolonged aversive state elicited by an uncertain threat that may occur in the future). An unresolved question, therefore, is whether anxiety leads to time underestimation, in contrast to fear-inducing events that lead to time overestimation. Methods: In order to test this hypothesis, we combined a commonly used timing task (temporal bisection task: Kopec & Brody, 2010, Brain. Cogn., 74,262-72.) with an established anxiety manipulation: threat of shock (Robinson, Vytal, Cornwell, & Grillon, 2013, Front Hum Neurosci., 7, 203). Given the uncertain nature of the threat (which should elicit anxiety rather than fear), we hypothesised that participants would allocate attentional resources away from the timing task at hand and towards anticipating the next shock, which should lead to the underestimation of time intervals. Results: In line with our hypothesis, across three experiments (with varying stimulus timings and shock amounts), participants significantly underestimated time in the anxiety condition, as indicated yb a rightward shift of the psychophysical function (meta-analytic effect size is d=0.68 with 95% confidence interval: 0.42- 0.94). Conclusions: Our results suggest, for the first time, that experimentally inducing anxiety leads to underestimating the duration of temporal intervals. Hence, although prior studies showed that time flies during aversive events, this might be true only for events in which there is imminent threat, which induce a fearful (rather than anxious) state. Mechanistically, this might be so because during fear, attention is A28 ABSTRACTS focused on closely timing the threatening object (thus overestimating time), while in anxiety, attention is be shifted away from the task at hand, and towards anticipating threatening events that might occur in the future (thus underestimating time). Our results might help explain different subjective experiences for fear-related disorders (e.g. post-traumatic stress disorder) and anxiety-related ones (e.g. generalised anxiety disorder). This study has been funded by a Wellcome Trust PhD studentship to I.S.

B01 THE EFFECT OF CANNABIDIOL ON THE GLUTAMATE SYSTEM: A SYSTEMATIC REVIEW Jones APM, DoP, UCL, 6th Floor, Maple House, 149 Tottenham Court Road, London, W1T 7NF augustus. [email protected] Bloomfield M A P(1), Freeman T P(2), Hindocha C(3) (1) As presenting author; (2) Institute of Psychiatry, Psychology & Neuroscience King’s College London 16 De Crespigny Park London SE5 8AF; (3) Room 451a, 1-19 Torrington Place Research Department of Clinical, Educational and Health Psychology, University College London WC1E 7HB Introduction: Of the phytocannabinoids present in cannabis, two compounds, ∆9-tetrahydrocannabinol (THC) and cannabidiol (CBD), have been the principle subjects of scientific investigation. THC is the major psychoactive ingredient in cannabis, acting predominantly as an endocannabinoid type 1 receptor (CB1) partial agonist. Conversely, CBD is not thought to interact significantly with CB1 and is a partial antagonist for CB2, most likely explaining its lack of psychotropic activity. It has been suggested that THC induces psychotic symptoms and dopamine dysfunction via its modulation of glutamatergic signalling. CBD however, has been shown to have anti-psychotic properties and is protective against the pro-psychotic influence of THC when co-administered. It may also have a clinically beneficial effect in treating other glutamate related disorders such as epilepsy and hypoxic ischaemia. Here we conducted a systematic review of studies examining the effect of CBD on the glutamate system. Methods: Our inclusion criteria for studies were: 1) Human, animal or in vitro studies, 2) studies involving acute or long-term application of CBD independent of other cannabinoids, 3) Studies measuring molecular markers for glutamate neurotransmission, 4) Papers reporting original research. We are excluding case studies. The search terms used to identify papers were: (cannabidiol or CBD) and (glutamate or glutamine or glutamic acid). The search was carried out in the Pubmed database with no restrictions placed on date of publication. Results: The search parameters identified 40 papers, of which 12 studies met our inclusion criteria. These included 8 animal and 4 in vitro studies. All eligible studies were published in English. In this systematic review, we found evidence to suggest that CBD has limited direct effects on glutamate release at the synapse while it may indirectly modulate glutamate receptor signalling pathways. CBD may have a beneficial clinical effect on glutamatergic cytotoxicity, which is potentially mediated by immune cell regulation and antioxidant properties. Conclusions: CBD acts as a multi-target drug in a variety of signalling systems, some of which may indirectly modulate the glutamate system. The body of research in this area is relatively small. More investigation into the specific effect of CBD on glutamate release and receptor activity is required to better understand the effects of this drug. No Sponsorship was received for this study.

B02 WHICH BIOLOGICAL AND SELF-REPORT FACTORS PREDICT ACUTE PSYCHOSIS-LIKE SYMPTOMS AND DRUG DEPENDENCY IN YOUNG CANNABIS USERS? Hindocha C, Clinical Psychopharmacology Unit, UCL, 1-19 Torrington Place, London, WC1E 7HB [email protected] Curran HV(1), Morgan CJA(2), ShaBan NDC(1), Das RK(1), Freeman TP(3) (1) As presenting author; (2) Dept of Psychology, University of Exeter, Washington Singer Building, Perry Rd, Exeter; (3) National Addiction Centre, Institute of Psychiatry, Psychology & Neuroscience, KCL, London Introduction: Accurate drug use metrics are essential for assessing the acute and long-term effects of a drug . Current cannabis use metrics are poor indicators of THC exposure and need to be developed to have greater predictive ability. No studies have investigated associations between multiple self- ABSTRACTS A29 reported and biological measures (including cannabis samples, hair and urine), and which are most strongly associated with adverse outcomes such as dependence and psychosis Methods: 418 participants aged 16-24 took part in two sessions (intoxicated with their own cannabis, non-intoxicated). Outcomes were Cannabis Dependence as measured by (1) Severity of Dependence (SDS) and (2) clinical diagnosis of cannabis dependence on DSM-IV-T and the change in psychotic-like symptoms as measured by the (3) Psychotomimetic States Inventory (PSI) and (4) Brief Psychiatric Rating Scale. Predictors were cannabinoids in cannabis (THC, CBD), urine (THC-COOH/creatinine), hair (CBD, THC, CBN, THC:COOH, and THC:OH) and self-reported cannabis use (days per month, years of use of cannabis, time taken to smoke 3.5g of cannabis, age of first use, time since last cannabis use, money spent of cannabis/week and preference for different types of cannabis. Age and sex were included as covariates. Predictors were included in the model fitting process if they were significant correlates at a conservative α ≤0.001. The 4 outcomes were fit using forward-fitting linear mixed models based on the yesianBa Information Criterion (BIC) and maximum likelihood estimation to fit both fixed and random effects thus assessing the putative self-report and biological risk factors for dependence and psychotic like symptoms. Results: The sample were 20.56 (±1.68) years old and consisted of 113 (27%) females. 43.7% were dependent according to the SDS. 48.4% met DSM-IV-TR criteria. Cannabis increased psychotic-like symptoms according to both self-reported assessment on the PSI (p<0.001, d=0.516) and clinical assessment on the BPRS (p<0.001, d=0.413). SDS and DSM were predicted by THC-COOH/creatinine and frequency of cannabis use. Change in psychotic-like symptoms (non-intoxicated to intoxicated) was best predicted by age of first cannabis use indicating tolerance and THC-COOH/creatinine in urine. No predictors met inclusion for the BPRS. Discussion: Combining self-report and urinary THC:COOH improves measurement of cannabis use and its association with adverse outcomes i.e. dependence and psychotic like symptoms. Samples of hair and cannabis itself are less important. These findings can help inform future research about the putative risks for cannabis use and psychosis. This research was funded by the UK Medical Research Council (G0800268).

B03 PROVISIONAL SUPPORTING EVIDENCE FOR THE CANNABIS DISCONTINUATION HYPOTHESIS - PRELIMINARY ANALYSIS OF THE INTERNATIONAL CANNABIS EXPERIENCES SURVEY 2018 Sami MB, Department of Psychosis Studies, IoPPN, 16 De Crespigny Park Denmark Hill, London, SE1 8AF [email protected] Rai A(1), Bhattacharyya S(1) (1) IoPPN, London SE5 8AF Introduction: We have recently posited the ‘cannabis discontinuation hypothesis’ based on previously published results of the Cannabis Experiences Survey 2016(Sami, M. et al (2018). Psychological Medicine, 1-10. e-published before print.). This posits that those at highest risk of psychotic disorder are more likely to discontinue due to increased psychotic-like experiences when using cannabis. This hypothesis has been suggested to explain relative stability of rates of psychotic disorder over time despite increasing cannabis use and potency. Limitations of our prior work include dichotomizing continuation/discontinuation as a yes/no outcome, not controlling for personality characteristics and lacking a measure of psychosis proneness. We aimed to replicate the association with psychotic-like experience and cannabis cessation and extend previous work by examining the impact of psychosis proneness on psychotic-like experiences, whilst controlling for personality traits. Methods: We are undertaking the International Cannabis Experiences Survey 2018 at thecannabissurvey.com url. Herein we report analysis from the first 405 cannabis-using participants using linear regression to analyse the relationship between psychotic- like experiences, the marijuana-quit ladder and psychosis-proneness whilst controlling for ‘Big Five’ personality characteristics (openness, conscientiousness, extraversion, agreeableness, neuroticism). Age, sex, age of first cannabis use and cumulative cannabis use were entered into regression models as covariates. Results: Psychotic-like experiences on cannabis use predict cannabis cessation (Standardized β 0.276, p<0.001), whilst euphoric experiences are inversely associated with cessation (Standardized β -0.239, p<0.001). Psychosis proneness predicts psychotic-like experiences (Standardized β 0.148, p=0.002). However psychosis proneness is not associated with marijuana cessation (Standardized β -0.022, p=0.649). Conclusions: These results are tentatively in line with the cannabis discontinuation hypothesis (psychosis- A30 ABSTRACTS proneness<-->psychotic-like experiences<-->cannabis cessation). The lack of direct correlation between psychosis-proneness and cannabis cessation observed maybe be due to the sensitivity of the measures used to index psychosis risk. Large population-based longitudinal studies to follow up those who develop psychotic disorders would be the optimal method to test the discontinuation hypothesis. Financial Sponsorship: MS if funded by a Medical Research Council Training Fellowship.

B04 USING PATIENT-DERIVED INDUCED PLURIPOTENT STEM CELLS TO UNDERSTAND THE MECHANISMS UNDERLYING THE BENEFICIAL EFFECTS OF ESTROGENS IN SCHIZOPHRENIA Srivastava DP, Basic and Clinical Neuroscience; MRC Centre for Neurodevelopmental Disorders, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, 125 Coldharbour Lane, London, SE5 9NU [email protected] Deans PJM(1), Perfect L(1), Dutan-Polit L(1), Shum C(1), Conforti M(1), Duarte RR(1), Powell T(3), Bhattacharyya S(2), Price J(2) (1) Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London; (2) Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King’s College London; (3) SGDP, Institute of Psychiatry, Psychology and Neuroscience, King’s College London Background: Estrogens, in particular 17β-estradiol (estradiol) have repeatedly been shown to exert powerful influences over cognitive function, and in particular, on learning and attention as well as anxious and depressive behaviours. These cognitive enhancing effects have been shown to be dependent on modulating the structure and function of glutamatergic synapses, resulting in long-lasting changes in synaptic connectivity. Interestingly, there is growing evidence that estrogenic-based compounds have a positive effect in the treatment of schizophrenia. Recent clinical studies have demonstrated that adjunct treatment with estradiol or the selective estrogen receptor modulator (SERM) raloxifene, ameliorates positive and negative symptoms and improves working memory and attention deficits in male and female schizophrenic patients. However, the mechanisms underlying these beneficial effects are not fully understood. Critically, as estrogenic-based compounds are not effective long-term treatment options owing to potential side effects, determining how estradiol exerts its positive effects will aid in the development of safer and effective estrogenic-based compounds. Methods: To gain an insight into estrogens beneficial effects in schizophrenia, we have used human induced pluripotent stem cell (iPSC)-derived from healthy or patients diagnosed schizophrenic. Initial experiments used iPSCs-derived from healthy male individuals, differentiated into immature cortical neurons. First, we assessed the ability of estrogens to modulate key neuronal and synaptic structures as well as synaptic and inflammatory genes. Next we assessed the expression and distribution of synaptic proteins were determined in both healthy iPSC-neurons and patient iPSC-neurons. Subsequently, using a pharmacological approach, we have explored the ability of estrogens to rescue cellular and molecular deficits in iPSC-neurons derived from schizophrenic patients. Results: Both healthy and patient iPSC differentiated into neuroepithelium, neural progenitors cells and finally into TBR1- and EMX1-positive neurons efficiently. Treatment of iPSC-neurons from healthy donors demonstrated that estrogens were able to modulate neuronal structure, as well as to protect against inflammatory insults. Consistent with previous reports, iPSC-neurons derived from schizophrenic individuals displayed reduced synaptic protein expression compared with healthy iPSC-neurons. Critically, treatment of patient iPSC-neurons with estradiol or raloxifene, an increase in synaptic protein expression to a level similar to that observed in untreated healthy iPSC-neurons was observed. Discussion: These data are the first to demonstrate that estrogens are capable of regulating synaptic proteins in human neurons taken from patients diagnosed with schizophrenia. Collectively, we hope these data will help us understand how estrogens may confer their positive effects in psychiatric disorders. Funding: MRC; NARSAD; Wellcome Trust via KHP ABSTRACTS A31

B05 LONGITUDINAL STUDY INVESTIGATING THE ASSOCIATION BETWEEN BDNF LEVELS AND TREATMENT RESPONSE IN FIRST-EPISODE PSYCHOSIS Bogdanova A, Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, The Maurice Wohl Clinical Neuroscience Institute, King’s College London, 8 Cutcombe Road, London, SE5 9RT [email protected] Bonaccorso S(2), DiForti M(2), Marques T(2), Pariante CM(1), Murray RM(2), Dazzan P(2), Mondelli V(1) (1) As presenting author; (2) Dept of Psychosis Studies, Institute of Psychiatry, Psychology and Neurosci, King’s College London, De Crespigny Park, London, SE5 8AF Background: Brain-Derived Neurotrophic Factor (BDNF) is an important mediator of neurogenesis and neuroplasticity and its blood levels have been reported to be decreased at the onset of psychosis. Increased inflammation, present at the onset of psychosis, has been suggested to contribute to lower BDNF levels. Although increased inflammation has been shown to predict poor treatment response in first episode psychosis, no study has yet explored the interaction between serum BDNF and treatment response in these patients. The aim of this study was to 1) investigate the association between BDNF levels and response to treatment in patients with first-episode psychosis and 2) to explore possible correlations with pro- inflammatory cytokine Interleukin-6 (IL-6). Methods: We recruited 35 first-episode psychosis patients as part of the Genetics and Psychosis study in London, United Kingdom, from inpatients and outpatients units within South London and Maudsley NHS Foundation Trust. Blood samples for measuring serum BDNF and IL-6 levels were collected at baseline and at 3-month follow-up. Response to treatment was assessed at 3-month follow-up according to the Andreasen criteria (Andreasen et al, 2005, American Journal of Psychiatry, 162(3), 441-9). Eighteen patients were classified as Non-Responders (age mean±SEM: 27.8±1.4 years, 78% males) and seventeen as Responders (age: 31.8±2.1 years, 65% males). Independent Samples T-test was used to investigate differences in BDNF levels between Responders and Non-Responders at baseline and at follow-up. Spearman correlation was used to test association between baseline IL-6 and follow-up BDNF levels separately in Responders and Non-Responders. Responders and Non-Responders did not differ in duration of treatment and medication dosages (chlorpromazine equivalents). Results: We found no difference in BDNF levels between Responders and Non-Responders at baseline (t(33) = -0.789, p = 0.436). In contrast, we found a significant difference in follow-up BDNF levels between Responders and Non-Responders (t(33) = -2.243, p = 0.032), with Non-Responders showing lower BDNF levels than Responders. In the Responder group, higher baseline levels of IL-6 were associated with higher BDNF levels at follow-up (Spearman’s rho=0.576, p=0.025), while no correlation was found in the Non-Responders. Conclusions: Our findings suggest that BDNF may serve not as a predictor, but as a mediator of treatment response in first-episode psychosis patients. The correlation between IL-6 and BDNF in Responders group may suggest that higher levels of BDNF may protect from the negative effects of increased IL-6 in these patients. This research has been supported by the NIHR Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London.

B06 A NOVEL GENETIC INSTRUMENT FOR LIFETIME SMOKING INDICATES THAT SMOKING IS A CAUSAL RISK FACTOR FOR DEPRESSION AND SCHIZOPHRENIA Wootton RE, School of Experimental Psychology, University of Bristol, 12a Priory Road, Bristol, BS8 1TU [email protected] Munafò MR(1) (1) School of Experimental Psychology, University of Bristol, Bristol, BS8 1TU Introduction: Smoking is highly co-morbid with several psychiatric conditions, but understanding the causal nature of this relationship is complicated by well-described issues of confounding and reverse causality. Mendelian randomisation uses genetic variants associated with an exposure (e.g., smoking) to examine causal pathways between the exposure and outcomes. Previous genetic instruments for smoking have only captured discrete aspects (e.g., initiation, heaviness of smoking), limiting power and requiring individual level data on smoking status for analyses of heaviness of smoking. To overcome A32 ABSTRACTS these issues, we developed a novel genetic instrument for comprehensive smoking exposure, which takes into account duration of smoking, heaviness of smoking, time since cessation, and a simulated half-life constant to capture the exponentially decreasing effect of smoking on health over time. Our instrument includes both smokers and non-smokers, removing the need to stratify on smoking status. We used our novel genetic instrument to explore bi-directional effects between smoking and mental health, focusing on schizophrenia and major depressive disorder. Method: We conducted a genome-wide association study (GWAS) of our comprehensive smoking measure in the UK Biobank (N=463,003) and identified 124 independent SNPs associated at the genome-wide level of significance. Our two-sample Mendelian randomisation validation analysis confirmed that smoking causes lung cancer and coronary heart disease. Having established the validity of our instrument, we used bi-directional two-sample Mendelian randomisation to explore its effects on schizophrenia and depression, using summary data from the recent GWASs conducted by the PGC (Ripke et al., 2014; Wray, Sullivan, & others, 2017). Results: We found evidence that higher smoking exposure caused increased risk of both schizophrenia (OR = 3.419, 95% CI = 2.104-5.556, p = 6.9x10-7): and depression (OR = 2.741, 95% CI = 2.176-3.453, p = 1.13x10-17). There was also evidence of a causal effect of higher depression on higher smoking (consistent with the self-medication hypothesis) (β= 0.069, 95% CI = 0.025-0.113, p = 0.002) but no clear evidence of an effect of schizophrenia on smoking (β= 0.013, 95% CI = -0.001-0.027, p = 0.076). Sensitivity analyses confirmed that these findings were not an artefact of pleiotropy. Conclusions: These findings indicate that the co-morbidity between smoking and both depression and schizophrenia is due, at least in part, to a causal effect of smoking on these outcomes. Our genetic instrument of comprehensive smoking exposure has the potential to be used widely in Mendelian randomisation to explore many other outcomes. This study was supported by the NIHR Biomedical Research Centre at the University Hospitals Bristol NHS Foundation Trust and the University of Bristol and by the MRC Integrative Epidemiology Unit at the University of Bristol: http://www. mrc.ac.uk [MC_UU_12013/6].

B07 THE EFFECT OF KETAMINE ON PSYCHOPATHOLOGY AND IMPLICATIONS FOR UNDERSTANDING SCHIZOPHRENIA: A META-ANALYSIS Beck K, Psychosis Department, IOPPN, Institute of Psychiatry, Psychology & Neuroscience King’s College London 16 De Crespigny Park London, SE5 8AF [email protected] Borgan F(1), McCutcheon R(1), Hindley G(1), Taylor M(1), Howes OD(1) (1) As presenting author Introduction: Ketamine’s ability to induce the full range of psychotic symptoms has established it as model of psychosis in humans and animals. This model has been important for gaining greater understanding about the nature of glutamate and NMDA receptor dysfunction in schizophrenia, and for the development of drugs targeting the glutamate system. Despite this, it is not known how consistently ketamine generates symptoms, the average magnitude of its effect, or the experimental design factors that might influence this. We conducted a meta-analysis to determine the effect of ketamine on psychopathology in healthy participants, and the experimental factors affecting this. Methods: MEDLINE, EMBASE and PsychINFO databases were systematically searched for studies investigating the change in the Brief Psychiatric Rating Scale (BPRS), in response to an acute ketamine challenge in healthy participants compared to placebo. At least two independent investigators selected the studies, and extracted study-level data for a random-effects meta-analysis. Standardized mean differences (Hedges’ g) between placebo and ketamine conditions for total, positive and negative BPRS scores were calculated. To determine the impact of the study design on the results, sub-group analyses were conducted examining the effect of: within-person versus independent group study design, blinding status, infusion method and different positive symptom inclusion criteria. Results: Of 7991 citations retrieved, 26 studies met inclusion criteria. The overall sample included 408 healthy participants exposed to the ketamine condition, and 412 healthy participants exposed to the placebo condition. Acute administration of ketamine induced an increase in psychopathology in healthy participants, seen as a statistically significant increase in the total BPRS (Hedges g = 1.64, 95% CI, 1.20 to 2.08, p= <0.0001) positive BPRS (Hedges g = 1.63, 95% CI, 1.28 to 1.98, p< 0.0001) and negative BPRS (Hedges g =1.46, 95% CI, 1.11 to 1.82, p<0.0001) compared with a placebo condition. Using a non-blinded or ABSTRACTS A33 single blinded method significantly increased the magnitude of the effect for total (p=0.002) and negative BPRS (p=0.001). Within-person design increased the magnitude of effect for the total BPRS (p=0.015). A meta-regression of effect size against age found that increasing age reduced the magnitude of effect for negative symptoms (p=0.02). Conclusion and Relevance: These findings suggest that acute etaminek administration consistently induces psychopathology, with a similar effect on positive and negative symptoms in healthy participants. They also highlight the importance of methodological design on the magnitude of the effect. Acknowledgements: This study was funded by Medical Research Council-UK (no. MC-A656-5QD30), Maudsley Charity (no. 666), Brain and Behavior Research Foundation, and Wellcome Trust (no. 094849/Z/10/Z) grants to ODH and the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. It was also funded by grants to KB from the Royal College of Psychiatrists, Rosetrees Trust and the Stoneygate Trust. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Declaration of interest KB, RM, LS, MS, NP and RR declare no conflicts of interest. ODH has received investigator-initiated research funding from and/or participated in advisory / speaker meetings organised by Astra-Zeneca, Autifony, BMS, Eli Lilly, Heptares, Jansenn, Lundbeck, Lyden-Delta, Otsuka, Servier, Sunovion, Rand and Roche. Neither Dr Howes nor his family have been employed by or have holdings / a financial stake in any biomedical company.

B08 DNA METHYLATION CHANGES OF GRIN1 AND GRIN2B NMDAR PROMOTER REGION IN RATS REARED UNDER ISOLATION Loureiro CM, Internal Medicine Department, Ribeirão Preto Medical School, University of São Paulo, Bandeirantes Avenue, 3900. Monte Alegre, 14040090 [email protected] Fachim HA(5), Corsi-Zuelli FMG(5), Shuhama R(5), Joca SRL(3), Menezes PR(4), Del-Ben CM(5), Dalton CF(2), Reynolds GP(2), Louzada-Junior P(1) (1) As presenting author; (2) Biomolecular Sciences Research Centre, Sheffield Hallam Univ; (3) Dept of Physics and Chemistry, School of Pharmaceutical Sciences, Univ of São Paulo; (4) Dept of Preventive Medicine, Faculty of Medicine, Univ of São Paulo; (5) Neuroscience and Behaviour Dept, Ribeirão Preto Medical School, Univ of São Paulo Background: N-methyl-D-aspartate receptor (NMDAR) dysfunction is involved in psychosis. NR1 and NR2B are essential subunits of NMDAR, which are encoded by genes Grin1 and Grin2B, and have been identified as candidate genes for psychiatric disorders. In parallel, knockout and knockdown animal studies for NR1 and NR2 subunits showed behavioural changes similar to schizophrenia (Wesseling et al., 2014. Mol Autism. 4;5:38). Recent evidence has also demonstrated that the epigenetic regulation of NMDAR plays a crucial role in schizophrenia (Gulchina et al., 2017. J Neurochem.143(3):320-333), suggesting that changes in DNA methylation may be responsible for deficiencies in excitatory neurotransmission. Aims: As we found altered NR1 and NR2 protein/mRNA levels in rats reared in isolation in brain tissue and peripheral blood, we hypothesised that the DNA methylation changes in the promoter region of the genes Grin1 and Grin2B may underlie these changes. We also verified if these alterations are tissue specific or if the changes found in the brain extend to the blood. Methods: In an environmental animal model of schizophrenia, male Wistar rats were kept isolated (n=10) or grouped (n=10) from weaning for 10 weeks. After this period the animals underwent an open field test and soon afterwards they were sacrificed.e W analysed DNA methylation of promoter sequences of NMDAR genes in the blood and target brain areas by pyrosequencing. ANOVA with a Bonferroni correction was used for statistical analysis and Pearson correlational analyses were carried out. Results: Isolation-reared animals presented hyperlocomotion at the two first time bins (0-5 and 5-10 min) in periphery of the arena when compared to grouped animals (p = 0.025; p = 0.002), respectively. Increased methylation of Grin1 CpG4 (p=0.018) were found in the prefrontal cortex of isolated-reared rats and increased methylation of Grin2B CpG4 were found in peripheral blood and hippocampus of isolated animals when compared to grouped (p=0.05; p=0.008). Conclusions: This study support our hypothesis that the NMDAR changes found in the brain could also be found in blood samples, as we found hypermethylation Grin2B CpG4 of the gene promoter in both hippocampus and blood and at CpG4 of Grin 1 in the PFC. At CpG4 we have binding sites for many A34 ABSTRACTS transcript factors, where may regulate the expression of genes with GC-rich elements in the promoter region and during early animal development for the specification of specific tissues. Therefore, these changes are highlighting the importance of the environmental influence during the development. Funding: FAPESP (2012/05178-0; 2013/08216-2; 2017/00624-5) and CAPES.

B09 PROTEIN TRANSLATION IN THE PSYCHIATRIC-RELEVANT CYFIP1 KO MOUSE MODEL: UNALTERED ACTIVITY OF UPSTREAM TRANSLATION PATHWAYS BUT IMPACT ON DOWNSTREAM FMRP TARGET ARC AND CYFIP1 ITSELF Trent S, Neuroscience & Mental Health Research Institute, Cardiff University, 3.40 (Fellows Office) Hadyn Ellis Building, Maindy Road, Cathays, Cardiff, cf24 4hq [email protected] Meeson N(1), Best C(1), Hall J(1) (1) Neuroscience & Mental Health Research Institute, Hadyn Ellis Building, Cardiff University Introduction: Human genomic studies implicate a convergent biological mechanism at the glutamatergic synapse, including Cyfip1, FMRP and Arc, in the pathogenesis of psychiatric illnesses including schizophrenia and autism spectrum disorder. Cyfip1, in concert with the Fragile X protein FMRP, represses the protein translation of synaptic ‘FMRP targets’ including ARC. Here we test whether key upstream protein translation pathways, including ERK and S6K1, are over-active in hippocampal synaptoneurosomes of Cyfip1+/- KO mice using phosphorylation-sensitive immunoblotting techniques, as similarly performed by others in the mechanistically-related Fmr1 KO model (Sharma et al., 2010, Journal of Neuroscience 30(2):694-702), and measure downstream targets such as Arc, mTOR and Cyfip1 itself. Methods: Brains were extracted from naïve adult male Cyfip1+/- KO mice (6NTac x JAX 6), alongside wild-type littermates (n=10/genotype). Dissected whole hippocampi were prepared into synaptosomes using Syn-PER™ reagent (Thermo Scientific). Proteins were separated on a 4-12% Bis-Tris gels (100 V) and transferred onto nitrocellulose membrane via wet transfer (85V, 2 hours). Subsequently, membranes were blocked in 5% BSA in TBST, before overnight incubation at 4 °C in primary antibody solution (1:1,000; P-ERK, ERK, P-S6K1, S6K, Arc, mTOR, Calnexin, Gapdh). After washes, blots were incubated in 5% milk in TBST with fluorescent secondary antibodies (1:15,000), before being imaged and quantified (Li-Cor Odyssey and ImageStudio). Statistical comparisons used 1-way ANOVAs, median splits with Chi-Squares and ANCOVAs (values > 2.5 STD from average were omitted). Results: Using an index of phosphorylated S6K1 and ERK signal over their respective total protein levels, we reveal no hyperactivity in either S6K1 or ERK-related protein translation pathways (P-ERK/ERK: F(1,18)=0.424, P=0.524). Interestingly, despite robust 50% decreases in Cyfip1 gene expression, Cyfip1 protein is not clearly reduced in Cyfip1O’s K (F(1,19)=1.979, P=0.177) with genotype insufficient to predict low Cyfip1 levels (χ (1) = 0.800, P= 0.3710).e W therefore performed within-sample normalisation to Cyfip1 levels, which revealed a specific and significant 50% increase in Arc levels (Arc: F(1,19)=8.337, P=0.010) that survives ANCOVA analysis when co-varying for Cyfip1 levels (F(1,17)= 5.561, p= 0.031). Conclusion: In contrast to the functionally-related Fmr1 KO model, we did not see evidence of heightened activity of upstream ERK/S6K1 pathways in Cyfip1 KO mice hippocampal synaptoneurosomes. Surprisingly, we do not show robust decreases of Cyfip1 protein level in these mice, suggesting compensation/subtle changes in FMRP-Cyfip1 function and extend these findings to cell-whole lysates, other brain regions and a Cyfip1 KO rat model. Additionally, within-sample normalisation to Cyfip1 levels reveals the specific, robust increase of ‘FMRP target’ Arc. This work was funded yb a Wellcome Trust Strategic Award (DEFINE) and a NMHRI Fellowship Award. ABSTRACTS A35

B10 ROLE OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) IN PSYCHOSIS AND DOPAMINE SENSITIZATION: A PROTEOMICS STUDY OF THE EFFECTS OF CHRONIC METHAMPHETAMINE IN BDNF VAL66MET MICE van den Buuse M, School of Psychology and Public Health, La Trobe University, Kingsbury Drive, Bundoora, Melbourne, Australia, VIC3086 [email protected] Greening DW(1), Notaras MJ(2) (1) La Trobe Institute for Molecular Sciences, La Trobe University, Melbourne, Australia; (2) Weill Cornell Medical College, Cornell University, New York, USA Introduction: Psychosis is consistently associated with dopaminergic dysfunction although the exact mechanisms involved remain unclear. Chronic intake of psychostimulants, such as methamphetamine (Meth), causes dopaminergic sensitization which has also been postulated in psychosis and schizophrenia. Indeed, Meth abuse can induce psychotic episodes similar to paranoid schizophrenia. Brain-derived neurotrophic factor (BDNF) is implicated in both Meth effects and schizophrenia. In his study in mice we further investigated the role of BDNF in psychosis and dopaminergic sensitization using high- resolution mass spectrometry (MS)-based proteomics. Methods: Transgenic mice expressing the human BDNFVal66Met polymorphism via endogenous mouse promotors were injected with an escalating Meth dose from 6-9 weeks of age before brain tissue was obtained at 13 weeks of age. MS-based proteomics, selective reaction monitoring analysis and global enrichment analysis, including an a priori list of 396 schizophrenia risk genes, was used to map the identified proteins to known pathways and functions. Analysis of variance with Benjamini-Hochberg multi-test adjustment was used to compare normalised abundance values between groups (EdgeR software v3.2). Differential expression of proteins was considered significant only if the following conditions were fulfilled: (i) pair-wise adjusted P < 0.05, (ii) protein identifications were in at least 2 biological replicates, and (iii) fold change atiosr were ≥2-fold for differentially abundant proteins. Results: Meth-treated mice showed persistent significant (P<0.05) sensitization to an acute challenge with Meth when tested for locomotor hyperactivity. Profiling of Nucleus Accumbens (NAc), Caudate Putamen (CPu) and Medial Prefrontal Cortex (mPFC) revealed 4808 quantified proteins identified. Meth differentially altered catecholamine and dopamine signaling pathways in hBDNFVal/Val and hBDNFMet/Met mice, implicating involvement of BDNF on Meth-induced reprogramming of the mesolimbic proteome. For example, across regions, Meth treatment selectively regulated tyrosine hydroxylase and SLc6a63 (dopamine transporter) in both genotypes but COMT only in hBDNFVal/Val mice. Meth furthermore modulated specific proteins associated with genetic loading for schizophrenia and in several cases hBDNFVal66Met genotype determined which markers were differentially expressed. Conclusions: This study is the first comprehensive analysis of the long-term effects of chronic Meth exposure within the mesocorticolimbic circuitry, and results show that these long- term changes are dependent upon BDNF genetic variation. Psychosis and schizophrenia are a group of devastating mental illnesses which cause immense suffering and a huge burden on society. These results may be important for our understanding of the role of dopaminergic sensitization in psychotic symptoms in schizophrenia as well as following Meth abuse. These studies were supported by a senior research fellowship from the National Health and Medical Research Council and a Research Focus Area grant from La Trobe University, Australia. A36 ABSTRACTS

B11 COMMUNICATION BREAKDOWN AND DECOUPLING OF PRELIMBIC CORTEX-VENTRAL HIPPOCAMPUS LINKAGE IN THE SUB-CHRONIC PHENCYCLIDINE SCHIZOPHRENIA MODEL: HOW LOCAL FIELD POTENTIAL PHASE UNDERPINS INTERNAL AND INTRA-REGIONAL PATHOLOGY Netherwood BR, Faculty of Biology, Medicine and Health, UoM, Stopford Building, Faculty of Medical and Human Sciences, Univ of Manchester, Oxford Road, Manchester M13 9PT netherwood.benjamin@ protonmail.com Gigg J(2), Montemurro M(2), Doostar N(2), Davy O(1) (1) Clinical Research Imaging Centre, University of Bristol, 60 St Michael’s Hill, Bristol BS2 8DX; (2) Stopford Building Faculty of Medical and Human Sciences The University of Manchester Oxford Road Manchester M13 9PT Introduction: Schizophrenia is a worldwide disorder with no current cure. This disease is speculated to be underpinned by hyperdopaminergic subcortical activity, coupled with cortical hypo-frontal glutamatergic dysfunction. This is most notable between the prefrontal cortex and hippocampus, where linkage is thought to be important in 1) transmitting actions plans to the hippocampus (an ‘efferent copy’), and 2) providing a self-referential component to behaviour; something profoundly lacking in schizophrenia (Numan, 2015, Frontiers in Behavioral Neuroscience, 9(323): 1-9). Widespread alterations to frequency bands such as theta are also readily detectible, however, the consequence(s) on neuronal firing to specific phases of field potentials in the physiological process of ‘phase-locking’ is largely unknown. Additionally, hippocampal gamma bursts, which are intrinsically linked to memory, also occur during specific theta phases. Methods: The sub-chronic phencyclidine glutamatergic-dopaminergic dysfunction model was assessed with regard to phase-locking, gamma burst entrainment, and prefrontal-hippocampal linkage using spectral analysis, cross-frequency coupling, Rayleigh assessment, wavelet and transfer entropy analysis. This was performed in urethane anesthetised Lister-Hooded rats during spontaneous (n=15/16) and toe pinch (n=5) recordings, for both the ventral hippocampus CA1 subfield, and the prelimbic cortex. Results: Artificially primed default state networks were apparent in the hippocampus, coupled with massively disrupted unit coherence in toe pinch (p<0.01). Contrastingly, the prelimbic cortex exhibits unaltered phase-synchrony, suggesting inflexibility (p<0.05). These results may be mediated by a lacking theta upswing observed in PCP animals, during toe pinch (p<0.05), as this reduces the capacity for neuronal entrainment. Two populations of gamma bursts phase preferences were detected in vehicle animals, whereas this distinction was not seen in PCP cohorts. Finally, prefrontal- hippocampal linkage was reduced for inter-regional theta coupling in PCP animals. A drastically reduced efferent copy transmission was also observed in PCP animals, whilst a ‘greater’ information flow from the CA1 subfield occurred in PCP animals, as assessed under the transfer entropy metric. Conclusion: Aberrant phase- locking indicates a profound impediment to function, because these mechanisms are through to transmit (added) information beyond both regular spiking, and the local field potential (Montemurro et al, 2008, Current biology, 18(5): 375-380). This explains the stereotypical schizophrenic ‘hypofrontality’, from a new, informatics level perspective. Furthermore, distinct gamma bursts are thought to reflect memory encoding and retrieval (Hasselmo et al, 2002, Neural Computation, 14: 793–817). Hence, pathological gamma overlap may explain how hallucinations can manifest in schizophrenia, because sensory stimuli may be interpreted as if it were committed memory. * No sponsorship received for study

B12 GABAERGIC, NOT SEROTONERGIC, ALTERATIONS APPEAR TO UNDERLIE REDUCED EFFICACY OF 5-HT6 RECEPTOR ANTAGONISTS IN A DUAL-HIT NEURODEVELOPMENTAL MODEL FOR SCHIZOPHRENIA King MV, School of Life Sciences, University of Nottingham, Medical School, QMC, Nottingham, NG7 2UH [email protected] Newton-Mann E(1), Dawe-Lane E(1), Evans C(1), Fowler M(1) (1) As presenting author Schizophrenia has a complex aetiology involving early-life environmental factors. One approach to improved preclinical modelling (to understand disease and evaluate therapeutics) incorporates dual neurodevelopmental ‘hits’. For example, neonatal phencyclidine then isolation rearing of rats (PCP-Iso) ABSTRACTS A37 produces greater behavioural deficits than either alone (Gaskin et al., 2014 Psychopharmacology 231:2533). Hippocampal slices from PCP-Iso show attenuated glutamate responses to the 5-HT6 receptor antagonist SB-399885 (but not the mGluR7 antagonist MMPIP; King et al., 2015 Eur Neuropsychopharmacol. 25:S272). Here we extend this by cognitive evaluation of SB-399885 in PCP-Iso versus single-hit isolates (Veh-Iso), then immunohistochemistry for hippocampal 5-HT and calbindin-positive GABAergic interneurons (that express 5-HT6 receptors; Helboe et al., 2015 Neuroscience 310:442) to investigate reduced activity of SB-399885 in PCP-Iso. 41 male Lister-hooded rats (Charles River UK) received saline (1ml/kg s.c.) or PCP (10mg/kg) on postnatal day (PND) 7, 9 and 11, before rearing in groups (Gr) or isolation from PND21. They underwent novel object discrimination (NOD: King et al., 2018; Mol. Neurobiol. In press) three times, following 0.5% methylcellulose 1% Tween-80 (1ml/kg i.p.), SB-399885 (10mg/kg) or MMPIP (10mg/ kg) on separate days (PND57-80). Brains were collected immediately after the final NOD. Data (n=13-14) were analysed by ANOVA with Sidak’s/Tukey’s post-hoc, and Pearson’s correlation. There was an object x neurodevelopmental condition interaction in the NOD choice trial (F(2,38)=6.382, P=0.004). Veh-Gr discriminated the novel object irrespective of acute treatment (post-hoc P<0.05-0.01 versus familiar). Isolation-induced impairments (P>0.05, following vehicle) were reversed by MMPIP (P<0.01-0.001), but by SB-399885 only in Veh-Iso (P<0.001) not PCP-Iso. PCP-Iso had unaltered hippocampal 5-HT-immunoreactivity (neurodevelopmental condition F(2,34)=1.043, P=0.3633), but fewer calbindin-positive cells throughout the dorsal hippocampus (neurodevelopmental condition F(2,35)=6.795, P=0.0032; post-hoc P<0.01/P<0.05 versus Veh-Gr/Veh-Iso), particularly in strata oriens (P<0.0001) and radiatum (P<0.01) of CA1. Calbindin (but not 5-HT) immunoreactivity correlated with NOD following SB-399885 (P<0.01, R2=0.2642). Seemingly robust cognitive and glutamatergic effects of 5-HT6 antagonists in other preclinical models were absent in PCP-Iso, potentially due to loss/dysfunction of the predominant 5-HT6 expressing hippocampal interneurons (rather than reduced 5-HT tone). Comparatively sparse clinical cognitive data for 5-HT6 receptor antagonists in schizophrenia (Morozova et al., 2014 CNS Spectr. 19:316) make it unclear whether earlier preclinical findings represent false positives or lack of efficacy in PCP-Iso a false negative, however calbindin dysfunction may feature in schizophrenia (Altar at al., 2005 Biol Psychiatry 58:85; Iritani et al., 1999 Prog Neuropsychopharmacol Biol Psychiatry 23:409). This study highlights the importance of improved understanding for selection of appropriate preclinical models, especially when disease neuropathology impacts upon pharmacological effects of potential therapeutics. Funded by the University of Nottingham

B13 NON-SPATIAL WORKING MEMORY DEFICITS IN THE SUB-CHRONIC PHENCYCLIDINE (PCP) MODEL FOR SCHIZOPHRENIA ASSESSED IN THE ODOUR SPAN TASK Burgess MA, Department of Pharmacy & Optometry, University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT [email protected] Podda G(1), Metcalf TO(1), Aarons T(1), Grayson B(1), Neill JC(1) (1) As presenting author Introduction: We have previously shown that sub-chronic phencyclidine (scPCP) treatment impairs cognitive performance in a rodent model of relevance for schizophrenia (Cadinu et al, 2017, Neuropharmacology, 10.1016/j.neuropharm.2017.11.045, pp 1-22). Patients with schizophrenia consistantly present with working memory impairments (Silver et al, 2003, Am J Psych, 160, pp 1809-1816). The odour span task (OST), developed by Dudchenko and colleagues (2000, JNeurosci, 20, pp 2964-2977), is designed to measure non-spatial working memory (WM) capacity in rats. This task may be useful for assessing non- spatial WM dysfunctions in animal models of schizophrenia. Methods: 10 adult female Lister Hooded rats were food restricted to 90% free feeding weight and trained daily for 9 weeks to identify novel scented lids from an increasing number of previously encountered scents, to obtain a food reward (Galizio et al, 2013, Psychopharm, 225, pp 397-406). When rats reached criterion in the OST they were either treated with vehicle (0.9% saline; i.p.) or PCP (2 mg/kg; i.p.) twice per day for 7 days followed by a 7-day washout period. Both treatment groups were tested in the novel object recognition (NOR) task to assess the scPCP-induced recognition memory deficits before being tested in the OST across 3 days. Once baseline was established, using a within subjects’ design, rats were treated with vehicle, risperidone (0.1 mg/kg; i.p.) or haloperidol (0.05 mg/kg; i.p.) and their WM capacity was assessed in the OST, followed by a 7-day washout period. A38 ABSTRACTS

Span was the number of novel scented lids correctly identified – 1. Both the first span per session and the highest span per session were analysed by one-way ANOVA, followed by post-hoc Tukey test. Results: During the initial training period, rats’ spans appeared to stabilise after 12 OST training sessions. scPCP treated rats could not discriminate between novel and familiar objects in the NOR, confirming the scPCP induced deficit. In the OST, scPCP treated rats demonstrated a significant reduction in spans compared to the vehicle control group, indicating a reduced working memory capacity (P<0.001). During the acute drug study, scPCP treated rats that received haloperidol performed similarly to scPCP control rats, both achieving reduced spans compared to vehicle treated rats (P<0.0001). Treatment with risperidone increased the scPCP treated rats’ spans, compared to scPCP controls (P<0.0001). Conclusion: These results suggest the scPCP-induced deficits present in the OST could be useful in identifying the underlying mechanisms of working memory deficits in schizophrenia. Declaration of interest/funding: MAB, TOM, and TA are full time students at the University of Manchester. JCN has received expenses to attend conferences and fees for lecturing and consultancy work (including attending advisory boards) from the manufacturers of various antipsychotic drugs. JCN, GP and BG are full-time employees of the University of Manchester. This work was funded by the University of Manchester and b-neuro.

B14 SPATIAL WORKING MEMORY DEFICITS IN THE SUB-CHRONIC PHENCYCLIDINE (PCP) MODEL FOR SCHIZOPHRENIA ASSESSED IN THE RADIAL MAZE TASK Farrow LE, Pharmacy, University of Manchester, Stopford Building, Oxford Rd, Manchester, M13 9PL [email protected] Burgess M(1), Podda G(1), Munni S(1), Grayson B(1), Neill JC(1) (1) Stopford Bldg, Univ Dept Pharmacy, Uni of Manchester, M13 9PL Introduction: We have developed a rat model for schizophrenia symptomatology using sub-chronic treatment with the non-competitive NMDA receptor antagonist, Phencyclidine (scPCP) representing a subtype of patients with enduring cognitive dysfunction, negative symptoms and cortical pathology (see Cadinu et al. Neuropharmacology 2017 for review). This study investigates whether consistent spatial working memory (WM) deficits are observed in our scPCP model. Methods: 20 adult female Lister Hooded rats were trained for a maximum of 8 minutes per day for 10 days to make minimal errors in the eight-arm radial maze (RAM) with an Inter-Trial-Interval (ITI) of 10s with all arms baited. Rats then received sub- chronic phencyclidine (scPCP; 2 mg/kg) or vehicle i.p. twice daily for 7 days, followed by a 7-day washout period. Confirmation of a memory deficit due to scPCP treatment was determined using the novel object recognition task (NOR) with a 3-minute acquisition trial, 1-minute ITI and a 3-minute retention trial. Rats were then tested in the RAM, under the same conditions as in training, to measure spatial WM performance. NOR data was analysed by ANOVA and post-hoc Bonferroni test and RAM data was analysed using the Mann- Whitney test. Results: In the retention trial, vehicle but not scPCP, treated rats, rats spent significantly more time (s) exploring the novel object compared to the familiar object (P<0.01). In the first RAM trial, vehicle- treated rats had a mean number of arm re-entries of 0.5 ± 0.22. ScPCP treated rats performed significantly worse (P<0.05) with a mean number of arm re-entries of 3.3 ± 1.01. A second and third trial performed 4 days and 14 days later did not find a significant difference between arm re-rentries for vehicle-treated and scPCP treated rats. There was no significant difference between the time taken to visit all 8 arms in the vehicle- treated and PCP-treated rats in any of the trials. Conclusion: These data do not demonstrate robust spatial WM deficits in our animal model. The 8-arm RAM may not be a suitable task in this case as the number errors caused by random selection due to probability is very low (~3) which is too similar to accidental errors caused by rats with normal WM However, non-spatial WM deficits have been demonstrated in this model (Burgess et al, this meeting) which support the use of this model to identify novel treatments to restore WM deficits in schizophrenia and other disorders with cortical and hippocampal dysfunction.. Source of funding and disclosures: LF is an undergraduate student at the University of Manchester completing their final year laboratory project. MB is an integrated masters student completing their masters project. JCN has received expenses to attend conferences and fees for lecturing and consultancy work (including attending advisory boards) from the manufacturers of various antipsychotic drugs. JCN, GP, SM, and BG are full-time employees of the University of Manchester. This work was funded by the University of Manchester. ABSTRACTS A39

B15 THE NEURAL BASIS OF WORKING MEMORY IMPAIRMENT IN PSYCHOSIS AND ITS RELATIONSHIP TO NEGATIVE SYMPTOMS: AN FMRI STUDY IN FIRST EPISODE PATIENTS Pepper F, Dept of Neuroimaging, IoPPN, King’s College London, PO 089, DeCrespigny Park, London, SE5 8AF [email protected] O’Daly O(1), Kotoula V(1), Jauhar S(2), Howes OD(2) (1) As presenting author; (2) Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, PO 089, DeCrespigny Park, London Aim: To investigate whether neural engagement during increased working memory load would be reduced in drug free first episode patients, and to determine whether this was related to the severity of negative symptoms. Method: 29 antipsychotic naïve/ free patients with first episode psychosis (FEP) and 30 healthy control volunteers were included in the study. Participants were studied using functional magnetic resonance imaging whilst performing the n-back working memory task. Blood oxygen level-dependent (BOLD) response and the Positive and Negative Syndrome Scale (PANSS) were measured. Results: Our analysis revealed that there was greater activation in healthy controls (HC) compared to patients (FEP) when participants performed the 2-back task compared to the 1-back condition in the thalamus (p = 0.010) and hippocampus (p = 0.007). There were no significant correlations between BOLD response and the PANSS negative symptom scores. Discussion: Our findings provide evidence that there is reduced activation in the hippocampus and thalamus in first episode psychosis patients during increased working memory load, but this is not associated with negative symptoms. This suggests that altered hippocampal and thalamic function could underlie cognitive impairments seen in schizophrenia and other psychotic disorders but that other neural systems are involved in negative symptoms. Funding: This research was funded by a grant awarded to Professor Oliver Howes from The Wellcome Trust

C01 THE EFFECT OF POLY (I:C)-INDUCED IMMUNE ACTIVATION ON MOUSE OFFSPRING: A SYSTEMATIC REVIEW AND META-ANALYSIS Kelly JP, Pharmacology and Therapeutics, NUI Galway, Human Biology Building, University Road, Galway, Ireland, H91 W5P7 [email protected] Concannon J(1), Costigan A(1), Gibling A(1), McInerney A(1), Olayiwola O(1), Philip A(1) (1) As presenting author Introduction: Poly (I:C) is a synthetic analogue of double stranded RNA which triggers an inflammatory response that resembles a viral infection. As such it has been used as an animal model if prenatal immune activation, being administered to pregnant animals and the consequent effects on the resultant offspring explored as a model of psychiatric disorders such as schizophrenia and autism. Systematic reviews and meta-analyses of individual investigations have become the mainstay of objectively evaluating the evidence for the efficacy of clinical interventions. However, it is only in very recent times that they have being conducted on laboratory animal investigations. Thus, the aim of this study was to conduct such a review of prenatal administration of Poly (I:C) in the mouse. Methods: This research followed the recommendations of recent publications on conducting systematic reviews in laboratory animals (Hooijmans, CR et al. 2014, ILAR Journal, 55: 418-426). The keywords “Poly (I:C)”, “prenatal immune activation” and “mouse” were used. From the resultant publications, a range of experimental parameters were identified relating both to the characteristics of exposure to the pregnant animals (dose, route, timing) and to the offspring with regard to the behavioural parameters investigated. For the meta-analysis, the mean, standard deviation and group size was derived for Poly (I:C) animals and compared to controls. Results: A total of 81 papers were evaluated for the review, conducted in a globally diverse number of laboratories. A single exposure to Poly (I:C) midway through gestation was most commonly employed, although multiple (2 to 6) exposures were occasionally used. Most studies utilised the intraperitoneal route (5 or 20 mg/kg), whilst the remainder used the intravenous route (5 mg/kg or less). Most commonly, male offspring alone would be investigated, but a number of studies used both male and female subjects A range of behavioural tests were conducted in the offspring, at the adolescent or adult stage. Prepulse A40 ABSTRACTS inhibition (PPI) test was selected for the conduction of a meta-analysis in adult offspring. The effect size (95% confidence intervals) was calculated for each individual study and the pooled effect size was 1.02 (0.12 to. 1.89). Conclusions: A systematic review of prenatal immune activation of Poly (I:C) in the mouse was successfully carried out, identifying its widespread used in a number of laboratories. The meta- analysis revealed a robust behavioural effect in PPI was observed demonstrating the value of the Poly (I:C) exposure as an animal model of schizophrenia. No sponsorship was received for the study

C02 NEUREXIN-1Α (NRNX1Α) HETEROZYGOSITY INDUCES HYPOFRONTALITY AND DEFICITS IN COGNITIVE FLEXIBILITY Hughes RB, BLS, Lancaster University, Bailrigg, Lancaster, LA1 4YW [email protected] Whittingham-Dowd J(1), Bristow G(1), Clapcote S(2), Broughton S(1), Dawson N(1) (1) As presenting author; (2) Institute of Membrane and Systems Biology, University of Leeds, Leeds, LS2 9JT Background: The risk of developing both schizophrenia (SZ) and autism (ASD) is increased by heterozygous deletions in Neurexin-1 (NRXN1). The mechanisms underlying this increased risk, and the symptom domains to which NRXN1 dysfunction contributes remains unclear. Individuals with SZ and ASD show deficits in cognitive flexibility and characteristic alterations in cerebral metabolism including ‘hypofrontality’. Methods: Nrxn1α heterozygous (Hz) mice and their wild-type (Wt) littermates, of both sexes, were tested at 3, 6, 9 and 12 months old using a between-groups design. Associative learning and cognitive flexibility (reversal learning) were assessed in a two choice odour based task. Mice completed two odour discrimination phases (OD1 and OD2) and one reversal learning phase (OD2R). Successful completion of each phase required 6 consecutive correct choices. 64 Nrxn1α Hz and 60 Wt mice entered the odour based task, however not all animals completed all phases of the task. Cerebral metabolism was determined in 49 brain regions using 14C-2-deoxyglucose functional brain imaging (n=40 Nrxn1α Hz, n=39 Wt,). The 14C-2-deoxyglucose uptake ratio in each of the discrete brain regions were statistically treated as independent variables as previously justified (Kelly and McCulloch, 1987. Brain Res. 425(2):290-300). For both the cognitive flexibility task and brain imaging any outliers (±1.96 standard deviations from the mean) were removed from the final analysis. Data were analysed using ANOVA with significance set at p<0.05. Results: Nrxn1α Hz mice showed a deficit in reversal learning (increased trials to criterion [F (1, 91) =4.544, p=0.0357] and decreased percentage correct [F (1, 90) =6.063, p=0.0157]). Nrxn1α Hz mice also showed a deficit in processing speed compared to Wt mice (significantly increased latency for correct choices in OD1 [F (1, 89) =9.475, p=0.00277] and OD2 [F (1, 100) =13.961, p=0.000311]). Functional brain imaging showed that Nrxn1α Hz mice have significantly decreased cerebral metabolism in the prefrontal cortex (medial prelimbic cortex, [F (1, 62) =16.839, p=0.000121]) and increased metabolism in dopaminergic (ventral tegmental area, [F (1, 63) =4.690, p=0.0341]) and serotonergic (dorsal Raphé, [F (1, 63) =13.265, p=0.000548]) brain regions. Conclusions: Nrxn1α Hz mice show SZ and ASD relevant deficits in cognition and cerebral metabolism, including a deficit in cognitive flexibility, processing speed and hypofrontality. Brain imaging data also support neuromodulatory neurotransmitter system dysfunction as a consequence of Nrxn1α heterozygosity. These data give new insight into the mechanisms by which NRXN1 heterozygosity increases the risk of developing SZ and ASD. Financial Support: This work was supported by Lancaster University.

C03 NEUREXIN 1 (NRXN1) HETEROZYGOSITY IMPACTS ON GUT ARCHITECTURE AND INDUCES GUT DYSBIOSIS Whittingham-Dowd JK, Division of Biomedical and Life Sciences, Lancaster University, LEC1 Lancaster, LA1 4YQ [email protected] Hughes R(2), Bristow G(2), McMaster E(2), Clapcote SJ(1), Rigby RJ(2), Dawson N(2) (1) Institute of Membrane and Systems Biology, University of Leeds, Leeds LS2 9JT; (2) As presenting author Introduction: The microbiota is central to gut homeostasis/ overall health with gut-dysbiosis linked to morbidity. Gut and brain are linked via multiple, bidirectional, communication mechanisms thus the ABSTRACTS A41 microbiota’s potential role in psychiatric/ neurodevelopmental disorders (PNDs) has received increased attention. Heterozygous deletions of Neurexin1 (NRXN1) are associated with increased risk of developing autism (ASD) and schizophrenia (SZ). Microbiome dysfunction has been reported in ASD (Li et al., 2017. Front Cell Neurosci. 11:120 ) and SZ (Lv et al., 2017. Oncotarget. 8(59)100899) however, whether genetic risk factors for these disorders can induce gut dysfunction/ dysbiosis is yet to be established. Here we characterise gut architecture/ microbiota composition in Nrxn1α heterozygous (Nrxn1αHz) mice to test the hypothesis that genetic risk factors for SZ/ASD can induce gut-dysbiosis. Methods: Nrxn1αHz mice and wild-type (Wt) littermates (8-12 weeks/both sexes) were housed in mixed genotype cages with ad-libitum access to food/ water (n=5 per sex/genotype). Gut samples were snap frozen or fixed in metha-carnoys. Community profiling of bacteria, extracted from intestinal contents, was achieved by Denaturing Gradient Gel Electrophoresis (DGGE) as previously described (Houlden et al., 2015. PlosOne. 10:e0125945). Multivariate analysis and non-parametric multidimensional scaling (NMDS) assessed bacterial communities using bray-curtis dissimilarities. qPCR determined bacterial phyla abundance and histological analysis examined gut architecture. Data were statistically analysed by two-way ANOVA with significance set at p≤0.05. Results: Nrxn1αHz mice showed significantly increased colonic crypt length (F=61.93 p<0.0001) and goblet cells (F=75.73 p<0.0001) in comparison to Wt, suggestive of gut hyperplasia. Overall gut bacteria composition was altered in Nrxn1αHz compared to Wt mice however, this effect only reached significance in females (F=7.6228 p=0.029) suggesting sex-dependent effects. qPCR analysis of the bacterial phyla; bacteriodetes, firmicutes and γ-proteobacter revealed a significant decrease (F=36.547 p=0.034) in the abundance of firmicutes, but not the other phyla, in Nrxn1αHz mice of both sexes, further supporting gut-dysbiosis. Conclusions: These data are the first showing gut-dysbiosis and structural alterations as a consequence of reduced Nrxn1α expression, and suggest that gut-dysbiosis may contribute to the influence of this gene on the risk of developing SZ/ASD. Further studies are required to test this hypothesis and explore the mechanistic link between gut-dysbiosis and brain dysfunction as a result of Nrxn1α heterozygosity. Future studies in other risk gene models will provide additional evidence to test the hypothesis that gut-dysbiosis is a key mechanism through which SZ/ASD risk genes increase the likelihood of developing these disorders. No sponsorship was received for this study.

C04 ASSESSING EFFECTS OF ATOMOXETINE AND METHYLPHENIDATE ON ATTENTION USING 5-CHOICE SERIAL REACTION TIME TASK (5-CSRTT) Jiang W, The University of Manchester, Manchester Pharmacy School, M13 9PT wanqing.jiang@student. manchester.ac.uk Burgess MA(1), Aarons T(1), Fitzpatrick CM(1), Hayward A(1), Grayson B(1), Neill JC(1) (1) As presenting author Introduction: Inattention is associated with psychiatric disorders such as attention deficit/hyperactivity disorder (ADHD) (Robbins, 2002, Psychopharmacology, 219(2), 341-352). Current pharmacotherapies were not developed to target different symptom types of ADHD (inattentive, hyperactive-impulsive and combination type) and precise mechanisms of atomoxetine (noradrenaline transporter (NAT) reuptake inhibitor) and methylphenidate (dual NAT and dopamine transporter (DAT) reuptake inhibitor) require investigation (Hayward et al., 2016, Pharmacology and Therapeutics, 158, 41-51; Fernando et al., 2012, Psychopharmacology, 219(2), 341-352). This study aimed to assess effects of atomoxetine and methylphenidate on attention in high (HA) and low attentive (LA) animals using the 5-choice serial reaction time task (5-CSRTT). Methods: Female Lister hooded rats were trained in a variant of 5-CSRTT previously described by Martin et al (Martin et al.,2015, Journal of Neuroscience Methods, 241, 37-43), in which the duration of visual stimuli was titrated between trials according to performance. Animals were separated into HA and LA subgroups according to baseline percentage correct responses after their performance stabilized under baseline conditions (stimulus duration (SD): 0.5 sec, inter-trial interval (ITI): 5 sec). During testing, animal attentional load was challenged using a variable SD (0.25, 0.5 and 0.75 sec) to assess the acute effects of atomoxetine (0.5, 1.0 and 2.0 mg/kg, i.p.) and methylphenidate (0.5, 1.0 and 2.0 mg/kg, i.p.). One-way and two-way ANOVA were used to analyse drug effects on the mean values of A42 ABSTRACTS each parameter averaged across all SD and within each SD respectively, followed by Dunnett’s post hoc test. Results: 1.0 and 2.0 mg/kg Atomoxetine dose-dependently increased omissions (1.0 mg/kg: p=0.0006; 2.0 mg/kg: p=0.0001) and decreased premature responses (1 mg/kg: p=0.0038; 2 mg/kg: p=0.0001) in all animals. 2.0 mg/kg atomoxetine also decreased accuracy in LA animals when challenged by 0.5 sec SD (p=0.048) and increased incorrect response latency in LA animals (p=0.011). Although no significant effect of methylphenidate was shown on accuracy or other behavioural parameters, 2.0 mg/kg methylphenidate significantly decreased omission levels in LA animals at 0.25 sec SD (p=0.030). Discussion: These findings suggest that atomoxetine was effective in reducing impulsivity while worsening attention in all animals. In contrast, methylphenidate increased attention in LA animals. Therefore, inhibition of noradrenaline reuptake is effective in decreasing impulsivity, while blocking both NAT and DAT is an important target for improving attention. This provides great insights in personalizing treatment for different ADHD subclasses and development of pharmacotherapies in the future. Experiments were conducted in accordance with the UK Animals (Scientific Procedures) 1986 Act and the ethical guidelines of the University of Manchester. Conflict of interest: None. Financial Sponsorship: This work was funded yb the University of Manchester and b-neuro

C05 A NEUROCOMPUTATIONAL ACCOUNT OF REWARD AND NOVELTY PROCESSING AND EFFECTS OF PSYCHOSTIMULANTS IN ATTENTION DEFICIT HYPERACTIVITY DISORDER Sethi A, Department of Neuroscience, BSMS, University of Sussex, Clinical Imaging Sciences Centre, Falmer Campus, Sussex, BN1 9RR [email protected] Voon V(2), Critchley HD(1), Cercignani M(1), Harrison NA(1) (1) As presenting author; (2) Department of Psychiatry, University of Cambridge Introduction: Computational models of reinforcement learning have helped dissect discrete components of reward-related function and characterize neurocognitive deficits in psychiatric illnesses. Stimulus novelty biases decision-making, even when unrelated to choice outcome, acting as if possessing intrinsic reward value to guide decisions toward uncertain options. Heightened novelty seeking is characteristic of attention deficit hyperactivity disorder (ADHD), yet how this influences reward-related decision-making is computationally encoded, or is altered by stimulant medication, is currently uncertain. Methods: Here we used an established reinforcement-learning task to model effects of novelty on reward-related behaviour during functional MRI in 30 adults with ADHD and 30 age-, sex- and IQ-matched control subjects. Each participant was tested on two separate occasions, once ON and once OFF stimulant medication. Results: OFF medication, patients with ADHD showed significantly impaired task performance (p = 0.027), and greater selection of novel options (p = 0.004). Moreover, persistence in selecting novel options predicted impaired task performance (p = 0.025). These behavioural deficits were accompanied by a significantly lower learning rate (p = 0.011) and heightened novelty signalling within the substantia nigra/ventral tegmental area (FWE p < 0.05). Compared to effects in controls, stimulant medication improved ADHD participants’ overall task performance (p = 0.011), increased reward-learning rates (p = 0.046) and enhanced their ability to differentiate optimal from non-optimal novel choices (p = 0.032). It also reduced substantia nigra/ventral tegmental area responses to novelty. Preliminary cross-sectional evidence additionally suggested an association between long-term stimulant treatment and a reduction in the rewarding value of novelty. Conclusions: These data suggest that aberrant substantia nigra/ventral tegmental area novelty processing plays an important role in the suboptimal reward-related decision- making characteristic of ADHD. Compared to effects in controls, abnormalities in novelty processing and reward-related learning were improved by stimulant medication, suggesting that they may be disorder- specific targets for the pharmacological management of ADHD symptoms. Funding: This work was supported by a Wellcome Trust Intermediate Fellowship (093881/Z/10/Z) to NAH, Brighton and Sussex Medical School and the Dr. Mortimer and Dame Theresa Sackler Foundation. ABSTRACTS A43

C06 METHYLPHENIDATE AND ATOMOXETINE NORMALISE FRONTO-PARIETAL ACTIVATION IN ADHD DURING SUSTAINED ATTENTION Kowalczyk OS, Child and Adolescent Psychiatry, IoPPN, KCL, De Crespigny Park, London, SE5 8AF [email protected] Cubillo A(1), Smith AB(1), Barrett N(1), Giampietro V(2), Brammer M(2), Simmons A(2), Rubia K(1) (1) As presenting author; (2) Dept of Neuroimaging, IoPPN, KCL, De Crespigny Park, London, SE5 8AF Introduction: Problems with sustained attention in Attention Deficit/Hyperactivity Disorder (ADHD) are evident in performance scores and functional Magnetic Resonance Imaging (fMRI) correlates. Methylphenidate (MPH) and atomoxetine (ATX) are widely used to improve inattention symptoms and have been shown to improve attention performance. Despite this evidence no fMRI study so far has compared the effects of these two drugs on the neurofunctional correlates of sustained attention. This study, therefore, tested the comparative neurofunctional effects of MPH and ATX during performance of a sustained attention task in ADHD adolescents. Methods: Fourteen medication-naive ADHD youths (10-17 years) and 27 age-matched healthy controls performed a parametric sustained attention/vigilance task in a 3T MRI scanner (Christakou et al., 2013, Molecular Psychiatry 18(2), 236–244). The task required to respond to a visual stimulus presented after varying long and short delays. Patients were scanned in a double-blind, placebo-controlled, randomised crossover design under a single dose of either placebo (Vitamin C, 50mg), MPH (Equasym, 0.3mg/kg), or ATX (Strattera, 1mg/kg). Healthy controls were scanned once, unmedicated, and compared to patients under each drug condition to test for potential normalisation effects of each drug. fMRI data were analysed using non-parametric data analysis in XBAM (www. brainmap.co.uk). A voxel-wise test at p<0.05 was conducted to identify activated voxels, subsequently a cluster-level threshold of p<0.01 was applied to remove any false positive clusters produced by the voxel-level test. Results: ADHD patients under placebo were impaired in task performance relative to controls which was normalised with MPH but not ATX. ADHD patients under placebo relative to controls had reduced activation in right dorsolateral/inferior prefrontal cortex and in a large posterior cluster including posterior cingulate/precuneus, inferior parietal, and striato-thalamic areas. When patients were compared to controls under MPH and ATX the differences were no longer observed. Conclusions: This study shows shared normalisation effects of MPH and ATX on fronto-parietal brain dysfunction in ADHD during sustained attention. The findings extend previous findings of shared normalisation effects on inferior frontal dysfunction during cognitive control (Cubillo et al., 2014, Cerebral Cortex 24(1), 174–185) and timing (Smith et al., 2013, Biological Psychiatry 74(8), 615–622) by showing more widespread shared normalisation effects on typical regions mediating sustained attention such as the dorsolateral prefrontal cortex, inferior frontal cortex, inferior and superior parietal, and striato-thalamic regions. The shared normalisation effects on attention network dysfunction in ADHD may underlie their clinical efficacy in improving inattention symptoms in ADHD. This study was supported by Lilly. OSK, AC, AS and ABS were supported by the Department of Health via the NIHR-BRC for Mental Health at SLaM and KCL.

C07 MATERNAL IMMUNE ACTIVATION IS ASSOCIATED WITH REDUCED PLACENTAL GROWTH AND ALTERED PLACENTAL GENE EXPRESSION IN A RAT MODEL FOR SCHIZOPHRENIA Kowash HM, Division of Developmental Biology and Medicine, University of Manchester, Maternal and Fetal Health Research Centre 5th Floor (Research) St. Mary’s Hospital Oxford Road Manchester, M13 9WL [email protected] Yinou X(1), Potter HG(2), Munni STM(3), Hager R(2), Neill JC(3), Glazier JD(1) (1) As presenting author; (2) Division of Evolution and Genomic Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, Manchester, M13 9PT, UK; (3) Division of Pharmacy & Optometry, Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, Manchester, M13 9PT, UK Introduction: Maternal immune activation (mIA) is associated with increased susceptibility to neurodevelopmental disorders such as schizophrenia in offspring, although underlying mechanisms A44 ABSTRACTS remain unclear. We hypothesised that mIA, induced by the viral mimetic polyinosinic:polycytidylic acid (poly(I:C)), promotes proinflammatory cytokine responses that impair placental growth and amino acid transporter capacity, leading to altered fetal development and predisposition to schizophrenia later in life. Methods: At gestational day (GD) 15 (GD1=day of mating), pregnant Wistar rats were treated with poly(I:C) (10mg/kg i.p.; InvivoGen, N=16) or saline control (N=14). Maternal weight was monitored and tail-vein blood collected at 2h and 3h post-injection for measurement of pro-inflammatory cytokines (IL-6, TNF-α, IL-1β). Litter size, placental, fetal and fetal brain weights were recorded on GD15 (3h post-injection), GD16 and GD21 respectively, and fetuses were sex-typed. Fetuses were randomly selected for cDNA generation from matched placental and fetal brain samples for quantification of Il6, Tnf and Il1b gene expression. Placental expression of Slc7a5, Slc7a8 and Slc43a2 genes encoding system L amino acid transporter subtypes (LAT1, LAT2 and LAT4 respectively) was also measured. A 2-way ANOVA with multiple comparisons was used for statistical analysis. Results: At 2h and 3h after poly(I:C) injection, on GD15, maternal plasma IL-6 and TNF-α concentration was significantly increased (P<0.05); but not IL-1β. This pro- inflammatory response was followed by a significant reduction in maternal bodyweight at 6h (P<0.0001). Litter size, fetal sex frequency, fetal weight and fetal brain:bodyweight ratio were unaffected by treatment. In poly (I:C) group, 13% (female) and 16% (male) at GD16; 13% (female) and 32% (male) at GD21, had a placental weight <5th centile of control population (index of restricted growth). At 3h following poly(I:C) treatment, placental Il6 gene expression was elevated (P<0.005), but was unaltered by GD16. Il6 mRNA expression in matched fetal brain was unaltered. Tnf and Ilb1 gene expression was unaffected in placenta and fetal brain at both GD15 and GD16. Placental expression of Slc7a5, Slc7a8 and Slc43a2 mRNA was significantly reduced at GD15 (P<0.05), but unaltered at GD21. Conclusion: Poly (I:C) injection elicited an acute inflammatory response in pregnant rat dams, with increased Il6 mRNA expression in placenta, but not fetal brain, demonstrating tissue-specific effects. Poly (I:C) treatment was associated with diminished placental growth, without impact on fetal weight or fetal brain:bodyweight ratio, suggesting altered placental function to maintain fetal growth. Reduced placental system L gene expression associated with mIA was observed on GD15, although not sustained. This is likely to evoke changes in placental transport capacity affecting fetal development. Supported by President’s Doctoral Scholar Award.

D01 THE USE OF DEPOT/LONG-ACTING INJECTABLE ANTIPSYCHOTIC MEDICATION FOR RELAPSE PREVENTION IN SCHIZOPHRENIA IN THE UK Barnes TRE, Centre for Psychiatry, Imperial College London, Commonwealth Building, Du Cane Road, London, SE5 8AF UK [email protected] Bari MJ(3), Craig TKJ(2), Paton C(1) (1) Centre for Psychiatry, Commonwealth Building, Imperial College London, SE5 8AF; (2) Institute of Psychiatry, Psychology and Neuroscience, King’s College London, SE5 8AF; (3) The Prescribing Observatory for Mental Health, Royal College of Psychiatrists, London E1 8BB Introduction: In 2017, the Prescribing Observatory for Mental Health initiated a quality improvement programme addressing compliance with evidence-based practice standards relating to continuing treatment with depot/LAI antipsychotic medication for relapse prevention in schizophrenia. Method: 59 NHS Trusts participated in the baseline audit, submitting data on the treatment of 7441 patients under the care of adult mental health services, prescribed depot/LAI antipsychotic medication. Results and conclusions: The audit revealed a high level of psychiatric morbidity in that a quarter of the patients in the national sample were detained in hospital under the Mental Health Act and just over half were outpatients subject to the Care Programme Approach. Those patients on a depot/LAI antipsychotic for more than a year tended to be relatively stable clinically: fewer than 20% admitted to hospital or in contact with a crisis/home treatment team in the previous year. However, the data on patients recently initiated on depot/ LAI antipsychotic medication suggested that such medication tends to be started during a period of clinical instability: over two-thirds (68%) admitted to hospital and/or in contact with a crisis/home treatment team in the past year. This finding has implications for the interpretation of observational, real-world studies of the effectiveness of depot/LAI antipsychotic treatment. Over 90% of the patients had an accessible care plan, and 80% of such plans included a crisis plan. In over a quarter of the care plans, self-neglect and ABSTRACTS A45 social withdrawal/isolation were noted as early signs of relapse, behaviours that may be less likely to come to the attention of clinical services. In over 10% of care plans, patient-specific (idiosyncratic), early signs and symptoms of relapse were not documented, so the opportunity to intervene at a prodromal stage may have been lost. Although the most common clinical rationale for initiating treatment with a depot/ LAI antipsychotic preparation was to improve medication adherence, the findings suggested that poor adherence can remain a problem, in that, over a six-month period, around 10% of patients failed to receive at least one of the injections prescribed. Further, there was no clinical plan to address default from depot/ LAI antipsychotic treatment in just over a third of the national sample. Further, more than 10% of those patients on long-term treatment had not had their medication reviewed within the past year. POMH-UK is funded solely by subscriptions from member healthcare organisations, principally NHS trusts.

D02 IMPACTS OF CAFFEINE INTAKE UPON CLOZAPINE USERS Patel KR, FY1 in Aston CMHT, BSMHFT, NHS, Orsborn House 0121 301 1710 55 Terrace Road, Handsworth, Birmingham, West Midlands, B19 1BP [email protected] Sain K(1) (1) As presenting author Introduction: Clozapine is a widely-used drug used in the management of treatment resistance schizophrenia. This study highlights a relatively unknown danger that caffeine may potentiate seizures in clozapine users. Clozapine is an atypical antipsychotic metabolised by CYP1A2. Patients with psychosis are reported to often consumer higher quantities of caffeine compared to the public with over 50% consuming greater than 500mg per day. Caffeine is an CYP1A2 inhibitor and therefore high levels will cause clozapine levels to rise in patients. High clozapine levels are associated with a host of side effects including seizures, cardiac arrhythmias and hepatitis. Methods: There are 94 patients using clozapine on our team’s caseload. We retrospectively analysed their latest clozapine level and found 15 users to have raised levels. We invited these patients to undergo a questionnaire regarding their side-effect profile and understanding of how caffeine interacted with their medication. We also measured their caffeine and clozapine blood levels. Patients found with high caffeine levels were counselled to reduce their caffeine intake and their clozapine and caffeine blood levels were measured at a two-weekly interval to see what impact it had on their clozapine level. Results: The questionnaire revealed that 53% of the patients were experiencing clozapine related side-effects and that 100% of the patients were unaware of the effects caffeine could have on their medication. Compliancy with the blood tests and factors such as polypharmacy were issues and only 55% of the original sample group were eligible for analysis of the relationship between caffeine and clozapine. Blood tests revealed 50% of patients with raised clozapine levels also had caffeine intakes significantly above the recommended daily intake. Reduction of caffeine intake to within recommended limits caused on average a 29% reduction in clozapine level over a two-week basis. Conclusions: Our results suggest that our patients require mandatory lifestyle advice regarding the impacts of caffeine on the medication. This is especially important when switching between in and outpatient environments where dietary habits are likely to change. We believe that caffeine levels should be assessed in any patient presenting with a high clozapine level and reductions to caffeine intake should be attempted prior to alterations to drug dosages. Given that the study was underpowered, statistical analysis was not appropriate, however we have presented our data to Birmingham and Solihull Mental Health Foundation Trust who have agreed to fund a larger study in the Aston community mental health team. A46 ABSTRACTS

D03 IS THERE REBOUND PSYCHOSIS ON ANTIPSYCHOTIC WITHDRAWAL IN SCHIZOPHRENIA? Taylor MJ, IOPPN, King’s College London, SE5 8AF [email protected] Yim S(1) (1) King’s College London Introduction: It is well established that dopamine antagonist medications, antipsychotics, have an important role in the prevention of relapse in schizophrenia and other psychoses. Meta-analysis of randomised controlled trials indicates continuation of medication is associated with fewer relapses over the next year than discontinuation. There has been ongoing debate as to whether adaptive changes such as dopamine supersensitivity may lead to rebound psychosis on medication withdrawal, which could inflate the apparent benefit of continuing medication. Some previous reviews including observational studies have suggested increases in relapse rate are most substantially elevated in the first three months following discontinuation, consistent with an early rebound effect. We report a meta-analysis of randomised trials comparing continuation and discontinuation strategies using time to event data to allow comparison of effects between different time periods post-randomisation. Methods: Studies in which people with a diagnosis of schizophrenia were randomised to either continue on, or withdraw, an antipsychotic medication, after initial stabilisation were identified from a previous systematic review. Of these studies the subset presenting survival curves were identified. Summary statistics were extracted from the published survival curve data to allow Hazard Ratios (HR) to be calculated. These were combined by generic inverse variance meta-analysis using R. Results: Studies in which thousands of people had been randomised to continue or discontinue medication were identified for analysis. Over the first three months following randomisation, data from k = 14 studies (n = 3390 participants randomised) showed a highly consistent reduction in risk of relapse with continuing pharmacological treatment of around HR 0.35 (95% CI 0.29 to 0.48). Data up to six months (k=12, n=2656) were also similar (months 4-6: HR 0.32, 95% CI 0.21 to 0.48). Conclusions: These data from meta-analysis of randomised controlled trials indicate a lower risk of relapse in those randomised to continue antipsychotic medications. The consistent hazard ratio over time indicates no general rebound phenomenon is seen, although a specific effect of particular agents, or in particular populations, cannot be excluded from this overall analysis. Financial Sponsorship: None

D04 A RETROSPECTIVE, MIRROR-IMAGE STUDY OF THE EFFECTIVENESS OF ARIPIPRAZOLE LONG ACTING INJECTION ON HOSPITALIZATION RATES AND HOSPITAL IN-PATIENT STAY FOLLOWING INITIATION OF ARIPIPRAZOLE LONG ACTING INJECTION Secchi A, Pharmacy, Kent and Medway NHS Partnership Trust, Priority House. Hermitage lane Maidstone, ME16 9PH [email protected] Background/Introduction: Long acting injection antipsychotics (LAIs) have been proved to reduce hospitalisation rates compared to oral antipsychotics (Kishimoto T. et al (2013). Journal of Clinical Psychiatry. 74 (10): 957-965). A previous naturalistic study conducted in North America has demonstrated the efficacy of aripiprazole long acing injection (AP LAI) in preventing relapse and hospital readmission (Kane JM et al (2013). J MedEcon. 16(7): 917-925). Hence, the need for a similar study to confirm these findings. Aims and Objectives: This evaluation explores whether the use of aripiprazole LAI (AP LAI) reduces the hospitalization rates and the hospital stay in patients with a diagnosis falling into the F20-F29 category of the International Classification of disease (ICD-10). Psychiatric hospitalizations (primary endpoint) and psychiatric hospital stay (secondary endpoint) were compared before and after initiation of AP LAI. Method/Design: This service evaluation was designed as a quantitative study. Data were collected retrospectively for 74 patients. Patients needed to have a minimum of 6 months of clinical data records before and after initiation of AP LAI. Data were analysed using the SPSS statistical package. Results: The mean number of admissions before and after initiating AP LAI dropped from 0.76 (median 1.00, standard deviation SD=0.718) to 0.47 (median 0.00, SD=0.968), p=0.006. Most of the participants had one (18.9%) or no admission (71.6%) after initiation of AP LAI (cumulative percent 90.5%). The analysis showed a mean increment of hospital stay (21.86 days before AP and 28 days after AP) and a median reduction in hospital ABSTRACTS A47 stay (5.50 to 0). However, this result was not statistically significant: p=0.429. The data were skewed by a small number of patients who required a long hospitals stay. Discussion and Conclusion: The analysis showed a reduction of hospital admissions after initiation of AP LAI. The results of the data verify previous research addressing in-patient psychiatric hospital admission rates and the use of AP LAI (Kane JM et al (2013). J MedEcon. 16(7): 917-925). However, length of stay was significantly impeded by lack of social care resource as the trust was unable to discharge patients who were deemed able and fit. The analysis showed that there was sometimes a lack of knowledge on the use of AP LAI leading to earlier discontinuations of the treatment or to dose reductions. No financial sponsorship form a private pharmaceutical company was granted for this study. Kent and Medway NHS Social care and Partnership Trust was the only sponsor for this study.

D05 A COMPLETED AUDIT CYCLE ON PHYSICAL HEALTH MONITORING OF PATIENTS ON ANTI- PSYCHOTICS Chinnasamy M, OAP, CAV, Castleside Offices, Campus for Ageing and Vitality, Westgate Road, Newcastle Upon Tyne, NE4 6BE [email protected] Wilkinson C(1), De Ivey R(1), Albarri M(1), Wilson S(1) (1) Mental Health Services for Older People, North Tynside General Hospital, North Shields NE29 8NH Background: NICE guidelines and the Maudsley Prescribing guidelines recommended specific monitoring of physical health parameters for patients initiated and maintained on anti-psychotic treatment. Previous audits have been done on anti-psychotic treatment on dementia patients but we would like to audit compliance with these guidelines among functional patients (elderly patients without dementia) managed by Community Mental Health Teams within Mental health Services for Older people, North Tyneside locality. Aims and Objectives: 1. To determine whether patients initiated or maintained on antipsychotic medications are monitored in accordance with the NICE endorsed Lester tool http://www. rcpsych.ac.uk/pdf/e-version%20NICE%20Endorsed%20Lester%20UK%20adaptation%20.pdf 2. In case of non-compliance with the guidelines, to find areas for improvement and to make recommendations to improve our clinical practice 3. Re-audit to see whether recommended changes has helped to improve the current clinical practice. Methodology: A list of functional patients on anti-psychotics, who were open to Community Mental Health Teams within Mental Health Services for Older people, was gathered between December 2016 and April 2017. Re-audit was done between October 2017 and December 2017. Results: In the initial audit, 41 patients were identified to be on anti-psychotics. Out of 41 patients, 20 patients were started on anti-psychotics during this time period and the rest were on maintenance anti-psychotics. This audit identified areas of particular concern including reviews at baseline, weekly, 3 monthly and also at annual review. Parameters like weight/BMI, waist circumference, adherence check, lifestyle review, Blood pressure/pulse rate, medical history review and Serum Prolactin measurements were monitored at variable rate. During re-audit, it was noted that anti-psychotic was started in 14 patients during that time period. Results of re-audit showed overall improvement in physical health monitoring and specifically on measuring serum Prolactin levels. There was no statistical analysis done to highlight the significance in difference. Conclusions: Initial audit results were discussed at the consultants meeting within Mental Health Services for Older people and it was agreed to make slight amendments to the monitoring standards after taking into consideration the co-morbidities associated with geriatric population and the practicality of monitoring their physical health. It was agreed not to emphasize on measuring weight/ waist circumference at the baseline and on weekly measurements of weight. This completed audit cycle demonstrates there is ongoing need to ensure physical health monitoring of patients on antipsychotics. No sponsorship/ funding needed to complete this audit A48 ABSTRACTS

D06 CELECOXIB PLUS STANDARD CARE FOR PEOPLE WITH SCHIZOPHRENIA: A COCHRANE REVIEW Kotecha AN, University of Birmingham, Medical School, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT [email protected] Upthegrove R(1) (1) The Barberry, 25 Vincent Drive, Birmingham, B15 2FG Introduction: There is some evidence that the COX-2 inhibitor celecoxib has use in the treatment of schizophrenia, as an adjunct to antipsychotics. However, there is also evidence which contradicts this conclusion, and evidence suggesting that celecoxib increases cardiovascular risk. Recently published reviews on this topic have several limitations, including performing literature searches in English and Chinese databases only. The objective of this systematic review was to evaluate the efficacy and safety of celecoxib, used as an adjunctive therapy, in people with schizophrenia. Methods: On January 26, 2018, a review of the Cochrane Schizophrenia Group’s Study-Based Register of Trials was conducted (including trial registers), with the aim to search a broader range of databases than previous reviews. We included all relevant ‘double-blind’ randomized controlled trials (RCTs) which compare adjunctive celecoxib, and either; antipsychotics, interventions other than antipsychotics, placebo in combination with antipsychotics, placebo, or no treatment. References of included studies were searched for relevant trials. Studies included in a 2017 meta-analysis were screened for eligibility. Mean differences (MDs), standardized mean differences (SMD), risk ratios (RR) and their 95% confidence intervals (CIs) were calculated. Sensitivity analyses, funnel plots, and a subgroup analysis were conducted. Results: 7 RCTs were included in quantitative synthesis, with a total of 552 patients with schizophrenia. Celecoxib did not significantly outperform placebo with regards to overall improvement in global state, overall improvement in mental state, or improvement in positive symptoms, negative symptoms, general psychopathology, or depressive symptoms. In the ‘early illness’ subgroup, celecoxib significantly outperformed placebo with regards to improvement in overall mental state, positive symptoms, negative symptoms and general psychopathology. However, celecoxib did not outperform placebo with regards to these outcomes in the ‘all other studies’ subgroup. There was no significant difference in the incidence of cardiovascular adverse effects between celecoxib and placebo in the overall analysis, or in either subgroup. Conclusions: Adjunctive celecoxib’s potential benefit with regards to overall mental state in patients with an early stage of schizophrenia may be the result of an accumulation of small improvements in specific symptoms. djunctiveA celecoxib is likely to be safe for use in patients with schizophrenia. Further high quality and large RCTs with longer follow up periods are needed to confirm whether celecoxib is safe and significantly efficacious in patient subgroups, such as first episode schizophrenia. However, evidence to date suggests that it may be an effective additional treatment. No financial sponsorship was received for this study.

D07 THE APPLICATION OF N-OF-1 TREATMENT TRIALS IN SCHIZOPHRENIA: A SYSTEMATIC REVIEW Marwick KF, Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK, EH10 5HF [email protected] Stevenson AJ(1), Davies C(1), Lawrie SM(1) (1) As presenting author Introduction: N-of-1 trials are prospective crossover studies of a single patient exposed to different treatment conditions. They allow evidence-based treatments for individual patients, rather than groups of patients. N-of-1 trials could therefore be particularly helpful in illnesses with multiple subtypes and chronic, relatively stable courses, such as schizophrenia. Their use is facilitated by the increasing availability of self-monitoring mobile phone applications, providing patient-entered and patient-centred measures of response and harm. This study therefore aimed to identify when and how n-of-1 trials have been used in schizophrenia. Methods: Major electronic databases were systematically searched for n-of- 1 studies in schizophrenia, published in English from the start of records until the end of January 2017. Reporting of studies was assessed against the CENT 2015 checklist and quality of studies was assessed using the Cochrane risk of bias criteria. Results: Six studies met inclusion criteria. The studies showed wide ABSTRACTS A49 variation in methodology and data analysis. Interventions were mixed in nature: two pharmacological, two psychological and two physical. All trials found positive outcomes for the intervention under investigation, however, all suffered from a lack of clarity and depth of reporting and were at high risk of bias. Conclusions: N-of-1 trials have been performed successfully but infrequently in schizophrenia. Future trials should employ more standardised methods of design, execution and analysis. Declarations of interest: SML has received grants and personal fees from Janssen, and personal fees from Otsuka and Sunovion, in the past three years, outside the submitted work. The other authors have no conflicts of interest to declare. Financial Support: This work was partially funded by the Wellcome Trust 4 year PhD programme in Translational Neuroscience – training the next generation of basic neuroscientists to embrace clinical research (Ref: 108890/Z/15/Z) (AS and CD), and by a Postdoctoral Clinical Lectureship awarded to KM by NHS Education for Scotland and the Chief Scientist Office (Ref: PCL/17/01).

D08 BLUNTED AFFECT AND SUICIDE IN SCHIZOPHRENIA: A SYSTEMATIC REVIEW Grigoriou MG, Psychiatry, University of Birmingham, 56 Bath Row, Flat 44, B15 2DG mxg424@student. bham.ac.uk Bortolotti LB(1), Upthegrove RU(2) (1) 52 Pritchatts Road University of Birmingham; (2) Institute of Clinical Science and School of Psychology The Barberry National Centre for Mental Health 25 Vincent Drive Birmingham B15 2FG Introduction: The lifetime risk of suicide and suicide attempt in patients is 5% and 25%–50% respectively. Most of the existing studies have focused solely on the association between positive symptoms and suicide (Palmer et al., 2005, Archives of general psychiatry, 62(3), pp.247-253; Hor et al., 2010, Journal of Psychopharmacology, 24(4_suppl), pp.81-90). This review serves to expand on the literature by additionally examining the association between affective symptoms and suicidal behaviour in schizophrenia. This review summarized the findings of papers on the relationship between blunted affect (BA) and suicide in schizophrenia. Methods: A comprehensive search strategy using PRISMA guidelines was adopted to identify the potential studies and data that met our inclusion criteria. We searched the original studies through MEDLINE (R) from 1946 to 2016, EMBASE from 1947 to 2016 and PsycINFO from 1806 to 2016. Inclusion criteria were met if an article has reported any kind of correlation between negative symptoms (NS) and suicide ideation, attempted suicide or completed suicide in patients with schizophrenia. Related studies were examined manually. Results: The initial search found 878 papers. Of those, only 12 papers fulfilled the inclusion criteria. Eight of the eligible papers reported a positive association between the negative symptom of blunted affect and suicide. Particularly diminished affective expression was the main factor these papers identify as potential risk factors for suicide, with one paper identifying a positive association between BA and suicidal behaviour (p<0.01 for BA to predict suicidal behaviour and r=o.33 indicating positive correlation between BA and suicidality).Another study suggests approximately 47% of those with affective symptoms attempted suicide. Two papers report no significance between AB and suicide, with NS being less prominent factors in suicide. One paper showed no direct link between BA and suicide, but it can lead to developing a suicidal behaviour through a negative evaluation of the self. The last paper demonstrated blunted affect as a suicide risk factor in patients with psychotic symptoms with suicidal themes. Conclusions: Based on the best available data, our results show that blunted affect and related emotional disturbances have a potential association with suicide in schizophrenia. Despite major suicide risk factors (e.g., hopelessness and depression), blunted affect may also be an important suicide risk factor. Understanding the link between blunted affect and suicide can lead to the development of suicide preventive strategies and fills the gap regarding what determines suicide. There was no financial sponsorship for this review. A50 ABSTRACTS

D09 AFFECTIVE SYMPTOMS PREDICT THE METABOLIC SYNDROME AND SYMPTOM SEVERITY IN PATIENTS WITH PSYCHOSIS SerranodeHaroPerez C, Dept of Psychosis Studies, IoPPN, King’s College, 16 De Crespigny Park, London, SE5 8AF [email protected] Ciufolini S(1), Gardner Sood P(2), Krivoy A(1), Young AH(1), Murray RM(1), Gaughran F(1), Juruena MF(1) (1) As presenting author; (2) Imaging Trials Unit, University College London and University College London Hospitals NIHR Biomedical Research Centre, 250 Euston Road, London NW1 2BU Introduction: Affective symptoms can worsen outcomes of individuals with psychosis and increase the risk of relapse. Patients with affective and non-affective psychosis show higher rates of metabolic syndrome (MS). However, research on the association between MS and affective symptoms in psychosis and their relevance to outcomes is lacking despite their well-described adverse health outcomes. We investigated the association between affective symptoms and MS in patients with psychosis, and how these factors could be used to predict clinical outcomes at 15 months. Methods: Four hundred and six patients (234 male; mean age was 44.18 years, SD = 10.12) with established psychosis were recruited as part of the Improving Physical Health and Reducing Substance Use in Severe Mental Illness; a randomised controlled trial (IMPaCT RCT). Depression (Montgomery-Åsberg Depression Rating Scale, MADRS), psychosis (Positive And Negative Syndrome Scale, PANSS), MS subcomponents (waist circumference, triglycerides, HDL- Cholesterol, blood pressure, HbA1c), age, gender, ethnicity, and substance use of patients were assessed at baseline and 15 months. Linear regression models were used to test the associations of MADRS scores at baseline with levels of MS subcomponents at baseline. The interaction between MADRS scores and MS subcomponents at baseline was added to the regression model to test its effect on PANSS scores at 15 months. Results: Higher depressive symptoms at baseline were associated with higher baseline levels of triglycerides (data available for 207 participants; β = .04, p = .003) and waist measurement (data available for 249 participants; β = .41, p = .001), after controlling for age, gender, ethnicity, and substance use. Depressive symptoms at baseline predicted total PANSS scores at 15 months, after controlling for baseline PANSS scores, age, gender, ethnicity, and substance use (data available for 198 participants; β = .28, p = .01). Baseline depressive symptoms and MS subcomponents displayed no significant interaction on PANSS scores at 15 months. Conclusion: These preliminary findings indicate that individuals with psychosis experiencing severe depressive symptoms are more likely to have increased levels of concurrent specific MS subcomponents and more psychosis symptoms at follow-up. Depressive symptoms in psychosis should be considered in the light of their impact on physical health and psychosis outcomes. These findings promote greater understanding of the interface between physical and mental illness and foster the development of precision psychiatry. The National Institute for Health Research funded the IMPaCT programme at King’s College London and the South London and Maudsley NHS Foundation Trust.

D10 REDUCING RISKS ASSOCIATED WITH VITAMIN D DEFICIENCY IN AN OLDER ADULT PSYCHIATRIC INPATIENT WARD Alalade A, The Limbrick Centre, Early Intervention Services, Sheffield Health and Social Care NHS .,FT S3 7GT [email protected] Morris S(1), Littlewood C(1) (1) Sheffield Health and Social Care NHS FT Introduction: Vitamin D deficiency is common in the older demographic of the population[1] It can lead to bone fragility and therefore increased risk of fracture, and subsequently related poor health outcomes. There are multiple factors which contribute to the risk of developing Vitamin D deficiency including an extended hospital admission. However, this risk is often unrecognised in this group of patients. The aim of the audit was to elevate awareness of the risks associated with vitamin D deficiency in patients admitted to a psychiatric inpatient ward by auditing the patients appropriately receiving Vitamin D prophylaxis against the NICE guidelines[1] and Sheffield Clinical Commissioning Group recommendations[3]. ABSTRACTS A51

Methodology: All inpatients’ electronic health records and medication charts were reviewed and audited. Data was collected for the 19 inpatients on 22nd November 2017. The retrospective data was assessed against adherence to NICE guidelines to be offered Vitamin D prophylaxis[1] Results: Only 47% of the patients were receiving Vitamin D prophylaxis, when 100% of patients were identified as at risk. The results show that the required standard for identifying those at risk of Vitamin D deficiency is not being met. Conclusions: The results show that prescription of prophylaxis is not occurring and the patients remain at risk of developing bone fragility and possible complications associated with this. Focusing on reducing the risks associated with vitamin D deficiency by prescribing prophylactic vitamin D will be helpful for future patients. Discussion of the audit findings within the multidisciplinary team setting to highlight the importance of identifying patients at risk of vitamin D deficiency will occur and a re-audit will be completed in May 2018. References: 1. NICE Guidance. Vitamin D: Supplement use in specific population Groups. Updated Aug 2017. 2. Scientific Advisory Committee on Nutrition (SACN) report on Vitamin D and health (SACN,2016) 3. Sheffield CCG Guidance on Optimising Vitamin D for Adult Bone Health. We did not have any financial sponsorship for this audit. The references are from NICE guidance and committe body of work. They do not include any specific authors’ name, and are as stated above.

D11 THE DOCUMENTATION OF ALCOHOL HISTORIES IN A COHORT OF DEMENTIA PATIENTS Balasubramanium B, Division of Brain Sciences, Imperial College London, 5th Floor Burlington Danes Building, 160 Du Cane Road, London, W12 0NN [email protected] Shastri A(2), Bailey A(2), Lingford-Hughes A(1), Venkataraman AV(1) (1) Centre for Psychiatry, Division of Brain Sciences, Imperial College London, 5th Floor Burlington Danes Building, 160 Du Cane Road, London, W12 0NN; (2) Westminster Older Adults Community Mental Health Team, CNWL NHS Foundation Trust, 190 Vauxhall Bridge Road London, SW1V 1DX; Introduction: Alcohol accounts for 5.9% of deaths and 5.1% of disability-adjusted life years globally according to the World Health Organisation. Both dementia and excessive alcohol consumption are inextricably interlinked. A recent French study which analysed a nationwide retrospective cohort consisting over 31 million individuals identified alcohol use disorder as a major risk factor for the onset of all types of dementia, especially early-onset dementia. The fact that alcohol plays such a vital role in dementia means that it is important that we take alcohol histories from patients to identify their alcohol use and offer support where necessary. In this project I have explored how well alcohol histories have been taken in a cohort of elderly patients diagnosed with dementia to identify whether an association between alcohol and dementia can be confirmed clinically and investigated the limitations that exist. Methods: Newly referred patients to CNWL Westminster Older Adults Community Mental Health Team between January 1st to December 31st 2017 with a diagnosis of dementia under ICD-10 code F0x were included. Data was collated from a clinical records system (JADE), including patient demographics as well as categories for type of dementia diagnosed, alcohol consumption recorded, the content of the alcohol consumption record and a rating out of 5 was given for how well alcohol history was recorded. A score of 1 was given for identifying patient alcohol use, 2 for quantified current alcohol intake, 3 for identifying first drink, 4 for clarifying and quantifying past alcohol use, 5 for a full alcohol history. Results: Eighty- nine patients were identified from the JADE database. Patient ages angedr from 65-98 and the mean age was 83±6.86yrs. Of the 89 patients 56% (n=50) did not have a record of alcohol consumption (RAC) and of those that did have RAC (n=39), all but 2 scored just 1/5 on the rating scale used. The top three dementia diagnoses were Alzheimer’s disease at 44% (n=39), unspecified dementia at 28% (n=25) and vascular dementia at 16%(n=14). Within these three diagnoses Alzheimer’s had the biggest proportion of RAC at 56%(n=22), followed by unspecified dementia at 48%(n=12) and vascular dementia with 36%(n=5). Conclusion: Without a complete alcohol history, it is difficult to identify any association between alcohol and dementia and any adverse contribution from their alcohol consumption to clinical presentation. We need to ensure that all healthcare professionals are trained to take alcohol histories and know its importance to aid future research. [No financial sponsorship] A52 ABSTRACTS

D12 PERSONAL EXPERIENCES OF THE EFFECTS OF BARIATRIC SURGERY ON PHYSICAL AND MENTAL WELLBEING IN SEVERE MENTAL ILLNESS: A QUALITATIVE STUDY Tomlinson A, Dept of Medical Sciences, Univ of Oxford, Green Templeton College, Woodstock Road, OX2 6HG [email protected] Every-Palmer S(2), Ghandi S(1), Huthwaite M(1), Stubbs R(3), Romans SE(1) (1) Department of Psychological Medicine, University of Otago, Wellington.; (2) Department of Psychological Medicine, University of Otago, Wellington.; (3) Wakefield Obesity Surgery, Wakefield Hospital, Wellington, New Zealand Introduction: The life expectancy of patients with serious mental illness (SMI) is significantly reduced compared with the general population. In people with SMI, high BMI and obesity are more prevalent compared to the general population. It appears people with SMI are not accessing bariatric surgery (BS). Despite little supporting evidence, there is an assumption that patients with more complex psychiatric histories have poor post-surgical weight-loss and worsening psychiatric symptoms following surgery. Consequently, those with SMI are excluded from surgery in many bariatric centres. Gathering qualitative data will be hypothesis generating, and will inform the further research stream, which could include a significant research grants and potentially a trial. Aim: We aimed to use phenomenological qualitative methods to explore people’s experiences of the impacts of BS on physical and mental wellbeing and quality of life in a group with a history of mental illness. Methods: The study was undertaken in Wellington, New Zealand, and used phenomenological study methodology. The sample consisted of nine adults with a history of BS, with a diagnosis of SMI at the time of surgery. SMI included severe depressive disorder, bipolar disorder and psychotic disorders. We interviewed each participant using a semi-structured schedule, and audio-taped each interview. Participants were interviewed about their experiences of BS. Interviews were divided into five key sections; exploring general reasons for and experiences of BS, the impact on physical health and general well-being, the impact on mental health, the impact of BS on quality of life and advice to others. The data were transcribed and entered into the qualitative data analysis software HyperRESEARCH, and a thematic analysis undertaken. Results: Three broad themes emerged from the interviews, diet and physical heath, mental health and participant reflections. The experiences of the participants indicated the profound impact of BS on various aspects of peoples’ lives. Participants acknowledged a difficulty adapting to their new diet following the surgery, which had gastrointestinal side effects. However, most participants experienced an overall weight loss and improvement in their physical health post-surgery. Many participants also suggested an improvement in their overall mental health and quality of life. Participants also stated the presence of pre-surgery eating behaviours such as emotional or stress-eating, being present post-surgery. Some participants expected their mental illness to improve following surgery and some patients experienced adverse effects related to their psychiatric medication. Conclusions: Participant reports emphasise the need for further research regarding the impact of bariatric surgery on people with SMI, particularly regarding the impact on psychiatric symptoms and psychiatric medication as well as strategies to cope with eating behaviours post- surgery. No financial declarations

D13 GLUCOSE AND LIPID ALTERATIONS IN ANTIPSYCHOTIC NAÏVE FIRST EPISODE PSYCHOSIS: EVIDENCE OF INTRINSIC CARDIOMETABOLIC RISK? McCutcheon R, Psychosis Studies, Institute of Psychiatry, King’s College London, 16 de Crespigny Park Camberwell, SE5 8AF [email protected] Beck K(1), Stubbs B(1), Jauhar S(1), Howes OD(1), Pillinger T(1) (1) Institute of Psychiatry, King’s College London Introduction: Schizophrenia is associated with an increased risk of type 2 diabetes and dyslipidaemia. However, it is not clear whether schizophrenia confers an inherent risk for glucose and lipid dysregulation in the absence of the effects of chronic illness and long-term treatment. We therefore set out to conduct meta-analyses examining whether individuals with first-episode psychosis already exhibit alterations in ABSTRACTS A53 glucose and lipid homeostasis compared with controls. Methods: The EMBASE, MEDLINE, and PsycINFO databases were systematically searched for studies examining measures of glucose and lipid homeostasis in antipsychotic-naive first-episode psychosis compared with controls. Data were extracted for studies reporting fasting glucose levels, glucose levels after an oral glucose tolerance test, fasting insulin levels, insulin resistance, HbA1c, total/LDL/HDL cholesterol, triglycerides, and leptin levels. Standardised mean differences between levels of these parameters for patients and controls were calculated. Results: For the glucose meta-analysis, of 3660 citations retrieved, 16 studies comprising 15 samples met inclusion criteria (731 patients and 614 controls). Fasting glucose (Hedges g=0.20; 95%CI, 0.02 to 0.38; P = .03), glucose levels after an oral glucose tolerance test (Hedges g=0.61; 95%CI, 0.16 to 1.05; P = .007), fasting insulin (Hedges g=0.41; 95%CI, 0.09 to 0.72; P = .01), and insulin resistance (Hedges g=0.35; 95%CI, 0.14 to 0.55; P = .001) were all elevated in patients compared with controls. However, HbA1c levels were not altered in patients compared with controls. For the lipid meta-analysis, of 2070 citations retrieved, 20 studies met inclusion criteria (1167 patients and 1184 controls). Total cholesterol (Hedges g=-0.19; 95%CI, -0.32 to -0.06; P = .005) and LDL cholesterol (Hedges g=-0.22; 95%CI, -0.35 to -0.09; P = .001) were decreased in patients compared with controls. Triglycerides (Hedges g=0.14; 95%CI, 0.00 to 0.28; P < .05) were increased in the patient group. However, HDL cholesterol and leptin levels were not altered in patients compared with controls. Conclusions: These findings show that glucose homeostasis is altered from illness onset in schizophrenia, indicating that patients are at increased risk of diabetes as a result. Elevated triglycerides in this cohort is also an indicator of increased risk of diabetes. These findings have implications for the monitoring and treatment choice for patients. By contrast, our data suggesting that total and LDL cholesterol are reduced early in the course of schizophrenia indicates that hypercholesterolaemia seen in chronic disorder is secondary and potentially modifiable. This study was funded by grants from the MRC-UK, the Brain and Behavior Research Foundation, the Wellcome Trust and the NIHR Biomedical Research Centre at SlaM&KCL.

D14 WHAT LEADS TO PSYCHOSIS TRANSITION? A META-ANALYSIS OF RISK AND PROTECTIVE FACTORS IN INDIVIDUALS AT CLINICAL HIGH RISK FOR PSYCHOSIS Oliver D, Psychosis Studies, King’s College London, 16 De Crespigny Park, London, UK, SE5 8AF [email protected] Reilly T(1), Baccaredda O(1), Petros N(1), Fusar-Poli P(1) (1) Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, SE5 8AF, UK Background: Thirty-five percent of individuals at clinical high risk for psychosis (CHR-P) transition within 3 years. It is currently unknown what differentiates those who develop psychosis and those who do not. In order to improve clinical outcomes, it is important to establish what psychosocial and clinical factors lead to increased risk of developing psychosis or how to protect against it. . To date, this is the first meta- analysis to explore this question Methods: A systematic search of the Web of Science and Ovid databases was carried out to identify any original articles published in English that investigated potential risk or protective factors for transition to psychosis in CHR-P individuals. 128 controlled studies, conducted by 13th May 2018, were retrieved.Random effects meta-analyses were used to control for the impact of sampling error. The association between each factor and transition to psychotic disorders was graded into convincing, highly suggestive, suggestive, weak, or non-significant categories. The adapted standardized classification was based on: number of subjects, random-effects p value, largest study 95% confidence interval, heterogeneity between studies, small study effect, and sensitivity analysis. Effect sizes were calculated using odds ratio (OR) or standardised mean difference (SMD). Results: Among the 26 factors, one factor (stress/trauma: OR = 1.146, 95%CI: 1.038, 1.265) presented a convincing level of association. Two further factors were associated with highly suggestive evidence: positive symptoms (SMD = 0.352, 95%CI: 0.282, 0.423) and functioning (SMD = -0.289, 95%CI: -0.370, -0.208). There was suggestive evidence for four further symptom severity/clinical factors: negative symptoms (SMD = 0.400, 95%CI: 0.320, 0.481), disorganized/cognitive symptoms (SMD = 0.333, 95%CI: 0.171, 0.496), total symptoms score (SMD = 0.307, 95%CI: 0.148, 0.467) and general symptoms (SMD = 0.252, 95%CI: 0.131, 0.373). There was either weak or no evidence of association with transition to A54 ABSTRACTS psychotic disorders for all other factors Conclusion: Our findings suggest that despite the large number of putative risk factors investigated in the literature, few associations were supported by robust evidence. Stress/trauma, positive symptoms and functioning were the only factors that had highly suggestive evidence or greater for association with transition to psychosis. The current findings provide opportunities for improved prognostication of clinical outcomes and future individualisation of treatment. Dominic Oliver is supported by the UK Medical Research Council (MR/N013700/1) and King’s College London member of the MRC Doctoral Training Partnership in Biomedical Sciences.

E01 INVESTIGATING THE EFFECTIVENESS OF NOVEL CALORIE/UNIT INDICATOR BEER MATS USING A GROUP TESTING PROCEDURE Przydzial KM, School of Psychological Science, University of Bristol, 12a Priory Rd. Bristol, BS8 1TU [email protected] Blackwell AKM(1), Maynard OM(1), Skinner AL(1), Hickman M(2), Munafò MR(1), Attwood AS(1) (1) As presenting author; (2) Bristol Medical School: Population Health Sciences, Univ of Bristol, BS8 2PS Alcohol is among the top three health behaviours contributing to ill health and death in the UK (Alcohol Health Alliance report). There is increasing evidence that all alcohol consumption carries health risk, and that many people in the UK drink above the recommended low-risk guidelines. However, findings consistently show that many drinkers are not aware of the guidelines and do not understand alcoholic units. This compromises the drinker’s ability to achieve low risk levels of consumption. Improved labelling of alcohol products is one way to address this problem, but this may require legislation change and therefore be slow to implement. We have produced novel calorie/unit indicator beer mats that circumvent this issue and provide another avenue of information delivery. This study investigated the effectiveness of these novel mats using a group testing procedure that modelled real world drinking situations. Forty weekly alcohol drinkers (53% male) were recruited and tested in groups of 2-5 (12 groups total). Groups sat together and consumed a lager drink over 20 minutes, either in the presence of our novel calorie/unit indictor mats or control (standard) beer mats. We measured alcohol craving (Alcohol Urges Questionnaire) and total alcohol consumed. At the end of the session, all participants were given the mats and independently asked to complete an evaluation questionnaire. There was no statistical evidence of an effect of mat-type on the amount of alcohol consumed (p = 0.39), but there was evidence of lower craving in groups who had drunk in the presence of novel calorie/unit indicator beer mats compared to standard beer mats (MD = -6.2, SED = 2.7, t(38) = 2.3, p = 0.03, CI 95% -11.7 to -0.6). A large majority of participants agreed or strongly agreed that the novel calorie/unit indicator mats were effective at providing unit/calorie information (93%), they had learned something from the mats (95%), the mats had real world benefits (88%) and the mats should be available in bars and public houses (65%). This study found support for the use of beer mats in alcohol-related health communication. Beer mats provide a means to deliver more comprehensive information than small sections of labels and increase exposure and reach of this information. We found evidence that people crave less when drinking in the presence of calorie/unit indicator mats. Furthermore, we found high ratings of effectiveness and good support for their implementation. Funding: Medical Research Council, Public Health Intervention Development award, (reference: MR/N027450/1) and Wellcome Trust Biomedical Vacation Scholarship.

E02 RISKY DECISION-MAKING INCREASES STRESS-INDUCED ALCOHOL CONSUMPTION IN SOCIAL DRINKERS Clay JM, School of Pharmacy and Biomedical Science, University of Portsmouth, Room 5.27 Old St Michael’s Building, White Swan Road, Portsmouth, PO1 2DT [email protected] Parker MO(1) (1) As presenting author Introduction: Chronic alcohol misuse can escalate into alcohol use disorder (AUD), characterised by physical dependence and psychological addiction. The underlying causal processes of AUD are ABSTRACTS A55 multifaceted and complex, involving several hypothesised personality-trait (e.g., impulsivity/risk taking) and environmental (psychosocial stress) influences. The aim of our study was to test the ypothesish that an acute psychosocial stressor would cause an increase in alcohol craving and voluntary alcohol consumption in a sample of healthy social drinkers. A second aim was to test the hypothesis that impulsivity, risk- taking, sensation seeking and decision making would mediate stress-induced craving and voluntary alcohol consumption. Methodology: Participants completed 3 questionnaires to asses their drinking behaviour (Alcohol Dependence Questionnaire; the Alcohol Use Disorders Identification est;T and the Binge Drinking Scale). Participants were randomly allocated to “stress” or “no-stress” groups; in the stress group, participants took part in the Trier Social Stress Test (TSST). Implicit and explicit measures of personality traits included: The Barratt Impulsiveness Scale (BIS) and the Stop Signal Task (SST; impulsivity); Balloon Analogue Risk Task (BART; risk-taking); The Arnett Inventory of Sensation Seeking (AISS; sensation seeking); and the Iowa Gambling Task (IGT; decision making). Both implicit and explicit craving were assed using an Approach Avoidance Task (AAT) and the Desires for Alcohol Questionnaire (DAQ) respectively. Finally, participants completed a Progressive Ratio Schedule (PRS) task, where increasing numbers of pressed on a computer keyboard were reinforced with 5ml shots of 40% ABV vodka. During the entire task, physiological parameters (including heart rate variability; HRV) were recorded. Results: Participants exposed to psychosocial stress showed increases in explicit craving (DAQ; pre-stress = 39.13, post-stress = 45.14, p < .01) and drank more in the PRS (stress = 0.7 more drinks, p < .01). A generalised linear model (negative binomial) showed that number of drinks consumed was predicted by slower heart rate recovery following stress (p < .001), poorer vagal recovery in HRV (p < .05), and risky decision making (IGT; p < .01). Finally, and surprisingly, DAQ-induced craving was not significantly predictive of number of drinks consumed. Conclusions: Psychosocial stress increases craving and drinking in social drinkers, and this is mediated by stress-reactivity and risk-taking. Our research suggests that people with risk-taking personality types may be more at risk of stress-induced alcohol consumption. This may provide a useful translational framework through which to study the changes between controlled recreational drinking and alcohol misuse, including AUD.

E03 EXAMINING THE TIME COURSE OF ETHANOL WITHDRAWAL AND CORRELATIONS WITH BASELINE IMPULSIVITY Collins DM, Psychology, Portland State University, 1825 SW Broadway, Portland, OR, 97201 dezarae2@pdx. edu Mitchell SH(1), Finn DA(2) (1) Department of Behavioral Neuroscience 3181 SW Sam Jackson Park Rd, Portland, OR 97239; (2) Portland VA Medical Center 3710 SW U.S. Veterans Hospital Rd. Portland, OR 97239 Introduction: In people who are alcohol dependent, absence of alcohol causes physiological withdrawal signs, such as seizures and tremors. Other withdrawal effects are psychological symptoms, such as anhedonia and social anxiety. Resuming alcohol drinking may be due to a desire to escape these effects (negative reinforcement). Research has suggested that impulsive individuals are more likely to relapse to drug use during cessation attempts (Mackillop & Kahler 2009 Drug Alcohol Depend., 104, 197-203). One mechanism underlying this relationship might be a heightened response to withdrawal signs and symptoms in more impulsive individuals. Our study examined the time course of a variety of ethanol withdrawal signs and symptoms in mice, and assessed the correlation between baseline impulsivity, measured using two different paradigms, and alcohol withdrawal severity. Methods: Genetically heterogeneous mice (males and females) completed either a go/no-go task (Gubner et al. 2010 Alcohol Clin Exp Res, 34, 1-10) or a delay discounting task (Mitchell 2014 Curr Protoc Neurosci, 66, 8.30.1–8.30.12) to assess impulsive response or impulsive choice. Ethanol dependence was induced by exposing a subset of mice to ethanol vapor over 72 hours, while control mice were exposed to air (Finn et al. 2007 Alcohol Clin Exp Res, 31, 939-949). Withdrawal measures were assessed multiple times over the week following vapor exposure and included seizure susceptibility (handling-induced convulsions), coordination deficits (balance beam foot-slips), anhedonia (sucrose preference), apathy (locomotor activity), and social anxiety (social approach and interactions). Results: We identified withdrawal symptom time courses for all A56 ABSTRACTS measures: some measures returned to baseline within 48 h (e.g., seizure susceptibility) but others required at least 72 h (e.g., anhedonia). The peak change from baseline was identified for each individual. Change scores (baseline to peak) and areas-under-the-withdrawal-time-course-curve were calculated for all withdrawal measures. Measures of withdrawal within subjects were significantly correlated (0.46

E04 RELATIONSHIP BETWEEN REWARD ANTICIPATION AND IMPULSIVITY IN ALCOHOL AND POLYDRUG ADDICTION: AN FMRI STUDY Hayes A, Neuropsychopharmacology Unit, Centre for Psychiatry, Division of Brain Sciences, Imperial College London, Burlington Danes Building, Hammersmith Campus, 160 Du Cane Road, London, W12 0NN [email protected] Wing V(1), McGonigle J(1), Turton S(1), Elliott R(4), Ersche KD(2), Flechais R(1), Orban C(1), Murphy A(4), Smith DG(2), Suckling J(2), Taylor EM(4), Deakin JFW(4), Robbins TW(3), Nutt DJ(1), Lingford-Hughes AR(1), Paterson LM(1) (1) As presenting author; (2) Behavioural and Clinical Neuroscience Institute, University of Cambridge, UK. Department of Psychiatry, University of Cambridge, UK; (3) Behavioural and Clinical Neuroscience Institute, University of Cambridge, UK. Department of Psychology, University of Cambridge, UK; (4) Neuroscience and Psychiatry Unit, Institute of Brain, Behaviour and Mental Health, University of Manchester, UK Introduction. Evidence suggests that increased impulsivity and abnormalities in reward circuitry contribute to the pathophysiology of addiction. However, the relationship between reward processing and impulsivity is not well characterised. This study investigated subjective and objective measures of impulsivity in alcohol and polydrug dependence and their association with striatal BOLD response during non-drug reward anticipation, a putative functional brain marker of addiction. We hypothesized a negative correlation between non-drug related reward anticipation and impulsivity in polydrug and alcohol dependence which would be weaker in alcohol dependence. Methods. Abstinent alcohol (AD, n=28), polydrug (PD, n=59) dependent and healthy control (HC, n=68) participants were recruited (ICCAM study; Paterson et al., 2015. J.Psychopharmacol., REC number 11/H0707/9). Participants underwent fMRI scanning (3-T) using the monetary incentive delay (MID) task. An a priori striatal region-of-interest approach was used to image the BOLD response during the contrast of win>neutral reward anticipation. Participants completed the Barratt Impulsiveness Scale (BIS), the sensation seeking sub-score of the UPPS-P (UPPS-Ps) and the Stop Signal Reaction time (SSRT) task. Data were analysed using ANOVA or Kruskal- Wallis tests (with Tukey or Mann-Whitney U post-hoc tests respectively) and Pearson’s or Spearman’s rank correlations, as appropriate. Results. There were significant group differences in SSRT, BIS and UPPS-Ps scores (p=0.042, p=0.000, p=0.001 respectively). Post-hoc tests revealed that SSRT and BIS scores were significantly higher in both PD (P<0.001) and AD groups (P<0.05) relative to HC. UPPS-Ps scores were significantly higher in PD relative to HC and AD groups (p=0.003 and p=0.013 respectively). There were no group differences in MID striatal BOLD response. A significant but weak positive correlation was observed in PD between UPPS-Ps score and MID BOLD response (r=0.314, p=0.008, Holm-Bonferroni corrected). There were no significant associations between MID striatal BOLD response and impulsivity measures in AD or HC groups. Conclusion. These data support previous evidence that increased subjective and objective impulsivity is associated with substance addiction, but do not replicate previous findings of reduced striatal response during reward anticipation. The finding of significantly higher sensation seeking in PD, and its positive correlation with striatal BOLD response is interesting. In contrast to our hypothesis, ABSTRACTS A57 this suggests that sensation seeking may be associated with increased, rather than decreased, striatal response to reward anticipation. Further work is required to better understand the modulation of striatal function in reward processing and its relationship with impulsivity. This study was funded by the MRC (G1000018) with support from GSK.

E05 INFLUENCE OF GLP-1 ANALOGUE, EXENATIDE, ON FOOD AND ALCOHOL CUE REACTIVITY, AND APPROACH BIAS IN HUMAN OBESITY, EX-SMOKERS AND ABSTINENT ALCOHOL DEPENDENCE Goldstone AP, PsychoNeuroEndocrinology Research Group, Centre for Psychiatry, Division of Brain Sciences, Imperial College London, UK, Room E516, 5th floor, Burlington Danes Bldg, Hammersmith Hosp, Du Cane Rd, London, W12 0NN [email protected] Nestor LJ(1), Pannekoek JN(1), Vanelli F(1), Akavarapu S(1), Herlinger K(1), Aiano F(1), Kobson B(1), Munafo MR(2), Ling YY(1), Lingford-Hughes AR(1), Nutt DJ(1) (1) As presenting author; (2) MRC Integrative Epidemiology Unit, School of Experimental Psychology, Uni of Bristol, BS8 1TH Introduction: Obesity and alcohol dependence are associated with altered reward responsivity to food and alcohol cues. The gut hormone glucagon-like peptide-1 (GLP-1) and analogues (e.g. Exenatide) suppress consumption and reward responses to food and alcohol in animals. One hypothesis of our MRC-funded human Gut Hormones in Addiction study is that Exenatide reduces brain responses and approach bias to salient food/alcohol pictures in obesity, ex-smokers and/or abstinent alcohol-dependence. Methods: Three groups were studied: (i) dieting obese (never-smoked, never-alcohol-dependent), (ii) abstinent nicotine- dependent (never-alcohol-dependent), or (iii) abstinent alcohol-dependent. Outcome measures during intravenous infusion of Exenatide (vs. Saline) included brain responses (BOLD signal) in mesocorticolimbic system during fMRI picture evaluation task with simultaneous appeal ratings, and approach bias using an approach-avoidance task, to high-energy food and alcohol pictures. ROIs for the fMRI task (nucleus accumbens (NAcc), caudate, putamen, orbitofrontal cortex (OFC), amygdala, anterior insula), were determined from response to food/alcohol pictures in never-smoked, non-obese, never-alcohol-dependent, healthy controls (n=24). Results: In preliminary analysis in obese subjects (n=19), Exenatide (vs. Saline) reduced BOLD signal in NAcc to alcohol (P=0.009), but not food. Furthermore, greater BOLD signal to food and alcohol at Saline visit was associated with greater reduction in BOLD signal by Exenatide in NAcc, caudate, putamen, and insula (r=0.49-0.73,P=0.032-0.001). In ex-smokers (n=15), Exenatide reduced appeal of food (P=0.032), and BOLD signal in putamen to food (P=0.028), and in NAcc and putamen to alcohol (P=0.044-0.008). Greater BOLD signal to food and alcohol at Saline visit was associated with greater reduction in BOLD signal by Exenatide in NAcc, caudate and OFC (r=0.57-0.84,P=0.015-0.0001), and for alcohol in putamen and amygdala (r=0.60-0.64,P=0.010-0.018). In abstinent alcohol-dependent subjects (n=10), Exenatide reduced appeal of food and alcohol (P=0.004-0.007), and BOLD signal to food and alcohol in caudate (P=0.027-0.014), and to food in amygdala (P=0.038). Greater BOLD signal to food at Saline visit was associated with greater reduction in BOLD signal by Exenatide in NAcc, caudate, putamen, and OFC (r=0.77-0.89,P=0.010-0.0005), and for food and alcohol in amygdala and insula (r=0.66-0.91,P=0.010-0.0003). In those with higher approach bias at Saline visit, Exenatide reduced approach bias to both food and alcohol in the obese (n=16, both P<0.05) and abstinent alcohol-dependent group (n=10, both P<0.05), and to food in ex-smokers (n=14, P=0.009). Conclusions: These initial results provide the first evidence that activation of the GLP-1 system can reduce cue reactivity to alcohol, as well as food, in clinically relevant populations, particularly in those with baseline higher reactivity. GHADD study is funded by UK MRC. A58 ABSTRACTS

E06 MONETARY REWARD PROCESSING AND FOOD ADDICTION IN OBESE WOMEN AND IMPACT OF GASTRIC BYPASS SURGERY Brian EJG, PsychoNeuroEndocrinology Research Group, Neuropsychopharmacology Unit, Centre for Psychiatry, Division of Brain Sciences, Imperial College London, Hammersmith Hospital, London, UK , W12 0HS [email protected] Chhina N(1), Nestor LJ(1), Hannan R(1), Nutt DJ(1), Lingford-Hughes AR(1), Goldstone AP(1) (1) As presenting author Introduction: ‘Food addiction’, measured by the Yale Food Addiction Scale (YFAS), has been associated with enhanced brain responses to anticipated receipt of food. Increased brain responses during monetary reward anticipation in nucleus accumbens (NAcc) and ventromedial prefrontal cortex (vmPFC) has been seen in obesity. Roux-en-Y gastric bypass (RYGB) surgery is the most successful treatment for obesity, reducing cue reactivity to high-energy foods. This study investigated if: (i) brain responses during monetary reward processing are greater in obese subjects with higher body mass index (BMI) or ‘food addiction’, and (ii) this changes after RYGB surgery. Methods: Obese women (n=15, BMI 38.8-55.5 kg/m2; age 39–56y; YFAS 1-7), performed a functional MRI monetary incentive delay task, after an overnight fast. Subjects were rescanned at ~14 weeks after RYGB (n=13). BOLD signal at baseline, during anticipation of potential monetary win or loss (vs. neutral) trials, was correlated with BMI and YFAS symptom score (max 7), using whole brain (cluster- wise FWE Z>2.3, P<0.05), and a priori functional ROIs analyses (NAcc, caudate, putamen, pallidum, anterior insula, amygdala, orbitofrontal cortex, ventral anterior cingulate cortex (vACC), determined from a separate cohort of n=17 healthy, non-obese adults). Secondly, BOLD signal was compared before and after RYGB. Results: At baseline, BMI did not correlate with YFAS (rS=+0.32, P=0.24), nor with BOLD signal to anticipation of monetary win or loss in whole brain or fROI analyses. In fROI analysis, YFAS positively correlated with BOLD signal during anticipation of potential monetary loss in NAcc (rS= +0.70, P=0.003), putamen (rs= +0.56, P=0.029) and vACC (rs= +0.63, P=0.012). After RYGB, weight fell by mean ± SD 37.3 ± 18.8 %, but YFAS score was unchanged (3.0 ± 1.9 vs. 2.1 ± 0.9, n=11, P=0.16). In whole brain analysis, BOLD signal during anticipation of potential monetary loss decreased after RYGB in vmPFC (cluster 609 voxels; peak Z 3.44, x-4, y+48, z-10). In fROI analysis BOLD signal during anticipation of monetary win or loss did not change after RYGB. In conclusion, in obese women, greater ‘food addiction’, but not BMI, was associated with enhanced NAcc, putamen and vACC response during anticipation of monetary reward. Weight loss after RYGB surgery was associated with decrease in vmPFC during anticipation of monetary reward. This indicates potential interactions between ‘food addiction’, and weight loss after bariatric surgery, with processing of non-food rewards in obesity. Sources of financial sponsorship: Wellcome Trust

E07 VALUE-BASED DECISION-MAKING OF CIGARETTES AND NON-DRUG REWARDS IN DEPENDENT AND OCCASIONAL CIGARETTE SMOKERS: AN FMRI STUDY Lawn WM, Clinical Psychopharmacology Unit, University College London, 1-19 Torrington Place, London, WC1E 7HB [email protected] Freeman TP(1), Benattayallah A(2), Bisby JA(3), Mitchener L(1), Curran HV(1), Dodds C(5), Morgan CJA(4) (1) As presenting author; (2) Exeter MR Research Centre, University of Exeter; (3) Institute of Cognitive Neuroscience, University College London; (4) PARC, University of Exeter; (5) Washington Singer Laboratories, University of Exeter Background: Value-based decision-making is theoretically impaired in substance use disorders. However, very little is known about the neural functioning that underpins drug valuation and purchase, within addiction. In a sample of dependent and occasional cigarette smokers, using a neuroeconomics paradigm, we aimed to: (1) identify the brain’s value signal for cigarettes and vouchers, (2) investigate neural and behavioural decision-making differences between the groups. Methods: Nineteen dependent smokers (smoked≥10/day; FTND≥5) and 19 occasional smokers (smoked 0.5-5/week; FTND=0), following ad libitum smoking, completed a decision-making task, in which cigarettes and vouchers could be purchased. In the first stage (outside of the MRI scanner), participants stated their willingness-to-pay (WTP) for a variety ABSTRACTS A59 of cigarette ‘bundles’ (e.g. 5 Marlboro cigarettes) and voucher ‘bundles’ (e.g. 5 Amazon vouchers). In the second stage (inside the MRI scanner), participants made a series of purchase decisions about the cigarette and voucher ‘bundles’. One decision, across both stages, for each reward type was selected at random and happened in reality. Scanning took place in a Philips 1.5T MRI scanner. Using whole brain and ROI analyses, and parametric modulation, we investigated which brain regions encode cigarette and voucher value and examined group differences in this value processing. We also investigated behavioural group differences in WTP, choices and their relationships. Results: In the first stage, dependent smokers had a higher WTP for cigarettes than occasional smokers (t(36)=4.182, p<0.001). In the second stage, dependent smokers made more cigarette than voucher purchases (t(18)=3.468, p=0.003), but there was no difference for occasional smokers. Moreover, dependent smokers were more sensitive to changes in WTP for cigarettes than vouchers (β=1.063, p<0.001) and they made an ‘irrationally’ large number of cigarette purchases, relative to their individual WTP scores (p=0.032). The decision to buy cigarettes was accompanied by significant activation in the medial prefrontal cortex, right nucleus accumbens and left amygdala. The decision to buy vouchers was accompanied by significant activation in left superior frontal gyrus. Within our pre-specified ROIs, value signals were observed in the left striatum and the ventromedial prefrontal cortex. No group differences in fMRI outcomes were observed. Conclusions: Behaviourally, dependent smokers compared to occasional smokers: valued cigarettes more, changed their cigarette purchasing behaviour more as value increased, and made an ‘irrational’ number of cigarette purchases. For the first time, we identified value signals for cigarettes in the ventromedial prefrontal cortex and left striatum. Distinct brain regions were associated with purchasing cigarettes and vouchers. However, we did not observe any group differences in the neural processing of value and purchase of cigarettes or non-drug reward. This study was funded by BBSRC PhD funding

E08 INFLUENCE OF GLP-1 ANALOGUE, EXENATIDE, ON CIGARETTE CUE REACTIVITY AND CRAVING IN EX-SMOKERS AND ABSTINENT ALCOHOL-DEPENDENT CURRENT SMOKERS Herlinger KE, PsychoNeuroEndocrinology Research Group, Neuropsychopharmacology Unit, Centre for Psychiatry, Division of Brain Sciences, Imperial College London, 5th Floor, Burlington Danes Building, Hammersmith Hospital Campus, Du Cane Road London, W12 0NN [email protected] Ling YY(1), Nestor LJ(1), Pannekoek JN(1), Vanelli F(1), Akavarapu S(1), Aiano F(1), Kobson B(1), Munafo MR(4), Lingford-Hughes AR(3), Nutt DJ(2), Goldstone AP(1) (1) As presenting author; (2) Department of Medicine, Imperial College London, London, UK; (3) Neuropsychopharmacology Unit, Centre for Psychiatry, Imperial College London, Hammersmith Hospital, London, UK, W12 0HS; (4) School of Experimental Psychology, Univ of Bristol, Priory Road Complex, Priory Road, Bristol, BS8 1TU Introduction: Nicotine dependence and the use of tobacco related products is the third most important contributor to the global burden of disease, with a high rate of relapse and limited treatment options. The satiety gut hormone glucagon-like peptide-1 (GLP-1), and its analogues, suppress consumption of and reward responses to not only food, but also nicotine in rodents, and to food in humans. Additionally, the GLP-1 analogue, Exenatide, prevents relapse-like alcohol drinking in mice. One part of our MRC- funded Gut Hormones in Addiction study (www.ghadd.co.uk) is therefore testing the hypothesis that GLP-1 receptor agonists would reduce brain responses to salient cigarette pictures and craving in ex- and current smokers. Methods: Abstinent nicotine-dependent (quit smoking 6 weeks - 2 years ago, without history of alcohol-dependence), and abstinent alcohol-dependent adults who are current smokers, were studied. Outcome measures during acute intravenous infusion of Exenatide (vs. Saline) included brain responses (blood oxygen level dependent (BOLD) signal) in mesocorticolimbic system during a fMRI picture evaluation task for cigarette cue reactivity with simultaneous picture appeal ratings, and cigarette craving rating (using QSU-brief). ROIs for the fMRI task (nucleus accumbens (NAcc), caudate, putamen, orbitofrontal cortex (OFC), amygdala, anterior insula), were determined from brain responses during evaluation of food/alcohol pictures in never-smoked, non-obese, non-alcohol-dependent healthy control adults (n=24). Results: From preliminary analysis, in ex-smokers (n=16), Exenatide (vs. Saline) increased BOLD signal in the OFC to cigarette pictures (P=0.028) However, in abstinent alcohol-dependent current A60 ABSTRACTS smokers (n=6), Exenatide reduced BOLD signal in the caudate, putamen and amygdala (P=0.02-0.0026). Furthermore, greater BOLD signal to cigarettes at the baseline visit was associated with a greater reduction in BOLD signal with Exenatide in the caudate in abstinent alcohol-dependent current smokers (rS=0.94, P=0.017). Exenatide had no significant effect on cigarette appeal atingsr or craving in either group. Conclusions: Our preliminary findings suggest that modulation of GLP-1 signalling can attenuate striatal and amygdala responses to cigarette pictures in abstinent alcohol-dependent current smokers, especially in those with higher baseline reactivity, though not in ex-smokers without a history of alcohol-dependence, and without any accompanying changes in subjective cigarette appeal ratings or craving. Therefore GLP-1 analogues may have a potential to help people quit smoking in those with a history of alcohol-dependence.

E09 EXAMINING REINFORCEMENT LEARNING ACROSS TWO DISORDERS OF COMPULSIVITY USING BAYESIAN HIERARCHICAL MODELLING Kanen JW, Psychology, Cambridge University, Sir William Hardy Building, Downing Site, Cambridge, CB2 3EA [email protected] Ersche KD(2), Robbins TW(1), Cardinal RN(3) (1) As presenting author; (2) Herchel Smith Building, Robinson Way, Department of Psychiatry, Cambridge University, CB2 0SZ; (3) Sir William Hardy Building, Downing Site, Department of Psychiatry, Cambridge University, Cambridge CB2 3EA Introduction: Optimal functioning and wellbeing requires flexible adaptation of behaviour to maximise rewards and minimise punishments. Many psychiatric disorders involve aberrant processing of, and responding to, rewarding and aversive experiences. Here we focus on the trade-off between updating behaviour when the environment changes, and ignoring rare events when the environment is stable. Probabilistic reversal learning paradigms are commonly used to model these processes in the laboratory. Participants are presented with two choices and learn by trial and error which option is correct most of the time. Ignoring spurious minority feedback leads to more rewards overall, and is thus adaptive. The contingencies are then reversed and participants must update their choices to maximise rewards again. In these experiments, analysed using classical statistics, individuals with stimulant dependence show perseverative deficits – impairments in the ability to update behaviour when circumstances change (Ersche et al., 2011, Biological Psychiatry, 70, 754-762). At the same time, individuals with depression (Taylor Tavares et al., 2008, Neuroimage, 42, 1118-1126 ) and separately obsessive–compulsive disorder (OCD), regardless of medication status (Ersche et al., 2011, Biological Psychiatry, 70, 754-762; Apergis-Schoute et al., unpublished), instead show hypersensitivity to spurious negative feedback, manifested by inappropriately changing behaviour following punishment when it is rare. Here we take a transdiagnostic approach to interrogate the computational processes underlying these behavioural effects in two disorders of compulsivity. Methods: We applied a hierarchical Bayesian method (Gronau et al., 2017, Journal of Mathematical Psychology, 81, 80-97) to probabilistic reversal learning data across three groups: individuals with OCD, stimulant dependence, and healthy controls. Results: Preliminary results from an initial model with parameters on reward learning rate, punishment learning rate, overall sensitivity to reinforced stimulus value, and “side stickiness” (the degree to which subjects responded to the same side of the computer screen as before, irrespective of stimulus) are consistent with prior conventional analyses. Individuals with OCD showed increased sensitivity to punishment compared to controls (difference in parameter per-group mean, posterior 95% highest posterior density interval [HDI] excluding zero): choices appeared to be dictated more by negative feedback. Participants with stimulant dependence demonstrated greater “side stickiness” than in the OCD group (group difference, 0 95% HDI). These results will be followed up with further models incorporating parameters on choice stochasticity, and the extent to which choice was based on recent versus accumulated experience, ∉ among others. Conclusions: Here we provide a parsimonious account of the computational processes that may underlie the differences in task performance between two disorders of compulsivity. By using Bayesian modelling we can begin to understand the subtle mechanisms that contribute to maladaptive responses on tests of behavioural flexibility. This may eventually inform susceptibility to illness, diagnosis, and treatment. Funding: This work was supported by a Gates Cambridge Scholarship to J.W.K. and a Wellcome Trust Senior Investigator Grant 104631/Z/14/Z to T.W.R. ABSTRACTS A61

E10 INVESTIGATION OF THE REINFORCING EFFECT OF BARBITURATES AND BENZODIAZEPINES IN RATS TRAINED TO SELF-ADMINISTER HEROIN Smith S, Drug Abuse, RenaSci Ltd, BioCity Nottingham UK, NG1 1GF [email protected] Keogh E(1), Holland S(1), Slade J(1), Heal D(1) (1) RenaSci Ltd, Biocity, Nottingham NG11 GF, UK Introduction: Benzodiazepines and barbiturates are sedative euphoriants. Benzodiazepines, which are subject to low level recreational abuse, were introduced in 1960’s to circumvent the abuse problems of the barbiturates. There are few articles on the intravenous self-administration of benzodiazepines and barbiturates in animals. Although they are moderately reinforcing in monkeys (eg, Fischer et al, 2016, Drug Alcohol Depend, 158, 22-9; Broadbear et al, 2005, Psychopharm, 178, 83-91), they were thought to be poor reinforcers in rats (eg Szostak et al, Neuropharm, 26, 1673-6; Pickens et al, 1981, JPET, 216, 205-9). We investigated the reinforcing effects of the barbiturate, methohexital, and the benzodiazepines, midazolam and diazepam, on a fixed-ratio 3 (FR3) schedule of reinforcement in heroin-trained rats. Methods: Mildly food-restricted, male, Sprague-Dawley rats (200-225g initially) were trained to lever-press for food rewards before being surgically implanted with in-dwelling jugular catheters. Rats were allowed to self administer heroin (15µg/kg/injection[inj]) on a FR3 schedule. After acquisition of robust and consistent heroin self administration (≥12 inj/session), the responding was extinguished on saline (≤6 inj/session). The reinforcing effects of diazepam (1, 3, 4.5, 10μg/kg/inj), midazolam (0.3, 1, 1.5, 2.25, 3μg/kg/inj) and methohexital (2.5, 5µg/ kg/inj) were then evaluated. Test sessions were 2hr. Results are mean±SEM. Results: Heroin maintained self administration (Midazolam/Diazepam group: 17.6±0.5inj/session, n=39; Methohexital group 19.0±0.4inj/ session, n=26) at levels significantly greater (p<0.001) than saline (Midazolam/Diazepam: 3.7±0.2inj/session, n=39; Methohexital: 4.6±0.3inj/session, n=26). Results for individual rats showed that diazepam served as a positive reinforcer in 50% (4/8) and 43% (3/7) rats at 3 and 10μg/kg/inj, respectively, midazolam in 29% (5/17) and 69% (11/16) rats at 1 and 1.5μg/kg/inj, respectively, and methohexital in 100% (7/7) and 86% (6/7) rats at 2.5 and 5μg/kg/inj, respectively. Group mean results showed diazepam (3μg/kg/inj = 7.0±2.1 inj/session, n=8) and midazolam (1.5μg/kg/inj = 7.3±1.3 inj/session, n=16) maintained self-administration at levels significantly greater than saline (p<0.05) at only 1 dose tested for each drug. Methohexital maintained self-administration (2.5μg/kg/inj = 13.8±1.5 inj/session, n=7; 5μg/kg/inj = 14.8±3.1 inj/session, n=7] significantly higher than saline (P<0.01) at both doses. The numbers of infusions of all doses of these 3 drugs were significantly lower (p<0.001 diazepam, midazolam; P<0.01 methohexital) than heroin. Conclusions: The results demonstrated that midazolam and diazepam maintained self-administration in heroin-maintained rats. They substituted for heroin only at one dose, indicating their weak reinforcing effects in this species. Methohexital maintained self-administration at both doses showing a more robust reinforcing effect. No sponsorship was received for this study.

E11 MODULATION OF NATURALISTIC MALADAPTIVE MEMORIES USING BEHAVIOURAL AND PHARMACOLOGICAL RECONSOLIDATION-INTERFERING STRATEGIES: A SYSTEMATIC REVIEW AND META-ANALYSIS OF CLINICAL AND ‘SUB-CLINICAL’ STUDIES Walsh KH, Clinical Psychopharmacology Unit, Research Department of Clinical, Educational and Health Psychology, UCL, University College London, Gower Street, London, UK, WC1E 6BT katie.walsh.14@ucl. ac.uk Das RK(1), Saladin ME(2), Kamboj SK(1) (1) Clinical Psychopharmacology Unit, Research Department of Clinical, Educational and Health Psychology, University College London, Gower Street, London, WC1E 6BT, UK; (2) Department of Health Sciences and Research, College of Health Professions, Medical University of South Carolina, Charleston, USA Introduction: Consolidated memories can undergo enduring modification through retrieval-dependent treatments that modulate reconsolidation. This has been suggested to represent a potentially transformative clinical strategy for weakening or overwriting the maladaptive memories that underlie A62 ABSTRACTS substance use and anxiety/trauma-related disorders. However, the ability to modulate naturalistic maladaptive memories may be limited by ‘boundary conditions’ imposed on reconsolidation by the nature of these memories. As such, the true potential of ‘reconsolidation therapy’ is currently unknown. Methods: Here, we report a meta-analyses of behavioural and pharmacological studies examining retrieval-dependent modulation of reward and threat memories in (sub)clinical substance use and anxiety/ trauma respectively. Of 4936 publications assessed for eligibility, 8 studies of substance use, and 10 of anxiety (phobia) and trauma-related symptoms were included in the meta-analyses. Results: Overall, the findings were in the predicted direction, with the majority of effect sizes favouring the ‘Retrieval + Treatment’ condition. However, the magnitude of effects depended upon the nature of the treatment type, with pharmacological interventions (g=0.59; relative to behavioural strategies; g=0.32) showing a clearer beneficial effect in studies of phobia/trauma, and post-retrieval behavioural strategies a (significantly; g=0.60) larger effect in substance use studies when compared to pharmacological (g=-0.09). Conclusions: High levels of heterogeneity and small sample sizes limit the strength of conclusions that can be drawn at this stage of inquiry. We hope this review will provide an impetus to address these issues in future research. The study was funded by a Medical Research Council (UK) grant awarded to SKK and RKD and a UCL PhD studentship to KHW.

E12 CHARACTERISTICS OF OPIATE DEPENDENT PATIENTS ON STABLE, “LOW DOSE” METHADONE Zhou K, Neuropsychopharmacology Unit, Centre for Psychiatry, Division of Brain Sciences, Imperial College London, Burlington Danes Building, Hammersmith Campus, 160 Du Cane Road, London, W12 0NN [email protected] Turton S(1), Golob D(2), Moore A(2), Lingford-Hughes A(1) (1) As presenting author; (2) Brent Addiction Recovery and Clinical Service, CNWL NHS Foundation Trust, London Introduction: Opioid dependence represents a significant public health and economic burden for the UK. Methadone, as an opioid substitution therapy, has achieved success in improving health and social harms. However, a picture has emerged of many opioid-dependent patients (ODP) remaining stable on ‘low doses’ without detoxifying i.e.<60mg, which is the recommended dose for clinical efficacy. It is unclear the reasons why. This project aimed to characterize this population to understand more about who they represent and their outcomes. Methods: Data was extracted from clinical records of ODPs prescribed methadone for heroin addiction, at the Brent Addiction Service, CNWL NHS Foundation Trust. Patients titrating and re- titrating on medication were not included for analysis. Variables analysed included gender, employment, care of dependants (children/ others under full- time care), relationship status, alcohol- use and on-top heroin use. Patients were classified according to dosage schemes: stable (stable dose >3 months), unstable (variable dose within 3 months) and reducing. ‘Low dose’ methadone (<60mg) was additionally classed as ‘very low’ (=<40mg) and ‘moderately low’ (41-59 mg). Results: 177 ODPs met criteria for analysis. 84% were male, and 44% of the cohort was stable on ‘low doses’. 64% of stable patients were on ‘low doses’. These patients were significantly more likely to have dependants (p= 0.002) and report alcohol- use (p= 1.775E^-05), than those prescribed doses higher. No significance was found with other variables, although individuals in employment and in relationships were more likely, than not, to be scripted on ‘low doses’. Comparing the ‘very low’ and ‘moderately low’ groups, those on ‘moderately low’ doses were significantly more likely to be using heroin on- top (p= 0.020). No other significant associations were identified, although individuals with dependants or in employment were more likely to be on ‘very low’ than ‘moderately low’ doses. Conclusion: ODPs with dependants are more likely to be stable on ‘low doses’ than doses higher. This supports current literature which emphasises the importance of illicit drug abstinence in social roles involving greater responsibility (Staff et al, Dev Psychopathol. 2010 Nov; 22(4): 917–932). This may be explained by a reluctance to detoxify in fear of disrupting stability. The absence of associations with other variables indicates our sample size may be too small, and further research with larger samples may be required. The observed high proportion of stable patients prescribed below the 60mg guideline, suggests a need for a review of this recommended limit. ABSTRACTS A63

E13 CHARACTERISTICS OF OPIATE DEPENDENT PATIENTS RECEIVING ‘HIGH’ AND ‘LOW’ DOSE METHADONE Perinpathasan K, Neuropsychopharmacology Unit, Centre for Psychiatry, Division of Brain Sciences, Imperial College London, Burlington Danes Building, Hammersmith Campus, 160 Du Cane Road, London, W12 0NN [email protected] Turton S(2), Golob D(1), Moore A(1), Lingford-Hughes A(2) (1) Addiction Recovery and Clinical Centre (ARCC), Willesden Centre for Health, Harlesden Road, NW10 3RY, United Kingdom; (2) As presenting author Introduction: Opioid substitution therapy (OST), with drugs such as methadone, is the most commonly used treatment for those with opioid dependence. According to guidelines, patients should be encouraged to progress from a maintenance stage on a stable dose of OST, to detoxification, in which OST is reduced, to achieve abstinence from all opiates. However, it has been found that although many patients successfully reduce their OST dose, they remain taking lower doses for extended periods of time. Interestingly, these doses often fall under that suggested by guidelines as optimal (>60mg). This study aims to characterise patients on ‘low-dose’ methadone (i.e. <60mg) to help our understanding of why these patients may not complete their detoxification. Methods: Retrospective clinical data was collected from all those receiving methadone at CNWL Addiction Recovery and Clinical Centre. Methadone dose <60mg was considered ‘low- dose’ and ≥61mg were considered to be ‘high-dose’. Demographic data, co-morbid psychiatric conditions and drug use, on-top heroin use (use within preceding 30-day period), as well as treatment stability (unchanged dose over past 3-months) was obtained. Statistical analysis was conducted with Chi-Square tests to compare those on ‘high’ vs. ‘low’ dose methadone. Results: 193 patients were receiving methadone, of which 62% were stable, with doses ranging from 8mg-200mg.The average dose of methadone in stable patients (n=119) was 56.3±31.6mg. Those taking ‘low-dose’ methadone (n=76) were compared to those with ‘high-dose’ (n=33), and were shown to have lower housing concerns (n=14 vs 9), reduced contact with their children (n=4 vs 2), co-morbid mental health conditions (n=42 vs 20) and co-morbid drug use (n=59 vs 27), however there were no significant (p>0.05) differences between the groups. There was a greater proportion of ‘low-dose’ patients using on-top heroin (n=40 vs 16), however this too did not meet statistical significance. Conclusions: The majority of patients receiving OST in the community addiction service are taking <60mg methadone, which is consistent with the national average. The lack of significant differences between the ‘high’ vs ‘low’ subgroups illustrates the complexity of treating opiate dependence. Some patients may be on ‘low-dose’ due to having achieved social and psychological stability. Others may not have reached stability and appear instead to prefer lower doses, as it allows them to suppress opioid withdrawal symptoms, without compromising the euphoria they experience when they use heroin on- top. The lack of clear defining characteristics for the patient groups show the importance of utilising a personalised approach to treatment.

E14 GENETIC VARIATION IN DOPAMINE AND OPIOID RECEPTOR GENES DOES NOT PREDICT STRIATAL BOLD RESPONSE TO REWARD ANTICIPATION IN SUBSTANCE DEPENDENCE Verdi S, Neuropsychopharmacology Unit, Division of Brain Sciences, Dept of Medicine, Imperial College London, Burlington Danes Building, Hammersmith Campus, 160 Du Cane Road, London, W12 0NN serena. [email protected] Turton S(1), Wing V(1), McGonigle J(1), Elliott R(4), Ersche KD(2), Flechais R(1), Orban C(1), Murphy A(4), Smith DG(2), Suckling J(2), Taylor EM(4), Deakin JFW(4), Robbins TW(3), Nutt DJ(1), Lingford-Hughes AR(1), Paterson LM (1) (1) As presenting author; (2) Behavioural and Clinical Neuroscience Inst, Dept of Psychiatry, Univ of Cambridge, UK; (3) Behavioural and Clinical Neuroscience Inst, Dept of Psychology, Univ of Cambridge, UK; (4) Neuroscience and Psychiatry Unit, Inst of Brain, Behaviour and Mental Health, Univ of Manchester, UK Introduction: Numerous GWAS and candidate gene studies suggest that genetic polymorphisms associated with dopaminergic and opioidergic function are associated with substance dependence consistent with A64 ABSTRACTS their receptor functionality in addiction circuitry. However, systematic reviews of genetic involvement cite multiple inconsistencies and lack of replication, ascribed to the heterogeneous nature of addiction and differences in biomarkers used. In a multi-centre neuroimaging study (ICCAM; Paterson et al.,2015, J.Psychopharmacol), we sought to determine whether genetic predisposition contributes to differences in reward processing in substance dependence. We evaluated the association between striatal BOLD response to non-drug reward anticipation, a putative functional brain marker of reward processing, with potential ‘risk’ variants of three candidate genes known to have a role in addiction circuitry networks; DRD2, OPRM1 and D3. We hypothesised that the proportion of genetic ‘risk’ variants would be higher in abstinent alcohol and polydrug dependent relative to healthy control participants, and that these variants would be associated with lower striatal BOLD response. Methods: Following informed consent (REC number 11/ H0707/9), DNA was extracted from blood samples (n=149) collected from abstinent alcohol dependent (n=28), polydrug dependent (n=56) and control participants (n=65). A SNP-specific KASPTM assay was used to determine genotypes for DRD2; Taq1A (rs1800497), D3; Ser9Gly (rs6280) and OPRM1; A118G (rs1799971) polymorphisms. Assuming a dominant model, DRD2 and D3 polymorphisms were categorised as T-allele (C:T,T:T) or C (C:C) and the OPRM1 polymorphism was categorised as G-allele (G:A,G:G) or A (A:A). χ2 tests were used to compare relative genotype frequencies across sub-groups. Participants underwent fMRI scanning (3-T) using the monetary incentive delay task (MIDT). Conditions included win, loss and neutral trials where participants could win or lose money (or neither win nor lose). Reward anticipation (BOLD signal contrast between win and neutral anticipation) was investigated using an a priori striatal region- of-interest (ROI) approach. Effects of group, genotype and group*genotype interaction were explored using factorial ANOVA. Results: No significant DRD2, D3, OPRM1 genotypic differences were observed in frequency distribution between abstinent alcohol dependent, polydrug dependent, and control participants (p>0.05). There were no significant effects of group or genotype on MIDT striatal BOLD response and no interaction was observed (p>0.05, multiple-comparisons corrected, adjusted for ethnicity). Conclusions: These data suggest that the polymorphisms examined do not impact on striatal function during reward anticipation. Future studies should consider other markers (e.g. emotional reactivity) and neuropsychological factors when investigating addiction aetiology. This research was funded by the MRC (G1000018) with support from GSK.

E15 SYNTHETIC CANNABINOID USE IS ASSOCIATED WITH SIGNIFICANTLY WORSE OUTCOMES COMPARED TO NATURAL CANNABIS: A MENTAL HEALTH ELECTRONIC CASE REGISTER STUDY Hobbs M, King’s College London, St Thomas’ Street, London, SE1 9RT [email protected] Kalk N(1), Morrison P(1), Patel R(1), Stone J(1) (1) IOPPN, 16 De Crespigny Park Denmark Hill, London SE5 8AF Introduction: International evidence suggests that the use of Synthetic Cannabinoid Receptor Agonists (SCRAs) is common among patients accessing secondary psychiatric services. SCRA intoxication is associated with aggression and psychotic symptoms, which outlast acute intoxication in 30% of cases and require higher doses of antipsychotics than cannabis induced psychosis. However, there is little UK data and the impact of SCRA use on psychiatric hospitalization is unknown. We investigated demographic details, diagnosis and length of stay in individuals who have used SCRAs with data from the South London and Maudsley NHS Foundation Trust Biomedical Research Centre (SLaM BRC) Clinical Record Interactive Search (CRIS) register. Methods: A total of 635 SCRA users (SCRA+) and 635 controls (SCRA-) were included in the study. The control group was matched on age, ethnicity, gender and diagnostic grouping. Subgroups of Natural Cannabis (NC) users and non-NC users within the ‘SCRA+’ and ‘SCRA-’ groups were also analysed, resulting in 4 four additional groups: SCRA+NC+ (n=629); SCRA-NC+ (406); SCRA+NC- (n=6); SCRA-NC- (n=229). Results: SCRA users had a mean age of 32.89 years (SD 10.81), were predominantly white (54.49%) and male (86.14%). SCRA users had a significantly higher incidence of cannabis use than non-SCRA users (p<0.001). They were also significantly more likely to be homeless than non-SCRA users (p<0.001). Users of both SCRAs and NC were significantly more likely to have been homeless compared to users of NC alone (p<0.001). SCRA users also experienced significantly more hospital bed days (BDs) (M = ABSTRACTS A65

85.54, SD = 199.74) than controls (M = 25.42, SD = 92.32), which remained the case when adjusting for age, sex, NC use and homelessness (p<0.001). Concurrent use of NC significantly increased BDs (SCRA+NC+: M = 86.34) compared to use of NC alone (SCRA-NC+: M = 37.62) (p<0.001). Conclusions: SCRA use is found in vulnerable groups of men in secondary psychiatric care. Importantly, SCRA use is associated with an increased length of stay in hospital. Further work is needed to ascertain if this is due to increased morbidity associated with SCRA use, especially compared to NC alone. This finding highlights the need for psychiatrists to ask specifically about SCRAs. Psychoeducation for patients regarding the additional risk posed by SCRAs compared to NC should be considered. No sponsorship was received for this study.

E16 ALAMA-NIGHTLIFE – ASSESSING THE REPRESENTATIVENESS OF RECRUITING ONLINE FOR A NIGHTLIFE AND DRUG USE SURVEY USING TARGETED SOCIAL MEDIA ADVERTISING Waldron J, CPU, Clinical, Educational and Health Psychology, UCL, 1-19 Torrington Place, London, WC1E 7HB [email protected] Grabski M(1), Freeman TP(2), Curran HV(1) (1) As presenting author; (2) National Addiction Centre, Institute of Psychiatry, Psychology & Neuroscience (IoPPN), Addiction Sciences Building, Denmark Hill, London, SE5 8BB Introduction: The nightlife scene has long been associated with the use of alcohol and other drugs. What is less known is what factors influence the trajectories of drug use associated with the nightlife economy, and what predicts escalation, decline or maintenance of use. This is now urgently needed in light of developments in the European drug market which have been associated with an increase in negative health related outcomes. ALAMA-Nightlife is a longitudinal study aiming to characterise drug use pathways amongst young adults engaging with the European night time economy in the UK, Netherlands, Belgium and Italy. This study assesses the representativeness of our baseline sample by comparing demographic traits, drug use and nightlife engagement with offline screener data collected from club and festival goers. To the authors’ knowledge, this is the first study to validate an online sample of the European nightlife scene. Methods: Participants were recruited to the baseline sample of the longitudinal cohort using targeted advertising on social media between May and September 2017. During the same time period, people attending clubs and festivals were screened offline at these events for demographic information, last year drug use and engagement with the night time economy using an innovative, random intercept method. Questions in the offline screener were also asked in the baseline survey, allowing comparisons between the two groups to assess the representativeness of our baseline sample with those attending clubs and festivals. Results: 6,017 young adults aged between 18 and 34 and living in the UK, Netherlands, Belgium or Italy were successfully recruited via social media advertising and completed the baseline survey. Offline screener data from 3,570 people attending clubs and festivals who met the inclusion criteria were collected. A higher proportion of those screened attended nightlife venues and used alcohol, cannabis, ecstasy, cocaine and amphetamines in the last 12 months than those recruited online (p<0.05), although effect sizes reveal these differences were ‘small’ (r<0.10). Those screened also attended venues and used the five drugs more frequently, with effect sizes showing these differences ranged from below small (r<0.10) to small (r<0.30). Conclusion: Participants recruited using online advertising reported less frequent past 12 month drug use and venue attendance than individuals screened at clubs and festivals. This finding highlights the importance of validating study samples recruited solely via online methods. Funded by ERANID A66 ABSTRACTS

F01 QUALITY OF MOTHER-INFANT INTERACTION IS ASSOCIATED WITH PERFORMANCE ON THE BAYLEY SCALE OF INFANT DEVELOPMENT Bind RH, Psychological Medicine, Institute of Psychiatry, Psychology & Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Cutcombe Road, London, SE5 9RX [email protected] Biaggi A(1), Hazelgrove K(1), DuPreez A(2), Osborne S(2), Conroy S(1), Sethna V(1), Pawlby S(1), Pariante CM(2) (1) IOPPN, King’s College London, De Crespigny Park, London, SE5 8AF; (2) Maurice Wohl Clinical Neuroscience Institute, King’s College London, Cutcombe Road, London SE5 9RX Introduction: Cognitive development begins in infancy and problems early on are predictive of difficulties in childhood and adolescence (Soysal et al., 2014). Infant development as a whole is influenced by many factors, including maternal sensitivity (Feldman et al., 2004), which is crucial for a positive relationship; however, few studies have explored whether the mother-infant relationship is directly linked to early infant cognition. This study investigates whether the dyadic bond is associated with cognitive development at 12 months. Methods: This sample included 52 mother-infant dyads (mean age = 31.7 years). At 12 months postnatal, dyads completed a mother-infant interaction task and infant developmental testing. For the interaction task, mothers were instructed to interact with their baby as they typically would, and videos were recorded and rated using the CARE-index, a reliable method for scoring mother-infant interactions. Videos were assessed for levels of: dyadic synchrony; maternal sensitivity, control, and unresponsiveness; and infant cooperation, compulsivity, difficulty, and passiveness. The infant developmental testing was conducted using the Bayley Scale of Infant and Toddler Development, an assessment that rates infants’ levels of cognitive, language, motor, and socioemotional development. Results: Relationships were found between the quality of the mother-infant interaction and the infant’s development. Firstly, positive correlations were found between: dyadic synchrony scores (how in tune the mother and infant are) and the language component of the Bayley (r=.53,p<.001); maternal sensitivity (how pleasantly responsive a mother is to her infant) and language (r=.53,p<.001); and infant cooperativeness (how responsive the infant is to its mother) and language (r=.52,p<.001). Secondly, negative correlations were found between maternal control (how negatively connected and hostile a mother is to her infant) and performance on the cognitive (r=-.31,p<.05) and language (r=-.40,p<.01) components. Thirdly, negative correlations were found between infant compulsivity (how inhibited an infant is to avoid punitive maternal behaviour) and performance on the language component (r=-.32,p<.05). Conclusions: Dyadic behaviour is closely linked with infant cognitive and language development, such that the higher the dyadic synchrony, maternal sensitivity, and infant cooperativeness, the greater the language development, and the higher the maternal control and infant compulsivity, the lower the language and cognitive development. An infant’s ability to develop across domains relies on maternal sensitivity and scaffolding, which should yield greater developmental outcomes; meanwhile, controlling behaviour, which is typically punitive and overbearing, does not take into consideration the infant’s developmental needs, and could therefore restrict and inhibit infant development. These results highlight the importance of the early mother-infant relationship when considering offspring developmental trajectories of cognitive functioning. Sources of financial sponsorship: NIHR Biomedical Research Centre at South London and Maudsley NHS Trust and King’s College London

F02 A NOVEL METHOD FOR MODIFYING FRONTOPARIETAL NETWORK PLASTICITY AND ITS EFFECTS ON DECISION-MAKING Nord CL, Dept. of Psychiatry, University of Cambridge, Level E4, Box 189, Addenbrookes Hospital, Cambridge, CB2 0QQ [email protected] Popa T(2), Smith E(1), Hannah R(3), Mandali A(1), Donamayor N(1), Weidacker K(1), Voon V(1) (1) As presenting author; (2) Human Motor Control Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Building 10, Room 7D42, 10 Center Drive, Bethesda, MD 20892- 1428; (3) Sobell Department for Motor Neuroscience and Movement Disorders, University College London, 33 Queen Square, London WC1N 3BG Introduction: Cortical paired associative stimulation (cPAS) is a neuromodulation technique where paired transcranial magnetic stimulation pulses are repeatedly applied over interconnected cortical regions, ABSTRACTS A67 increasing plasticity between the two regions via spike-timing-dependent-plasticity. However, most studies have been limited to the motor cortex. We tested whether cPAS could modify the plasticity of prefrontal- parietal networks. Methods: Healthy volunteers underwent three testing sessions, in a random order, at least one week apart: right dorsolateral prefrontal cortex (DLPFC) stimulation preceding right inferior parietal cortex (iPC) stimulation by 10ms, iPC stimulation preceding DLPFC stimulation by 10ms, and a control condition, where half the participants received DLPFC preceding iPC by 100ms, and the other half iPC preceding DLPFC stimulation by 100ms. Following stimulation, participants completed the two-stage decision-making task (Daw et al., 2011, Neuron 69(6): 1204-1215) and the delay discounting task (Kirby et al., 1999, J Exp Psychol Gen 128(1):78-87). Results: In the two-stage task, we found a main effect of cPAS condition on participants’ learning rates (p<0.05), such that DLPFC-to-parietal stimulation increased participants’ learning rates in both stages of the task. Hierarchical drift diffusional modelling revealed a shift in the starting point, or prepotent bias, of the drift process, with no effect on threshold or diffusion rate. Specifically, there was a main effect of cPAS condition (log BF10=7.67), driven by parietal-to-DLPFC stimulation increasing the starting point, relative to the control condition. In the delay discounting task, stimulation in the same direction (parietal-to-DLPFC) increased the steepness of participants’ delay discounting functions, making them more likely to select smaller more immediate rewards than larger delayed rewards, compared to baseline (p<0.05). Conclusion: We find that modulating plasticity of DLPFC- parietal networks has several effects on decision-making: increasing learning rate, shifting prepotent biases, and increasing discounting of future rewards. These methods may represent a new way forward in the neuromodulation of cognitive processes, with potential relevance for neuropsychiatric disorders that involve disrupted decision-making. Financial sponsorship: this study was funded by an MRC Senior Clinical Fellowship (Dr. Valerie Voon).

F03 NEUROCOGNITIVE CORRELATES OF WORKING MEMORY IN POSTPARTUM PSYCHOSIS Kowalczyk OS, Child and Adolescent Psychiatry, IoPPN, KCL, De Crespigny Park, London, SE5 8AF [email protected] Pauls A(2), Dazzan P(2), Mehta MA(1) (1) Dept of Neuroimaging, IoPPN, KCL, De Crespigny Park, London, SE5 8AF; (2) Dept of Psychosis Studies, IoPPN, KCL, De Crespigny Park, London, SE5 8AF Introduction: Postpartum psychosis (PP) is a severe postpartum disorder. Working memory (WM) related brain activations are consistently impaired in disorders related to PP (e.g. bipolar disorder, non-puerperal psychosis), however, few studies have investigated this in PP. The aim of this study is to compare women at risk of PP and healthy postpartum women on measures of brain activation and functional connectivity related to WM. Methods: Twenty-four women at risk of PP (11 developed an episode – PE; 13 remained well – NPE) and 20 healthy postpartum women completed a functional Magnetic Resonance Imaging (fMRI) scan within a year of delivery, including a classic WM task (n-back). All fMRI data analysis was performed with FSL, following a standard preprocessing pipeline. General linear models were used to examine peak activations and psychophysiological interaction (PPI) analysis was performed to investigate task- related connectivity. For the PPI analysis the principal seeds were placed in the left and right dorsolateral prefrontal cortices (DLPFCs) based on previous studies. Two additional seeds (primary motor area – M1, and supplementary motor area – SMA) were used to capture connectivity associated with the motor response to the experimental conditions. Randomise (FSL) with threshold-free cluster enhancement was used for non-parametric permutations-based test of between-group differences (5000 permutations, corrected p<0.050). Results: Hyperactivity of lateral visual areas during 0- (605 voxels), 1- (1705 voxels), and 3-back (1453 voxels) conditions was observed in the PE group compared to controls. PE and NPE women had increased connectivity with the right DLPFC and parietal, lateral visual, bilateral temporal, and cerebellar regions, during 1- (PE=1118 voxels, NPE=6847 voxels) and 2-back compared to controls (PE=48355 voxels, NPE=21826 voxels). Similarly, NPE and PE groups both had increased connectivity of bilateral parietal and visual regions with M1 compared to controls during 2-back (PE=91 voxels, NPE=16935 voxels). Additionally, the PE group had increased connectivity of the right middle temporal gyrus with the right DLPFC during 2-back compared to the NPE group (164 voxels). All p-values were A68 ABSTRACTS

<0.050. Conclusions: This study reveals that while increased connectivity during the n-back task is evident in all women at risk of PP, there are specific increases in connectivity between the prefrontal cortex and temporal lobes in those who developed an episode. Importantly these changes differ from the reduced connectivity with the DLPFC usually observed in bipolar disorder and schizophrenia, and provide initial evidence of the potentially differential nature of abnormalities in PP. These results require replication and extension into other cognitive domains and may contribute to the development of different treatment strategies for women at risk of PP compared to those with non-puerperal psychosis. The research was supported by NARSAD, the MRC, Medical Research Foundation, the Psychiatry Research Trust, and NIHR- BRC for Mental Health at SLaM and KCL.

F04 A NOVEL RAPID SERIAL VISUAL PRESENTATION TASK FOR INVESTIGATING ATTENTION IN MICE Brennan LJ, PPN, University of Bristol, Biomedical sciences building, University of Bristol, Bristol, BS8 1TD [email protected] Goikolea A(1), Sorenson O(1), Robinson E(1) (1) Biomedical Sciences Building, University of Bristol, Bristol, BS8 1TD Introduction: Attentional impairments are observed in a wide range of psychiatric and neurological disorders. (Bari, A. et al. 2008. Nat. Protocols 3, 759-767) Continuous performance tasks are commonly used to assess attentional impairments in humans including the rapid serial visual presentation task (RSVP). (Rosvold, H. E. 1956. Journal of Consulting Psychology, 20; 343-350) We have developed a rat RSVP task using touch screens where we present a sequence of images containing a target (active responses) and distractors (no-go responses) within each discrete trial. In this study, we evaluate the same task in mice. We have investigated the effects of ageing on performance, and the influence of attention modifying drugs scopolamine (SCP), amphetamine (AMP) and atomoxetine (ATO) on performance. Methods: Animals (12 C57bl/6 female mice) were trained and tested over 3 months in a rapid serial visual presentation task. This task is run in a touchscreen operant chamber with a 6-image presentation sequence. The effects of SCP (0.1, 0.3, 1.0 and 3.0mg/kg), AMP (0.15, 0.5 and 1.0mg/kg) and ATO (0.3, 1.0, 3.0mg/kg) on attention, were observed in animals aged ~4-9mths. Animals then underwent a 3-month period without testing, were re-baselined, and the effects of ageing were recorded. Results: At the highest dose of 3.0mg/kg SCP significantly (p<0.01) affected attention, with reduced accuracy and increased incorrect responses. At 1.0mg/kg AMP was shown to improve accuracy significantly (<0.05) compared to 0.1 and 0.3mg/kg AMP. ATO had no effect on attention at any of the doses tested. Following 3 months without testing, all mice returned to a similar level of accuracy suggesting no impairment associated with ageing over this time period. Conclusions: Mice can successfully perform an RSVP task, and accurately detect and respond to discrete target images and withhold responding from distractor images. Initial characterisation of the effects of the muscarinic antagonist found this impaired performance in the task whilst the psychostimulant, amphetamine improved performance. Although previously shown to improve attention, atomoxetine had no effects in this task. Animals also did not show a decline in performance after a period of 3 months without testing. NHS Bursary sponsorship for this study

F05 THE COGNITIVE AND NEURAL MECHANISMS OF MOTIVATION TO EXERT COGNITIVE EFFORT Mkrtchian A, ICN/ETPB, UCL/NIMH, 10 Center Drive, Bldg. 10, Bethesda, MD, USA, 20892 anahit.mk1@ gmail.com Hauser TU(3), Magerkurth J(1), Gormley S(2), Valton V(2), Josephs O(3), Roiser JP(2) (1) Birkbeck-UCL Centre for Neuroimaging, UCL, London, WC1H 0AP; (2) Institute of Cognitive Neuroscience, UCL, London, WC1N 3AR; (3) Wellcome Centre for Human Neuroimaging, UCL, London WC1N 3BG Introduction: Aberrant motivated behaviour is a common symptom in psychiatric disorders, yet poorly understood. It has been suggested that these symptoms result from abnormal motivation-related effort ABSTRACTS A69 computations, as demonstrated by physical effort tasks. Few have however examined neural mechanisms of cognitive effort-related decision-making using a patient-appropriate task. This is vital as motivation to exert cognitive effort is important for adaptive functioning in society, and may be an important aspect of aberrant motivation. Here, we aimed to characterise the neural mechanisms of cognitive effort-related decision-making by adapting a physical effort task specifically designed to minimise cognitive demands during the decision phase. Methods: In order to better understand cognitive and neural mechanisms of willingness to exert cognitive effort, it is essential to first characterise its function in a healthy population prior to clinical use. We had healthy participants (N=22) perform a cognitive effort decision-making task during simultaneous EEG-fMRI recording. Participants received offers to perform a cognitive challenge varying in effort and reward magnitude, allowing us to assess effort evaluation independently from reward evaluation. The challenge consisted of correctly categorising 10 odd/even digits under time pressure. Different effort levels were achieved by varying the challenge duration. Results: In line with expectations, the probability to accept an offer increased with increasing reward levels (F(1.16,24.38)=45.48, p<0.001) and decreased with increasing effort levels (F(1.18,24.78)=19.37, p<0.001). During decisions about whether to accept or reject the offer, the effort magnitude modulated activation in the left precentral gyrus, cingulate, left parietal lobe, middle occipital gyrus, left middle temporal gyrus (F-contrast, cluster-level FWE p<0.05 corrected). All areas were associated with a ‘U-shaped’ effort modulation such that activation was greater during easy than medium effort, and during high than medium effort, but no difference between easy and high effort. Conclusions: The results show expected behavioural patterns and robust neural mechanisms underlying cognitive effort sensitivity. The task thus demonstrates potential to examine cognitive and neural substrates of motivation to exert cognitive effort in a patient-appropriate design. The neural pattern of effort evaluation was, however, surprising, and its explanation is currently unclear. A key challenge for future research will be to examine motivational processes in populations with impaired motivational symptoms. Sponsored by Wellcome-NIH PhD Studentship.

F06 ADAPTIVE LEARNING FROM ENVIRONMENTAL CONTINGENCIES IN EATING-DISORDER RISK GROUPS Pike AC, Department of Psychiatry, University of Oxford, Warneford Hospital, Warneford Lane, Oxford, OX3 7JX [email protected] Pulcu E(1), Sharpley AL(1), Park RJ(1), Cowen PJ(1), Browning M(1) (1) As presenting author Background: Eating Disorders (EDs) are severe and often chronic mental illnesses. EDs have been linked to cognitive inflexibility, which is partly thought to underpin the compulsive behaviours evident in this disorder. Here we investigate whether this cognitive inflexibility might be due to an inability to learn adaptively from environmental contingencies. Methods: 25 participants who scored over 20 in the EAT- 26 questionnaire, 25 participants who had recovered from Anorexia Nervosa, and 32 healthy controls completed a two-option learning task which can be modelled computationally (Pulcu and Browning/2017/ eLife/6/e27879), in which wins and losses vary in volatility between the three blocks. All participants completed the SCID-5-RV and the learning task. Parameters were on the infinite real line, obtained by using an inverse logit transform. Results were obtained using repeated-measures ANOVAs. To examine overall behaviour group and task version (which determined block order) were between-subject factors, and block volatility (win volatile or loss volatile) and parameter valence (win learning rate, loss learning rate) were within-subject factors. To examine differences in adjusting learning rates between groups, difference in learning rates (volatile-stable blocks) was the dependent variable, with group and task version as between- subject factors, and parameter valence as a within-subject factor. Results: Participants were able to adjust their learning rates between blocks successfully, as shown by an interaction effect between block volatility and parameter valence F(1, 76)=77.6, p<0.0001, η¬2G =.09. Overall, there was no significant interaction effect of group on difference in learning rate F(2,76)=1.57, p=0.21, η2G =.02 . However, there was a significant interaction effect of group and task version: F(2,76)=4.07,p=0.02, η2G =.04. This seems to be driven by a significant interaction between group, block volatility and parameter valence when using the A70 ABSTRACTS task version in which the loss-volatile block was before the win-volatile block: F(2,41)=5.57, p=0.007, η2G =.10. In this case, it appears that those who have recovered from Anorexia Nervosa decrease their learning rate more when outcomes become stable than the other groups: t(21.43)=3.06, p=.006, d=.998. Conclusions: The study confirms the results of previous work, which indicated that human participants are able to alter their learning rate in response to changing environmental contingencies. Clinical results indicate that those who have recovered from Anorexia Nervosa reduce their learning rate for negative events more than others in environments where losses are considered to be stable. This may lead to a difference in how those who have recovered from anorexia nervosa learn about the environment. This study was supported by the MRC, the NIHR Oxford Health Biomedical Research Centre, and Department of Psychiatry at the University of Oxford.

F07 INTEGRATION OF POST-DECISION EVIDENCE AND CONFIDENCE JUDGEMENTS IN DEPRESSION Payne MEM, Institute of Cognitive Neuroscience, UCL, Alexandra House, 17 Queen Square, WC1N 3AR [email protected] Rollwage M(2), Fleming SM(2), Roiser JP(1) (1) UCL Institute of Cognitive Neuroscience, 17 Queen Square, WC1N 3AR; (2) Wellcome Centre for Human Neuroimaging, 12 Queen Square, London, WC1N 3BG Background: The ability to reflect on one’s own thoughts (metacognition) is considered important in the development and maintenance of depression. We recently reported that depressive symptoms were associated with metacognitive bias (lowered confidence) in perceptual decision-making (Rouault et al., 2018, Biological Psychiatry, advance online publication). Here, we investigated whether shifts in metacognitive function would extend to integration of post-decision evidence into confidence judgements. Methods: 416 participants completed a confidence task and a post-decision evidence integration task via Amazon Mechanical Turk. In both tasks, participants made a decision about which of two squares contained more dots. In the confidence task, participants rated confidence in their choice from 0% (certainly incorrect) to 100% (certainly correct). In the post-decision evidence integration task, participants observed a new sample of flickering dots before rating their confidence. In half the trials, the new sample was identical; in the other half the difference in dots was stronger. Finally, participants completed a depression questionnaire (Zung, 1965, Archives of general psychiatry, 12(1), 63-70) and a single-item self- esteem measure from 0 (very low) to 100 (very high). Analysis: Metacognitive bias was calculated using overall mean confidence, reflecting an individual’s tendency to use higher or lower confidence ratings regardless of performance. Metacognitive sensitivity was calculated using meta-d’, which measures to what extent an individual’s confidence discriminates correct and incorrect trials. Post-decision evidence integration was calculated using an interaction term, which incorporates adjustment of confidence to additional evidence when correct or incorrect. To investigate associations with depressive symptoms and self-esteem, we used linear regression analyses with robust fits and two-tailed tests. In all analyses, we controlled for performance, evidence strength and demographics. Results: We found a significant association between post-decision evidence integration and depression (r=.119, p=.045) - participants with greater depressive symptoms showed greater adjustment of confidence after post-decision evidence. eW also found a marginal association between metacognitive bias and depressive symptoms (r=-.099, p=.056). Our self-esteem measure, however, was better able to account for differences in overall confidence (r=.203, p<.001), and this effect remained significant when controlling for depression. eW did not find any associations of metacognitive sensitivity (meta-d’) with either the depression or self-esteem measures. Conclusions: Our results indicate that depressive symptoms have a small but significant effect on metacognitive function. More evidence is needed, perhaps with larger patient populations, to deconstruct these differences further. The Wellcome Centre for Human Neuroimaging is supported by core funding from the Wellcome Trust (203147/Z/16/Z). ABSTRACTS A71

F08 COMPUTATIONAL NEUROPHARMACOLOGY OF IMPULSIVE PREMATURE RESPONDING IN HUMANS Cole DM, Dept of Psychiatry, Psychotherapy & Psychosomatics, Univ of Zurich, Univ Hosp of Psychiatry, Lenggstrasse 31, Zurich, Switzerland, CH-8032 [email protected] Rigoux L(5), Diaconescu AO(7), Mathys C(8), Nagy Z(4), Müller D(3), Steuer AE(2), Seifritz E(1), Quednow BB(1), Stephan KE(6) (1) As presenting author; (2) Dept of Forensic Pharmacology & Toxicology, Zurich Inst of Forensic Med, Univ of Zurich, Winterthurerstrasse 190/52, CH-8057 Zurich, Switzerland; (3) Inst for Clinical Chemistry, Univ Hosp Zurich, Ramistrasse 100, CH-8091 Zurich, Switzerland; (4) Lab for Social and Neural Systems Res, Univ Hosp Zurich, Ramistrasse 100, CH-8091 Zurich, Switzerland; (5) Max Planck Inst for Metabolism Res, Gleueler Strasse 50, 50931 Cologne, Germany; (6) Translational Neuromodeling Unit, Inst for Biomed Engineering, Univ of Zurich & ETH Zurich, Wilfriedstrasse 6, CH-8032 Zurich, Switzerland; (7) Univ of Basel, Dept of Psychiatry, Wilhelm Klein Strasse 27, CH-4012 Basel, Switzerland; (8) Wellcome Trust Centre for Neuroimaging, Inst of Neurology, Univ College London, 12 Queen Square, London WC1N 3BG Introduction. The behavioural construct of impulsivity is multifactorial, with broad relevance for neuropsychiatric conditions such as addiction, psychosis and ADHD. The serotonin (5-HT) and dopamine (DA) neuromodulatory systems are hypothesised to serve complementary roles in the expression, specifically, of the ‘premature responding impulsivity’ (PRI) behavioural subtype. However, PRI remains under-researched in humans. We provide a computational neuroimaging assessment of the serotonergic and dopaminergic bases of PRI in healthy volunteers. We hypothesised interactions between 5-HT- and DA-promoting drugs and reward/punishment task effects on behaviour and neural encoding of computational quantities under environmental uncertainty. Methods. Ninety-three males (24.9±4.3 years) enacted probabilistic decision-making during fMRI in double-blind, placebo-controlled, crossover designs with either the selective 5-HT reuptake inhibitor escitalopram (15mg; n=50), or the DA reuptake inhibitor methylphenidate (20mg; n=43). The task embodied reversal learning procedures wherein the likelihood of which binary cue was the correct, rewarding choice varied across trials. Within trial, participants opted to either wait longer to receive more accurate choice information, or respond sooner to maximise reward/minimise loss if correct. Behavioural analysis used hierarchical Bayesian modelling, computing PRI parameters during decision-making and prediction error (PE) signals during feedback. We acquired BOLD fMRI data at 3T. Computational neuroimaging analysis regressed PRI and PE trajectories against each fMRI run, followed by group analyses examining main effects and interactions of drug and task ‘win/loss’ condition (P<0.05). Results. Relative to placebo, escitalopram significantly increased the number of cues viewed before making a decision, specifically during loss avoidance in periods of high uncertainty. Similarly, fMRI analyses revealed a significant escitalopram:task context interaction in the encoding of outcome-related PEs in the serotonergic dorsal raphe. Conversely, a computational ‘baseline urgency’ parameter, representing trait-level PRI, was reduced under methylphenidate, relative to placebo, across win/loss task contexts. Moreover, methylphenidate reduced the neural representations of (i) a computational PRI parameter describing evidence accumulation rate and (ii) uncertainty-related PEs, respectively, in bilateral frontopolar cortex and left putamen. Conclusions. Our findings suggest greater nuance to PRI associations with DA/5-HT than hypothesised. We observed 5-HT increase to primarily affect non-computational PRI behaviour measures, with only subtle, context-specific modulation of serotonergic brain activity. Conversely, we identified comparatively broad effects of DA in attenuating the encoding of computational PRI- and uncertainty-related variables in regions important for managing competing task goals. Further investigations may combine this computational pharmaco-imaging approach with genetic testing to elucidate the relative contributions of phasic/tonic monoaminergic mechanisms to PRI in health and disease. Sponsorship: Univ of Zurich, the Hartmann Müller Foundation & the René and Susanne Braginsky Foundation A72 ABSTRACTS

F09 THE EFFECTS OF COMT AND COMT INHIBITION ON EMOTIONAL PROCESSING Martens MAG, Department of Psychiatry, Univeristy of Oxford, Neurosciences Building, Warneford Hospital, Oxford, OX3 7JX [email protected] Dalton N(1), Scaife J(1), Harmer C(1), Tunbridge EM(1), Harrison PJ(1) (1) As presenting author Introduction: The enzyme catechol-O-methyltransferase (COMT) metabolises dopamine in the prefrontal cortex (PFC) and influences PFC dependent cognitive task performance. The human COMT gene contains a functional polymorphism (Val158Met) that influences enzyme activity: the ancestral Val158 allele has ~40% greater activity than the Met158 allele. COMT activity can also be altered pharmacologically by inhibitors, like tolcapone. Previous research linked the Met158 allele with better PFC-dependent performance. Moreover, COMT genotype and tolcapone interact, with the drug having opposite effects on cognition in Met158 and Val158 subjects. However, COMT’s role in other cognitive processes, such as emotional processing, is relatively unexplored. Neuroimaging studies implicate COMT in modulating neural activity during emotional processing, but no studies have examined the impact of COMT inhibitors on behavioural measures of emotional processing in human participants, nor whether their effects interact with genotype. Methods: We performed a double-blind, randomised, placebo-controlled, experimental medicine study which investigated non-smoking healthy males (n=74) homozygous for COMT Val158Met. We administered a single, 200mg dose of tolcapone (or placebo) and assessed emotional processing (assessed via the Emotional Test Battery [ETB]). Subjects also completed visual analogue scales (alertness, drowsiness, anxiety, sadness, happiness and nausea) and Profile of Mood States (POMS) questionnaires at four time points during the test day (upon arrival, 1.5 hours, 3.5 hours and 5 hours following tablet administration). Data were analysed by using repeated measures ANOVA with COMT genotype (Met/Met vs Val/Val) and drug (placebo vs tolcapone) as the between-subjects factors and emotion/valence as the within-subjects factor. Results: There were no robust effects of Val158Met genotype, inhibition nor their interaction on any of the emotional processing measures. Thus, there were no effects on the accuracy or speed of facial expression recognition (F’s<.1.22, P’s>.31), assessment of word valence (F’s<.61, P’s>0.05), recall of positive or negatively valenced words (F’s<.55, P’s>0.47), nor attentional vigilance towards happy or fearful faces (F’s<1.61, P’s>.12)). Neither were there any genotype or drug effects on subjective VAS ratings (P’s>0.05) or total mood disturbance (P’s>0.05). Conclusion: Therefore, we found no effects of COMT on behavioural measures of emotional processing. Notably, the ETB is a battery of tests sensitive to detect and investigate the antidepressant action of novel compounds, suggesting that tolcapone is unlikely to have antidepressant effects. Future studies are required to understand how COMT impacts on the relationship between behavioural output and neural activity during emotional processing. Funded by MRC research grant (K013092) to PJH and EMT. MM supported by Oxford Health NHS Foundation Trust NIHR Biomedical Research Centre.

F10 THE ROLE OF THE ADENOSINE SYSTEM IN HUMAN COGNITION: PILOT FINDINGS USING ISTRADEFYLLINE Hook RW, Psychiatry, University of Cambridge, Herchel Smith Building for Brain and Mind Sciences, Forvie Site, Robinson Way, Cambridge Biomedical Campus, Cambridge, CB2 0SZ [email protected]. ac.uk Isobe M(1), Christmas D(2), Ioannidis K(2), Chamberlain SR(1) (1) As presenting author; (2) Cambridge and Peterborough NHS Foundation Trust, Cambridge, CB2 0SZ Introduction: There have been indications that adenosine A2A receptors may play an important role in cognitive function. Istradefylline is a selective adenosine A2A receptor antagonist currently developed for Parkinson’s Disease. Adenosine A2A antagonists, such as Istradefylline, have demonstrated improved cognitive function in PFC-lesioned rats (Horita et al, 2013, Psychopharmacology, 230, 345-352) and have been shown to modulate reversal learning and goal-directed habit formation in animals (Chen, 2014, Int Rev Neurobiol, 119, 257-307). These findings may have implications for other dopaminergic disorders, ABSTRACTS A73 including Attention Deficit Hyperactivity Disorder (ADHD), where caffeine – whose cognitive effects are largely mediated via adenosine receptor antagonism – shows efficacy in treating the disease (Ioannidis et al., 2014, J Psychopharmacol, 28(9), 830-6.). The aim of this pilot study was to evaluate the cognitive effects of single-dose istradefylline in healthy adults. Methods: 15 healthy male participants aged between 18 and 49 were recruited via a newspaper advert. The participants provided informed consent and agreed to abstain from caffeine for 24 hours prior to participation. All participants completed a pre-screening form and were screened for psychiatric illnesses by a psychiatrist before taking part. They received single doses of Istradefylline (20mg) and placebo in a randomised, double-blind, placebo controlled, crossover design. On each visit, participants completed neuropsychological tests approximately 90 minutes after dosing (corresponding approximately with the expected time of peak plasma levels). Effects on cognition of istradefylline versus placebo were evaluated using paired t-tests. Results: The mean age of the participants was 30.07(SD 8.89). There was no significant difference of istradefylline versus placebo on the Spatial Working Memory (SWM)(Total errors: t=1.036, p=0.318), Rapid Visual Processing task (RVP) (t=0.994, p=0.337) or Intra-Dimensional/Extra-Dimension set-shifting task (IDED)(IED errors: t=1.074, p=0.301). Therefore, the null hypothesis cannot be rejected. Conclusions: This pilot study did not find that istradefylline improved cognitive performance on tasks measuring decision-making, set-shifting and sustained attention. This may have been due in part to the small sample size (N=15). The results will be re-analysed once 20 people have completed the study. Additionally, other neuropsychological tests were included in this study and will be examined once study recruitment is complete. There is a need for further research into the adenosine system and cognitive function, possibly with diseases such as ADHD. This research is funded by a Wellcome Trust Fellowship to Dr Chamberlain.

F11 ACUTE CITALOPRAM ADMINISTRATION REDUCES INFORMATION SAMPLING IN HEALTHY VOLUNTEERS Livermore JJA, School of Psychology, University of Sussex, Pevensey Building, University of Sussex, Falmer, BN1 9QH [email protected] Holmes C(1), Brittain J(1), Cutler J(1), Moga G(1), Campbell-Meiklejohn D(1) (1) As presenting author Introduction: Monoaminergic pathways have received attention for their role in sampling information for decision making, linked to impulsivity. Crockett et al (2012, Psychopharmacology, 219(2), 587-597) demonstrated increased information sampling under acute tryptophan depletion. However, previous research has not looked at serotonergic treatments used clinically (notably SSRIs), nor incorporated Bayesian modelling to fully understand the information set available and consequent expected value - accounting for the sampling cost - of the decision chosen by participants. This study aimed to bridge the explanatory gap, testing healthy volunteers with acute citalopram challenge and using atomoxetine as a high-level control due to a similar side effect profile. Methods: 51 healthy volunteers were recruited, with 27 in the citalopram and 24 in the atomoxetine treatment group. Each participant was tested twice, with single doses of 20mg of citalopram and 40mg atomoxetine respectively, as well as a placebo administered in a double-blind crossover design. Only the treatment group was known in advance by participants and researchers. Participants were tested with a modified version of the Information Sampling ask.T The data for two participants from the atomoxetine group were excluded from further analysis due to non- adherence to instructions and a further one due to sickness. Results: A Bayesian model was generated of the information available to participants at decision time due to their sampling choices, and the resultant expected value of the decision. Between-subjects comparison of mean change from baseline under pharmacological challenge showed opposite effects of the two drugs. Citalopram reduced the information set chosen (M=-.026, SD=.074), while atomoxetine increased it (M=.020, SD=.060), with the difference being significant between the groups (t(46)=2.32, p=.025, Cohen’s d=.0.69). For the citalopram group, multilevel mixed-effects regressions on trial-wise data showed significantly reduced information sets and expected values under citalopram than placebo: a random-intercept model incorporating the drug as a fixed effect had a significantly better fit than the intercept-only model for both information set (χ2(1)=9.10, p=.0025, Cohen’s f2=.023) and expected value of the decision (χ2(1)= 5.03, p=.025, Cohen’s f2=.0098). By A74 ABSTRACTS contrast, atomoxetine significantly increased information required before decision compared to placebo (χ2(1)=5.20, p=.023, Cohen’s f2=.014), but did not show a significant change in expected value (χ2(1)=.38, p=.54). Conclusion: This study demonstrated that serotonergic challenge through acute citalopram administration reduced information sampling, which previous research has linked to higher impulsivity, with lower expected values and thus poorer choice outcomes. This has important implications for early- stage citalopram treatment prior to onset of clinically-relevant effects. Further research is necessary to understand the underlying neural mechanisms. Funded by a grant from Lundbeck Foundation

F12 THE OFF-PRESCRIPTION USE OF MODAFINIL: AN ONLINE SURVEY OF PERCEIVED RISKS AND BENEFITS Teodorini RD, Division of Psychology, LSBU, Division of Psychology, School of Applied Sciences, London South Bank University, 103 Borough Road, London, SE1 0AA, UK., SE1 0AA [email protected] Rycroft N(2), Smith-Spark JH(1) (1) Division of Psychology, School of Applied Sciences, London South Bank University, 103 Borough Road, London, SE1 0AA, UK; (2) Division of Psychology, School of Applied Sciences, London South Bank University, 103 Borough Road, London, SE1 0AA, UK Introduction: While many studies have investigated the off-prescription use of cognitive enhancing drugs, little is known about the characteristics of cognitive enhancing drug users or their perceived experience with these drugs. The present study aimed to provide a detailed profile of the cognitive enhancing drug user and the perceived risks and benefits of modafinil. Methods: An online survey recruiting a convenience sample, targeting international cognitive enhancing drug users and students who were aware of cognitive enhancing drugs, was advertised on forum sites and measured demographics, illicit drug use, mental health and experience of modafinil use. Results: Of the 336 respondents who completed the survey, 219 had taken modafinil, the majority of whom were male, American or British, university-educated and currently employed, with a mean age of 27 years. Reported levels of illicit drug use were higher amongst users of modafinil than among the general population of Europe and America. One-quarter of the 336 respondents reported a psychiatric diagnosis. A three-way mixed-design ANOVA was used to explore the relationships between frequency of use of modafinil, perceived benefit-to-risk tradeoff (perceived positive and negative effects) and the timeframe over which effects were reported (immediate and longer-lasting). Frequent users of modafinil reported a higher number of positive effects whilst negative effects did not differ in terms of frequency of use to the frequency of use. Conclusions: Modafinil users perceived the drug as safe and appeared knowledgeable about recommended dosages. Modafinil users were more likely to be young, male, and in education or employment. The findings of this study contribute to the understanding of the cognitive enhancing drug user profile and how modafinil is perceived by those taking it. To the authors’ knowledge, this is the first paper to report a detailed insight into the perceived experience of modafinil and the modafinil users’ profile. This study was completed as part of the presenting author’s PhD and funded by a fee-waiver bursary from the Centre for Addictive Behaviours Research at London South Bank University.

F13 GRIN2B PROMOTER METHYLATION DEFICITS IN EARLY SCHIZOPHRENIA AND CORRELATION WITH INTELLIGENCE QUOTIENT (IQ) PERFORMANCE Fachim HA, Biomedical Sciences Research Centre, Sheffield Hallam University, Howard Street, S1 1WB [email protected] Fachim HA(1), Loureiro CM(2), Corsi-Zuelli F(2), Shuhama R(2), Louzada-Junior P(2), Menezes PR(3), Dalton CF(1), Del-Ben CM(2), Reynolds GP(1) (1) Biomedical Sciences Research Centre, Sheffield Hallam University; (2) School of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto - Brazil; (3) University of Sao Paulo- Sao Paulo- Brazil Background: Among the adversities found in schizophrenia the alterations in neurodevelopment and dysfunctions in the glutamatergic system, specifically the N-methyl-D-aspartate receptor (NMDAR) are ABSTRACTS A75 apparent. GRIN2B (coding a NMDAR subunit) has a critical role in synaptic plasticity and important participation in CNS neurodevelopment, this gene is closely associated with behavioural and cognitive impairments (Cull-Candy et al., 2006; Akashi et al., 2009). One of the mechanisms that may underlie the deficiencies seen in the glutamatergic system in psychosis may be DNA methylation, as it is known to regulate gene expression. Aims: to investigate the methylation levels of GRIN2B promoter region in patients in first episode of psychosis compared with siblings and population-based controls and correlate it with cognitive functions using the intelligence quotient (IQ) scale. Methods: Blood samples were collected from patients in FEP (n = 35) after their first contact with the mental health assistance, siblings (n = 21) and population-based controls (n = 35). Bisulfite conversion and yrosequencingp were used to determine methylation levels in 5 CpG sites within GRIN2B promoter region. One-way ANOVA with a Bonferroni correction was used for statistical analysis and Pearson correlational analyses were carried out. Results: Overall hypomethylation was found among the 5 CpGs analysed within GRIN2B promoter sequence (p < 0.01) in schizophrenia, individually CpGs 1, 4 and 5 showed significant reduction in methylation in FEP patients compared to control and siblings. The effect in the blood samples reflected decreases in methylation in FEP at CpG1 (F= 8.12; p = 0.001), CpG4 (F= 4.29; p= 0.017) and CpG5 (F= 3.11; p= 0.049). We also found a positive correlation between CpG4 methylation and the intelligence IQ scale (r = 0.424; p < 0.001). Conclusions: this is the first evidence showing changes in GRIN2B promoter methylation in psychosis and the correlation between GRIN2B methylation and a measure of cognitive function. The results together suggest that these epigenetic findings may relate to the reduction of protein expression of components of the glutamatergic system seen in this disease. Additionally the differences seen in the patients IQ performance scale compared to controls and siblings may be relate to the variation in DNA methylation seen in GRIN2B promoter region. Funding: FAPESP (2012/05178-0; 2013/08216-2; 2017/00624-5).

F14 DIFFERENTIAL EFFECTS OF MGLU5 POSITIVE ALLOSTERIC MODULATORS ON COGNITION AND PREFRONTAL CORTEX SIGNALLING IN THE SUB-CHRONIC PCP ANIMAL MODEL Grayson B, Pharmacy, University of Manchester, Division of Pharmacy & Optometry, Oxford Road, Manchester, M13 9PT [email protected] Iacovelli L(1), Podda G(2), Idris NF(2), Munni STM(2), Di Cicco G(1), Ngomba RT(3), Neill JC(2) (1) Department of Physiology and Pharmacology “V. Erspamer”, Sapienza University of Rome, Italy; (2) Division of Pharmacy & Optometry, University of Manchester, Oxford Road, Manchester, M13 9PT; (3) School of Pharmacy in College of Science, University of Lincoln, Lincoln LN6 7TS, UK Introduction: Disruption of glutamatergic signalling linked to NMDAR hypofunction has been associated with the core symptoms of schizophrenia. Endogenous glutamate activates mGlu5 receptors (mGluR5) expressed within key circuits in several brain regions, involved in the pathophysiology of schizophrenia. mGluR5s are known to induce PI-3K/p-AKT and ERK1/2/MAPK signalling pathways, regulating synaptic plasticity (Sengmany and Gregory, 2016 Br J Pharmacol. 173(20):3001-3017). Here we investigate efficacy of two mGluR5 positive allosteric modulators (PAMs) with a differing mechanism of action, VU0409551 and VU0360172, to restore cognitive function in our carefully validated animal model of cognitive impairment in schizophrenia, sub-chronic PCP treatment in rats. To better understand the neurobiological mechanisms underlying behavioural effects, we also examined effects of both compounds on mGlu5 signalling in various brain regions in this model. Methods: 60 adult female Lister Hooded rats received sub-chronic phencyclidine (scPCP; 2 mg/kg) or vehicle i.p. twice daily for 7 days, followed by 7 days washout. Then scPCP-treated rats received acute treatment with VU0409551 or VU360172 (1 & 10 mg/kg, i.p.) and tested in the novel object recognition (NOR) task. Following behavioural assessment, rats were sacrificed, prefrontal cortex (PFC) and hippocampus were dissected and stored at – 80°C. Tissue samples were subsequently homogenised in Triton X-lysis buffer (10 µl/mg tissue, see Di Menna et al., 2018 Neuropharmacology. 128:301-313), sonicated in ice and clarified by centrifugation. Protein cell lysates (35 μg) were separated by SDS-PAGE electrophoresis, blotted onto nitrocellulose, and a western blot analysis of p-AKT and p-ERK1/2 in PFC from rats treated with VU0360172 and VU0409551, at both doses was performed. Data are expressed as the mean ± SEM and analysed by ANOVA &/or Student’s t-test. Results: In the retention trial of NOR, vehicle treated rats spent significantly (P<0.05) more time (s) exploring the novel compared with A76 ABSTRACTS familiar object. This effect was abolished in sub-chronic PCP-treated rats. VU0360172 failed to attenuate the scPCP-induced deficit, whereas VU0409551 significantly (P<0.05) reversed this cognitive impairment at both doses. VU0409551 also significantly (P<0.01-P<0.05) decreased p-AKT and p-ERK1/2 phosphorylation at both doses effective in NOR in the scPCP-treated rats, whereas VU0360172 didn’t affect p-AKT phosphorylation and significantly (P<0.05) decreased p-ERK1/2 phosphorylation at 1 mg/kg. Conclusion: These data demonstrate the efficacy of VU0409551 but not VU0360172 to restore recognition memory deficits in the scPCP model. Efficacy of VU0409551 was accompaniedy b a reduction in p-AKT and p-ERK1/2 phosphorylation, supporting an important role for these signalling pathways in improving cognitive function in psychiatric disorders. No sponsorship was received for this study.

F15 EFFECT OF SEROTONIN TRANSPORTER OVEREXPRESSION ON BEHAVIOURAL FLEXIBILITY IN CONTINGENCY DEGRADATION/REVERSAL TASK IN MICE Bien Z, Medical School, University of Oxford, Medical Sciences Divisional Office, Level 3, John Radcliffe Hospital, Oxford, OX3 9DU [email protected] Murphy RA(1), Baker AG(2) (1) Dept of Experimental Psychology, Univ of Oxford, Anna Watts Building, Radcliffe Observatory, Woodstock Rd Quarter, Oxford OX2 6GG; (2) Dept of Psychology, 2001 McGill College, 7th floor, Montreal, QC, H3A 1G1 Introduction: Serotonin transporter (5HTT) gene polymorphism (5HTTLPR) is associated with variation in 5HTT expressivity and extracellular serotonin levels. Serotonin (5HT) has been shown to encode aspects of reward-driven learning – a prerequisite of flexible behaviour and decision-making. ccordingly,A pharmacological and genetic inactivation of 5HTT, analogous to 5HTTLPR short allele in humans, was shown to improve behavioural flexibility in reversal learning in mice (Brigman et al 2009 Cereb Cortex 20(8): 1955-1963). We hypothesized that conversely, 5HTT-overexpressing (5HTTOE) mice will show impaired flexibility, indexed as a level of change of behaviour in response to an alteration of response- outcome contingency in an operant learning task. Methods: Wild type (WT) and 5-HTTOE mice were trained with a response lever on a variable ratio schedule for sucrose reward delivery using a procedure modelled after Dickinson & Charnock (Q J Exp Psychol 1985; 37(4): 397-416). Based on the order of experimental schedules, animals were split into groups Degraded-Contingent (D-C; n=16) and Contingent- Degraded (C-D; n=15) with balanced number of WT and 5-HTTOE subjects. In phase 1, for Group D-C the response-outcome contingency was degraded by equating probability of reward delivery in presence and absence of response. Group C-D was maintained on contingent schedule. In phase 2, training contingency was reinstated for Group D-C and degraded for group C-D. Results: The manipulation of contingency had a significant influence on response rates, such that the group on Degraded schedule responded at a lower rate in both phase 1 (group D-C, F = 5.43, p = 0.028, η²= .167) and phase 2 (group C-D, F = 11.47, p = 0.002, η²= .283). Regarding the within-group genotype effect, no significant difference was found between 5-HTTOE and WT animals in group C-D. In group D-C, 5-HTTOE animals had diminished rates of responding in phase 1 (F = 10.20, p = 0.007, η²= .421), which could indicate better adaptation to contingency degradation. In phase 2, however, 5-HTTOE animals retained significantly lower response rates (F = 13.64, p = 0.002, η²= .493), which may suggest a failure to adapt to contingency reinstatement. Conclusion: Observed decrease in response rates following contingency degradation confirmed the validity of the chosen behavioural paradigm. Although the direction of the relationship is equivocal, the difference in responding between 5-HTTOE and WT animals in group D-C could indicate that variability in 5-HTTOE expression influences acquisition of instrumental learning and behavioural flexibility. This research was funded by Department of Experimental Psychology, University of Oxford. ABSTRACTS A77

F16 NEURODEVELOPMENTAL CHANGES AND MATERNAL CARE BEHAVIOUR IN A RAT MODEL FOR SCHIZOPHRENIA Potter HG, School of Biological Sciences, Faculty of Biology, Medicine, and Health, The University of Manchester, Michael Smith Building, Dover Street, Manchester, M13 9PT harry.potter@postgrad. manchester.ac.uk Wang AT(1), Munni STM(3), Kowash HM(2), Glazier JD(2), Neill JC(3), Hager R(1) (1) As presenting author; (2) Maternal and Fetal Health Research Centre, St Mary’s hospital, Division of Developmental Biology and Medicine, School of Medical Sciences, Faculty of Biology, Medicine, and Health, The University of Manchester, Manchester, M13 9WL; (3) Stopford building, Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine, and Health, The University of Manchester, Manchester, M13 9PT Introduction: Maternal immune activation (mIA) during mid-late gestation is a risk factor for neurodevelopmental disorders such as schizophrenia in the adult offspring, mediated by transient increases in pro-inflammatory cytokine concentration in the maternal plasma. Injecting pregnant rats with the viral mimetic polyinosinic:polycytidylic acid (poly I:C) recapitulates this risk inducing schizophrenia-related behavioural dysfunction in the adult offspring. The mechanism underlying this is unknown, but evidence suggests that maternal provisioning is impaired in mIA-exposed dams. Here, we investigate how poly I:C treatment affects fetal neurodevelopment, pup ultrasonic vocalisations (USVs), maternal-offspring interactions, and offspring behaviour. Methods: Eighteen pregnant Wistar rats received a single intraperitoneal injection of 10mg/kg poly I:C (or vehicle; InvivoGen) on gestational day 15 (GD15). Plasma concentrations of the pro- inflammatory cytokines interleukin-6 (IL-6) and tumor-necrosis factor-alpha (TNF-α) were measured before pregnancy (baseline) and 3h post-treatment. USVs were recorded from individual pups for 3 minutes during a 1h maternal separation on postnatal days (PD) 6, 10, and 14. Maternal-offspring interactions were scored every 30 seconds for 30 minutes on each testing day by two observers giving a total of 360 observations per litter. Offspring will be tested for short-term recognition memory (novel object recognition), anxiety-like behaviour (elevated plus maze), and social interaction during adolescence (PD34-35) and adulthood (PD100). Results: All dams had low baseline plasma IL-6 and TNF-α (mean ± SEM of 30.3 ± 0.5 and 49.6 ± 12.9pg/ml respectively). Poly I:C induced an immune response indicated by a significant increase in maternal plasma IL-6 (p=0.0087) and TNF-α (p=0.0022) after 3h compared to controls. Poly I:C-treated dams displayed a significant decrease in weight-corrected food intake 24h post-treatment (p=0.0374). No effect of treatment was observed on licking (p=0.0598) or nursing behaviour (p=0.9864). Poly I:C induced a significant increase in the total time female, but not male, pups spent vocalising on PD6 (p=0.0243), which was normalised by PD10 (p=0.6256). Conclusions: Poly I:C causes mIA by inducing an upregulation of maternal plasma IL-6 and TNF-α and causes sickness behaviours in pregnant rats. Poly I:C did not appear to cause a deficit in licking or nursing behaviours during early postnatal life, but caused a sex- and time-specific increase in total vocalisation time. Further analyses to be presented will show whether poly I:C affects offspring recognition memory, anxiety-like behaviour, and sociability during adolescence and at adulthood. This work is supported by a BBSRC DTP studentship and a President’s Doctoral Scholar award from the University of Manchester.

F17 DEFICITS IN WORKING MEMORY AND DECREASED PREFRONTAL PARVALBUMIN EXPRESSION IN THE 16P11.2 DUPLICATION MOUSE MODEL WITH RELEVANCE TO SCHIZOPHRENIA Openshaw RL, Institute of Neuroscience and Psychology, University of Glasgow, Level 3, West Medical Building University of Glasgow University Avenue Glasgow, G12 8QQ [email protected] Thomson DM(3), Mitchell EJ(3), Bristow GC(2), Dawson N(2), Pratt JA(3), Morris BJ(1) (1) As presenting author; (2) Division of Biomedical and Life Sciences, University of Lancaster, Bailrigg Ln, Bailrigg, Lancaster LA1 4YE; (3) Strathclyde Institute of Pharmacy & Biomedical Sciences, University of Strathclyde, Cathedral St, Glasgow, G4 0RE Introduction: Duplications in the 16p11.2 chromosomal region are one of the most well-established and substantial genetic risk factors for schizophrenia (Giaroli et al. (2014) Schizophrenia Research. 159(2-3):340- A78 ABSTRACTS

346). Working memory (WM) deficits (Perlstein et al. (2003) Biological Psychiatry. 53(1):25-38) and reduced parvalbumin in the prefrontal cortex (PFC; Beasley and Reynolds (1997) Schizophrenia Research. 24(3):349-355) are robustly observed in patients. Here, we examine the WM capability of 16p11DUP+/- mice and determine the expression of parvalbumin in 16p11DUP+/- PFC. Methods: WM was assessed by training and performance on the N-back task in an automated 8-arm radial maze. 12 wildtype (7 male) and 12 16p11DUP+/- (7 male) mice were used, aged 10 weeks and housed in groups of 2-3, with 12:12 light cycle, lights on at 7am. Mice were food restricted to 85% of their free-feeding body weight throughout the experiment. Data was analysed by a repeated measures ANOVA with treatment, N-back, genotype and sex as factors, and individual mouse nested within genotype and sex. PV expression was determined by in situ hybridisation (ISH). 12 wildtype (6 male) and 12 16p11DUP+/- (6 male) mouse brain slices (20µm) were hybridised with parvalbumin mRNA- specific oligonucleotide radioactively labelled with [35S]-d-ATP overnight, then exposed to Biomax MR film (Kodak) for 3.5 weeks. Images were analysed using ImageJ, followed by ANOVA (with genotype and sex as factors), and Tukey’s post-hoc tests. Results: 16p11DUP+/- mice performed significantly worse (% correct) than wildtype mice in the N-back task, both throughout training (F(1,1924)=19.01; p<0.0001) and during the final 5 days of the task when performance stabilised (F(1,40)=16.07; p<0.0001). 16p11DUP+/- mice were also slower to complete each session on average (F(1,96)=9.00; p=0.003) and obtained fewer rewards (F(1,96)=7.68; p=0.007) than wildtype mice. There were no effects of sex (p>0.05). ISH showed decreased parvalbumin expression in the PFC of 16p11DUP+/- mice compared to wildtypes (F(1,91)=6.99; p=0.01), which occurred to a larger extent in males (F(1,91)=4.89; p=0.03). Conclusions: We have shown that 16p11DUP+/- mice exhibit schizophrenia-related abnormalities: decreased parvalbumin expression in the PFC and a WM deficit. These findings support altered GABAergic interneuron activity as a possible mechanism for the WM deficits (Chen et al. (2014) Neuroimage: Clinical. 4:531-539). This data contributes towards an understanding of how duplication in the 16p11.2 region could lead to behavioural deficits seen in schizophrenia and further establishes 16p11DUP+/- mice as an important translational rodent model with relevance to schizophrenia. Research funded through MRC award MR/N012704/1 to BM, JP and ND.

F18 16P11.2 DUPLICATION MICE SHOW ACQUISITION DEFICITS IN THE TOUCHSCREEN CONTINUOUS PERFORMANCE TASK Thomson DM, SIPBS, University of Strathclyde, 161 Cathedral St, Glasgow, G4 0RE David.m.thomson@ strath.ac.uk Thomson DM(1), Mitchell E(4), Openshaw RL(3), Bristow GC(2), Dawson N(2), Morris BM(3), Pratt JA(4) (1) As presenting author; (2) Faculty of Health and Medicine, Lancaster University, Lancaster; (3) Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow; (4) SIPBS, University of Strathclyde, Glasgow Introduction: The 16p11.2 chromosomal duplication is strongly associated with schizophrenia (Mcarthy et al 2009 Nature Genetics. 2009;41(11):1223) with a penetrance similar to that of the well-studied 22q11 deletion. Although basic behavioural characterisation has been conducted on corresponding mouse models (16p11DUP mice) (Arbogast et al 2016 PLoS-Genet,12(2)), to date no examination of these animals’ attentional profile, known to be disrupted in schizophrenia (Nuechterlein et al 2015 Schizophr Res, 163(1- 3):38 has been conducted. We sought to profile the attentional ability of these animals in a novel task of attention: the rodent continuous performance task (Kim et al 2015 Psychopharmacology,232:3947). Method: Mice(n=12 C57BL6J, n=12 16p11.2DUP, both groups 50% male), were food restricted to within 85% of free feeding weight, housed in groups of 2-3 animals per cage, and maintained under a 12-hour day/night cycle (lights on at 7am). Apparatus Campden instruments touchscreen boxes, running ABETII touch-software running the rodent continuous performance task. 3 panels 5”x5” of the touchscreen were exposed . The centre panel presented the task stimulus, either a S+ stimulus (striped/vertical bars, counterbalanced across groups), that the animals had to respond to, or an S- stimulus (vertical/horizontal or diagonal striped bars), which the animals had to withhold a response from. With the 2 flanking panels used to present distractor stimulus during the distractor probe-trial set. Food reward was (YazooTM) strawberry milkshake delivered at 70microlitres/reward. Parameters monitored were hit rate, false- alarm rate, and the composite measure of perceptual sensitivity (d’) and response bias (ln-Beta). Results: Stage 3 acquisition: 16p11.2dup mice ABSTRACTS A79 showed a reduced perceptual sensitivity compared to wild-type for the first 9 days of training (main effect of genotype:F1,20=13.50 p=0.002). 16p11.2DUP mice showed reduced response bias during Stage 3 compared to the wild type with a significant effect of genotype seen for the responsivity index (F1,20=5.04 p=0.036). During the distractor phase there was a significant effect of distractor type (F2,40=8.29 p=0.001.) Post hoc pairwise analysis revealed this was significant between the non-distractor and the incongruent distractor condition (P=0.001). Restricted one way ANOVA analysis of the genotype effects for the non-distractor trials did reveal a significant effect of genotype (F1,23=4.70 p=0.041) with 16p11.2DUP mice showing a marked reduction in hit rates compared to wild-type. Conclusion: The current task demonstrates a transient deficit during the initial acquisition stage of the rCPT in 16p11DUP mice. In the presence of a highly distracting environment 16p11.2DUP mice show reduced hit rates for non-distractor trials. These findings suggest that the 16p11.2DUP mouse has subtle deficits detectable by the rCPT task – a finding with potentially great translational value. Research funded through MRC award MR/ N012704/1 to BM, JP and ND.

F19 EXAMINATION OF HOME-CAGE ACTIVITY IN A MOUSE MODEL OF 16P11.2 DUPLICATION Mitchell EJ, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral St, Glasgow, G4 0RE [email protected] Thomson DM(2), Bristow GC(3), Openshaw RL(1), Dawson N(3), Morris BJ(1), Pratt JA(2) (1) Institute of Neuroscience and Psychology, University of Glasgow; (2) As presenting author; (3) Division of Biomedical and Life Sciences, University of Lancaster Introduction: Accumulating evidence implicates copy number variants (CNVs) in the pathogenesis of psychiatric disorders. Of particular interest is a duplication (DUP) at the 16p11.2 locus, which is associated with a ~ 15 fold increased risk of schizophrenia (McCarthy et al., 2009. Nature Genet. 41(11): 1223). Despite representing a strong genetic risk factor for schizophrenia, the consequences of 16p11.2 duplication remain poorly characterised at the preclinical level. Here, we monitored the home-cage activity of heterozygous 16p11.2 duplication (DUP) mice (Horev et al., 2011. PNAS. 108: 17076) in order to probe behavioural phenotypes directly linked to this CNV. Methods: 12 16p11.2 DUP mice (6 males + 6 females) and 12 wildtype (WT) littermates (6 males + 6 females) housed in groups of 3 were implanted with RFID transponders. Each home-cage was placed over an RFID baseplate for 72 h for automated tracking of the spatial location of each individual mouse (Actual HCA-Capture). The following measures were acquired: distance travelled (mm), frequency of antenna transitions, time spent mobile (distance moved > 0 mm), separation (mean distance to closest cage-mate (mm)) and isolation (time spent > 100 mm apart from cage-mates (s)). Analysis was performed via GLM ANOVA. Results: 16p11.2 DUP mice showed global hypoactivity whereby total distance travelled (F (1, 407) = 33.97; p < 0.0001), total frequency of antenna transitions ((F (1, 407) = 36.04; p < 0.0001) and total time spent mobile ((F (1, 407) = 16.26; p < 0.0001) were significantly reduced relative to WT mice. Furthermore, 16p11.2 DUP mice were more separated from their cage-mates compared to WT mice (F (1, 407) = 4.56; p = 0.05) which is suggestive of potential social dysfunction. Conclusion: Thus, 16p11.2 DUP mice exhibit altered locomotor and social activity and these phenotypes may be relevant to aspects of the human 16p11.2 DUP syndrome. This mouse model has potential predictive validity for future treatment development. Funding sources: MRC award (MR/N012704/1) to ND, JP, and BM.

F20 DISRUPTION OF THE ZDHHC9 INTELLECTUAL DISABILITY GENE LEADS TO BEHAVIOURAL ABNORMALITIES IN A MOUSE MODEL Kouskou M, SIPBS, University of Strathclyde, 161 Cathedral Street, Glasgow, G4 0RE marianna.kouskou@ gmail.com Thomson DM(1), Brett RR(1), Wheeler L(1), Pratt JA(1), Chamberlain LH(1) (1) As presenting author Introduction: Mutations in Zinc finger DHHC domain- containing protein 9 (ZDHHC9) gene located in the Xq26 chromosomal region cause mild to moderate intellectual disability (ID) in male patients. Moreover, A80 ABSTRACTS oromotor impairment, focal seizures and hypoplasia of corpus callosum are consistent findings in those patients. ZDHHC9 encodes the main part of a heterodimer palmitoyltransferase highly expressed in brain. The aim of this study is to examine how disruption of Zdhhc9 in mice affects behaviour, brain anatomy and protein palmitoylation and to determine if the Zdhhc9 mutant mice can serve as a model of ID. Methods: Mutant mice lacking the first coding exon of Zdhhc9 were purchased from Mutant Mouse Resource and Research Center and backcrossed for at least 6 generations onto a C57BL/6 genetic background. Behavioural tasks were conducted in mutant and wild type (WT) adult male littermates in order to test motor coordination, sensorimotor gating, general locomotor activity, anxiety, and hippocampal related learning and memory. Moreover, magnetic resonance imaging (MRI) of mutant and WT mouse brain was conducted to assess the volume of corpus callosum and hippocampus, and palmitoylated proteins were purified to identify any changes in this post-translational modification catalysed by zDHHC9. Data were analysed using either unpaired t-test or general linear model repeated measures. Results: Compared to WT littermates, Zdhhc9 mutant mice exhibited hypotonia in the hanging wire (t(31)=-3.3, p=0.002 in time spent on the wire), reduced startle reactivity (F(1,44)=13.622, p= 0.001) and reduced anxiety levels in the elevated plus maze (t(29)=-2.84, p= 0.008 on time spent in closed arms). In addition, they showed impaired acquisition of spatial learning in the Morris water maze (F(1,44)=8.935, p=0.005 on distance moved and F(1,44)=9.677, p=0.003 on latency). A 36% reduction in corpus callosum volume was revealed by MRI (p=0.008). Palmitoylation of H-Ras, which is proposed to be a major substrate of zDHHC9, was not disrupted in whole brain or hippocampus of Zdhhc9 mutant mice. Conclusions: Zdhhc9 mutant mice exhibit a range of behavioural abnormalities consistent with the phenotype of humans carrying ZDHHC9 mutations and with other mouse models of ID. Palmitoylation of H-Ras is not affected in the mutant mice implying that other substrates of zDHHC9 are linked to the observed behavioural and anatomical changes. Overall, this study identifies a key role for zDHHC9 in brain development and behaviour, and supports the utility of the Zdhhc9 mutant mouse line to investigate molecular and cellular changes linked to ID. No sponsorship was received for this study.

F21 THE EFFECTS OF CANNABIDIOL ON REWARD PROCESSING: A SYSTEMATIC REVIEW Yim LL, Divison of Psychiatry, UCL, Maple House, 149 Tottenham Court Rd, Fitzrovia, London, WIt 7BN [email protected] Freeman T(2), Bloomfield MAP(1), Hindocha C(3) (1) As presenting author; (2) National Addiction Centre, Institute of Psychiatry, Psychology & Neuroscience (IoPPN), Addiction Sciences Building, Denmark Hill, London, SE5 8BB; (3) Research Department of Clinical, Educational and Health Psychology, University College London WC1E 7HB Introduction: Cannabidiol (CBD), a non-psychotropic component of Cannabis sativa, is being investigated as a potential treatment for disorders associated with reward dysfunction, including addictions, depression and psychosis. CBD’s therapeutic effects in these psychiatric disorders are potentially mediated by its effects on reward processing. This systematic review aimed to summarise the results of both animal and human studies on the effects of CBD on hedonic impact (‘liking’), incentive salience (‘wanting’) and reward learning. Method: Data source: Electronic searches on MEDLINE and PUBMED were performed with keywords in titles and/or abstracts including: “cannabidiol”, “reward”, “addiction”, “dopamine”, “NACC” or “depression”. Reference lists of relevant articles were also examined. Eligibility criteria: English language studies that evaluated the outcomes of CBD administration on at least one of the following: motivation, willingness or behavioural response to earn a reward; subjective, neural or physiological response to reward anticipation and/or reward delivery/feedback; or indices of reward learning. Rewarding stimuli were defined as primary rewards and secondary rewards. All types of study designs were included: both animal and human studies, clinical and experimental trials (randomized or not), naturalistic, behavioural and neuroimaging studies. Results: A total of 21 studies (6 humans and 15 animal studies) were included. 15 studies were included of those out of the 647 entries found on electronic databases, and 6 studies were added from reference lists. In both animal and humans, CBD consistently reduced the likelihood of recurrent drug-seeking behaviours, by reducing the magnitude of the predicted reward induced by conditioned stimuli. Importantly, these effects were only observed when CBD was administrated after the ABSTRACTS A81 initial reward reinforcement. When administrated before or during the initial reinforcement, CBD did not differ from vehicle or placebo in any behavioural measures in animals. In humans, CBD had no effect on explicit measures of hedonic impact (i.e. subjective liking) of rewarding stimuli. Conclusions: The existent research suggests that firstly, CBD repairs over-sensitised reward processing, by attenuating incentive salience and motivation for reward-seeking. Secondly, CBD does not affect the conscious hedonic impact of stimuli. Finally, CBD plays little or no role in behavioural and subjective measures of reward learning during initial reinforcement. Taken together, CBD modulates anticipatory rewards, without altering pleasantness of rewards. This suggests that CBD is potentially a safe and effective treatment for reward dysfunctional disorders. Further neuroimaging and physiological measures on humans are needed to elucidate CBD’s effects on unconscious hedonic impact and reward learning.

F22 THE ROLE OF THE CANNABINOID SYSTEM IN MEMORY: A SYSTEMATIC REVIEW AND META- ANALYSIS OF THE EFFECTS OF CANNABINOID RECEPTOR 1 RECEPTOR AGONISTS AND ANTAGONISTS ON MEMORY Borgan F, Psychosis Studies Department, King’s College London, 16 De Crespingy Park Road, SE5 8AF faith. [email protected] Beck KB(3), McCutcheon RM(3), Vernon AV(2), Veronese MV(1) (1) Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK; (2) Department of Basic and Clinical Science, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, UK; (3) Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, UK Introduction: The cannabinoid 1 receptor (CB1R) modulates memory performance via intracellular and extracellular mechanisms that alter mitochondrial energy metabolism, neurotransmission and synaptic plasticity. Methods: We conducted a systematic review and meta-analysis to investigate the magnitude, consistency and dose-dependent effects of CB1R agonists (ACPA, WIN 55-212-2, CP 55,940, Δ9-THC, anandamide) and CB1R antagonists (AM251, AM630, AM281, SR1617A, SR1417778) on memory performance in rodents, non-human and human primates. In accordance with the PRISMA guidelines, the EMBASE, MEDLINE, and PSYCHINFO databases were systematically searched for studies examining the effects ofCB1R agonists and CB1R antagonists on memory performance. Results: Systemic and local hippocampal administration of CB1R agonists consistently impaired memory performance in rodents with large effect sizes (Hedge’s g=-2.08, p=0.0009 and Hedge’s g=-2.82, p=0.026, respectively). In contrast, systemic administration of CB1R antagonists consistently improved memory performance in rodents with a large effect size (Hedge’s g=1.07, p=0.0004). Although there were insufficient studies to examine the consistency of these effects in non-human or human primates in a meta-analysis, our systematic review showed that CB1R agonists consistently impaired memory performance irrespective of the species, drug, dose, route of administration or memory paradigm. A number of studies also demonstrated that CB1R antagonists blocked the detrimental effects of CB1R agonists on memory in rodents, non-human and human primates. Conclusions: Since psychiatric and neurodegenerative disorders show greater endogenous levels of CB1R agonists in the context of memory impairments, future studies are warranted to investigate the therapeutic potential of CB1R antagonists for targeting memory deficits in psychiatric disorders. Funding: F.B. and O.H. were supported by the METSY EU FP7 grant, K.B was supported by the Rosetrees Trust, R.M. was supported by the Wellcome Trust (no. 200102/Z/15/Z), A.V. was supported by the Medical Research Council (MR/N025377/1), MV was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. A82 ABSTRACTS

F23 THE EFFECTS OF CANNABIDIOL ON EMOTIONAL PROCESSING AND ANXIETY: A SYSTEMATIC REVIEW Yamamori Y, Division of Psychiatry, UCL, Maple House, 149 Tottenham Court Rd, Fitzrovia, London, W1T 7BN [email protected] Freeman TP(3), Hindocha C(1), Bloomfield MAP(2) (1) Clinical Psychopharmacology Unit, University College London, WC1E 7HB, London, United Kingdom; (2) Division of Psychiatry, B Wing, 6th Floor, Maple House, 149 Tottenham Court Road, London, W1T 7BN; (3) National Addiction Centre, Institute of Psychiatry, Psychology & Neuroscience (IoPPN), Addiction Sciences Building, Denmark Hill, London, SE5 8BB Introduction: There is much interest in the therapeutic potential of cannabidiol (CBD) including its application to anxiety-related disorders. However, studies to date have been inconclusive in terms of the drug’s subjective anxiolytic effects. In parallel, the cognitive processes and neurological pathways underlying CBD’s potential anxiolytic effects are also yet unclear. Our aim, therefore, was to systematically review the literature on the effects of CBD on emotional processing and anxiety, and to assess its anxiolytic action from a cognitive perspective. Methods: We performed a systematic literature search across the PubMed database for English language articles up to 01 May 2018, using the search terms ‘cannabidiol’ and ‘emotion’ or ‘anxiety’ or ‘mood’ or ‘face’. Human studies comparing CBD with a control condition were included. Measures within articles were categorised as ‘subjective’, ‘cognitive’ and ‘neurocognitive’ to determine CBD’s effects at these different levels of processing. Results: A total of 24 articles were included. A sub-total of 22 studies tested for the subjective effects of CBD on anxiety and nine found significant subjective effects, where four were instances of attenuation of THC-induced anxiety, and four were of attenuation of experimentally-induced anxiety. Three studies have directly tested for the cognitive effects of CBD on emotional processing, and significant effects were found in the domains of attention, memory/learning and perception of emotional information. The effects of CBD through neuroimaging were investigated by four studies, all of which converge on the hypothesis that CBD produces inhibitory effects on the limbic circuit during the processing of emotional stimuli, with the most consistent effects at the amygdala and hippocampus. Conclusions: The evidence for CBD’s anxiolytic effects is not consistent. Despite this, there are some robust effects that are evident from the current literature. Firstly, CBD appears to be most powerful for individuals in a heightened state of anxiety, for example for those in stressful situations. Secondly, significant effects have been observed in multiple domains of cognitive processing relevant to emotion. Finally, CBD elicits consistent effects on limbic activity which is critical for emotional processing. Several hypotheses are considered to explain the data: the ‘on-demand’ effect of CBD, the primarily cognitive-affective effect of CBD, and the effect of dose where CBD is thought to produce an inverted U-shaped dose-response curve. No sponsorship was received for the study.

F24 ASSESSING A NOVEL SYSTEM FOR HEAD-FIXATION IN AWAKE, BEHAVING MICE PERFORMING A CUED GOAL LOCALISATION TASK Stuart SA, Physiology, Pharmacology and Neuroscience, University of Bristol, Biomedical Sciences, University Walk, Bristol, BS8 1TD [email protected] Mellor JR(1) (1) As presenting author Introduction: The development of novel experimental approaches to probe the cellular and molecular properties of neuronal networks in awake, behaving rodents promises to shed new light on cognitive behaviours such as learning and memory. Head-fixing animals to provide stability during neurophysiological experiments is common practice, and the most widely used approach involves mice running on a treadmill within a virtual reality (VR) environment. More recently however a novel system, the “Mobile HomeCage”, has been developed to allow a head-fixed mouse to move around an air-lifted platform and explore a tangible environment, and may provide advantages over a VR setup where the animal must rely solely on visual stimuli. In the present study we used a cued goal localisation task in ABSTRACTS A83 order to assess the behavioural performance of head-fixed mice in the Mobile HomeCage system. Methods: Seven male C57BL/6J mice underwent daily training sessions where the animal was head-fixed within a circular foam homecage and required to locate a sandpaper ‘target zone’. In the first 5 mins the mice were assisted by the experimenter to stay in the target zone for a delay period of 2s before receiving a sucrose reward via a lick-port. The animal was then allowed to explore unassisted for a further 20 mins and was required to stop within the target zone for the delay period to be rewarded. The animals’ success rate, number of non-target zone stops and total target crosses were analysed from the unassisted trials across 13 sessions. Results: The mice showed a significant increase in task success ater across the 13 days of training (RM ANOVA: F12,72=5.7, p<0.01) whilst showing a reduced tendency to stop in non-target locations within the Mobile HomeCage (RM ANOVA: F12,72=8.7, p<0.001). General locomotor activity as indicated by the total number of target crosses in each session did not change across the study period. Conclusions: We show that head-fixed mice are able to effectively learn the location of a cued reward within the Mobile HomeCage system. We propose that this system has advantages over those using a VR maze as a similar performance can be achieved in fewer sessions, most likely as it allows the animals to use both visual and textural cues to navigate. Our initial study provides the basis for future experiments investigating the neural and molecular mechanisms underlying spatial navigation and memory in head-fixed mice. SAS is funded by the Wellcome Trust

F25 EFFECTS OF CONVENTIONAL ADHD MEDICATIONS ON IMPULSIVE ACTION IN THE MOUSE 5-CHOICE SERIAL REACTION TIME TASK Fitzpatrick CM, Drug Design and Pharmacology, University of Copenhagen, Universitetparken 2, Jagtvej 160, Copenhagen, 2100 [email protected] Andreasen JT(1) (1) As presenting author Introduction: Impulsive deficits are found in a number of psychiatric disorders such as attention deficit hyperactivity disorder (ADHD) (Dalley and Robbins, 2017, Nature Reviews Neuroscience, 18, 158-171). The 5-choice serial reaction time task (5-CSRTT) is a paradigm extensively used to assess attention and impulsive control (Robbins, 2002, Psychopharmacology, 163, 362-380). We recently developed a protocol to habituate mouse impulsive action rates on a variable inter-trial interval (ITI) schedule before pharmacological testing occured (Fitzpatrick et al., Neuroscience Letters, 662, 351-5). Methods: 14 female C57BL/6J mice underwent a 15 day variable ITI (5, 10 or 15 s) study (four training days followed by one drug day per week for three weeks). Then, the effects of the atomoxetine (1, 3 mg/kg), methylphenidate (1, 2 mg/kg) and guanfacine (0.03, 0.1 mg/kg) were investigated, using a Latin-square within-subject design, to assess the effects of these conventional ADHD medications on impulsive action using an repeated measures mixed-model approach. Results: Mice acheived consistent premature response rates in the first week of baseline testing. Both 1 and 3 mg/kg atomoxetine (main drug effect: F2,26 = 6.23; p < 0.01) reduced premature responding at the 10 (p<0.001; p<0.05) and 15 (both p<0.001) s ITIs. 2 mg/kg methylphenidate (main effect drug: F2,26 = 1.80; p = 0.18) increased impulsive action at the longest 15 s ITI (p<0.05). Guanfacine exerted no effects on premature responding rates at any dose or ITI. No effects on any other 5-CSRTT parameters were affected by any of the three drugs. Conclusion: Atomoxetine robustly reduced impulsive action at both the 1 and 2 mg/kg doses, whilst methylphenidate increased impulsivity at the highest 2 mg/kg dose. No effects were observed with guanfacine. Conventional ADHD medications have differential effects on impulsive action, as has been suggested previously with atomoxetine being particularly effective at reducing impulsivity (Sanchez-Roige et al., 2012, Psychopharmacology, 219, 253-70; Robinson et al., 2008; Neuropsychopharmacology, 33, 1028-37). Financial support: University of Copenhagen, Lundbeck Foundation A84 ABSTRACTS

G01 IS PSYCHOSIS A MULTI-SYSTEM DISORDER? CONSIDERING IMMUNE, CARDIOMETABOLIC, AND ENDOCRINE FUNCTION IN FIRST EPISODE PSYCHOSIS AND COMPARISON WITH CENTRAL NERVOUS SYSTEM ALTERATIONS McCutcheon R, Psychosis Studies, Institute of Psychiatry, King’s College London, 16 de Crespigny Park Camberwell, SE5 8AF [email protected] D’Ambrosio E(1), Howes OD(1), Pillinger T(1) (1) Institute of Psychiatry, King’s College London Introduction: People with schizophrenia and related psychotic disorders show abnormalities in several organ systems in addition to the central nervous system (CNS); and this contributes to excess mortality. However, it is unclear how strong the evidence is for alterations across multiple non-CNS systems at the onset of psychosis, how the alterations in non-CNS systems compare to findings in the CNS, or how they relate to symptoms. Here, we consider these questions, and suggest potential models to account for findings. Methods: We conduct a systematic meta-review to summarize effect sizes (ES) for CNS (brain structural, neurophysiological, and neurochemical parameters) and non-CNS dysfunction (immune, cardiometabolic, and hypothalamic-pituitary-adrenal (HPA) systems) in first episode psychosis (FEP). Pubmed was systematically searched from 1990 to May 2017 for meta-analyses focusing on these parameters. Case control data was extracted for 165 studies making up these meta-analyses, comprising a total sample size of 13,440. Random effects meta-analyses were re-run and ES magnitudes calculated for: immune (IL-1b, sIL2R, IL-6, TNFa, TGFb, CRP, lymphocyte count), cardiometabolic (glucose, glucose post-OGTT, insulin, insulin resistance, triglycerides, total and LDL cholesterol), HPA (cortisol awakening response and prolactin), brain structural (total brain, total grey matter, total CSF, ventricular, thalamic, hippocampal, caudate nucleus volumes), neurophysiological (auditory P300 amplitude and duration deviant mismatch negativity), and neurochemical alterations (N-acetyl aspartate concentrations within frontal lobe, temporal lobe, and thalamus). We then statistically compare summary ES for overall CNS and overall non-CNS alterations, as well as for each organ system separately. Finally, we consider how non-CNS alterations compare with CNS alterations in FEP, and how non-CNS alterations correlate with psychopathological symptoms. Results: We demonstrate alterations in immune (ES:g=1.19(95%CI:0.82-1.56)); cardiometabolic (ES:g=0.23(95%CI: 0.15-0.31)); HPA (ES:g=0.68(95%CI: 0.32- 1.04)); brain structural (ES:g=0.40(95%CI: 0.33-0.47); neurophysiological (ES:g=0.80(95%CI: 0.64-0.96); and neurochemical systems (ES:g=0.43(95%CI: 0.26-0.60). ES for overall non-CNS alterations (summary ES:g=0.58(95%CI: 0.44-0.72)) was not significantly different from ES for overall CNS alterations (summary ES:g=0.50(95%CI:0.44-0.56))(P=0.28). We found some, but limited and inconsistent, evidence that non-CNS alterations were associated with CNS changes and symptoms. Conclusions: Our findings indicate there are robust alterations in non-CNS systems in psychosis, and that these are broadly similar in magnitude to a range of CNS alterations. We consider three models that could account for these findings and discuss implications for future research and treatment This study was funded by grants from the MRC-UK, the Brain and Behavior Research Foundation, the Wellcome Trust and the NIHR Biomedical Research Centre at SlaM NHS Foundation Trust and KCL. ABSTRACTS A85

G02 METABOLIC-INFLAMMATORY STATUS AS PREDICTOR OF CLINICAL OUTCOME AT 1-YEAR FOLLOW- UP IN PATIENTS WITH FIRST EPISODE PSYCHOSIS Nettis MA, Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, G.33.81, The Maurice Wohl Clinical Neuroscience Institute, SE5 9RT [email protected] Pergola G(2), Kolliakou A(3), O’Connor J(3), Bonaccorso S(3), David A(3), Gaughran F(3), Di Forti M(4), Murray RM(3), Marquez TR(3), Blasi G(2), Bertolino A(2), Pariante CM(1), Dazzan P(3), Mondelli V(1) (1) As presenting author; (2) Group of Psychiatric Neuroscience, Dept of Basic Medical Sciences, Neuroscience and Sense Organs, Univ of Bari Aldo Moro, Bari 70124, Italy; (3) Dept of Psychosis Studies, IoPPN, King’s College London, London, UK; (4) Dept of Social Genetics and Developmental Psychiatry, IoPPN, King’s College London, London, UK Introduction: Metabolic abnormalities and peripheral inflammation have been increasingly reported in patients at the onset of psychosis and associated with important physical health disorders and increased mortality (Correll et al/2014/JAMA Psychiatry Dec 1;71(12):1350-63). However, the impact of an abnormal metabolic-inflammatory status on the psychiatric outcome of these patients has not yet been investigated. The aims of this study were 1) to explore whether, in a sample of patients at their first episode of psychosis (FEP), an overall metabolic-inflammatory status may be measured, by combining metabolic and inflammatory variables in metabolic-inflammatory factors; 2) to explore the association between these factors and clinical outcome at 1-year follow-up (FU), in terms of symptoms severity and treatment response. Methods: In this longitudinal study we recruited 43 FEP patients and 50 healthy controls (HC) matched with patients for age, gender and ethnicity. At baseline (T1) we measured high sensitivity C-reactive protein (hsCRP) as biomarker of inflammation, and body mass index (BMI), lipid profile and gluco-metabolic parameters (glycated hemoglobin (HbA1c) and fasting glucose) as metabolic variables. A principal component analysis (PCA) was then used to reduce the dimensionality of the dataset accounting for both inflammation and metabolic status. In FEP patients, we assessed symptom severity at T1 and at 1-year FU (T2) as well as treatment response at T2. Results: FEP showed higher HbA1c (p=0.034), triglycerides (TG (p=0.044) and BMI (p=0.023) than HC at T1. PCA identified 3 factors. Factor 1, accounting for hsCRP, TC and BMI, was associated with T1 negative symptoms severity (p=0.018) and predicted T2 positive (p=0.003) and overall symptoms severity (p=0.004), as well as general psychopathology (p=0.001). Conclusion: In a sample of patients at the onset of psychosis, Inflammation and metabolism, closely interdependent, proved to play a key role as predictors of the clinical course of psychosis when combined in a single factor. These findings offer an important potential target for early screening and interventions. This research has been supported by the National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London.

G03 EXPLORING THE RELATIONSHIP BETWEEN INFLAMMATORY BIOMARKERS AND DEPRESSION IN FIRST EPISODE PSYCHOSIS IN A 1-YEAR LONGITUDINAL STUDY Worrell C, Psychological Medicine, IOPPN, Stress, Psychiatry & Immunology Lab (SPI) The Maurice Wohl Clinical Neuroscience Institute, Cutcombe Road, London, SE5 9RT [email protected] Russo M(1), Falcone A(1), Bonaccorso S(1), Marques TR(1), Di Forti M(1), Gaughran F(1), Pariante CM(1), Murray R(1), Dazzan P(1), Mondelli V(1) (1) Institute of Psychiatry, Psychology and Neuroscience Introduction: The past decade has seen a rise in research investigating the association between elevated levels of inflammatory biomarkers and mood disorders. Despite the emphasis, a certain lack of clarity remains with regards to the exact nature of the association between increased inflammation and depression within psychosis, particularly at onset. This study aimed to investigate the relationship between levels of C-reactive protein (CRP) as an inflammatory biomarker, and depressive symptoms measured by the Calgary Depression Scale for Schizophrenia (CDS). Methods: Participants were recruited between 2005 to 2010 as inpatients within the South London and Maudsley NHS Foundation and Trust. A A86 ABSTRACTS sample of n=750 patients with first episode psychosis were recruited. The sample was comprised of 495 males and 248 females all within the age range of 18-61 years, mean age of 29.4±9. Data were collected at three different time points; at baseline then again at two follow up points, at three months and one year. A one-way repeated-measures analysis of variance (ANOVA) was conducted to test the association between participants CRP levels at each of the three time points, with their depression status at one year. Depression status was defined according to a threshold (>5 classifying depression) detailed in the CDS. Results: From this analysis, findings demonstrated that after controlling for depressive symptoms at baseline, there was a statistically significant effect of the level of CRP on participants depression at one year. The model accounts for a large proportion of the variance (F(2,78)=3.893, p=.024). A significant linear trend emerged, (F(1,39)=4.964, p=.032) with CRP increasing across the time points for those who were classified as depressed at the one year follow up. Furthermore, there was a marked distinction between levels of inflammation in those who were depressed compared to those who were not from the three month time point particularly. Mauchly’s test for Sphericity indicated that sphericity for this model could be assumed, x²(2)=5.92, p=.052. Conclusions: Findings as such suggest that there is an association between increased levels of the inflammatory biomarker CRP and depression in a sample of first episode psychosis patients. This finding could indicate that increased inflammation in the early stages of psychosis yma be associated with the development of depressive symptoms. Research supported by the NIHR Mental Health Biomedical Research Centre at SLaM and KCL. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.

G04 HOW TREATMENT AFFECTS PERIPHERAL INFLAMMATORY MARKERS IN MOOD DISORDERS? A SYSTEMATIC REVIEW Wijayaweera SS, Academic Unit of Clinical and Experimental Sciences, University of Southampton, Langstone Centre, St James Hospital, Locksway Road, Portsmouth, PO4 8LD [email protected] Hou R(1) (1) University Department of Psychiatry Academic Centre, College Keep, 4-12 Terminus Terrace, Southampton SO14 3DT Introduction: Targeting inflammation as a means of improving outcome in mood disorders has been a growing area of interest in research. Studies have demonstrated that non steroidal anti-Inflammatory drugs and Cyclo-oxygenase 2 inhibitors reduce inflammatory levels and improve outcome in mood disorders. The aim of our review was to assess current evidence from randomised controlled trials (RCT) investigating how pharmacological or psychological interventions affect peripheral inflammatory marker levels and clinical outcomes in patients with mood disorders. Methods: We performed a systematic search of literature using the following databases: EMBASE, Pubmed, COCHRANE, Web of Science and OVID, published before 28th February 2018 and supplemented with manual searches. We used combinations of following search terms: Randomized Control Trial, C-reactive protein, cytokine, biomarker, depression, bipolar disorder, post traumatic disorder, anxiety disorders and their variants. Screening, data extraction and quality assessment were conducted. Primary outcome measures were pre and post treatment levels of peripheral inflammatory cytokines and assessment of depression using rating scales. Results: Five RCTs were identified for qualitative review: four studies were Major Depressive Disorder and one was Bipolar Disorder. Probiotic supplements (n=40) significantly reduced high-sensitivity-C-Reactive Protein (hs-CRP) levels (p=0.03) and Beck Depression Inventory (BDI) scores (p=0.001). Infliximab (n=60) demonstrated reduction in Hamilton Scale for Depression (HAM-D) with a baseline hs-CRP > 5mg/L, while with baseline hs-CRP < 5mg/L placebo demonstrated reduction in HAM-D. In terms of HAM-D scores, there were no overall difference between two groups. In treatment responders baseline hs-CRP level was significantly reduced in Infliximab treated group compared to placebo. In the Vitamin D study (n=40) both groups had low Vitamin D at baseline. In the Vitamin D group BDI was reduced significantly (p=0.04). Reduction of hs-CRP levels were not significant (p=0.80). Narrative Cognitive Therapy (NCT) and Cognitive Behaviour Therapy (CBT) Hamilton Depression Rating Scale (HDRS) scores were reduced significantly(p=<0.001) while CBT significantly reduced TNF α (p=0.05) and IL-6 (p=0.042). The Bipolar II Depression study assessed Memantine as an adjunct to Valproic Acid (n = 214). TNF α levels were significantly lower in the Memantine treated group (p=0.013). HDRS (p=0.739) and ABSTRACTS A87

Young Mania Rating Scale (p=0.972) failed to significantly improve between the groups. Conclusions: Data from eligible RCTs suggest neuroinflammatory pathway may underlie the beneficial effects of treatment in mood disorders, especially in Depression and sub-groups of individuals with high level of inflammation at baseline. Diversity of treatments and small sample sizes limited interpretation of the current review. Larger prospective studies are warranted. No financial sponsorship was received for the study

G05 TREATMENT-RESISTANT DEPRESSION: A POSSIBLE ‘INFLAMMATORY SUBTYPE’ OF DEPRESSIVE DISORDER Strawbridge R, Centre for Affective Disorders, Department of Psychological Medicine, IoPPN, KCL, 103 Denmark Hill London, SE5 8AZ [email protected] Young AH(1), Cleare AJ(1) (1) As presenting author Background: Some key findings have emerged from recent research into inflammatory activity within depressed individuals: people with major depressive disorder (MDD) have elevated inflammation, but high heterogeneity within and between samples indicates that clinically relevant inflammation is confined to a subset of patients. This is suggested also in the variability of anti-inflammatory medications’ effectiveness for MDD. Raison and Miller (2013, The Psychiatric Times, 30, 9) proposed that treatment resistant depression (TRD) might best represent such an inflammatory subtype. Most of the known risk factors for TRD are associated with inflammatory states; examples include metabolic disturbances and physical ill health. We sought to explore associations between a comprehensive panel of 20 inflammatory markers and affective characteristics in a highly resistant sample of depressed inpatients. Methods: 36 TRD patients were assessed upon admission to an inpatient unit. The extent of TRD was assessed using the Maudsley Staging Method (MSM), in addition to information relating to medication, physical illness, cognitive function, age, BMI, severity of current depressive symptoms and age of illness onset. Results: Patients with the most severe resistance to treatment in the current episode were, unsurprisingly, taking more medications (r = 0.438, p = 0.009) and had higher levels of pro-inflammatory markers. Specifically, tumor necrosis factor (TNFa; p = 0.026) and macrophage inflammatory protein-1 beta (Mip1b; p = 0.035) were higher in patients with more treatment resistance, and were not correlated with additional factors. Macrophage chemoattractant protein-1 (MCP1) was correlated with both TRD severity (p = 0.048) and medication (p = 0.04). Interleukin-6 (IL-6) and c-reactive protein (CRP) were associated with both higher TRD severity (p = 0.043 and p = 0.031, respectively) in addition to both medication (p = 0.03; p = 0.008) and age (p = 0.042; p = 0.015). Interleukin 12 (IL-12) was only associated with greater treatment resistance (p = 0.031) and greater cognitive impairment (p = 0.022). While additional proteins were correlated with medication, age, cognitive impairment and (to a lesser extent) physical illness severity, inflammation was not strongly associated with BMI or age of depression onset. Discussion: Collinearity between factors rendered it inappropriate to adjust for possible moderation or mediation between variables in this small sample of patients with TRD. The results do however lend support to the notion of an elevated inflammatory profile in a subset of older, cognitively impaired individuals with TRD treated with multiple pharmacotherapy. No sponsorship was received for the study.

G06 INFLAMMATION POPULATION SUB-GROUPS BASED ON LONGITUDINAL CRP ASSESSMENTS AS PREDICTORS OF DEPRESSION: FINDINGS FROM THE ALSPAC BIRTH COHORT Osimo EF, Department of Psychiatry, University of Cambridge, Herchel Smith Building for Brain and Mind Sciences, Forvie Site, Robinson Way, Cambridge Biomedical Campus, Cambridge, CB2 0SZ [email protected] Stochl J(1), Khandaker GK(1) (1) As presenting author Introduction: Longitudinal studies have linked increased levels of the systemic inflammatory markers interleukin 6 (IL-6) and C-reactive protein (CRP) in infancy with the risk of developing depression and A88 ABSTRACTS psychotic symptoms later on in life. This work investigates whether persistently high levels of CRP across the ages of 9, 15 and 18 years are linked with the development of depression later in life. Methods: The ALSPAC birth cohort comprises 14,062 live births from pregnant women resident in county Avon, in England. This study is based on 1627 cohort members who provided data on serum CRP levels at all time points of 9, 15 and 18 years of age; we excluded 66 participants who had CRP levels >10 mg/L (active infection). 1462 participants took part in psychiatric assessments at age 18 years and were therefore included in our analyses. Depression was measured using the CIS-R. Our population was divided into clusters based on CRP levels at 9, 15 and 18 years using a data driven approach (model-based clustering and classification based on finite normal mixture modelling). Demographic factors were examined in the different groups in cross-tables and tested through -squared tests. Odds ratios (ORs) and 95% confidence intervals (CIs) for depression were calculated using multinomial log-linear models. Results: The classification using longitudinal CRP levels yielded four inflammation groups: persistently low (29.5%), decreasing (23%), increasing (23.5%), persistently high (24%). The increasing and persistently high groups showed a significant excess of female subjects, and an excess of subjects whose mothers had a low degree of educational attainment (below A level). These same groups also represented subjects with a significantly higher BMI at 18 years. In a logistic model adjusted for sex, maternal depression in pregnancy, maternal level of education, BMI at 18 years, co-morbid atopic disorder, and IQ at 8 years, the risk of moderate or severe depression at 18 years was higher in the increasing (OR = 6.06; 95% CI, 1.69-21.71; p = 0.006) and persistently high (OR = 5.17; 95% CI, 1.34-19.91; p = 0.02) CRP groups as compared to the persistently low (reference) group. Conclusions: Subjects who show a persistently high or increasing pattern of inflammation during their childhood and adolescence appear to be at higher risk of developing the most severe forms of depression in later life. This work helps to characterise the biological phenotype of moderate to severe depression, and, if confirmed, would suggest that the most severe forms of depression might be more amenable to concomitant treatment with anti-inflammatories. GMK is supported yb an Intermediate Clinical Fellowship from the Wellcome Trust (201486/Z/16/Z) and a Clinical Lecturer Starter Grant from the Academy of Medical Sciences, UK (grant no. 80354).

G07 CHARACTERISTICS OF YOUNG ADULTS WITH DEPRESSION AND LOW-GRADE INFLAMMATION IN THE ALSPAC BIRTH COHORT Oltean BP, Psychiatry, University of Cambridge, Herchel Smith Building, Cambridge Biomedical Campus, Cambridge, UK, CB2 0SZ [email protected] Lewis G(1), Jones PB(2), Khandaker GM(2) (1) UCL Dept of Psychiatry, Maple House, 149 Tottenham, Court Rd, London W1T 7NF; (2) Univ of Cambridge, Dept of Psychiatry, Cambridge Biomedical Campus, Camrbidge CB2 0SZ Introduction: There is a robust association between low-grade inflammation and depression. Meta- analysis of cross-sectional studies confirm that a sub-set of depressed individuals presents with evidence of low-grade inflammation (i.e. increased serum C-reactive protein or CRP levels) which normalizes after recovery but continues in treatment resistant patients. However, little is known about the characteristics of depressed individuals who show evidence of inflammation. We report a study evaluating clinical and other characteristics of young adults with ‘inflamed’ depression. Methods: Data on serum CRP levels at age 18 years were available from 3000 participants from the ALSPAC birth cohort who were also assessed for ICD-10 diagnosis of depression. Depressed cases were group based on CRP levels according to CDC criteria: >1mg/L=low; 1-3mg/L=medium; >3mg/L=high inflammation. We examined the association of depression with sociodemographic factors, specific symptoms, childhood neurodevelopment, maternal depression, and substance misuse for all cases of depression (compared with non-depressed), and separately for cases with medium and high inflammation (compared with cases with low inflammation). Results: At age 18 years, 219 (6.7%) individuals met ICD-10 criteria for a depressive episode, of which 135 (61.6%) had low, 58 (26.5%) had medium, and 26 (11.9%) had high levels of CRP. The prevalence of moderate/severe depression increased by increasing levels of CRP: 52.6% in low, 63.8% in medium and 73.1% in high CRP group, although depression severity score was not associated with CRP levels. Diagnosis of depression at age 18 years was associated with female sex, lower maternal education, higher BMI, maternal depression, ABSTRACTS A89 psychotic experiences, psychotic disorder, and substance misuse. ‘Inflamed’ depression (CRP >3mg/L) was associated with female sex, lower maternal education, older age, higher BMI, and psychotic experiences. Conclusions: This is one of the first studies characterizing inflamed depression in young adults. Further studies based on inpatients and older adults are needed. This work is supported by a Wellcome Trust Intermediate Fellowship awarded to Dr Golam Khandaker.

G08 THE SYNERGISTIC EFFECT OF MATERNAL IMMUNE ACTIVATION (MIA) AND ADOLESCENT THC TREATMENT IN ADULT OFFSPRING: TOWARDS A 2HIT MODEL FOR SCHIZOPHRENIA Podda G, Division of Pharmacy & Optometry, University of Manchester, Stopford Building, Oxford Rd, Manchester, M13 9PT [email protected] Cadinu D(1), Munni S(1), Grayson B(1), Neill JC(1) (1) Division of Pharmacy and Optometry, University of Manchester, Stopford Building, Oxford Rd, Manchester, M13 9PT Introduction: Pregnancy and adolescence are critical stages of brain development. Infection during pregnancy and adolescent cannabis use have both been identified as risk factors for schizophrenia (Patterson 2007, Science, 318: 576–577; Henquet et al. 2005, BMJ, 330: 11–14). The “two hit” hypothesis of schizophrenia suggests an interaction between genetic susceptibility and/or early and late developmental insults in the onset of the disease (Feigenson et al. 2014, Neurosci Biobehav, Rev. 38: 72–93). The aim of this study is to characterize the behavioural phenotype of adult offspring of mIA Wistar dams that were further challenged with tetrahydrocannabinol (THC) during adolescence. Methods: 12 pregnant Wistar dams were injected with vehicle or polyinosinic-polycytidylic acid (poly I:C) on gestational day 15 (GD15) (10 mg/kg; i.p., n=6 per treatment). After parturition, litters were culled to 4 males and 4 females from each dam. On post-natal day (PD) 35, pups were randomly divided into 4 groups (Veh/Veh, Veh/THC, Poly:IC/Veh and PolyI:C/THC). Two pups from each litter received increasing i.p. doses of THC twice a day (2.5 mg/kg PD 35–37; 5 mg/kg; PD 38–41; 10 mg/kg PD 42–45) the other two received vehicle. Offspring were tested at adulthood from PD75 in novel object recognition (NOR) (analysed by ANOVA and students t-test) and the attentional set shifting task (ASST) for cognition; social interaction and locomotor activity (response to d-amphetamine 0.5 mg/kg i.p.) (analysed by ANOVA, followed by planned post-hoc LSD test). Results: In female offspring, the PolyI:C/THC group failed to discriminate between the novel and the familiar object (P=0.767) in NOR. In social interaction we observed a significant main effect of treatment on sniffing only (F(3,47) = 3.273, P<0.05). Sniffing duration was significantly reduced in the PolyI;C/THC treated group (P<0.01) compared to Veh/Veh animals. There was no significant main effect of treatment on the extra dimensional shift phase (EDS) of the ASST (F (3,41) = 2.067, P=0.12). However, a planned post-doc analysis showed a significant increase in trials to criterion in the EDS in the poly/THC group compared to vehicle (P<0.05) while in the poly I:C/veh group, this effect approached significance (P=0.063) No significant differences were observed in baseline locomotor activity or following acute treatment with d-amphetamine. Data from male offspring are currently being analysed. Conclusion: These results suggest that combined mIA and adolescent THC treatment impair some dimensions of cognitive and social behaviour in adult female offspring. Declaration of interest: Jo Neill has received expenses to attend conferences and fees for lecturing and consultancy work (including attending advisory boards) from the manufacturers of various antipsychotic drugs. Sources of financial sponsorship: This work is supported yb b-neuro at the University of Manchester Division of Pharmacy & Optometry. A90 ABSTRACTS

G09 CHILDHOOD MALTREATMENT AND INFLAMMATION IN FIRST-EPISODE PSYCHOSIS AND UNAFFECTED SIBLINGS: RESULTS FROM THE STREAM STUDY IN BRAZIL Corsi-Zuelli F, Dept of Neuroscience and Behaviour, Ribeirão Preto Medical School, Univ of São Paulo (FMRP-USP), Brazil, 3.900, Bandeirantes Avenue - Monte Alegre 4º floor, room 434. Ribeirão Preto Clinical Hospital, 14048-900 [email protected] Loureiro CM(2), Fachim HA(1), Shuhama R(1), Menezes PR(3), Louzada-Junior P(2), Mondelli V(4), Del-Ben CM(1) (1) As presenting author; (2) Dept of Internal Medicine. Ribeirão Preto Medical School, Univ of São Paulo (FMRP-USP), Brazil; (3) Dept of Preventive Medicine at Faculty of Medicine, Univ of São Paulo, Brazil; (4) Dept of Psychological Medicine, King’s College London, IoPPN, London, UK Introduction: Epidemiological studies suggest an association between childhood maltreatment and psychosis, and that the cessation of childhood trauma would reduce the incidence of psychosis (Varese et al., 2012, Psychol Med, 42(5):1025-36). An inflammatory state in psychosis is reported, and childhood adversity may underlie this relationship (Baumeister, et al., 2016, Molecular Psychiatry 21(5):642–649). Nevertheless, investigations between childhood trauma and inflammation in psychosis are scarce. We investigated: (1) plasma levels of IL-1β, IL-6, IFN-γ, TNF-α, IL-4, IL-10, TGF-β in first-episode psychosis (FEP) patients, their unaffected siblings and population-based controls; (2) the association between childhood trauma/childhood trauma subtypes (emotional abuse, physical abuse, sexual abuse, emotional neglect, physical neglect) and inflammation controlling for confounding factors (age, gender, BMI, waist circumference, tobacco smoking, cannabis use, and pharmacological treatment). Methods: This study is part of the epidemiological investigation “Schizophrenia and Other Psychoses Translational Research: Environment and Molecular Biology” (STREAM), conducted in Ribeirão Preto (SP, Brazil), which is part of the consortium “European Network of National Schizophrenia Networks Studying Gene-Environment Interactions” (EU-GEI). We recruited 156 FEP patients (64.7% males), 75 siblings (30.7% males) and 257 community-based controls (51.0% males). Childhood trauma was assessed using the Childhood Trauma Questionnaire. Plasma cytokines (pg/mL) were analysed by Multiplex (Luminex) and log10 transformed. We performed two-way ANCOVA with Bonferroni corrections. Results: The three groups significantly differed in IL-6 [F(2,487)=13.886], TNF-α [F(2,487)=19.957], IL-10 [F(2,487)=20.179], IL-1β [F(2,487)=8.093] and TGF-β [F(2,487)=13.750] (p < 0.001) but not IFN-γ [F(2,487)=0.2) or IL-4 [F(2,487)=0.6] (p>0.05). FEP had significantly higher levels of IL-6, TNF-α, IL-10 and TGF-β when compared with controls (p < 0.001). Compared with their siblings, patients had higher levels of TNF-α, IL-10, and TGF-β (p < 0.05). Siblings (p<0.001) and FEP (p=0.049) presented decreased IL-1β when compared with controls. FEP patients with physical abuse had higher levels of TGF-β when compared with patients without physical abuse (raw values: 1079.0±157.3 vs. 735.4±53.8; p=0.019); furthermore, the higher the severity of physical abuse, higher the levels of TGF-β (520.2±88.0 vs. 1040.1±151.8; p=0.017). This difference remained significant after controlling for tobacco smoking (p=0.044) and duration of treatment (p=0.036). Among controls, physical abuse was associated with lower TGF-β levels (304.3±68.6 vs. 561.4±35.9; p = 0.017), whereas among siblings, emotional abuse was related to higher IL-6 (2.9±0.9 vs. 1.7±0.2; p = 0.037). Conclusion: This is the first study to investigate childhood trauma on inflammation in a large population-based sample of FEP. We will next investigate other factors moderating inflammation.FAPESP, CNPq, CRID. ABSTRACTS A91

G10 PROLONGED PERIODS OF SOCIAL ISOLATION FROM WEANING IS MARKED BY AN IMPAIRED BLOOD-BRAIN ANTI-INFLAMMATORY RESPONSE Corsi-Zuelli F, Dept of Neuroscience and Behaviour, Ribeirão Preto Medical School, Univ of São Paulo (FMRP-USP), Brazil, 3.900, Bandeirantes Avenue - Monte Alegre 4º floor, room 434. Ribeirão Preto Clinical Hospital, 14048-900 [email protected] Fachim HA(1), Loureiro CM(2), Shuhama R(1), Bertozzi G(3), Joca SRL(4), Menezes PR(5), Louzada-Junior P(2), Del-Ben CM(1) (1) As presenting author; (2) Dept of Internal Medicine, Ribeirão Preto Medical School, Univ of São Paulo, Brazil; (3) Dept of Pharmacology, Ribeirão Preto Medical School. Univ of São Paulo, Brazil; (4) Dept of Physics and Chemistry, School of Pharmaceutical Sciences, Univ of São Paulo, Ribeirão Preto, Brazil; (5) Dept of Preventive Medicine at Faculty of Medicine, Univ of São Paulo, Brazil Introduction: Post-weaning social isolation (pwSI) is an early stress paradigm with the appropriate triad of validity to study the neurobiology of schizophrenia (SZ) and isolation-induced hyperlocomotion in rodents is described as a suitable marker to confirm the development of the “isolation-induced stress syndrome” (Fone; Porkess, 2008, Neurosci Biobehav Rev.;32(6):1087-102); yet, investigation of blood-brain inflammatory markers through this model remains scarce. We investigated: a) inflammatory cytokines (IL- 6, TNF-α, IL-10; pg/mL) at blood, prefrontal cortex and hippocampus tissues of male Wistar rats submitted to the pwSI, including cytokines gene expression (mRNA); b) the correlation between cytokines and locomotion in social isolated-animals. Methods: Male Wistar rats (n=10/group) were kept isolated (n = 1/ cage) or grouped (n = 4/3 per cage) since weaning during 10 weeks. After, rats were submitted to the open field (20 min). Cytokines were measured using Milliplex (Luminex), and qRT-PCR performed using TaqMan mastermix. We performed repeated measures ANOVA for behavioural analysis, and T test for cytokine analysis. Results: Isolated animals presented hyperlocomotion at periphery and centre of the arena when compared with grouped animals (group & local & time interaction F(3,13) = 7.047; p = 0.005]. Additionally, isolated rats had lower IL-10 (t = 2.265; d.f = 17; p = 0.044; n = 9-10) and IL-10 mRNA (t = 2.342; df = 12; p = 0.037; n = 7) blood levels when compared with grouped-housed animals. Likewise, the concentration of IL-10 in the hippocampus of isolated-reared rats was significantly lower than in group-housed rats (t = 2.318; d.f = 15; p = 0.035; n = 8-9). In the prefrontal cortex, isolated-reared rats had reduced levels of IL-6 (t = 2.280; d.f = 16; p = 0.037; n = 9), and reduced IL-6 mRNA than grouped-housed animals (t = 2.234; d.f. = 17; p = 0.039; n = 9-10). There was a significant negative correlation between the total number of square crossings and IL-10 concentration in the hippocampus of isolated rats (rho: -0.739; p = 0.029). Conclusion: Our study shows for the first time that prolonged periods of social isolation since weaning reduces the anti-inflammatory cytokine IL-10, and this is translated from blood-to-brain. Although the unexpected decrease in IL-6 and unchanged TNF-α levels relative to controls contrast to the expected pro-inflammatory phenotype, this may suggest that chronic stress may reduced anti-inflammatory cytokine signalling and this may be critical for eliciting abnormal behaviour in adulthood. Financial Support: FAPESP, CNPq, CAPES, CRID. A92 ABSTRACTS

G11 INFLAMMATORY PATHWAYS IN DEPRESSION AND OBESITY McLaughlin AP, Psychological Medicine, King’s College London, SPI Lab, Maurice Wohl, Room G.33.70, Cutcombe Road, London, SE5 9RT [email protected] Nikkhleshat N(1), Hastings C(1), Nettis MA(1), Zajowska Z(1), Mariani N(1), BIODEP Wellcome Trust Neuroinflammation Consortium (2), Cowen P(6), Cavanagh J(5), Harrison N(3), Bullmore E(4), Cattaneo A(1), Pariante C(1), Mondelli V(1) (1) As presenting author; (2) Cambridgeshire & Peterborough NHS Foundation Trust & Univ of Cambridge, UK; (3) Dept of Neuroscience, Brighton & Sussex Medical School, Univ of Sussex, Brighton, UK; (4) Dept of Psychiatry, Behavioural and Clinical Neurosciences Institute, Univ of Cambridge, UK; (5) Mental Health and Wellbeing, Sackler Institute, Neurology Block, Queen Elizabeth Univ Hospital, Glasgow, UK; (6) Univ Dept of Psychiatry, Warneford Hospital, Oxford, UK Introduction: Depression and obesity are highly comorbid disorders, but the biological reason for this is unclear. Low-grade inflammation, present in both depression and obesity, may be an underlying biological mechanism linking these conditions. Therefore, we investigated whether markers of inflammation were shared or divergent across obese and non-obese patients. Methods: Clinical data and blood samples were collected from 174 participants as part of a multi-centre study investigating immune biomarkers in depression (BIODEP). Groups compromised of: 32 obese patients with depression, 89 non-obese patients with depression, 8 obese controls, and 45 non-obese controls. Gender was not significantly different between groups (p=0.1), however age was higher in obese patients (mean age in years±SEM: 40.9±1.2) and obese controls (44.1±2.1) compared with non-obese patients (34.8±0.8) and non-obese controls (32.6±0.9) at the p<.001 level, so further analyses were adjusted for age. Markers of inflammation included logarithmic-transformed C-reactive protein (CRP) and the relative gene expression ratio of inflammatory cytokines: tumor necrosis factor alpha (TNF- ), interleukin 6 (IL-6) and interleukin 1 beta (IL-1ß), which were normalised to the mean of reference genes to compare relative cytokine expression in patients compared with controls. Results: Analysis of covariance showed CRP levels were significantly different across groups (F(3/169)=11.22, p<0.001). Obese patients had higher CRP (mean±SEM: 0.58±0.04 mg/L) compared with non-obese patients (0.34±0.03, p<0.001) and non-obese controls (0.26±0.04, p<0.001), but not compared with obese controls (0.38±0.08, p=0.2). TNF-a and IL-1ß levels were significantly different across groups (F(3/103)=11.22, p<0.001; F(3/103)=20.92, p<0.001, respectively), where obese patients had higher TNF-a and IL-1ß (mean±SEM: 1.37±0.03, mean±SEM: 1.29±0.03, respectively), compared with obese controls (1.03±0.06, p<0.001, 1.06±0.06, p=0.001, respectively) and non-obese controls (1.07±0.03, p<0.001, 1.08±0.03, p<0.001, respectively), but not non-obese patients (1.3±0.02, p=0.4, 1.29±0.02, p=1, respectively). IL-6 levels were also significantly different across groups (F(3/99)=10.68, p<0.001), however obese patients’ levels (mean±SEM: 1.23±0.04) were only significantly higher compared with non-obese controls (1.08±0.03, p=0.027), but not compared with non-obese patients (1.27±0.02, p=0.9) or obese controls (1.04±0.07, p=0.1). Conclusion: Our results suggest that being obese was associated with higher CRP regardless of depression diagnosis, whereas higher TNF- and IL-1ß were associated with depression diagnosis regardless of obesity status. IL-6 levels were increased in all groups compared with non-obese controls. The inflammatory phenotype observed in obese patients seems to be due to obesity and depression each having an additive effect on inflammation via overlapping and distinct biological pathways. Acknowledgments: BIODEP is funded by the Wellcome Trust, Janssen, Lundbeck, Pfizer and GlaxoSmithKline. ABSTRACTS A93

G12 P2X7R AS BIOMARKER OF TREATMENT RESPONSE IN DEPRESSED PATIENTS Mariani NM, Dept of Psychological Medicine, IoPPN, King’s College London, The Maurice Wohl Clinical Neuroscience Institute, Cutcombe Road, London, SE5 9RT, SE5 9RT [email protected] Cattaneo A(4), Malpighi C(2), McLaughlin A.P.(4), Nikkheslat N(4), Hastings C(4), Nettis M.A.(4), Zajowska Z(4), Byrom H(4), Cowen P(6), Cavanagh J(5), Harrison N(3), Bullmore E(1), the Wellcome Trust Neuroimmunology of Mood Disorders and Alzheimer’s Disease (NIMA) Consortium, Mondelli V(4), Pariante C(4) (1) Behavioral and Clinical Neuroscience Inst and Dept of Psychology, Univ of Cambridge, Cambridge, UK; (2) Biological Psychiatry Unit, IRCCS Fatebenefratelli San Giovanni di Dio, Brescia, Italy; (3) Brighton and Sussex Medical School, Univ of Sussex Campus, Brighton, UK; (4) Dept of Psychological Medicine, King’s College London, IoPPN; (5) Mental Health and Wellbeing, Sackler Institute, Neurology Block, Queen Elizabeth Univ Hospital, Glasgow, UK; (6) University Dept of Psychiatry, Warneford Hospital, Oxford, UK Introduction: An increasing body of evidence suggests alterations in immune and inflammatory signaling in depression, with higher levels of pro-inflammatory cytokines in depressed patients as compared to controls. Importantly, we and other research groups have also demonstrated an association between high levels of inflammation and a poor treatment response. Here we aimed to investigate a broader anger of inflammatory genes in a well-characterized group of depressed patients that have been recruited within the NIMA Consortium, who have been characterized for treatment response. Methods: Clinical data and blood samples from PaxGene tubes have been collected from 132 patients with depression (36 untreated, 60 treatment resistant and 36 treatment responsive) and from 40 healthy controls, as part of BIODEP, a multicenter study investigating immune biomarkers in depression within the NIMA Consortium. Mean age of all groups were ranging 35 years, 67% female. Using qPCR, we have measured the mRNA levels of P2X7 and those of other genes involved in inflammation (IL-1b, TNF-alpha, MIF) and stress response (NR3C1, SGK1 and FKBP5). Results: We have found that, compared with controls, untreated and treatment resistant patients had higher levels of P2X7R (+23% and +17%, p<0.001), while responder patients showed significantly lower levels of the P2X7R (-24%, p<0.001). We also found a positive correlation between P2X7R levels and pro-inflammatory cytokines and a negative correlation with GR. Conclusion: Our analyses suggest that increased P2X7, which is a potent stimulant of inflammation and immunity may represent a biomarker of treatment response and a potential novel target for the prevention and treatment of depression. Acknowledgments: The Neuroimmunology of Mood Disorders and Alzheimer’s Disease (NIMA) consortium is funded by the Wellcome Trust, Janssen, Lundbeck, Pfizer and GlaxoSmithKline.

G13 SERUM LEVELS OF ADRENOCORTICOTROPIC HORMONE AND THYROID STIMULATING HORMONE ARE ASSOCIATED WITH SUICIDAL THOUGHTS IN PATIENTS WITH MAJOR DEPRESSIVE DISORDER Hou RH, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, College Keep, 4-12 Terminus Terrace, Southampton, SO14 3DT [email protected] Li XR(2), Baldwin DS(1), Sun XL(3) (1) As presenting author; (2) Department of Psychiatry, Shandong Mental Health Centre; (3) Mental Health centre, West China Hospital, Sichuan University Background: Patients with major depressive disorder (MDD) have a substantially higher prevalence of suicidal thoughts than is seen in non-depressed individuals in the general population. Potential biological correlates of suicidal thoughts in first-episode MDD are relatively under-investigated. eW examined suicidal thoughts and their associations with clinical features and endocrine measures in patients with first-episode, drug-naïve (FEDN) MDD using a cross-sectional design. Method: 91 FEDN patients meeting DSM-IV diagnosis of MDD were recruited. Depressive and anxiety symptoms, suicidal thoughts and other aspects of psychopathology were assessed by the Hamilton Depression Rating Scale (HAMD), Hamilton Anxiety Rating Scale (HAMA), and Brief Psychiatric Rating Scale (BPRS). Sociodemographic characteristics (including age, sex, marriage, education, working status), life experiences (Life Event Scale, LES) and A94 ABSTRACTS clinical features were recorded systematically. Serum levels of cortisol, adrenocorticotropic hormone (ACTH), thyroid stimulating hormone (TSH), free thyroxine (FT4) and free triiodothyronine (FT3) were measured. Results: There were 52 patients with suicidal thoughts and 39 without. Serum levels of ACTH and HAMD scores (t=-2.80, p=0.006 and t=-2.14, p=0.04, respectively) differed significantly between groups with and without suicidal thoughts, whereas there were no between-group differences in cortisol, TSH, FT4, or FT3 levels. After controlling for potential demographic and clinical variables, logistic regression analysis indicated that ACTH levels were positively associated with suicidal thoughts (OR=1.047, 95% CI: 1.017~1.077, p=0.002), whereas TSH levels were negatively associated with suicidal thoughts (OR=0.557, 95% CI: 0.365~0.849, p=0.006). Conclusion: Our study indicates high serum ACTH and low TSH levels were associated with suicidal thoughts in patients with first-episode drug-naïve MDD. Further research using a prospective study design is warranted to examine how these associations might change over time. Role of funding source: This study was funded by Shandong Natural Science Foundation(ZR2017BH079).

G14 DIFFERENCES IN CORTISOL LEVELS USING SALIVA, HAIR AND FINGERNAIL SPECIMENS IN DEPRESSIVE AND HEALTHY PEOPLE Herane-Vives A, Psychological Medicine, Inst of Psychiatry, Psychology and Neurosciences, King’s College of London, 103 Denmark Hill, SE5 8AF [email protected] Saint-Pierre C(2), Aguirre J(3), Arnone D(4), Tsapekos D(4), Fischer S(1), De Angel V(4), Papadopoulos A(4), Young A.H(4), Cleare A(4) (1) Clinical Psychology and Psychotherapy, Institute of Psychology, University of Zurich, Zurich, Switzerland.; (2) Departamento de Ciencia de la Computación, Pontificia Universidad Católica de Chile, Santiago, Chile.; (3) Departamento de Psiquiatría, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile; (4) IoPPN, King’s College London Background: Hair cortisol is the most appropriate sample for measuring cortisol output levels because it accumulates the hormone over long periods without being affected by extraneous acute influences. But not all of those influences are extraneous. Environmental factors are highly associated with Major Depressive Episode (MDE) and they may have a long-term effect on cortisol reactivity levels, constituting a potential biomarker for MDE. Fingernail may accurately measure that cortisol’s profile over long-term, because, apart from also accumulating this hormone it may preferably do this during its endogenous (morning) and exogenous (environmental factors) peaks of secretion. However, so far, Fingernail Cortisol Concentration (FCC) have not been compared with cortisol reactivity levels using those measures that integrates cortisol output levels restricted to its endogenous (morning) peak of secretion or using other output measures that average a complete day or months of cortisol output. Methods: We compared Fingernail Cortisol Concentration (FCC) and Hair Cortisol Concentration (HCC), which represented the previous 15 and 90 days of retrospective cortisol accumulation in 72 MDE outpatients and in an age and gender matched sample of 40 controls. FCC was also correlated and regressed with HCC and with other short-term saliva cortisol output measures, such as over one single morning (AUCg1/2) and day (AUCg) of secretion, using 3 and 6 saliva samples, respectively. Results: FCC was significantly higher in comparison to HCC in the whole sample, as well as in MDE and controls (all p<0.01). FCC was significantly associated with UCg1/2A in controls (Rs=-0.51; p<0.05). Increases in FCC predicted rises in HCC in controls (p<0.05). While a negative tendency was observed between the AUCg1/2 and FCC in controls (p=0.15), an increased AUCg predicted rises in FCC in MDE patients (p<0.05). Conclusion: Fingernail may preferably accumulate cortisol during its peaks of secretion, constituting a more reliable long-term cortisol reactivity level biomarker. However, future larger studies should compare FCC with series of short-term cortisol output and reactivity samples. This research was supported by the NIHR Biomedical Research Centre at the South London and Maudsley NHS Foundation Trust, Psychiatric Research Trust (PRT) and the Institute of Psychiatry (King’s College London). The NIHR and PRT had no further role in the study design; collection, analysis and interpretation of data; in the writing of the report; and in the decision to present the poster for this event. ABSTRACTS A95

G15 MARKERS OF CENTRAL INFLAMMATION IN MAJOR DEPRESSIVE DISORDER: A SYSTEMATIC REVIEW AND META-ANALYSIS Enache ED, Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK, Stress, Psychiatry and Immunology Lab, The Maurice Wohl Clinical Neuroscience Institute, Cutcombe Road, King’s College London, London, SE5 9RT [email protected] Mondelli MV(1), Pariante PC(1) (1) As presenting author Background: Increased peripheral inflammation has been consistently associated with major depressive disorder (MDD). However, fewer studies explored the markers of central inflammation in MDD subjects. The aim of this study is to systematically review in vivo and post-mortem markers of central inflammation in subjects suffering with MDD compared with normal controls. Methods: PubMed database was searched up to January 2018. We included in vivo studies measuring cerebrospinal fluid (CSF) cytokines and chemokines, positron emission tomography (PET) for microglial activation, and post-mortem studies measuring cytokines, chemokines and cell specific markers of microglia and astrocytes in MDD. Results: A total of 51 studies met the inclusion criteria. CSF levels of IL-6 and TNFα were higher in patients with MDD compared with normal controls (standardised mean difference SMD 0.36, 95%CI: 0.16-0.56 and SMD 0.57, 95%CI 0.25-0.89, respectively). Post-mortem brain levels of tumor necrosis alpha (TNF-α) were also found increased in MDD. Translocator protein, a PET marker of microglia activation, was elevated in the anterior cingulate cortex and temporal cortex of patients with MDD compared with normal controls (SMD 0.77, 95%CI: 0.39 - 1.14 and SMD 0.51, 95%CI: 0.18 – 0.84 respectively). Abnormalities in CSF and PET inflammatory markers were not correlated with those in peripheral blood. The variability was high across all studies. In post-mortem studies two studies found increased markers of microglia in MDD brains, while 4 studies found no MDD related changes. Seventeen studies investigated expression of glial fibrillary acidic protein (GFAP), a specific marker for astrocytes, in post-mortem brains of MDD. Eight studies reported a decreased GFAP expression; two studies reported increased GFAP expression, whereas seventh studies did not detect any change in GFAP expression. Conclusions: In vivo CSF and PET studies suggest increased IL-6, TNFα and microglial activity in MDD patients compared with normal controls. Post-mortem studies suggest an increase in TNF-α, but a reduction in the total number of astrocytes in MDD brains. There are no financial conflicts of interest.

G16 THE ROLE OF BASELINE PERIPHERAL CORTISOL LEVELS IN THE EFFICACY OF ANTIGLUCOCORTICOID TREATMENT IN PATIENTS WITH MOOD DISORDERS: A META-ANALYSIS Lombardo G, Department of Psychological Medicine, Institute of Psychiatry, Psychology & Neuroscience (IoPPN), King’s College London, The Maurice Wohl Clinical Neuroscience Institute, Cutcombe Road, King’s College London, SE5 9RT [email protected] Enache D(1), Gianotti L(2), Pariante C(1), Mondelli V(1) (1) As presenting author; (2) Department of Psychology, University of Turin (Unito), Via Giuseppe Verdi, 8, 10124 Turin (TO), Italy Introduction: Given the previous strong evidence of a hyperactivity of the Hypothalamic-Pituitary-Adrenal (HPA) axis and high cortisol levels in patients with mood disorders, several studies investigated the efficacy of antiglucocorticoid treatment in this population. However, as suggested by Gallagher and colleagues (Gallagher et al, 2009. Cochrane Database of Systematic Reviews, Issue 1 “Antiglucocorticoid treatments for mood disorders”), findings from these trials have been inconsistent. These inconsistencies may be partly related to the biological evidence that the HPA axis hyperactivity is not present in all patients with mood disorders. The aim of this meta-analysis is to estimate whether baseline peripheral cortisol levels can influence the efficacy of antiglucocorticoid drugs in patients with mood disorders. Methods: We systematically reviewed the literature from inception until February 2017 in PubMed database. We focused on Metyrapone, Ketoconazole, Mifepristone treatments in major depressive disorder (MDD), bipolar disorder (BD) and psychotic major depression (PMD). We identified 14 studies, which included A96 ABSTRACTS measurement of cortisol levels and mood scales, such as the Hamilton Depression Rating Scale (HAMD) and Montgomery-Asberg Depression Scale (MADRS). For the purpose of this meta-analysis, we were able to retrieve data from a total of 6 studies. For each study, we divided the sample of treated subjects into responders (those with a reduction equal or greater than 30% in depression scales) and non-responders (those with a reduction less than 30% in depression scales). We calculated Standardized Mean Difference (SMD), 95% confidence interval (CI), Test for overall effect (Z) and p value. Results: In this selected sample, the overall effect of the baseline cortisol levels on the efficacy of antiglucocorticoid treatment almost reached significance (SMD = 0.37 95% CI [0.01, 0.73]; Z = 1.99; p= 0.05), with a low heterogeneity (I2= 0%). In particular, responders show higher baseline cortisol levels than non-responders. Conclusion: Our data suggest that previous inconsistent findings on the efficacy of antiglucocorticoid treatment in patients with mood disorders could be partially explained by the lack of stratification for baseline HPA axis activity. Patients with mood disorders who show baseline higher cortisol levels may be more likely to benefit from antiglucocorticoid treatment. Acknowledgments : This research has been supported by the National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. There are no conflicts of interest.

G17 THE EFFECT OF POLYMORPHISMS RELATED TO HPA AXIS ON TREATMENT RESPONSES: A SYSTEMATIC REVIEW Kuter BK, Genes, Environment and Development in Psychology and Psychiatry, Institute of Psychiatry, Psychology & Neuroscience (IoPPN), King’s College London PO72, De Crespigny Park Denmark Hill London SE5 8AF, SE5 8AF [email protected] Cleare AJC(1), Juruena MFJ(2) (1) Institute of Psychiatry, Psychology and Neuroscience King’s College London PO72, De Crespigny Park Denmark Hill London SE5 8AF; (2) PO74 Affective Disorders 103 Denmark Hill Denmark Hill London United Kingdom Introduction: Polymorphisms are the presence of different genetic sequences at a locus which can effect characteristics of a population differently. They can also affect neurological structures in the body like hypothalamic pituitary adrenal (HPA) axis. HPA axis is a major neuroendocrine system shown to play an important role in neurobiological reaction to stress through controlling cortisol levels. Thus, it plays an extensive part in handling depression and is most beneficial when normalised. Treatments can be used to regulate the function of the HPA axis to stress to regulate depression patterns. However, depending on the polymorphism patterns that express HPA axis functions, responses can differ. Methods: The systematic review looked at the effect of polymorphism patterns on HPA axis and depression, and how this in turn effects treatment responses. Embase, Ovid MEDLINE(R) and PsycINFO databases were used to search papers related to ‘HPA axis, depression, polymorphism and treatment response’ from 1806 till 2018, combined using Boolean operators “AND”/”OR”. Results: We chose twelve (12) relevant research papers (no review papers) to perform the systematic review on. In total, 112 different candidate HPA axis function single nucleotide polymorphisms (SNPs) were looked at from 14 different candidate genes and tested for their treatment responses on various antidepressants. 9/12 researches found a significant relationship between treatment outcomes and SNPs using various statistical measures (e.g. regression). Depending on the specific focus on the study, 11/12 studies found at least one significant SNP amongst the tested SNPs that influence a factor related to depression such as severity, cortisol secretion, diagnosis, remission and more. On the other hand, more singificantly unrelated polymorphisms than related polymorphisms were found to effect depression. It seems to be an existing yet specific pattern. Conclusion: Being able to detect and be aware of the correct polymorphisms can help to determine better antidepressant choices and thus better treatment outcomes for patients. A limitation within the research area of treatment responses is the absence of treatments for non-medication treatments. Thus, this could be a a potential new research area. More researches and bigger sample sizes are needed to be more confident in the effect of polymorphisms on treatment outcomes. There was no funding for this review. ABSTRACTS A97

G18 CAN THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS FUNCTION AS A BIOMARKER FOR DEPRESSION IN PATIENTS WITH A HISTORY OF EARLY LIFE STRESS? – A SYSTEMATIC REVIEW Bourne M, Centre for Affective Disorders, IoPPN, KCL, PO72, De Crespigny Park, Denmark Hill, London, SE5 8AF [email protected] Cleare AJ(1), Juruena MF(1) (1) IoPPN, KCL, PO72, De Crespigny Park, Denmark Hill, London SE5 8AF Introduction: A consistent finding throughout current psychiatry is the association between ypothalamic-h pituitary-adrenal (HPA)-axis abnormalities and major depressive disorder (MDD). One explanation for these abnormalities can be explained by the presence of early life stress (ELS; sexual-, physical- or emotional abuse; physical- or emotional neglect), which is suggested to increases the individuals risk for MDD. However, the use of HPA-axis biomarker for MDD in patients with ELS has not been systematically reviewed at present. Therefore, the primary objective of this systematic review is, to summarise existing research exploring HPA-axis functioning in participants with/without MDD and/or ELS, interchangeably, to explore whether the HPA-axis can be a reliable biomarker when ELS is present. Methods: We reviewed articles from 2011 – 2018 (PubMed, EMBASE, SCOPUS and Web of Science) with the following search terms; “early life stress” OR “childhood trauma” OR “childhood maltreatment” AND “hypothalamic- pituitary-adrenal*” OR “HPA*” OR “cortisol” OR “corticotropin releasing*” OR “glucocorticoid” OR “adrenocorticotropic hormone” OR “ACTH” OR “dehydroepiandrosterone” OR “DHEA” AND “depress*”. Studies were screened against STROBE statement checklist to assess for biases, and against our inclusion criteria; human participants (18-75years), with current MDD diagnosis and report ELS (as defined above) prior to 18 years. Additionally, studies must contain a healthy control and a HPA-axis challenge (dexamethasone test, dexamethasone test/Corticotropin-Releasing-Factor, Trier Social Stress Test). Results: Our search produced 19 eligible articles, which we separated by biomarker source; saliva (n=16) and plasma (n=3). In total we found that in 13 studies participants with a history of ELS had higher levels of post-challenge cortisol, of which 4 showed no significant difference due to the presence of MDD. Additionally, in 2 studies a blunted cortisol response was observed in participants with both MDD and ELS. Finally, of our 16 saliva studies, 5 identified lower saliva cortisol in participants with both MDD and ELS. Discussion: The results from this systematic review supported the research that individuals with MDD and a history of ELS more commonly present hypo-HPA-axis functioning in response to a HPA-axis challenge compared controls. The variations observed in our results could be explained by the following factors, which were not accounted for in the included studies; severity and/or the sub-type of ELS and/or sub-type of MDD. Some literature suggests that specific sub-types of ELS or MDD could lead to different HPA-axis functioning outcomes, and therefore, further research is needed specific to sub-types of ELS and MDD to confirm the reliability of the HPA-axis as a predictive biomarker. No funding received.

G19 POST-TRAUMATIC STRESS SYMPTOMS FOLLOWING CHILDHOOD SEPSIS: THE IMPACT OF INFLAMMATION AND CORTICOSTEROIDS Corbet Burcher G, Child and Adolescent Psychiatry, Imperial College London, Centre for Psychiatry, Imperial College, W12 0NN. [email protected] Caspani G(1), Cooper M(3), Pierce C(2), Als L(1), Garralda E(1), Nadel S(3) (1) As presenting author; (2) Dept. Intensive Care, Great Ormond Street Hospital; (3) Dept. Paediatrics, Imperial College Introduction: Survivors of critical illness in childhood frequently display subsequent emotional and behavioural difficulties. Symptoms of post-traumatic stress disorder (PTSD) have been demonstrated in approximately a third of children following discharge from paediatric intensive care (PICU). Individuals with PTSD have been shown to present a number of biological alterations. In particular a skew towards a pro-inflammatory state and a dysregulated cortisol response. A greater understanding of possible mediating pathways may assist the development of preventative strategies. In the current study our aims were two-fold. Firstly, to investigate whether abnormal peripheral blood inflammatory markers measured A98 ABSTRACTS during PICU admission were associated with PTSD symptoms after discharge. Secondly, to examine whether corticosteroid use in PICU was associated with PTSD symptom burden. Methods: This prospective observational cohort study involved recording the demographics, illness severity and characteristics of admission from PICU case notes of children aged 8-16 years. Inflammatory and related biological markers (white cell count, lymphocytes, neutrophils, C-reactive protein (CRP), platelets, fibrinogen and lactate) were transcribed from PICU admission notes. At-follow up (3-6 months post discharge) children completed the Impact of Events scale (a PTSD symptom questionnaire assessing overall symptoms with intrusion and avoidance subsets). Participants also provided salivary samples for cortisol profile analysis. Results: 33 children completed the IES-8 questionnaire and provided saliva samples. 35% received corticosteroids during admission. In children with sepsis (n=15), corticosteroid use was associated with a significant reduction in PTSD intrusion symptom scores (p=0.04). In addition, partial correlation indicated IES-8 scores were significantly and positively associated with CRP after controlling for age and gender (r=0.714; p=0.020). There was an overall trend towards lower total PTSD scores and evening cortisol levels (p=0.1). Conclusion: These results support the hypothesis that acute inflammation may play a role in the development of post-traumatic symptoms following PICU admission and suggest this as an area deserving further investigation. Corticosteroid use may result in fewer PTSD symptoms following PICU admission in children with sepsis and contribute to a normalisation of cortisol regulation. A possible underlying mechanism may be the neuroprotective effects of a reduction in the systemic inflammatory response. In addition, corticosteroids may correct for an inadequate cortisol stress response leading to reduced consolidation of traumatic memories. Sources of Financial Sponsorship: GCB was funded by the NIHR as an Academic Clinical Fellow. GC was funded by the MRC. This research was undertaken at Imperial College Academic Health Science Centre and Great Ormond Street Hospital for Children NHS Trust, both of which are supported by the Department of Health National Institute for Health Research Biomedical Research Centres funding scheme. The original research was supported by a grant from the Meningitis Research Foundation.

G20 CHRONIC HALOPERIDOL TREATMENT DRIVES CENTRAL MICROGLIAL ACTIVATION IN RATS EXPOSED PRENATALLY TO MATERNAL IMMUNE ACTIVATION – DO ANTIPSYCHOTICS INFLAME THE BRAIN? Vernon AC, Basic and Clincial Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, Maurice Wohl Clinical Neuroscience Institute, 5 Cutcombe Road, London United Kingdom, SE5 9RT [email protected] Cotel MC(1), Polacek R(1), Lenartowicz E(1), Natesan S(2) (1) As presenting author; (2) Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, De Crespigny Park, London SE5 8AF Background: Evidence-based medicine suggests that a subset of schizophrenia cases may be due to neuroinflammation, characterized by microglial activation, leading to trials of immunomodulatory drugs. However, we lack a basic understanding of the impact of antipsychotic drugs on neuroinflammation. To address this, we investigated the effects of chronic haloperidol treatment on rat brain microglia in a maternal immune activation (MIA) model. Based on observation that chronic antipsychotic exposure increases microgliosis in naive rats (Cotel et al., European Neuropsychopharmacology; 2015; 25(11): 2098-107.), we hypothesized that chronic haloperidol will interact with MIA to drive central microgliosis. Methods: Pregnant rat dams were exposed to poly (I:C) on GD15 (4 mg/kg, i.v.; n=5; POL) or saline (n=5; CON) (Crum et al., Brain Behaviour and Immunity, 2016; 63:50-59). At 4 months of age, male offspring from CON and POL (n=2 per litter) were allocated to treatment with either haloperidol (0.5 mg/kg/d s.c.) or vehicle for 28days using osmotic minipumps (all groups n=10). Fixed brain tissues were sectioned (1 in 12 series, 40 um) and stained for Iba1 (Cotel et al., European Neuropsychopharmacology; 2015; 25(11): 2098-107). Density and soma size of Iba1+ microglia were quantified using unbiased stereology in the cingulate cortex and striatum. Data were analysed using 2x2 ANOVA in SPSS, with main effects of prenatal, postnatal and pre x post-natal interactions. Post-hoc Bonferroni corrected t-tests were performed when p(ANOVA)<0.05 and effect sizes for ANOVA are given (η2). Results: There were significant main effects of ABSTRACTS A99 prenatal POL exposure on Iba1+ microglia density in both the striatum (F[1,32]=18.09; p<0.001; η2 = 0.5) and cingulate cortex (F[1,32]=5.04; p<0.05; η2 = 0.21). Iba1+ microglia soma size also increased in POL exposed offspring in the striatum (F[1,32]=88.5; p<0.001; η2 = 0.80) and cingulate cortex (F[1,32]=45.06; p<0.001; η2 = 0.6). Strikingly, there were also significant interactions between pre- and post-natal treatments for both Iba1+ microglia density in the striatum (F[1,32]=11.6; p<0.01; η2 = 0.34) and cingulate cortex (F[1,32]=11.7; p<0.01; η2 = 0.34). Post-hoc testing on this interaction confirmed a significant increase in Iba1+ microglia density and soma size (data not shown), in POL + haloperidol offspring, relative to all other groups, in both the striatum (p<0.01) and cingulate cortex (p<0.01). Conclusion: Chronic haloperidol treatment interacts with pre-natal exposure to MIA to drive central microgliosis. Although preliminary, these data suggest that antipsychotic treatment could exacerbate neuroinflammation in those schizophrenia patients where neuroinflammation may be an underlying cause. This study was funded by an MRC New Investigator Award to ACV (MR/N025377/1)

G21 SCHIZOPHRENIA RISK GENE CYFIP1 IS REQUIRED FOR MICROGLIAL REGULATION OF NEURONAL NUMBER IN THE POSTNATAL HIPPOCAMPUS Haan N, NMHRI, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ haann@cardiff. ac.uk Carter J(1), Westacott LJ(1), Hall J(1), Wilkinson LS(1) (1) As presenting author Introduction: Neuroimmunology has been implicated in the pathophysiology of schizophrenia through both genetic and functional evidence. Microglia, the resident immune cells of the brain, can module both neuronal development, connectivity, and activity throughout development and adulthood. Through these mechanisms, they can have profound effects on brain functioning, and alterations in microglial functioning have been implicated in pathogenesis of numerous diseases. Many immune genes are risk factors for schizophrenia, but other risk genes may also have previously undescribed immune functions. Cytoplasmic FMR1-interacting protein 1 (Cyfip1) is part of the 15q11.2 region, deletion of which significantly increases risk of schizophrenia. Cyfip1 regulates cytoskeleton dynamics through WAVE1 and mRNA translation through FMRP. Previous work has shown roles in regulation of dendritic spines, but here we investigate its role in microglia biology. Methods: To mimic the 15q11.2 deletion, we used a Cyfip1 heterozygous knockout mouse model. Mixed sex animals 0f 8-12 weeks old were conventionally housed, with ab lib access to food and water. We used a combination of immunohistochemistry, immunocytochemistry and measurements of secreted factors in primary cultures to assess both activation and functioning of microglia. Immunocytochemistry in primary post-natal hippocampal cultures were used to assess microglial-neuron interactions. Results: Cyfip1 is expressed at high levels in primary microglia, and transcription is strongly upregulated following a lipopolysaccharide (LPS) challenge (15-fold increase, p<0.001). Cyfip1+/- microglia showed only a mild activation deficit, and secretion of a panel of cytokines and chemokines was unaltered. However, while secreted factors from wild-type microglia were able to induce a robust apoptotic response in developing primary hippocampal neurons (89% increase, p<0.01), Cyfip1+/- microglia were completely unable to induce this response. Indeed, in hippocampal cultures, there were both increased numbers (74% increase, p<0.05) and decreased apoptosis (80% decrease, p<0.05) in immature neurons. In vivo, greater numbers of immature (54% increase, p<0.001) and adult born mature (41% increase, p<0.05) neurons were observed in the hippocampus, in the absence of any effects on progenitor cells or proliferation rates. Conclusions: Haploinsufficiency of schizophrenia risk gene Cyfip1 impairs microglia functioning. This leads to a dysregulation of neuronal number in the postnatal hippocampus, though a novel interaction between microglia and immature neurons. This microglial dysfunctioning likely has wider implications for neuronal morphology, connectivity and functioning. This work was funded by a Wellcome Trust Strategic Award. A100 ABSTRACTS

G22 A LONGITUDINAL INVESTIGATION OF THE NEURODEVELOPMENTAL IMPACT OF MATERNAL IMMUNE ACTIVATION ON PARVALBUMIN INTERNEURONS IN THE PREFRONTAL CORTEX AND DORSAL HIPPOCAMPUS IN THE RAT Munni STM, Department of Pharmacy and Optometry, The University of Manchester, Oxford Road, Manchester, Stopford Building, M13 9PT [email protected] Grayson B(1), Podda G(1), Yeo ZH(1), Neill JC(1), Harte MK(1) (1) As presenting author Introduction: Prenatal environment affects the developing fetus (Knuesel et al, 2014, Nat Rev Neurol, 10:643-660). Maternal immune activation (mIA) in rodents by administration of a viral mimetic polyriboinosonic-polyribocytidylic (poly I:C) is used to study effects of prenatal infection on offspring neurodevelopment (Meyer, 2014, Biol Psych, 75:307-315). Our aim is to investigate the longitudinal development of PV deficits and to determine whether cognitive deficits and PV reductions in the offspring occur at the same stage of development. Methods: Pregnant female Wistar rats from two cohorts (c1 & c2) were injected i.p with poly I:C (10 mg/kg, n=14) or vehicle (n=11) on gestational day (GD) 15. Body weight (BW) and core body temperature (CBT) were recorded at baseline, 3h, 6h and 24h post injection. Tail vein blood sample taken 3h post-injection to measure IL-6. At GD19 dams were housed singly before parturition on GD21. Pups were sex typed at postnatal day (PND) 1, weaned at PND21 and randomly assigned to two groups (n=1-2 pups per dam). Pups from c1 were culled at different time points- PND35 (adolescence) and PND70 (young adulthood) to create a PV expression timeline in this model. The female offspring (c2) were culled at PND 130. PV levels were analysed (c1 & c2) in the prefrontal cortex (PFC) and dorsal hippocampus (DHC) using Western Blotting (WB). Data analysed by Student’s t test. Results: Poly I:C significantly increased IL-6 at 3h compared to vehicle (p<0.05), indicating an inflammatory response in the dams. There was a significant decrease in BW (p<0.05) but not in CBT in the first 24h post injection (c1 & c2). Analysis with WB showed no changes in PV in the PFC or DHC at PND35 or PND70 in both male and female offspring brain (c1). However, significant decrease (p<0.05) in PV in the PFC at PND130 in the female offspring with no change in the DHC was observed (c2). This agrees with our previous findings which showed no behavioural deficits in offspring until adulthood. Conclusion: No changes in PFC PV at PND35 or PND70 but a significant decrease in female offspring in adulthood, suggesting a co-occurrence between the timing of behavioural deficits and reduced PV in the PFC. This supports the hypothesis that PV deficits are a mechanism for cognitive dysfunction in this model although further studies are required to understand the origin of the reduced PV. Declaration of interest: Jo Neill has received expenses to attend conferences and fees for lecturing and consultancy work (including attending advisory boards) from the manufacturers of various antipsychotic drugs. ZY is an undergraduate student at the University of Manchester. All other authors are full-time employees at the University of Manchester. Sources of financial sponsorship: This work is supported by b-neuro at the University of Manchester and the Rosetrees Trust.

G23 DIFFERENTIAL EFFECT OF AEA AND 2-AG IN INFLAMMATION Zajkowska ZE, Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, The Maurice Wohl Clinical Neuroscience Institute, Cutcombe Road, London, SE5 9RT [email protected] Russell A(3), Hepgul N(1), Borsini A(5), Nikkheslat N(5), Forton D(2), Agarwal K(4), Mondelli V(5), Zunszain PA(5), Pariante CM(5) (1) Cicely Saunders Institute, King’s College London , Bessemer Road Denmark Hill, SE5 9PJ; (2) Department of Gastroenterology & Hepatology, St George’s University of London, UK; (3) Guy’s and St Thomas’ Hospital, King’s College London, Westminster Bridge Rd, Lambeth, London SE1 7EH ; (4) Institute of Liver Studies, King’s College Hospital, Denmark Hill, London, UK; (5) Maurice Wohl Clinical Neuroscience Institute, King’s College London, Cutcombe Road, London, SE5 9RT Introduction: The endocannabinoid (eCB) system is one of the emerging key players in immunoregulation. For example, studies conducted mostly in animals show that immune stimulation increases the ABSTRACTS A101 eCB activity, and that both endogenous and synthetic cannabinoids induce an immunosuppressant effect (Hu et al., 2012, Neuroscience, 227: 211-222; Pandey et al., 2009, Pharmacol Res. 60(2): 85-92). However, data on prospective changes in humans detailing the relationship between inflammation and endocannabinoids (eCBs) are lacking. In this study, we investigated whether the circulating eCBs, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), are involved in the immune response following the inflammatory challenge of interferon-alpha treatment in patients with chronic hepatitis C. Methods: We measured serum concentrations of AEA and 2-AG using High Performance Liquid Chromatography with Tandem Mass Spectrometry, and serum concentrations of cytokines using Meso Scale Discovery (MSD) electrochemiluminescence V-PLEX assay, in 75 patients and 42 healthy controls. The samples were collected at baseline, treatment weeks (TW) 4 and 24, end of treatment and six months follow up (6mFU). Results: Both, AEA and 2-AG concentrations significantly increased during treatment in the whole sample, although 2-AG increased at TW4 and remained elevated at TW24, whereas AEA increased later during treatment, at TW24 (AEA: F = 73.657, p<.001; 2-AG: F = 47.899, p<.001). Interestingly, 2-AG levels normalized at 6mFU (controls: 5.88±0.81, 6mFU: 6.39±0.58; t=.474, p=.64), whereas AEA levels remained elevated in the whole sample (controls: 1.18±.05, 6mFU: 1.46±0.08; t=3.109, p.002). AEA levels were negatively correlated with IL-2 levels at TW24 (rs=-.312, p=.04), end of treatment (rs=-.513, p=.001) and 6mFU (rs=- .382, p=.02), and with IL-6, and IL-17a levels at 6mFU (r=-.412, p=.01; rs=.-361, p=.03). 2-AG levels were negatively associated with IL-2 and IL-4 levels at the end of treatment (rs=-.336, p=.03; rs=-.331, p=.04). Conclusions: The increase in AEA and 2-AG at different stages of interferon-alpha treatment suggests that both eCBs participate in different phases of immunomodulation. The negative association between eCBs and cytokines suggests the potential immunosupressant effect of AEA and 2-AG. This study represents independent work supported by the Medical Research Council (UK) MR/J002739/1 and the Commission of European Communities Seventh Framework Programme (Collaborative Project Grant Agreement no. 22963, Mood Inflame), and part funded by the NIHR/Wellcome Trust, King’s Clinical Research Facility and the National Institute for Health Research (NIHR) Biomedical Research Centre [and Dementia Unit] at South London and Maudsley NHS Foundation Trust and King’s College London.

H01 TRAJECTORIES AND MILESTONES OF CORTICAL AND SUBCORTICAL DEVELOPMENT OF THE MARMOSET BRAIN FROM INFANCY TO ADULTHOOD Sawiak SJ, 1Behavioural and Clinical Neuroscience Institute, University of Cambridge, Downing Site, CB2 3EB [email protected] Shiba Y(1), Oikonomidis L(1), Santangelo A(1), Windle CP(1), Grydeland H(2), Cockcroft G(1), Bullmore ET(1), Roberts AC(1) (1) As presenting author; (2) Department of Psychiatry, University of Cambridge, Cambridge CB2 0SZ Introduction: Disorders of mental health affect up to half the population at some point in their lifetime but half of these will already be established by age 14, rising to 75% by age 24: strongly suggestive of a developmental component. The detailed cause of most mental health disorders remains elusive but it is likely to be related to disruption of brain circuits underlying attention, decision making, mood and emotion. Understanding the development of these circuits will be pivotal in creating the sophisticated interventions required to address the burden these disorders place on individuals, their families and society. The marmoset, Callithrix jacchus, is a small primate with a compact lifespan (10-15 years) ideal for studying all stages of development. Here, we use MRI to track the growth of each cortical brain region and use this to parcellate cortical and subcortical regions by their growth rate patterns. Methods: Forty-one marmosets were scanned in 141 sessions in a mixed cross-sectional and longitudinal design, with the youngest animals scanned at 3 months of age. A 4.7T scanner was used to produce images optimised for grey-white matter contrast at a resolution of 250 µm. These were compared using tensor- based morphometry (TBM), using local deformation volume to find where changes occurred through development. Growth curves of structural volume were then extracted from each region and fitted with cubic b-splines for analysis. For TBM, t-tests (FDR-corrected p < 0.05) were used. For trajectory milestones, bootstrap resampling was used (p < 0.05). Results: We identified three milestones of grey A102 ABSTRACTS matter development: (i) age at peak volume; (ii) age at onset of volume decline; and (iii) age at maximum rate of volume decline. These milestones not only differentiated the growth trajectories of primary sensorimotor cortical areas from that of association cortex but also revealed distinct trajectories between association cortices. Hierarchical cluster analysis of growth trajectories showed that prefrontal cortex was the most heterogenous of the association regions, comprising multiple areas with distinct milestones and trajectories of grey matter development. Relative to primary cortical areas, association areas show a protracted shrinkage throughout adolescence, which is compatible with their known role in psychiatric disorders presenting at homologous ages in patients. Conclusions: Our findings provide an atlas of structural growth with milestones of development that we will now use to design functional studies to identify changing patterns of activity occurring as the brain matures. These data are crucial for planning studies targeting the developmental processes underlying mental dysfunction. This study was supported by an MRC Programme Grant (MR/M023990/1) and Wellcome Trust Investigator award (108089/Z/15/Z) to ACR and performed within The Behavioural and Clinical Neuroscience Institute, jointly funded by the MRC and Wellcome Trust.

H02 SCHIZOPHRENIA-RELEVANT ALTERATIONS IN CEREBRAL METABOLISM AND NEUROTRANSMITTER SYSTEM DYSFUNCTION IN A MOUSE MODEL OF 16P11.2 DUPLICATION Bristow GC, Biomedical and Life Sciences, Lancaster University, Lancaster, UK, LA1 4YQ g.bristow@ lancaster.ac.uk Thomson DM(3), Mitchell EJ(3), Openshaw RL(2), Pratt JA(3), Morris BJ(2), Dawson N(1) (1) As presenting author; (2) Institute of Neuroscience and Psychology, Univ. of Glasgow, United Kingdom; (3) Strathclyde Institute of Pharmacy & Biomedical Sciences, Univ. of Strathclyde, United Kingdom Introduction: Duplication at 16p11.2, affecting approximately 30 genes, is associated with increased risk of schizophrenia (Psychiatric Genomics Consortium, 2017. Nat Genet 49: 27). We currently have little understanding of how this copy number variation (CNV) impacts on brain and neurotransmitter system function. Here we use a mouse model of 16p11.2 duplication (DUP mice, Horev et al. 2011. PNAS. 108: 17076) to determine the impact of this CNV on cerebral metabolism. In addition, we characterize in vivo glutamate and monoamine neurotransmitter system function by challenging these animals acutely with ketamine and d-amphetamine, respectively. Methods: DUP mice and wild-type (WT) littermate controls were treated intraperitoneally with ketamine (25mg/kg), d-amphetamine (5mg/kg), or saline (2ml/kg). n=11 (6 male, 5 female) for each genotype per treatment group. Cerebral metabolism was determined by 14C-2- deoxyglucose functional brain imaging (Dawson et al., 2015.Transl Psychiatry. 5:e569). Data were analysed using repeated measures ANOVA with post-hoc Tukey’s HSD. Results: DUP mice show hypermetabolism in the hippocampus (CA1, F=14.161 p=0.0002), amygdala (central amygdala, F=8.033 p=0.005), and prefrontal (frontal association cortex, F=22.586 p<0.0001) and temporal cortex (entorhinal cortex, F=13.982 p=0.0002; perirhinal cortex, F=8.966 p=0.003). By contrast, DUP mice show significant hypometabolism in the thalamic reticular nucleus (F=5.595 p=0.019), mesolimbic system (ventral tegmental area, F=6.048 p=0.015) and neuromodulatory (dorsal raphé, F=6.321 p=0.013) regions. Hypometabolism was also seen in the striatum of female (p=0.002), but not in male (p=0.92), DUP mice. The impact of ketamine on cerebral metabolism was attenuated in DUP mice (range of change after ketamine administration: WT 17-24%, DUP 5-11%, p<0.05). By contrast, DUP mice showed a widespread exaggerated response to d-amphetamine in cerebral metabolism (range of change after amphetamine administration: WT 9-27%, DUP 16-39%, p<0.05) and locomotor activity (F=21.137 p=0.0002). Discussion: DUP mice show altered cerebral metabolism in brain regions implicated in schizophrenia, including hippocampal and temporal cortex hyperactivity. In addition, DUP mice demonstrate a reduced response to ketamine, supporting NMDA receptor hypofunction as a result of 16p11.2 duplication and consistent with the glutamate hypofunction hypothesis of schizophrenia. By contrast, DUP mice show an exaggerated response to d-amphetamine, supporting monoamine neurotransmitter system dysfunction as a consequence of 16p11.2 duplication. These data provide new insight into the mechanisms through which 16p11.2 duplication increases the risk of developing schizophrenia. This research was funded through an MRC award (MR/N012704/1) to ND, JP, and BM. ABSTRACTS A103

H03 LOW LEVELS OF VITAMIN D ARE ASSOCIATED WITH REDUCED CORTICAL THICKNESS AND SURFACE AREA IN FRONTAL, TEMPORAL AND OCCIPITAL REGIONS OF PATIENTS AT THEIR FIRST-EPISODE PSYCHOSIS Ciufolini SC, Dept of Psychosis Studies, Inst of Psychiatry, Psychology and Neuroscience, King’s College London, 16 De Crespigny Park, London, SE5 8AF [email protected] Lally JL(1), Stubbs BS(1), Smith SS(1), DiForti MD(1), Dazzan PD(1), Howes OH(1), Murray RM(1), Gaughran FG(1) (1) Institute of Psychiatry, Psychology and Neuroscience, King’s College London Introduction: Vitamin D is a neuro-steroid hormone important in brain development, maturation and function. It has recently emerged that vitamin D contributes to neuroprotection, by modulating the production of numerous brain growth factors. Indeed insufficient levels seem to compromise brain development and confer an increased risk of developing schizophrenia later on in life. Furthermore, patients with first-episode psychosis have lower levels of vitamin D than matched controls. However, whether and how Vitamin D levels relate to brain structure in people with psychosis is unclear. To understand that, we examined the relationships between vitamin D levels and brain structure in a sample of individuals at their first episode of psychosis. Methods: Brain structure was evaluated with a 3T MRI scan in 49 first episode psychosis patients (FEP) (mean age: 27.8 SD ± 9.1 years) and Vitamin D (serum 25-hydroxyvitamin D) levels determined by immunoassay. Patients were considered to have insufficient vitamin D if its concentration was below 20 ng/ml, with higher concentrations deemed optimal. Twenty patients had sub-optimal levels of Vitamin D where 29 had optimal Vitamin D concentration. FreeSurfer 5.3.0 was used to correlate Vitamin D levels with both cortical thickness and surface area in a vertex- by-vertex analysis. We then investigated differences in cortical thickness and surface area between FEP participants with both optimal and insufficient levels of Vitamin D using a vertex-by-vertex General Linear Model analysis in FreeSurfer 5.3.0. Results: Vitamin D positively correlated with cortical thickness in the left superior-frontal gyrus and surface area in the right peri-calcarine and right inferior-parietal gyrus (all p<0.05 FWE corrected). Patients with insufficiency in Vitamin D had reduced cortical thickness in the left post-central and lingual gyrus compared to those with optimal levels of Vitamin D (all p<0.05 FWE corrected). Similarly, participants with Vitamin D insufficiency had smaller surface areas in the middle-temporal, lateral-occipital and superior-parietal gyrus in the left hemisphere and in the medial- orbitofrontal, pre-central, inferior-parietal, precuneus and fusiform gyrus in the right hemisphere than those with optimal levels (all p<0.001 FWE corrected). Conclusions: These results suggest that reduced levels of Vitamin D are associated with reduced cortical thickness and surface area in certain brain regions in individuals with FEP. These areas are involved in social adjustment, mood control and drive; functions often compromised in psychosis. Interestingly, these areas complete maturation well into late adolescence, thus potentially being exposed to the effect of low Vitamin D levels over a long period of time. These findings promote greater understanding of the interface between physical and mental illness and foster the development of precision psychiatry. This study was partly funded by the EU as part of the Childhood Trauma and Psychosis (EUGEI), and BRC as part of the BRC Psychosis Theme study on Genetics and Psychosis (GAP).

H04 REMISSION FROM ANTIPSYCHOTIC TREATMENT RELATED TO LONGITUDINAL CHANGES IN BRAIN GLUTAMATE LEVELS Merritt K, Psychosis Studies, IOPPN, De Crespigny Park London, SE5 8AF [email protected] Perez-Iglesias R(1), Goozee R(1), Sendt KV(1), Jauhar S(1), Pepper F(1), Barker GJ(1), Stone J(1), Howes O(1), Dazzan P(1), McGuire P(1), Egerton A(1) (1) As presenting author Background: Cross-sectional neuroimaging studies link ineffective antipsychotic treatment to elevated brain glutamate levels. We investigated whether non-remission following antipsychotic treatment is A104 ABSTRACTS related to longitudinal changes in glutamate levels over the course of treatment. Methods: Proton magnetic resonance spectroscopy (1H-MRS) measured Glx in the thalamus and anterior cingulate cortex (ACC) in minimally-medicated patients with first episode psychosis (n=23) at clinical presentation, after 6 weeks and 9 months of treatment. At 9 months, patients were classified into Remission (n=12) and Non-Remission (n=11) groups according to Andreasen criteria. Healthy volunteers (n=15) were scanned at the same timepoints. Results: Non-remission was associated with a longitudinal increase in thalamic Glx levels over 9 months following presentation (P=0.007). This reflected an increase between 6 weeks and 9 months in the non-remission but not the remission subgroup (P=0.179), and higher Glx levels in the non-remission than the remission subgroup at 9 months (P=0.022). Furthermore, the longitudinal change in thalamic Glx levels over the course of treatment was directly correlated with changes in PANSS positive, total and general symptoms (P<0.05). There were no differences in Glx levels between patient subgroups in the ACC, or between the total patient sample and healthy volunteers in thalamus or ACC. Conclusions: These results suggest that a poor response to antipsychotic medication is associated with a longitudinal increase in thalamic Glx levels. The findings add to existing evidence that the pattern of brain glutamate dysfunction in psychosis varies between patient subgroups, and is linked to the effectiveness of antipsychotic medication. This work was funded by a grant from the European Commission within the 7th Program (HEALTH-F2-2010-242114). Dr Egerton received additional funding from the Brain and Behaviour Research Foundation (YIA 2012–18777).

H05 THE RELATIONSHIP BETWEEN CORTICAL GLUTAMATE AND STRIATAL DOPAMINE FUNCTION IN PSYCHOSIS: A MULTI-MODAL PET AND MRS IMAGING STUDY IN FIRST EPISODE PSYCHOSIS Jauhar S, Centre for Affective Disorders, King’s College, London, Institue of Psychiatry, Psychology and Neuroscience, Denmark Hill, London, SE5 8AF [email protected] McCutcheon RA(3), Veronese M(1), Nour MM(4), Rogdaki M(4), Stone J(2), Egerton A(4), Turkheimer F(2), McGuire P(4), Howes OD(4) (1) Centre for Neuroimaging Sciences, King’s College; (2) Centre for Neuroimaging Sciences, King’s College, London; (3) Psychosis Studies, King’s College; (4) Psychosis Studies, King’s College, London Introduction: The dopamine hypothesis of schizophrenia has been one of the most enduring scientific hypotheses in psychiatry. From origins relating to the mode of action of antipsychotic drugs. it has evolved into a nuanced model of dopamine dysregulation leading to psychosis. Current theories have incorporated the impact of various genetic and environmental factors on this system, and interactions amongst neurotransmitter systems (Howes and Kapur, 2009, Schizophrenia Bulletin; 35: 549-62). It has been proposed that disruption in cortical glutamatergic signalling precipitates aberrant striatal dopamine function at the onset of psychosis (Carlsson et al, Biol Psychiatry 1999; 46: 1388-95), but this has not been previously tested in vivo. We therefore aimed to test the relationship between glutamate and dopamine function and symptoms in patients with a psychotic disorder. Methods: Twenty-eight individuals with first episode psychosis (25 antipsychotic naïve/free) and twenty healthy controls received an 18F-DOPA positron emission tomography scan, measuring striatal dopamine synthesis capacity, and proton magnetic resonance spectroscopy, measuring anterior cingulate glutamate levels. Symptom severity was measured using the Positive and Negative Syndrome Scale (PANSS). Statistical analyses consisted of linear regression models, accounting for demographic factors (age, ethnicity, gender) and medication status (on/off antipsychotic medication), and symptom correlations with DOPA and MRS measures. Results: The initial model included glutamate concentration as sole predictor of striatal dopamine synthesis capacity, and showed a statistically significant relationship (beta=-1.71*10-4, SE 7.63*10-5, p=0.03). Adding demographic variables of age, gender, and ethnicity, did not change the overall model fit, and anterior glutamate concentrations remained a predictor of striatal dopamine synthesis capacity (beta= -2.02*10^- 4, SE = 7.66*10^-5, p=0.014), indicating these variables were unlikely to act as confounders. When medication status (on medication at time of scan, or medication free) was added to this model, glutamate concentration remained a significant predictor (beta=-1.81*10^-4, SE = 8.06*10^-4, p=0.036), indicating that antipsychotic medication did not explain the significant relationship. In controls, adding demographic variables did not have any significant effect on the dopamine-glutamate relationship, which remained non- ABSTRACTS A105 significant (p=0.36). The difference between the two correlation coefficients was significant (r-to-z z=-2.1, p=0.04). Positive psychotic symptoms were positively correlated with striatal dopamine synthesis capacity (r=0.38, p=0.05) and negatively correlated with cortical glutamate levels (r=-0.41, p=0.03). Conclusion: These results reflect the hypotheses that frontal glutamate levels are linked to subcortical dopamine disinhibition and presence of positive psychotic symptoms. Alteration of glutamatergic pathways may be a treatment target in psychotic illness. This study was funded by Medical Research Council grant MC- A656-5QD30, Maudsley Charity grant 666, support from the US Brain & Behavior Research Foundation, and Wellcome Trust grant 094849/Z/10/Z to Dr Howes and the National Institute for Health Research Biomedical Research Centre at South London and Maudsley National Health Service Foundation Trust and King’s College London to Professor Howes, Dr Veronese and Dr Jauhar. Dr Jauhar is funded by a JMAS Sim Felllowship form the Royal College of physicians, Edinburgh.

H06 HEARING NON-EXISTENT VOICES: A RESTING STATE FMRI STUDY ON SCHIZOPHRENIA WITH AUDITORY VERBAL HALLUCINATIONS Chu KM, Psychology, University of Birmingham, The Barberry, National Centre for Mental Health, 25 Vincent Dr, Birmingham, B15 2SJ [email protected] Upthegrove R(1), Mallikarjun PK(1) (1) As presenting author Introduction: Auditory verbal hallucinations (AVHs) are commonly seen on schizophrenia patients. Previous studies suggested that AVHs are associated with aberrant activations within brain networks (e.g., default mode network). However, recent findings regarded to the connectivities between these brain networks are rare and inconsistent. The present study aimed to explore the aberrant activations within, as well as the connectivities between these brain networks towards the cause of AVHs. Methods: Independent component analysis was conducted on imaging data collected from 14 schizophrenia patients with AVHs and 18 healthy controls, where they were asked to stay wakeful rest with their eyes closed in a functional MRI scanner for 10 minutes. Results: The schizophrenia patients showed a significantly greater activation within their auditory network than the healthy controls (p= 0.003). Also, the connectivity between the auditory network and the salience network was significantly reduced in the schizophrenia patients than the healthy controls (p=0.002). The reported p-values are false discovery rate corrected. Conclusions: The salience network is responsible in shifting our attention between internal state and external world, while the auditory network is responsible in perceiving auditory stimuli (e.g., spoken words). Therefore, our findings suggested that AVHs are caused by the mis-attributions of internally-generated thoughts as voices coming from the external world. This study was funded by the Caring Minds charity (Birmingham & Solihill Mental Health Foundation Trust) and the Aberrant Experiences and Beliefs These LES (University of Birmingham)

H07 INNER SPEECH MODELS OF AUDITORY VERBAL HALLUCINATIONS: A SYSTEMATIC REVIEW AND META-ANALYSIS Barber LB, The University of Birmingham, Medical School, College of Medical and Dental Sciences, Edgbaston Birmingham, B15 2TT [email protected] Upthegrove RU(1), Reniers RR(1) (1) The Barberry National Centre for Mental Health, 25 Vincent Drive, Edgbaston, Birmingham, B15 2FG Introduction: Inner speech is the process of covertly speaking to oneself to fulfil functions such as planning and self-regulation. Auditory verbal hallucinations (AVHs) may result from the misattribution of inner speech to an external source. This could be due to dysconnectivity between language-related areas and areas involved in self-referential processing. The purpose of this review was to evaluate existing inner speech models of AVHs using the findings from diffusion tensor imaging studies. Methods: Studies were identified by searching MEDLINE, PsycINFO, Embase and reference lists of relevant systematic reviews and meta-analyses. Included studies investigated subjects with schizophrenia with AVHs using diffusion tensor A106 ABSTRACTS imaging. Review Manager 5.3 was used to perform the meta-analyses. Results (for the fractional anisotropy of the left arcuate fasciculus only): A reduced fractional anisotropy indicates a reduced structural integrity. The left arcuate fasciculus connects Broca’s area (speech production area, including inner speech) and the left temporal cortex (speech perception area). Those with AVHs had a significantly lower fractional anisotropy when compared to healthy controls (mean difference [95% confidence interval]: -0.02 [-0.03 to -0.02]; p < 0.00001). Those with schizophrenia without AVHs also had a significantly lower fractional anisotropy when compared to healthy controls (mean difference [95% confidence interval]: -0.02 [-0.02 to -0.01]; p < 0.00001). There was no significant difference for the fractional anisotropy of the left arcuate fasciculus between those with AVHs and those with schizophrenia without AVHs (mean difference [95% confidence interval]: 0.0 [-0.01 to 0.00]; p = 0.43). Conclusions: Previously, Geoffrey et al / 2014 / Schizophr Res / 159 / 234-237 found a significantly lower fractional anisotropy of the left arcuate fasciculus in those with schizophrenia with AVHs compared to healthy controls. However they did not compare those with AVHs to those with schizophrenia without AVHs. By performing this comparison, it was shown that a reduced fractional anisotropy of the left arcuate fasciculus is a general abnormality of those with schizophrenia, rather than specific to those with AVHs. This finding does not support the theory explaining that AVHs are caused by the misattribution of inner speech, due to aberrant connectivity between Broca’s area and the left temporal cortex. No sponsorship was received for this study.

H08 THE EFFECTS OF CHILDHOOD TRAUMA ON BRAIN STRUCTURE AND FUNCTION IN PEOPLE WITH PSYCHOTIC EXPERIENCES: A SYSTEMATIC REVIEW OF NEUROIMAGING STUDIES Modaffar M, Division of Psychiatry, UCL, Gower St. London, WC1E 6BT [email protected] Bloomfield MA(1) (1) As presenting author Introduction: Developmental trauma is associated with increased risk of psychosis. Compared to those without trauma history, trauma-exposed individuals at-risk of or experiencing psychosis have a worse prognosis, poorer response to standard treatments and greater cognitive impairment. Despite this, we lack precise mechanistic understanding of how trauma alters brain function to give rise to psychosis. It has been hypothesised that trauma exposure results in clinically distinct psychosis phenotypes. This hypothesis was tested by systematically reviewing the literature for differences in brain structure and function in people with psychotic experiences, with or without developmental trauma histories. Methods: Studies were identified by searching PUBMED, MEDLINE and reference lists of relevant publications for neuroimaging studies of brain structure and function in people with psychotic experiences and developmental trauma, compared to people with psychotic experiences without developmental trauma. Studies excluded did not perform neuroimaging or compare brain structure and/or function between individuals with psychotic experiences, with or without trauma. Results: 22 imaging studies were found of psychotic and at-risk individuals (n=1,834 trauma-exposed subjects, 807 healthy controls) including 1 molecular, 13 structural, 7 functional and 1 combined structural and functional analysis. Trauma exposure was consistently associated with structural and functional deficits in psychotic individuals relative to non- exposed individuals, including globally reduced cortical thickness and surface area. Volumetric deficits were repeatedly found in the amygdala, hippocampus and prefrontal cortex, especially in grey matter. Trauma was associated with functional hypoconnectivity between the amygdala and visual processing areas, hyperactivation of the threat detection system and hyperactivation of regions associated with self- imagery. There was also evidence of white matter hypoconnectivity in trauma survivors including the corpus callosum, cingulum, corona radiata, thalamic and inferior longitudinal fasciculi. One study found at-risk participants with severe childhood maltreatment had a higher striatal dopamine synthesis capacity compared to low exposure participants. All but one study matched for medication dosage and studies were limited by heterogeneous trauma assessment. Conclusions: There is imaging evidence in favour of trauma phenotypes in psychosis. Individuals with psychotic experiences and developmental trauma show trauma- specific alterations in brain structure and function, particularly in domains of executive function and emotional processing. Such differences may need to be considered in the development of more tailored ABSTRACTS A107 and effective treatments for patients with developmental trauma. Further studies are necessary to help elucidate the mechanisms behind increased vulnerability, and the effect on resilience to psychosis, in those with developmental trauma compared to those without. This study was funded by UCL and the UCLH Mental Health National Institute for Health Research Biomedical Research Centre.

H09 INCREASED CEREBRAL BLOOD FLOW AFTER SINGLE DOSE OF ANTIPSYCHOTICS IN HEALTHY VOLUNTEERS DEPENDS ON DOPAMINE D2 RECEPTOR DENSITY PROFILES Selvaggi P, Department of Neuroimaging, King’s College London, Institute of Psychiatry, Psychology and Neuroscience 16 De Crespigny Park, London, SE5 8AF, SE5 8AF [email protected] Hawkins PCT(2), Dipasquale O(2), Rizzo G(3), Bertolino A(1), Dukart J(4), Williams SCR(2), Turkeimer F(2), Veronese M(2), Mehta M(2) (1) Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari Aldo Moro, Bari BA, Italy; (2) Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom; (3) Imanova Ltd., Centre for Imaging Sciences, Hammersmith Hospital, London, UK; (4) Translational Medicine Neuroscience and Biomarkers, F. Hoffmann-La Roche Ltd, Basel, Switzerland Introduction: Antipsychotic drugs produce marked functional effects as measured with MRI haemodynamic markers like Cerebral Blood Flow (CBF) . These effects are thought to depend on dopamine D2 receptor (D2R) blockade (Goozee et al. 2014, Neuroscience & Biobehavioral Reviews 43, 118–136), although their relationship with antipsychotic pharmacodynamics has not been fully established yet. In fact, the haemodynamic nature of CBF measures makes difficult to interpret drug effects in terms of altered neurotransmission function. In the present work, we tested whether CBF changes induced by different antipsychotics mirror receptor distribution profiles of one of the main target of these compounds, namely the D2R. We evaluated the correlation of CBF variation with receptor density as measured with PET and brain mRNA expression extracted from the Allen Human Brain Atlas. Methods: Forty-two healthy male subjects were enrolled in a double-blind, randomized, placebo-controlled, crossover study. Participants were randomized into two equal parallel groups to receive a single dose of antipsychotic/placebo in three separate sessions. In Group 1 placebo, olanzapine 7.5mg (OLA) or haloperidol 3mg (HAL) were administered before the MRI scan. In Group 2 participants received placebo, 0.5mg (lowRIS) or 2mg (highRIS) of risperidone (Hawkins et al. 2018 Hum Brain Mapp 39: 319–331). Regional CBF was assessed with pseudo-continuous ASL (pCASL) sequence. For each antipsychotic, a paired T-test was performed in SPM12 with global CBF values as a covariate of no interest. A template image of dopamine D2 receptor density was derived from 6 PET scans in healthy volunteers using the high-affinity D2/D3 antagonist ligand [18F]-Fallypride. Brain mRNA expression values for the DRD2 gene (coding for D2R) were extracted from the ABA dataset by using the MENGA toolbox (Rizzo et al. 2016 PLoS ONE 11: e0148744–20). The contrast images and the [18F]Fallypride BPND template were segmented into 83 ROIs by using the Desikan-Killiany Atlas. The regional changes in CBF against placebo (∆CBF) were compared with regional BPND values and gene expression maps using multivariate correlations. Results: For all antipsychotics, CBF changes in each ROI were directly proportional to [18F] Fallypride non displaceable binding potential (BPND) values (OLA R2= 0.24, HAL R2= 0.61, lowRIS R2= 0.54, highRIS R2= 0.52, all p<0.001) and DRD2 mRNA expression levels (OLA R2= 0.04, HAL R2= 0.15, lowRIS R2= 0.19, highRIS R2= 0.20 all chance likelihood <2%). Discussion: In the present study, we were able to show that the CBF increase induced by antipsychotic is directly proportional to D2R concentration in the brain, as indexed by PET BPND maps and mRNA expression levels. Interestingly, the association strength between ∆CBF and brain receptor distribution profiles mirrored differential D2R affinity between the tested drugs. Overall, these results indicate that CBF increases after administration of a single dose of antipsychotics actually reflect known pharmacodynamics profile of these compounds. In addition, these results further reinforce previous evidence suggesting the role of D2R blockade as a mechanism behind increased CBF induced by antipsychotics. Finally, CBF is ultimately a functional marker and this work is important in bridging the considerable gap between the pharmacokinetic and pharmacodynamic effects of compounds with unclear brain functional effects like antipsychotics. Sponsorship: Hoffman La-Roche A108 ABSTRACTS

H10 MESOLIMBIC DOPAMINE FUNCTION AND SALIENCE NETWORK CONNECTIVITY: AN INTEGRATIVE PET AND MR STUDY McCutcheon RA, Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, De Crespigny Park London, SE5 8AF [email protected] Nour M(1), Jauhar S(1), Expert P(2), Dahoun T(4), Pepper F(1), Mehta M(3), Howes O(1) (1) As presenting author; (2) Department of Mathematics, Imperial College London, London, SW7 2AZ, UK; (3) Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, Kings College London, De Crespigny Park, London SE5 8AF, UK; (4) Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, W12 0NN Introduction: The salience network, composed primarily of the anterior insula and dorsal anterior cingulate, and the mesolimbic dopamine system both play a role in identifying salient features of the environment. Dysfunction of both systems is associated with a range of neuropsychiatric illnesses. Despite overlap in function, the relationship between the two systems remains poorly understood, and has not been directly studied in humans. Method: In 21 healthy controls, we used 18F-DOPA positron emission tomography to measure dopaminergic functioning within the limbic striatum, and resting state MRI to evaluate salience networks at rest. We used a graph theoretical approach to integrate PET and MRI data. First, we used the network based statistic (NBS) to identify dopamine-associated subnetworks within the salience network. We next defined nodes as information processing hubs based on degree, betweenness centrality, participation coefficient, and a combination of these measures. We determined whether there was a statistically significant overlap between the dopamine-associated nodes identified using NBS and the MRI hub nodes by comparing overlap of the true nodes and 10,000 randomly generated node selections. Results: Mean salience network strength positively correlated with limbic dopamine synthesis capacity (r=0.53, p=0.01). NBS identified dopamine-associated networks across a anger of thresholds (t=1.3-3.6). Regardless of the threshold or metric used to define MRI nodes as hubs, these nodes were significantly likely to overlap with the dopamine-associated nodes identified using NBS(p<0.05) across a wide range of NBS defining thresholds. Conclusion: We demonstrated that increased limbic dopamine synthesis capacity is associated with greater salience network strength, and that the specific nodes driving this relationship are those classified as information processing hubs based on a range of metrics. This is the first time, to our knowledge, that the relationship between limbic dopamine function and salience network connectivity has been directly studied in humans. We suggest that these findings are relevant to models of brain function in health and disease that attempt to integrate the role neurochemical action and distributed neural networks. Funding: R.M.’s work is supported by the Wellcome Trust (no. 200102/Z/15/Z). This study was funded by Medical Research Council-UK (no. MC-A656-5QD30), and Wellcome Trust (no. 094849/Z/10/Z) grants to O.H. and the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.

H11 ABNORMAL FRONTOSTRIATAL CONNECTIVITY IN PSYCHIATRIC DISORDERS: A REVIEW Walker HR, Division of Psychiatry, University College London, 6th Floor, Maple House, 149 Tottenham Court Road, London, W1T 7NF [email protected] Freeman TP(2), Bloomfield MAP(1) (1) Division of Psychiatry, B Wing, 6th Floor, Maple House 149 Tottenham Court Road London W1T 7BN; (2) National Addiction Centre, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London SE5 8BB Introduction: Connectivity between the frontal cortex and the striatum is important for mediating self- regulatory processes. Human and animal studies have characterised parallel frontostriatal pathways that play a vital role in executive function and other cognitive, motor, and affective processes. Frontostriatal dysconnectivity has been reported across a range of psychiatric disorders including schizophrenia, obsessive-compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), depression, and ABSTRACTS A109 addictions. We therefore sought to synthesise the literature on frontostriatal connectivity in psychiatric disorders, implications for understanding pathophysiology, and potentially targeting these processes. Methods: We performed a literature search on the Pubmed database using variations of the terms ‘frontostiatal’, ‘connectivity’, and variations of psychiatric disorders included addictions, schizophrenia, psychosis, depression, anxiety, OCD, ADHD, and eating disorders. Only human studies were included. Results: This search resulted in 227 papers of which 154 were on humans. Resting state and task-based fMRI functional connectivity analyses in humans have revealed abnormal frontostriatal connectivity across many psychiatric disorders. The profile of frontostriatal connectivity within individual psychiatric disorders is complex and varies significantly between dorsal and ventral circuits. Reduced functional frontostriatal connectivity has been found to predict symptom severity in schizophrenia, with close relatives and at-risk populations displaying similar connectivity deficits. Functional hypoconnectivity observed in addictions and disordered eating, as well as hyperconnectivity in ADHD (hyperactive- impulsive subtype), suggests that frontostriatal circuits are important for mediating impulse control. Structural MRI and diffusion tensor imaging studies have uncovered reduced structural connectivity and white matter tract integrity of frontostriatal circuits in schizophrenia and other psychiatric disorders, supporting functional findings. Conclusions: There is evidence that distinct frontostriatal connectivity signatures are associated with specific psychiatric disorders. Targeting these mechanisms using pharmacological or other techniques may improve treatment outcomes for a range of disorders.

H12 INVESTIGATING THE EFFECTS OF ACUTE Δ⁹-TETRAHYDROCANNABINOL ON CEREBRAL BLOOD FLOW – AN ARTERIAL SPIN LABELLING STUDY Ogunbiyi MO, Division of Psychiatry, UCL, Maple House, 149 Tottenham Court Rd, Fitzrovia, London, W1T 7BN [email protected] Lees R(3), Petrilli K(3), Hindocha C(3), Howes O(3), Freeman TP(3), Hales P(2), Curran HV(3), Bloomfield MAP(1) (1) Maple House, 149 Tottenham Court Rd, Fitzrovia, London; (2) UCL GOSH Institute of Child Health 30 Guilford Street London WC1N 1EH; (3) University College London, Gower Street, London, WC1E 6BT Introduction: Long-term heavy cannabis use is associated with increased risk of several neuropsychiatric disorders including psychotic illnesses. Δ9-tetrahydrocannabinol-induced (THC) effects on cerebral blood flow (CBF) could provide a mechanistic link underlying the increased risk of psychopathology associated with cannabis use. Previous studies reporting the effects of acute THC administration on CBF are scarce and do not consider associations with the psychotomimetic effects of THC. Objective: To investigate the effects of acute THC administration on CBF in humans with a history of cannabis use and the relationship between THC-induced CBF changes and the classical psychotomimetic effect of THC. Methods: Seventeen (10 Female, 23.6 (3.9) years of age) participants were administered 15 mg oral THC, or placebo, in a double-blind randomised control design. Pulsed arterial spin labelling (pASL) was used to measure global CBF in grey and white matter, and other hypothesised regions including the frontal lobe and prefrontal cortex. The Psychotomimetic State Inventory (PSI) was used to assess psychotomimetic effects pre- and post- administration. Results: Acute THC administration caused a significant psychotomimetic effect in comparison to placebo (10.05, p<0.05). However, acute THC administration did not cause a significant change in global or region-specific CBF and there was no correlation between CBF and the psychotomimetic effects of the drug. Conclusions: We did not find evidence for effects of oral THC on changes in resting CBF in people with a history of cannabis exposure. Our findings suggest that oral THC- induced changes in CBF do not underlie the psychotomimetic effects observed with THC administration. Standardised methodology in acute and longitudinal studies are required to accurately investigate the impact of THC exposure on CBF and its relationship with brain function and psychopathology. The study was sponsored by UCL and funded by the BMA. A110 ABSTRACTS

H13 FUNCTIONAL MAGNETIC RESONANCE SPECTROSCOPY IN PATIENTS WITH SCHIZOPHRENIA AND BIPOLAR AFFECTIVE DISORDER: GLUTAMATE DYNAMICS IN THE ANTERIOR CINGULATE CORTEX DURING A WORKING MEMORY TASK Jelen LA, Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience (IoPPN), King’s College London 16 De Crespigny Park Camberwell London, SE5 8AF [email protected] King S(1), Lythgoe DJ(1), Stone JM(1) (1) As presenting author Background: The glutamate system is increasingly implicated in the pathophysiology of schizophrenia and mood disorders (Moghaddam B and Javitt D. Neuropsychopharmacology. 2012;37(1):4-15; Sanacora G et al. Nature reviews Drug discovery. 2008;7(5):426-437). Although standard magnetic resonance spectroscopy allows estimation of brain glutamate and glutamine levels, there is debate as to whether these are derived from metabolic or neurotransmitter pools. Using functional magnetic resonance spectroscopy (1H-fMRS), it is possible to monitor glutamate dynamically in activated brain areas and may give a closer estimate of glutamatergic neurotransmission (Jelen LA et al. J Psychopharmacology. 2018:269881117747579). Methods: 14 patients with schizophrenia, 15 patients with bipolar disorder II (BPII) and 14 healthy volunteers underwent a 15-min n-back task in a 48-s block design during 1H-fMRS acquisition (TE=105ms, TR=2000ms, NEX=8, GE Discovery MR750 3T scanner). Data from the first, second and third 16s group of 8 spectra for each block were processed using TARQUIN (Wilson M et al. Magn Reson Med 65:1-12). Levels of glutamate and Glx (glutamate + glutamine), scaled to total creatine (TCr), across the 0-back and 2-back conditions were analysed using 6x3 repeated-measures analyses of variance (rmANOVA). Paired t-tests were used to compare metabolite levels between 0-back and 2-back conditions. Pearson coefficients were used to examine any associations between changes in Glu/TCr and Glx/TCr, and clinical rating scores (Scale for the Assessment of Positive/Negative Symptoms and Montgomery-Asberg Depression Rating Scale). Results: 6x3 rmANOVA determined a significant main effect of time for Glx/TCr (P=0.022) but not for Glu/TCr (P=0.673), with no significant time by group interactions or main effects of group for Glu/TCr or Glx/TCr. No groups showed significant changes in Glu/TCr or Glx/TCr between total averaged task conditions. There was a significant increase in Glu/TCr (P=0.004) and Glx/TCr (P<0.001) between the final spectra of the 0-back and first spectra of the 2-back condition in the healthy control group only. Depressive symptoms were inversely correlated with changes in Glu/TCr and Glx/TCr between these averaged spectra across groups; (r= -0.632, P<0.001) and (r= -0.532, P<0.001), and specifically within the BPII group; (r= -0.639, P=0.047) and (r=-0.585, P=0.036) respectively. Conclusions: While healthy volunteers showed significant increases in glutamatergic measures between task conditions, the lack of such a response in patients with schizophrenia and BPII may reflect abnormalities of glutamatergic neurotransmission. Furthermore, this study suggests depressive symptoms are associated with such impairments and supports further investigation of compounds which may act to modulate glutamate neurotransmission in depression. Funding: This work was supported by the NIHR BRC for Mental Health at the SLaM NHS Foundation Trust and IoPPN, KCL. LA Jelen is an Academic Clinical Fellow at KCL, funded by the NIHR.

H14 CAN THE LOCUS COERULEUS ACTIVITY BE MEASURED BY MAGNETIC RESONANCE IMAGING? A FEASIBILITY STUDY Hou R, Dept. of Psychiatry, Univ. of Southampton, Academic Centre, College Keep 4-12 Terminus Terrace, Southampton, SO14 3DT [email protected] Ollington R(2), Lewis E(1), Everitt C(1), Holmes C(2), Darekar A(1) (1) Medical Physics, University Hospital Southampton NHS Trust, Tremona Road, Southampton SO16 8HQ; (2) Memory Assessment & Research Centre, Moorgreen Hospital, Botley Road, West End, Southampton SO30 3JB Introduction: The locus coeruleus (LC) is a tiny nucleus in the brain stem which is the major souce of noradrenaline (NA). While cognitive decline in Alzheimer’s Disease (AD) has primarily been related to dysfunction within the cholinergic system, evidence indicates that there is extensive LC degeneration ABSTRACTS A111 in AD which is among the earliest pathologies. However, most evidence comes from animal and post- mortem studies. The absence of reliable non-invasive direct measures of LC activity in humans remains challenging. Our research group have developed a novel imaging protocol to directly measure LC signal changes using a high-resolution magnetic resonance imaging (MRI) imaging technique, which is different from conventional MRI technique. The study proposed here was to demonstrate the feasibility of detecting signal intensity changes using the proposed MRI imaging technique. Methods: An optimised neuromelanin-sensitive MRI imaging protocol using high-resolution fast spin-echo T1-weighted sequence was developed in detecting LC signal intensities in AD patients and matched healthy controls. Data was acquired on a Siemens 3T Skyra MRI scanner, using a 20-channel head coil. A novel pre-processing system using ImageJ was developed and applied to the analysis of raw imaging data. This system was created with the goal of increasing intra-rater reliability. The pre-processing included removing of noise, isolating maxima and comparing LC signal intensity to reference region of interest (ROI). A region was set in the dorsal pontine tegmentum (PT). LC contrast ratios were calculated according to the equation (SLC-SPT)/ SPT where SLC is the average signal intensity of the LC and SPT is the signal intensity of the dorsal PT. Results: There were clear visible differences in neuromelanin concentration in the LC region (dorsal PT) compared to the reference region (adjacent mid-portion of PT). There were significant difference between average reference ROI and LC ROI signal intensities (p<0.05, Wilcoxon Signed Rank Test) and the LC region was significantly brighter than the reference region. Conclusion: Findings from this feasibility study indicate that the neuromelanin sensitive MRI imaging protocol we developed provides a direct measure of the LC signal intensity. We are currently using this imaging technique to collect data to compare LC signal intensity difference between AD patients and healthy controls. This will be used to inform a future investigation of the role of the LC in AD, which will advance our understanding of the role of the LC in the pathogenesis of AD which may lead to the development of new treatment targets. Funding: This study was funded by Alzheimer’s Research UK.

H15 THE ROLE OF ANTERIOR CINGULATE CORTEX IN PREDICTING TREATMENT RESPONSE IN DEPRESSION Godlewska BR, Psychiatry, University of Oxford, Warneford Lane Oxford, OX3 7JX beata.godlewska@ psych.ox.ac.uk Browning M(1), Norbury R(3), Igoumenou A(2), Cowen PJ(1), Harmer CJ(1) (1) As presenting author; (2) Barnet Enfield and Haringey Mental Health NHS Trust; (3) Dept of Psychology, University of Roehampton Introduction: Identification of biomarkers of response to antidepressant treatment is one of the key tasks, and the one of great clinical importance. The existence of reliable bimarkers could transform a currently often lengthy process of establishing the correct treatment for a given individual and shorten time needed to achieve remission. One of the best established biomarkers is pre-treatment pregenual anterior cingulate cortex (pgACC) activity. The objective of this study was to assess wehether 1) increased pgACC to masked sad facial expressions at baseline would predict later treatment response; and 2) provide an estimate of the degree to which this effect was able to predict treatment response at the individual level, using a leave- one-out validation approach. Methods: Thirty-two medication-free patients with depression were treated for 6 weeks with a selective serotonin reuptake inhibitor, escitalopram. Patients underwent an fMRI scan before treatment was started, which assessed response to brief (30ms) sad and happy facial expression, masked with a neutral face (70ms), which was shown to interfere with an explicit processing of the emotional face. Results: 20 responders and 12 non-responders were identified after 6 weeks of treatment. Increased pre-treatment pgACC responce to masked sad versus happy facial expressions was shown in responders relative to non-responders (family wise error (FWE)-corrected P<0.05, SVC; 248 voxels, Z-value of the peak voxel 3.48, p=0.005). A leave one out analysis suggested that activity in the ACC was a good predictor of response status at the individual level. Conclusions: The study supports the notion of pgACC as a promising predictor of antidepressant response, at the heneral and individual level. The study was funded by Medical Research Council. A112 ABSTRACTS

H16 SUBGENUAL CINGULATE ACTIVATION AND THE FINGER OF BLAME: INDIVIDUAL DIFFERENCES AND DEPRESSION VULNERABILITY Zahn R, Psychological Medicine, King’s College London, 16 De Crespigny Park London, SE5 8AF roland. [email protected] Lythe K(3), Gethin JE(3), Workman CI(3), LambonRalph MA(3), Deakin JFW(2), Moll J(1) (1) Cognitive and Behavioral Neuroscience Unit, D’Or Institute for Research and Education (IDOR), 22280- 080 - Rio de Janeiro, RJ, Brazil; (2) The University of Manchester & Manchester Academic Health Sciences Centre, Institute of Brain, Behaviour and Mental Health, Neuroscience & Psychiatry Unit, Manchester, M13 9PL, UK; (3) The University of Manchester & Manchester Academic Health Sciences Centre, School of Psychological Sciences, Neuroscience and Aphasia Research Unit, Manchester, M13 9PL, UK Introduction: Subgenual cingulate (SC) activation in response to self-blame-evoking stimuli has been reported in individuals who are prone to blaming themselves, suggesting that SC activation reflects the experience of self-blaming emotions such as guilt. The aim of this study was to resolve the conundrum that SC activation is not observed consistently across individuals and how it relates to vulnerability to major depressive disorder (MDD). Methods: Seventy medication-free patients with remitted MDD and 39 healthy control participants underwent fMRI whilst seeing self- and other-blame evoking sentences. A factorial model in SPM was employed to disentangle the influence of MDD vulnerability (MDD vs. Control) and direction of blame (self- vs. other). We further correlated these effects with validated measures of individual differences on self-blaming tendencies and selected reliable factors from a principle component analysis to correlate with independently extracted SC fMRI effects for self- vs. other-blame. Results: A significant interaction effect between group (MDD vs. Control) and agency (self- vs. other-blaming) was observed in the right SC (BA24, voxel-based familywise error-corrected P<.05 over a priori ROI, Figure 1). This was due to higher SC signal for self-blame in the MDD group compared with the Control group and lower SC signal for other-blame in the MDD group compared with the Control group. There were no main effects of group or condition in the SC ROI. SC activity during self- versus other-blame was further predicted by a linear regression model (F(3,105)=4.78, p=.004) which included measures of self-blaming tendencies: sociotropy/dependency (B=0.27, t=0.42, p=.67) and autonomy/self-criticsim/self-hate (B=1.51, t=2.33, p<.05), as well as adaptive guilt (B=0.32, t=2.73, p<.01). Conclusions: Proneness to adaptive and maladaptive self-blame was positively associated with an individual’s SC activation; confirming earlier studies. Nevertheless, our results necessitate a re-interpretation of earlier findings in that SC activation cannot be related to the experience of self-blame or guilt per se. Instead, our results suggest that SC activation is associated with blame irrespective of direction. We speculate that patients with remitted MDD and those prone to self-blame have a richer representation of blame-related information in the SC in the context of self- vs. other-blame with the opposite pattern occurring in healthy controls at low risk. Funding: This study was funded by an MRC clinician scientist fellowship to RZ.

H17 EFFECTS OF SEROTONIN AND DOPAMINE DEPLETION ON NEURAL CORRELATES OF EMOTIONAL EXPRESSION PREDICTION McCabe C, Psychology Department, University of Reading, Harry Pitt Building, Earley Gate, Reading, RG6 7BE [email protected] Frey AL(1) (1) University of Reading, Psychology Department, Harry Pitt Building, Earley Gate, Reading, RG6 7BE Introduction: Being able to predict other people’s emotional responses is crucial to navigate social situations. We recently found that, compared to controls, individuals with high depression scores are less accurate in predicting the likelihood of observing emotional expressions, and that these inaccuracies correlate with social withdrawal. Given that dopamine (DA) and serotonin (5HT) are implicated in both the pathology of depression and the neural computation of outcome predictions, the current study aimed to elucidate the role of these neurotransmitters in emotion prediction using 5HT (tryptophan) and DA (tyrosine/phenylalanine) depletion. Methods: In a double-blind design, 70 healthy volunteers ABSTRACTS A113 were randomly allocated to the 5HT depletion (N=24), DA depletion (N=24), or placebo (N=22) group. During fMRI scanning, participants were shown name cues followed by faces which probabilistically displayed happy, neutral, or fearful expressions. On each trial, subjects rated the likelihood of seeing an emotional face after the name cue. Using computational modelling, we examined neural correlates of emotion prediction. Results: Behaviourally, the happiness likelihood ratings of the 5HT depletion group were less accurate than those of the placebo group at high (p=0.029) and low (p=0.006) probabilities. On the neural level, whole brain analysis revealed that, compared to placebo, 5HT depletion reduced happiness prediction responses to the name cue in the temporal lobe (p<0.001), insula/ amygdala (p<0.001), and lateral to medial prefrontal cortex (p<0.001). By contrast, compared to placebo, DA depletion only decreased dorsal anterior cingulate/ medial prefrontal cortex happiness prediction responses (p<0.001). Conclusion: Our results indicate that 5HT depletion impairs happiness prediction on both the behavioural and the neural level, possibly partly by increasing attention to and memory of negatively interpreted neutral faces. DA depletion, by contrast, had a less pervasive effect on emotion prediction. Interestingly, the behavioural and neural responses observed after 5HT depletion in the current study closely resemble our previous findings in individuals with high depression scores. It may thus be the case that decreased 5HT levels in depression contribute to deficits in social outcome prediction. This study was funded yb the MRC studentship of Anna-Lena Frey.

H18 FMRI STUDY OF IMPULSE CONTROL IN GO/NO-GO TASK – NEURAL CORRELATES IN DISORDERED GAMBLING Immonen J, Neuropsychopharmacology Unit, Centre for Psychiatry, Division of Brain Sciences, Imperial College London, UK, W12 0HS [email protected] Turton S(3), Paterson LM(3), McGonigle J(3), Mick M(3), Clarke L(1), Limbrick-Oldfield E(1), Nutt DJ(3), Bowden-Jones H(2), Lingford-Hughes AR(3) (1) Centre for Gambling Research at UBC, Department of Psychology, University of British Columbia, Canada; (2) National Problem Gambling Clinic, CNWL NHS Foundation Trust. Department of Medicine, Imperial College London, London, UK; (3) Neuropsychopharmacology Unit, Centre for Psychiatry, Division of Brain Sciences, Imperial College London, UK Introduction. Impulsivity is a core contributing factor to disordered gambling. Disordered gamblers (DG) have been shown to make more commission errors and to exhibit higher BOLD response in dorsolateral prefrontal (dlPFC) and anterior cingulate cortex (ACC) during response inhibition tasks compared with healthy controls (HV)(Van Holst et al 2012,PLoS One). The current study sought to investigate the fMRI BOLD response during a Go/No-go impulse control task and its relationship to subjective severity and impulsivity measures. Based on the Impaired Response Inhibition and Salience Attribution models of addiction, we hypothesized that DG would be more impulsive than HV, and would have higher BOLD response compared with HV in regions associated with impulsive response inhibition. Methods. DG (n=20) and HV (n=28) completed a Go/No-go task during a 3T fMRI scan. The BOLD signal contrast between successful No-go>Go trials was investigated in an a priori region-of-interest (ROI) analysis. ROIs selected were dlPFC, ACC, inferior frontal cortex (IFC), and medial prefrontal cortex (mPFC) due to their role in impulse control. Group differences were determined using permutation testing. Pearson or Spearman’s rank correlations were used to explore associations between Barratt Impulsiveness scale motor impulsivity subscore (BISm), Canadian Problem Gambling Index (CPGI) scores with ROI BOLD response. Bonferroni correction for each set of analyses was applied. Results. DG had significantly higher BISm and CPGI scores than HV (p<0.001). There were no significant group differences in Go/No-go task performance, or in BOLD response in any of the ROIs. However, BOLD response in ACC and mPFC were positively correlated with BISm score across groups (p<0.01), and exploratory analyses revealed that within the mPFC, this effect was primarily driven by a significant correlation within the DG group (p=0.03). CPGI scores did not correlate with ROI BOLD response. Conclusions. The lack of a group difference in BOLD response between HV and DG is inconsistent with earlier findings and further research is needed to improve understanding on this. However, we have shown that higher BISm is associated with higher ACC and mPFC BOLD responses during impulse control, which may represent a greater cognitive work load A114 ABSTRACTS required. In substance dependent individuals using the same Go/No-go task, we found greater activation in IFG compared with HV in the absence of significant correlation with BIS total score (Murphy et al 2017,Neuropsychopharmacology). Neural correlates of impulsivity might thus differ between DG and substance addictions. This study was funded by the MRC (grant code G1002226).

H19 ALTERED CORTICAL CANNABINOID 1 RECEPTORS AND FUNCTIONAL CORRELATES OF MEMORY IN FIRST EPISODE PSYCHOSIS: A MULTI-MODAL PET-FMRI STUDY Borgan F, Psychosis Studies Department, King’s College London, 16 De Crespingy Park Road, SE5 8AF faith. [email protected] O’Daly OD(1), Veronese MV(1), Howes OH(1) (1) Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, England Introduction: Although memory deficits are a core stable feature of schizophrenia, the neurobiology of these deficits remain poorly understood and unaddressed by current treatments. Converging lines of evidence show that the cannabinoid 1 receptor (CB1R) modulates memory formation by altering mitochondrial function as well as synaptic transmission and plasticity. We aimed to investigate the association between cortical CB1R availability and neural correlates of cognition, for the first time as far as we’re aware in vivo. Method: Forty volunteers including 20 male first episode psychosis patients (17 un-medicated, 3 medicated) and 20 male matched healthy volunteers completed 1) a dynamic positron emission tomography scan using a cannabinoid 1 receptor selective radiotracer [11C]MePPEP with arterial blood sampling; and 2) the Sternberg working memory paradigm during a functional magnetic resonance imaging scan. Results: Cannabinoid 1 receptor volume of distribution was significantly lower in the anterior cingulate in patients (M=23.21; SD=9.64) relative to controls (M=30.75; SD=10.71), t(38)=2.341, p=0.025 with a large effect size (Hedge’s g=0.74). Relative to healthy volunteers, patients showed greater functional activation in the anterior cingulate during memory encoding (T=3.91, Z=3.53, pFWE=0.040). Conclusions: We show, for the first time as far as we’re aware, that first episode psychosis patients show altered cortical functional activation during a memory task, in the context of fewer cortical cannabinoid 1 receptors. Future studies should investigate the therapeutic potential of cannabinoid 1 receptor modulators for treating cognitive deficits in schizophrenia. Funding: F.B., H.L., J.H. and O.H. were supported by a EU-FP7 METSY grant. MV was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London.

H20 CANNABINOID 1 RECEPTOR IN FIRST EPISODE PSYCHOSIS: A POSITRON EMISSION TOMOGRAPHY STUDY USING [11C]MEPPEP AND [18F]FMPEP-D2 Borgan F, Psychosis Studies Department, King’s College London, 16 De Crespingy Park Road, SE5 8AF faith. [email protected] Laurikainen HK(4), Veronese MV(1), Marques TM(1), Dahoun TD(2), Rogdaki MR(2), Hietala JH(4), Howes OH(3) (1) Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, England; (2) MRC London Institute of Medical Sciences, Faculty of Medicine, Imperial College London, England; (3) Psychosis Studies Department, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, England; (4) Turku PET Centre, Turku University Hospital, Finland Introduction: Although cognitive impairments predict clinical and functional outcomes in psychosis, the neurobiology of these deficits remain poorly understood and unaddressed yb current treatments. Since converging lines of evidence show that cognition is altered following cannabinoid 1 receptor modulation, we aimed to investigate whether the 1) cannabinoid 1 receptor may be altered in first episode ABSTRACTS A115 psychosis, without the confounds of antipsychotic medication, illicit substance use and illness chronicity; and whether 2) cannabinoid 1 receptor alterations are linked cognitive function in psychosis. Methods: Study 1: Forty volunteers including 20 FEP patients (17 un-medicated, 3 medicated) and 20 controls underwent a dynamic positron emission tomography (PET) scan using a CB1R-selective [11C]MePPEP. Study 2: Eighteen volunteers including 7 FEP patients and 11 controls completed a PET scan using a CB1R- selective [18F]FMPEP-d2. Cognition was measured using the Wechsler Adult Intelligence scale (WAIS). Results: A rmANOVA using a 2 (group: patient vs. control) x 4 (region: anterior cingulate, thalamus, hippocampus and striatum) design was used. For [11C]MePPEP, a main effect was found for group, F(3, 37)=3.526, p=0.024; region, F(2.312, 85.55)=11.163, p<0.001 but the group x region interaction was not significant, F(6.937, 85.551)=0.870, p=0.533. For [18F]FMPEP-d2, a main effect was found for group, F(1, 16)=20.214, p<0.001; region, F(3, 48)=96.744, p<0.001 and the group x region interaction was significant, F(3,48)=4.530, p=0.007. Post-hoc analyses showed that patients relative to controls showed fewer CB1R in the anterior cingulate, thalamus and hippocampus using [11C]MePPEP and [18F]FMPEP-d2. Sensitivity analysis showed that un-medicated, symptomatic patients relative to controls only showed reductions in the anterior cingulate (p=0.038). Although patients and controls were matched on IQ, patients showed a positive association between CB1R volume of distribution in the anterior cingulate and WAIS intelligence quotient estimates (R=0.611, p=0.009). Conclusions: We showed for the first time, as far as we’re aware in first episode psychosis, that the cannabinoid 1 receptor is reduced, where a greater reduction is associated with poorer cognitive function. Our findings identify the cannabinoid 1 receptor as a novel therapeutic target for psychotic disorders, potentially to treat cognitive dysfunction. Funding: F.B., H.L., J.H. and O.H. were supported by a EU-FP7 METSY grant. MV was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London.

H21 ENDOGENOUS OPIOID RELEASE MEASURED IN THE HUMAN BRAIN: A POSITRON EMISSION TOMOGRAPHIC STUDY WITH [11C] CARFENTANIL AND SODIUM ACETATE CHALLENGE Ashok AH, Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neurosciences, 16 De Crespigny Park, London, SE5 8AF [email protected] Myers J(2), Frost G(1), Turton S(1), Gunn R(3), Passchier J(3), Colasanti A(5), Marques TR(4), Nutt DJ(1), Lingford-Hughes A(1), Howes OD(4), Rabiner EA(3) (1) Faculty of Medicine, Department of Medicine, Imperial College London, Hammersmith Campus, London W12 0NN; (2) Faculty of Medicine, Imperial College, E517 Burlington Danes Hammersmith Campus, London W12 0NN; (3) Invicro, Burlington Danes Building, Imperial College London, Du Cane Rd, White City, London W12 0NN; (4) MRC London Institute of Medical Sciences, Robert Steiner MR Unit Imperial College- Hammersmith Campus Hammersmith Hospital, Du Cane Road London, W12 0NN; (5) Trafford Centre for Medical Research, BSMS, University of Sussex, BN1 9RY Introduction: A recent pre-clinical study in the mouse brain has shown that acetate administration increases the transcription of proopiomelanocortin (POMC) mRNA by four-fold (Frost et al, 2014, Nature Communications, 29;5:3611). POMC is cleaved to peptides including β-endorphin, an endogenous opioid agonist that binds preferentially to the µ-opioid receptor. We hypothesised that an acetate challenge will increase the levels of endogenous opioids (EO). Alterations in endogenous opioid release have been evaluated in the human brain using positron emission tomography (PET) and the selective u-opioid receptor radioligand [11C]carfentanil. We used this approach to study the effects of an acute acetate challenge on EO levels in the brain of healthy human volunteers. Materials & Methods: Seven healthy male volunteers were recruited. Six subjects completed [11C]carfentanil PET scans followed by an infusion of 150 mmol of sodium acetate in 1 L normal saline over 60 min, completed 30-60 min before a second [11C]carfentanil PET scan. In one participant the baseline PET scan failed due to technical reasons, and was repeated several weeks after his post-acetate scan. He was excluded from further analysis due to low injected activity and low BPND in baseline PET scan (on average 15% lower than the average of the remaining participants). Dynamic PET data were acquired over 90 minutes, corrected for attenuation, scatter and subject motion, and regional [11C]carfentanil BPND values were estimated using the simplified A116 ABSTRACTS reference tissue model (occipital grey as the reference). A previously reported cohort of six healthy subjects who received [11C]carfentanil PET before and after a sub-pharmacological “ultra-low” dose of amphetamine (1.25 mg total), was used as a placebo group (Colasanti et al, Biol Psychiatry. 2012;72:371- 7). The cerebellum, insular cortex, temporal lobe, cingulate cortex, parietal lobe, amygdala, orbitofrontal cortex, striatum, thalamus and hypothalamus BPND percentage change was calculated and differences were tested statistically by means of paired students t-tests, a two-way repeated measures ANOVA and independent sample t-test. Results: Following sodium acetate administration, [11C]carfentanil BPND was reduced in all regions and was statistically significant in cerebellum, temporal lobe, orbitofrontal cortex, striatum, thalamus. Repeated measure ANOVA showed significant effect of acetate administration on [11C] carfentanil BPND measures (p=0.037). The magnitude of change in [11C]carfentanil BPND in acetate group was greater than ultra-low dose amphetamine group and independent sample t-test showed significant difference in change in [11C]carfentanil BPND in thalamus and striatum (p= 0.025 and 0.045 respectively). Repeated measure ANOVA did not show between group (acetate and low-dose amphetamine cohort) effect on change in BPND (p=0.92). Conclusions: We have showed an apparent increase in EO release following acetate administration in the human brain. The magnitude of the [11C]carfentanil BPND PET signal is modest and need to be replicated in larger sample studies. This study provides a potential mechanistic link between plasma acetate fluctuations and their effect on human appetite and mood. Funding: This study was partly funded by MRC grant (MC-656-5QD30) to Prof Howes.

H22 COMPARING SPRAY VS NEBULIZED OXYTOCIN MODULATION OF BRAINWIDE RESTING-STATE FUNCTIONAL CONNECTIVITY: A PERIPHERALLY CONTROLLED PHARMACO-MRI STUDY Martins D, Neuroimaging, King’s College London, Department Of Neuroimaging (P089), King’s College London, De Crespigny Park Road, Denmark Hill, SE5 8AF [email protected] Dipasquale O(1), Zelaya F(1), Mazibuko N(1), O’Daly O(1), O’Muircheartaigh J(1), Maltezos S(2), Schuschnig U(3), Williams S(1), Paloyelis Y(1) (1) As presenting author; (2) King’s College London, Department of Forensic and Neurodevelopmental Science (SM), Institute of Psychiatry, Psychology and Neuroscience, London, UK; (3) PARI GmbH, Gräfelfing, Germany Introduction: We investigated changes in whole-brain resting-state functional connectivity comparing two methods of intranasal oxytocin administration (standard spray vs PARI SINUS nebulizer, expected to maximize oxytocin deposition in the olfactory region - putatively involved in direct nose-to-brain transportation) to intravenous administration. We aimed to understand the extent to which intranasal effects are explained by peripheral signalling or result from a privileged route of transport to the brain. Methods: We recruited 17 healthy males who received 40 IU of oxytocin intranasally (through a spray or a nebulizer), 10 IU of oxytocin intravenously, or placebo, in 4 visits. Resting-state fMRI was acquired 60 min after last drug administration using a multi-echo EPI sequence in a 3T scanner. Blood samples for plasma oxytocin quantification were collected before and at several time-points after drug administration. After denoising our data using the ME-ICA approach and regressing out white-matter and CSF signals, we explored ROI-ROI functional connectivity across 132 anatomical regions using the CONN toolbox. Connectivity matrices were compared between sessions using T-contrasts (p<0.05, FDR-corrected). Results: Oxytocin spray resulted in widespread changes across the connectome, involving mostly decreases in the connectivity of the medial temporal gyrus, the lingual gyrus and the temporal and frontal poles. Increased connectivity could be observed between the supramarginal gyrus and the superior frontal gyrus (T(15) = 4.45, p-FDR= 0.034). Despite identical pharmacokinetic profiles, nebulized oxytocin only produced increases in connectivity, involving mostly the functional connectivity between the precuneus and the paracingulate cortex (T(15) = 4.48, p-FDR = 0.0289) and between the subcallosal cortex and postcentral gyrus (T(15)=4.29, p-FDR=0.0424). Importantly, intravenous oxytocin did not fully explain the pattern of changes in connectivity observed for the spray or the nebulizer. Conclusion: We showed that two different methods of intranasal administration result in distinct changes in connectivity despite producing similar changes in plasmatic oxytocin. This observation raises the hypothesis these two intranasal methods may differ in the achieved bioavailability of oxytocin in the brain. Disclosure: This study represents ABSTRACTS A117 independent research funded by: (1) an Economic and Social Research Council fellowship to YP (grant number ES/K009400/1); (2) part funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London; (3) part funded by an unrestricted research grant by PARI GmbH to YP. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.

H23 OXYTOCIN MODULATION OF RESTING STATE REGIONAL CEREBRAL BLOOD FLOW (RCBF): COMPARING THE EFFECTS OF INTRANASAL AND INTRAVENOUS METHODS OF ADMINISTRATION Paloyelis Y, Neuroimaging, King’s College London, Department Of Neuroimaging (P089), King’s College London, De Crespigny Park Road, Denmark Hill, SE5 8AF [email protected] Zelaya F(1), Mazibuko N(1), Maltezos S(2), Schuschnig U(3), Williams S(1) (1) As presenting author; (2) King’s College London, Department of Forensic and Neurodevelopmental Science, Institute of Psychiatry, Psychology and Neuroscience, De Crespigny Park, London, SE5 8AF, United Kingdom.; (3) PARI GmbH, Gräfelfing, Germany Introduction: To illuminate the pathways though which synthetic oxytocin exerts its effects in the living human brain, we compared two methods of intranasal administration (standard spray vs PARI SINUS nebulizer, expected to maximize oxytocin deposition in the olfactory region - putatively involved in direct nose-to-brain transportation) to intravenous administration. Methods: 16 healthy males received 40IU of oxytocin intranasally (through a spray or a nebulizer), 10IU intravenously, or placebo, in 4 visits, in a triple-dummy, double-blind, placebo-controlled, crossover design. We visualized and quantified (mL blood/100 g tissue/min) oxytocin-induced changes in rCBF, and hence neuronal activation, using arterial spin labelling in a 3T scanner, in eight 8-min CBF maps. Blood samples for plasma oxytocin quantification were collected at baseline and throughout the observation period. We used mass univariate analysis and conducted cluster level inference (PFWE<.05). Results: The intranasal administration methods did not differ in their pharmacokinetic profiles. As expected, when administered intravenously, plasma oxytocin was significantly elevated throughout the observation period, compared to intranasal administration. Preliminary analyses demonstrated that the two intranasal methods resulted in markedly different patterns of increases in rCBF (intranasal spray: anterior insula, superior frontal gyrus, superior temporal gyrus; nebuliser: robust increases in rCBF at the precuneus at multiple time points; all clusters significant at PFWE<.05). These increases in rCBF could not be accounted by plasma levels of synthetic oxytocin. However, significant decreases in rCBF over the amygdala and dorsal CCA using intranasal spray could be explained by increases in plasma oxytocin. Conclusions: The two different methods of intranasal administration resulted in distinct changes in rCBF despite achieving similar changes in plasmatic oxytocin, suggesting that they may differ in the achieved bioavailability of oxytocin in the brain. Our evidence is partially consistent with the notion of a direct nose-to-brain pathway, but also suggests that some of the effects of intranasal oxytocin may be due to peripheral signalling. Disclosure: This study represents independent research funded by: (1) an Economic and Social Research Council fellowship to YP (grant number ES/K009400/1); (2) part funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London; (3) part funded by an unrestricted research grant by PARI GmbH to YP. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. A118 ABSTRACTS

I01 RESCUE OF CYTOKINES INDUCED REDUCTION OF HUMAN NEUROGENESIS AND INCREASE IN APOPTOSIS BY OMEGA-3 FATTY ACIDS Borsini A, Psychological Medicine, King’s College London, The Maurice Wohl Clinical Neuroscience Institute, Cutcombe Road, London, SE5 9RT [email protected] Pariante CM(2), Su K(1), Zunszain P(2) (1) Department of Psychiatry & Mind-Body Interface Laboratory (MBI-Lab), China Medical University Hospital; College of Medicine, China Medical University, Taichung, Taiwan; (2) Section of Stress, Psychiatry and Immunology Laboratory, Institute of Psychiatry, Psychology and Neuroscience, Department of Psychological Medicine, King’s College London, UK Introduction: Both increased inflammation and reduced neurogenesis have been associated with the pathophysiology of major depression (Kohman et al., 2009, Brain Behav Immun., 22–32). We have previously described how distinct inflammatory cytokines, including interleukin (IL)-1beta, IL-6 and interferon (IFN)- alpha, involved in the development of depression, decrease neurogenesis and increase apoptosis in human hippocampal progenitor cells (Borsini et al., 2017, Int J Neuropsychopharmacol., 187-200), and how two principal omega-3 fatty acids, eicosapentanoic acid (EPA) and docosahexanoic acid (DHA), prevent the detrimental changes provoked by IL-1beta (Borsini et al., 2017, Brain Behav Immun., 230-238). Here, using the same human in vitro model, we extend our investigation to IL-6 and IFN-alpha, providing further understanding for nutritional interventions for patients with neuroinflammatory conditions, such as depression. Methods: We allowed neural cells to proliferate for 3 days and further differentiate for 7 days in the presence of IL-1beta (10ng/ml), IL-6 (5pg/ml) and IFN-alpha (5000pg/ml) alone or in combination with EPA (10 µM) or DHA (10 µM). Immunocytochemistry was performed to identify neuronal differentiation (doublecortin (DCX)+ immature neurons and microtubule associated protein-2(MAP2)+ mature neurons) as well as cell death (caspase 3 (CC3)+ apoptotic cells). Results: Confirming our previous data, co-incubation with EPA and DHA prevented the decrease in DCX+ cells induced by IL-1beta (from -30% to +16%, p<0.05, with EPA and to +10%, p<0.01, with DHA) and MAP2+cells (from -37% to +5%, p<0.05, with EPA and to +2%, p<0.001, with DHA). However, as shown for the first time, only DHA was able to prevent IL-1beta-induced increase in CC3+cells (from +50% to -5%, p<0.05). IL-6 did not affect the number of DCX+ and MAP2+ cells, but its detrimental effect on CC3+ cells was fully prevented only by EPA (from +50% to -5%, p<0.05). Finally, co-incubation with EPA and DHA prevented IFN-alpha-induced decrease in DCX+ cells (from -28% to +12%, p<0.05, with EPA and to +14%, p<0.001, with DHA) and MAP2+cells (from -36% to +12%, p<0.05, with EPA and to +6%, p<0.05, with DHA). Interestingly, only DHA was able to prevent IFN-alpha-induced increase in CC3+cells (from +5% to -2%, p<0.05). Conclusions: Our results demonstrate differential effects of omega-3 fatty acids to regulate neurogenesis: DHA was able to prevent the reduction in neurogenesis and increase in apoptosis caused by IL-1beta and IFN-alpha, whereas EPA was able to prevent the increase in apoptosis caused by IL-6, but not by IL-1beta and IFN-alpha. Further characterization of the underlying mechanisms of EPA and DHA action will be of benefit towards future personalized medicine approach for patients with neuroinflammatory conditions. This work was supported by the Medical Research Council (UK) grant ‘AMBROSIAC - A Menu for Brain Responses Opposing Stress-Induced Alterations in Cognition’ (MR/ N029488/1), and by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London.

I02 ACUTE KETAMINE TREATMENT REVERSES STRESS-INDUCED SOCIAL AVOIDANCE AND MODULATES INFLAMMATORY SIGNALLING Sokolowska E, Transpharmation Ireland Ltd, Room 3.47, Institute of Neuroscience (TCIN) Lloyd Institute, Trinity College Dublin, Dublin 2 Ireland [email protected] Burke T(1), Dunphy-Doherty F(1), McDonnell CW(1), Prenderville JA(1), Bianchi M(1) (1) As presenting author Chronic social defeat (CSD) is a stress model involving daily physical interaction and 24h sensory contact with an unfamiliar aggressive male. After CSD mice can be classified as resilient or susceptible to stress ABSTRACTS A119 based on the social avoidance test. This paradigm results in comorbid depression- and anxiety-like phenotype. Additionally, growing evidence suggest that repeated stress promotes inflammation and immune dysfunction which are implicated in development of mood disorders. Here, we investigate social avoidance behaviour and cytokines levels in mice subjected to CSD and single ketamine (10 mg/ kg, s.c.) injection which exerts rapid antidepressant efficacy in depressed patients We subjected C57BL/6J mice to 10 days of CSD paradigm followed by a social preference test (SP) to assess CSD effect on social avoidance. SP consists of two 150 sec trials with no target (empty cylinder) and target (unfamiliar CD1 in the cylinder). Following baseline SP recordings mice received either acute vehicle (0.9% NaCl, s.c.) or ketamine (10 mg/kg, s.c.). Twenty-four hours later mice were once again submitted to SP. Proinflammatory Panel 1 Kit (Meso Scale Diagnostics, USA) was used to measure plasma levels of cytokines/chemokines. Behavioural data were analysed using a two-way repeated measurement ANOVA, whereas cytokines data were analysed using a one-way ANOVA, both analysis were followed by Fisher’s LSD test. A 46.4% of mice that experienced repeated defeat presented stress susceptible (SUS) phenotype and significant social avoidance (no target: 35.45±4.12 vs. target: 23.63±2.95, p<0.0001) during baseline SP. In contrast, control (CTRL) (no target: 15.38±2.94 vs. target: 34.4±5.27, p<0.0001) and stress resilient (RES) animals (no target: 20.13±2.35 vs. target: 43.52±3.8, p<0.0001) presented significant social preference. cuteA ketamine reversed avoidance phenotype in SUS mice at 24h post-administration (no target: 11.9±4.5 vs. target: 29.5±6.37, p<0.05). Cytokines analysis revealed significantly decreased level of interleukin 2 in both RES and SUS CSD mice injected with vehicle (RES+VEH: 0.78±0.1 vs. CTRL: 1.06±0.07, p<0.05, SUS+VEH: 0.81±0.08 vs. CTRL, p<0.05). Increased interleukin 17p20 was observed in both RES and SUS CSD mice injected with ketamine (RES+KET: 153.8±10.77 vs. CTRL: 82.5±5.43, p<0.0001, SUS+KET: 134.9±21.27 vs. CTRL, p<0.005). KC-GRO showed a tendency towards increased levels in both SUS and RES CSD mice. Repeated social defeat resulted in highly significant social avoidance phenotype in SUS mice which is here shown for the first time to be reversed by acute ketamine at the dose of 10 mg/kg (s.c.). Changes in plasma cytokine following CSD and ketamine administration were evident, but similarly affecting both SUS and RES mice. Thus, inflammatory response following CSD appears not to be linked to either stress behavioural response or antidepressant treatment. Supported by Transpharmation Ireland Ltd.

I03 EFFECTS OF ANTIDEPRESSANT DRUGS ON PLASMA MICROTUBULAR PROTEINS IN “HEALTHY” SPRAGUE DAWLEY AND “DEPRESSED” WISTAR KYOTO RATS McDonnell CW, Psychiatry, 3.05 Lloyd Building Trinity College Dublin Dublin 2, Ireland conor.mcdonnell@ transpharmation.co.uk Prenderville JA(1), Rouine J(1), Burke T(1), Dunphy-Doherty F(1), Lobato JP(1), Gill M(1), Bianchi M(1) (1) As presenting author One third of major depressive disorder patients (MDD) are unresponsive to antidepressant drugs, a recognised subtype of MDD known as treatment resistant depression (TRD). Biomarkers of pharmacological efficacy and disease severity are required for patient stratification and personalised medicine. Here, plasma microtubular proteins, alpha-tubulin post translational modifications (PTMs), are investigated as potential biomarkers in “healthy” Sprague Dawley (SD) and “depressed” Wistar Kyoto (WKY) rats treated with: first- line blockbuster selective serotonin reuptake inhibitor (SSRI) Escitalopram (ESC), tricyclic antidepressant Desipramine (DMI), and Ketamine (KET) as the only efficacious drug for TRD when given at a sub-anaesthetic dose. WKY rats are an endogenous model of MDD and have been shown to be resistant to SSRI treatment. Male SD and WKY rats (3-4 months old, 350-400g, housed 2-3/cage, 12-hour day/night cycle) were randomly assigned to treatment groups (n=10-11/group): vehicle (Veh), chronic ESC, chronic DMI, and acute KET. Rats were administered chronically (daily for 21 days) with either ESC (10mg/kg,s.c.), DMI (10mg/kg,s.c.), or corresponding vehicle solution (Injectable water,s.c.). KET (5mg/kg,s.c.) was administered acutely on day 21 to rats receiving daily injection of vehicles for 20 days. On day 21, animals were sacrificed 2h post treatment and plasma was obtained from trunk blood. Infrared-Western Blotting was used to measure plasma expression (optical density) of alpha-tubulin PTMs: Acetylated-alpha-tubulin (Acet-Tub), Tyrosinated- alpha-tubulin (Tyr-Tub), and Detyrosinated-alpha-tubulin (Glu-Tub). Total-alpha-Tubulin (Tot-Tub) was also analysed and Transferrin (Trf) was used as a housekeeper. Data were Log10 transformed and analysed A120 ABSTRACTS in InVivoStat by 2-way ANOVA where strain and treatment effects were investigated followed by Fisher’s LSD post hoc test. Data is represented as mean±SEM. WKY rats significantly overexpress Tot-Tub in plasma compared to SD (SD Veh=0.2717±0.0416 vs WKY Veh= 0.8000±0.06989, p<0.001; Strain F(1,128)=623.25, p<0.0001; Treatment F(6,128)=0.59, p=0.7399). Tyr/Glu-Tub (SD Veh=0.1505±0.0319, WKY Veh=0.2931±0.0363, p<0.001; Strain F(1,128)=109.62, p<0.0001; Treatment F(6,128)=0.66, p=0.6795) and Acet/Trf (SD Veh=- 0.6994±0.0428, WKY Veh=-0.0625±0.0645, p<0.001; Strain F(1,128)=811.52, p<0.0001; Treatment F(6,128)=0.33, p=0.9216) were significantly overexpressed in WKY rats compared to SD. No effect of treatment was found. The results show that plasma alpha-tubulin PTM expression is significantly overexpressed in WKYs than SDs, suggesting their potential as peripheral preclinical markers of depression in addition to central markers (Bianchi et al. 2005). The over-expression of the Tyr/Glu-Tub and Acet/Trf ratios, demonstrates a disruption of microtubule metabolism and dynamics compared to healthy SDs. Interestingly, WKYs have greater variability in the expression of these markers than SDs, which may indicate an altered stress response induced by chronic injections. Supported by the Irish Research Council and Transpharmation Ireland Ltd.

I04 INCREASED MYELINATION AND SYNAPTIC PROTEINS IN MICE EXPOSED TO INTERMITTENT (R,S)- KETAMINE: LINKING MAGNETIC RESONANCE IMAGING FINDINGS TO CELLULAR PATHOLOGY Vernon AC, Basic and Clincial Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, Maurice Wohl Clinical Neuroscience Institute, 5 Cutcombe Road, London, United Kingdom, SE5 9RT [email protected] Chesters RA(1), Cooper JD(1), Stone JM(2) (1) As presenting author; (2) Centre for Neuroimaging Sciences, Department of Neuroimaging, IOPPN, De Crespigny Park, London SE5 8AF Background: Major knowledge gaps remain regarding the long-term brain effects of repeated ketamine infusions as a therapy for patients with treatment-resistant major depressive disorder (MDD). Magnetic resonance imaging (MRI), including diffusion tensor imaging (DTI), studies in chronic ketamine users suggest decreased frontal lobe grey matter volume (Liao et al., Biological Psychiatry. 2011; 69(1): 42-8; 2) and a loss of white matter integrity (Edward-Roberts et al., Neuropsychopharmacology.2014; 39(2): 329- 38). We therefore investigated the impact of intermittent ketamine exposure in mice using MRI, followed by post-mortem histology to link MRI findings to their cellular correlates, something impossible in human studies. Methods: Adult male C57/Bl6/J mice were intermittently exposed to either (R,S)-ketamine (20 mg/ kg/d i.p.) or 0.9% saline (both n=15) with 1 injection/day, repeated every 3rd day for a period of 30 days (10 injections of either saline or ketamine in total). Dosing was based on literature searches for behaviorally effective ketamine doses in mice. Twenty-four hours after the final injection, mice were culled and transcardially perfused (0.9% saline then 4% PFA). Post-perfusion, high field (7T) 3D T2- weighted ex vivo anatomical MR and DTI images were acquired as described elsewhere (Richetto et al., Cerebral Cortex. 2017; 2017; 27(6):3397-3413). Group-level voxel-wise differences in apparent volume change (ΔV) and fractional anisotropy (FA) were analyzed voxel-wise and corrected for multiple comparisons (FDR, q<0.05). Brain tissues were then processed for histology to assess myelin, neurofilment (axons), microglia, astrocytes and the synaptic protein synaptophsyin in the pre-frontal cortex and corpus callosum, as two regions with opposite changes in MRI measures Results: Voxel-wise analysis revealed that intermittent ketamine exposure resulted in apparent increases in cortical volume and decreases in sub-cortical and cerebellum volume (p<0.001; q<0.05). Diffusion tensor imaging (DTI) revealed that fractional anisotropy (FA) increased in the corpus callosum (p<0.001; q<0.05). Post-mortem analysis confirmed increases in synaptophysin protein (p<0.05; 2-tailed t-test) in the prefrontal cortex and in the corpus callosum both myelin basic protein and neurofilament (both p<0.01; 2-tailed t-test) following etaminek exposure. No changes were found in astrocyte or microglia markers. Conclusion: These data suggest that the mouse brain undergoes significant anatomical and microstructural neuroadaptations to chronic, intermittent ketamine exposure, as revealed by MRI, which is distinct from patterns seen in ketamine abuse. At the cellular level, these changes map onto increases in synaptophysin, myelin and neurofilament. Further studies are now required to link these of behavioural measures and test contextual effect of stress exposure. This study was funded by a grant from the Guys and St. Thomas’ Charitable trust to ACV. ABSTRACTS A121

I05 FLUOXETINE PRE-EXPOSURE DECREASES COCAINE AND SUCROSE PREFERENCE IN FEMALE MICE Iniguez SD, Psychology, University of Texas at El Paso, 500 West University Avenue, El Paso, TX, USA, 79968 [email protected] Flores-Ramirez FJ(1) (1) Department of Psychology, 500 West University Ave, El Paso, TX, USA, 79968 Introduction. Preclinical literature indicates that exposure to antidepressant medications, during early stages of development, results in long-term altered behavioral responses to drugs of abuse (Iñiguez et al., 2015, Sci Rep, 5:15009). However, to date, these studies have been conducted in male subjects primarily. This is surprising, given that females, when compared to males, are more likely to be diagnosed with mood-related disorders, and thus, be prescribed with antidepressants. Therefore, the objective of this study is to assess whether exposure to the selective serotonin reuptake inhibitor fluoxetine (FLX) results in long-lasting alterations in sensitivity to the rewarding properties of cocaine and sucrose, using female mice as a model system. Methods. Adolescent (postnatal day [PD]-35) and adult (PD70) female C57BL/6 mice were exposed to FLX (in their drinking water, 250 mg/l) for 15 consecutive days. Twenty-one days later (PD70+ and PD105+, respectively), mice were assessed on behavioral responsivity to cocaine (0, 2.5, 5, 7.5 mg/kg) using the conditioned place preference paradigm, or their sensitivity to a 1% sucrose solution using the 2-bottle choice test. Results. Data was analyzed with ANOVA techniques, with antidepressant pre-exposure and cocaine post-exposure as sources of variance, followed with Tukey post hoc tests. Our results indicate that female mice pre-exposed to FLX during adolescence or adulthood displayed reliable conditioning to the cocaine-paired compartment, in a dose-dependent manner. However, when compared to respective age-matched controls, antidepressant pre-exposure decreased the magnitude of conditioning at the 5 (p<0.05, R2= 0.21) and 7.5 mg/kg (p<0.05, R2= 0.51) cocaine doses. Similarly, independent of age of antidepressant pretreatment, FLX-pretreated mice also displayed a decrease in sucrose preference (p<0.05, R2= 0.62), without altering total liquid intake (p>0.05). Conclusions. Collectively, our results suggest that exposure to FLX, in adolescent and adult female C57BL/6 mice, leads to prolonged decreases in sensitivity to the rewarding properties of both drug- and natural-rewards. This data further highlight the need for investigations assessing the potential enduring neurobiological side effects that may arise later in life, as a result of antidepressant exposure, in a sex dependent manner. Funding: NIH-NIGMS SC2GM109811

I06 PSYCHOPHARMACOLOGICAL EVALUATION OF A RODENT PROBABILISTIC REVERSAL LEARNING TASK Wilkinson MP, School of Physiology, Pharmacology and Neuroscience, University of Bristol, Biomedical Sciences Building, University Walk, Bristol, BS8 1TD [email protected] Mellor JR(1), Robinson ESJ(1) (1) As presenting author Introduction: Deficits in reward processing are a key feature of psychiatric and neurodegenerative disorders. MDD patients show characteristic alterations in sensitivity to positive and negative feedback in probabilistic learning tasks (Pizzagalli et al, 2008. Psychiatr Res;43:76-87) alongside Parkinson’s patients showing dopamine dependent impairments in probabilistic learning (Frank et al, 2004. Science;3606(5703):1940-1943). A rodent translational probabilistic reversal learning task (PRLT) has been developed in rats, allowing greater cross-species validity (Bari et al, 2010. Neuropsychopharmacology;35(6):1290-1301). This study aimed to investigate the PRLT using acute antidepressant and dopamine antagonist drug treatment and further understand the link between probabilistic learning and psychiatric disease. Methods: Adapting the paradigm developed by Bari et al we trained a cohort of 12 male LH rats in the PRLT. In this task, rats were required to learn to spatially bias responses, touching either a left or right window on a touchscreen to receive food reward. Stimuli were probabilistically rewarded so that the “rich” stimulus was rewarded 80% of the time and the “lean” stimulus was rewarded only 20% of the time. After 8 consecutive choices for the rich stimulus, the reward contingencies switch. Once baseline stability was established, rats were treated with either the SSRI A122 ABSTRACTS citalopram, the SNRI venlafaxine (both 0, 1, 3, 10 mg/kg i.p 30m pre-treatment) or the D1/D2/D3 antagonist flupentixol (0, 0.03, 0.1, 0.3 mg/kg i.p 60m pre-treatment) before the start of testing in the PRLT. Results: Citalopram significantly increased overall win-stay behaviour, a proxy for positive feedback sensitivity (PFS) (RM 1-way Anova, p=0.031) while also decreasing negative feedback sensitivity (NFS) (lose-shift behaviour) during acquisition of the first rule (RM 2-way Anova, significant interaction of treatment and behaviour, p=0.025). Overall performance in learning the first rule was also increased (Rm 1-way Anova, p=0.0239). Venlafaxine had no effect on feedback sensitivity, probabilistic learning or any other variable measured. Flupentixol reduced overall probabilistic learning as measured by number of reversals (mixed model, p<0.0001) while decreasing overall PFS (mixed model, p<0.0001) but had no effect on NFS. Conclusions: These findings suggest that the PRLT can detect alterations in reward learning and feedback sensitivity caused by acute pharmacological treatment. They also indicate that while elevating 5-HT alone with citalopram causes changes in PFS and NFS this effect is not observed when using the mixed SNRI venlafaxine, possibly due to its noradrenergic effects. Dopamine antagonism had a specific effect on PFS consistent with the role of dopamine in reinforcement learning. MPW is funded by the BBRSC SWBio DTP

I07 FURTHER VALIDATION OF THE REWARD-BASED JUDGEMENT BIAS TASK: IMMEDIATE POSITIVE BIASES ARE INDUCED BY DRUGS WITH KNOWN CLINICAL RAPID ONSET ANTIDEPRESSANT ACTION Hales CA, Physiology, Pharmacology & Neuroscience, University of Bristol, Biomedical Sciences Building, University Walk, Bristol, BS8 1TD [email protected] Bartlett J(1), Hengerer B(2), Robinson ESJ(1) (1) As presenting author; (2) CNS Research, Boehringer Ingelheim Pharma GmbH & Co- KG, Biberach, Germany Introduction: Affective biases are thought to be an important factor in the development, maintenance and treatment of depression. Affective biases can also be measured in animals, for example in ambiguous cue interpretation (also known as judgement bias) tasks. Previous work has shown that acute treatment with the rapid onset antidepressant ketamine, but not conventional antidepressants, induces a positive bias in a reward-based operant version of the judgement bias task (Hales et al., 2017, Eur Neuropsychopharmacol, 27:1268-1280). This study set out to provide further validation of this task by testing how other drugs with clinical rapid onset antidepressant action alter decision making biases, as well as other NMDA receptor antagonists that have not shown clinical efficacy for major depressive disorder. Methods: Male lister- hooded rats were trained to discriminate between two distinct reference tones and make a response on the appropriate lever to obtain high value (four pellets) or low value (one pellet) reward. In separate dose response studies rats (n=15-16; ~400-500g) were treated acutely with CP-101,606 (0.0/0.3/1.0/3.0mg/ kg, i.p., t=-60min), scopolamine (0.0/0.03/0.1/0.3mg/kg, i.p. t=-30min), lanicemine (0.0/0.3/1.0/3.0mg/kg, i.p., t=-60min), memantine (0.0/0.1/0.3/1.0mg/kg, i.p. t=-60min) and MK-801 (0.0/0.01/0.03mg/kg, i.p. t=-30min). Experiments followed within-subject study designs with fully counterbalanced drug treatments and were separated by at least one week of baseline sessions. Judgement bias was measured on twice-weekly test sessions (Tue/Fri) by presenting a midpoint ambiguous tone as well as reference tones. Results: CP-101,606 (3.0mg/kg) and scopolamine (0.1mg/kg) caused a positive change in responding to the ambiguous midpoint tone (mean±SEM=7.27±3.18% and 11.37±4.89%; one sample t-tests: p=0.038 and p=0.035 respectively). No other drugs tested had any effect on judgement bias. CP-101,606 (3.0mg/kg) also caused response latencies to decrease for the midpoint tone (rmANOVA F3,42=4.858, p=0.005; post-hoc: ps≤0.015) whilst scopolamine (0.03, 0.1mg/kg) increased response latencies and omissions across all three tones (Fs≥17.263, ps<0.001) and also increased premature responding (F1.554,23.305=4.597, p=0.028; post-hoc 0.1 mg/kg: p=0.041). Conclusions: This study provides further pharmacological validation for the reward-based judgement bias task, showing that drugs with known rapid antidepressant action positively bias decision making, whilst NMDA receptor antagonists that do not show antidepressant action have no effect on judgement bias. This supports previous data suggesting this form of rodent judgement bias task is sensitive to drugs with rapid-onset antidepressant efficacy. This study was funded by a BBSRC Industrial Partnership Award in collaboration with Boehringer Ingelheim. ABSTRACTS A123

I08 CAN THE ‘BURROWING’ TEST PROVIDE MORE INSIGHT INTO PATHOPHYSIOLOGY OF DEPRESSION COMPARED TO TRADITIONAL TESTS? Nabi L, Department of Pharmacology and Therapeutics, Institute of Pharmaceutical Sciences, King’s College London Franklin-Wilkins Building, 150 Stamford Street, London, SE1 9NH [email protected] Borbely E(2), Hajna Z(2), Tekus V(2), Fernandes M(1), Pinter E(2), Helyes Z(2), Keeble J(1) (1) As presenting author; (2) Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Hungary Introduction: Depression is the leading cause of disease and disability; with a significant contribution to global burden of disease according to World Health Organisation. The lack of response to conventional antidepressant treatment in one third of the patients (Socala and Wlaz., 2016, Behavioral Brain Research,303: 19-25) and the unknown pathophysiology of the disorder demonstrates the need for new animal models to find new and more effective treatment approaches. Transient receptor vanilloid type 1 (TRPV1) contributes to depressive behaviour and knocking out the receptor produces antidepressant- like effect in rodents (Abdelhamid et al., 2014, Pharmacological Research,79: 21– 27) with unknown mechanism of action. The aim of the study was to investigate the role of TRPV-1 in pathophysiology of depression and to evaluate the potential of burrowing, a novel test that measures functionality which is impaired in depression, as a new depression model by comparing it with traditional depression tests such as tail suspension test (TST) and sucrose preference test (SPT). Methods: N= 4-7 adult male mice were used in this study where animals were housed in temperature- (22 ± 2°C) and humidity-controlled (50 ± 10%) colony rooms maintained under filtered positive pressure ventilation on a 12-h light-dark cycle beginning at 7:00 AM with free access to water and food. The protocol is based on Deacon (2006., Nature Protocol, 1: 118–121.) where burrowing activity of adult male C57BL/6 (wildtype (WT)) and TRPV1 knockout mice was measured after overnight and three 2-hour tests over three consecutive days. Burrowing was measured as the weight of gravel removed from a plastic tube. TST and SPT were carried as elsewhere (Nielsen et al., 2004, European Journal of Pharmacology,499: 135-146 and Jurgenson et al., 2012, Brain Research,1447,106-118). Data was analysed using independent t-tests and two-way ANOVA, followed by post-hoc tests. Results: We found no significant differences between TRPV-1 KO and WT mice using the traditional tests (TST and SPT). However, TRPV1 KO mice burrowed (i.e. the quantity of gravel removed from the tunnels) significantly more than WT mice in overnight test (p ≤ 0.01) and days 1 and 2 resulting in non-significant interaction ((F(2,16)=1.7), p = 0.2) and significant time (F(2,16)=5.1), p= 0.01) and genotype( F(1,8) = 8.5), p= 0.01) however, there was no significant difference in burrowing between the two groups on day 3. Conclusion: To our knowledge, this is the first study investigating burrowing as a test for depression and comparing it with traditional depression tests. The burrowing results indicate that TRPV-1 KO mice show ‘enhanced functionality’ compared to WT mice which may be valuable for antidepressant pharmacotherapy. Alternatively, it may suggest that TRPV-1 KO mice have a hyperactive phenotype (Wanner et al., 2011, Aging, 3 (4): 450-454). However, the traditional tests did not show any difference between TRPV-1 KO and WT mice in hedonic and despair behaviours. More research is needed to confirm burrowing as a test for depression. Acknowledgment: Study supported by “Biotechnology and Biological Sciences Research Council Capacity Building Award in Integrative Mammalian Biology.

I09 INVESTIGATING THE EFFECTS OF SEX ON DEPRESSION-RELATED BEHAVIOUR EVOKED BY KAPPA OPIOID RECEPTOR ACTIVATION IN THE FORCED SWIM TEST Lalji HM, University of Bath, Department of Pharmacy and Pharmacology, Bath BA2 7AY hml50@bath. ac.uk Sadler AM(1), Bailey CP(1), Bailey SJ(1) (1) Pharmacy and pharmacology, University of Bath. BA2 7AY Introduction: Emerging evidence across a number of disciplines highlight that there are significant sex differences in psychopharmacology (Bolea et al. J Psychopharmacol. 2018; 32; p125-133). Kappa opioid (KOP) receptors play a role in the response to stress and have been investigated as potential targets for A124 ABSTRACTS the treatment of psychiatric disorders including depression and drug dependence (Carlezon & Krystal. Depress Anxiety. 2016; 33; p895-906). Studies have shown the sexual dimorphic nature of the response to KOP receptor activation in preclinical behavioural tasks, for example; California mice develop a conditioned place aversion at different doses of U50,488. In addition, the females show a biphasic response to U50488 but not the males (AR Laman-Maharg et al. Behav Brain Res. 2017; 332; p299-307). Here we have investigated the effects of the KOP receptor agonist, U50,488, on behaviours in the forced swim test in C57BL/6J and CD1 mice of both sexes. Methods: Adult female and male C57BL/6J and CD1 mice (7-10 weeks) were housed in groups of 4. Female and male mice received either saline (0.9%) or U50,488 (0.1mg/kg, 1mg/kg or 5mg/kg) subcutaneously at a volume of 10ml/kg and n=5-8 per treatment group. Pilot studies evaluated the locomotor effects of U50,488 in an open field test. Drugs were administered 45 min prior to testing in a 6 min forced swim test. A video camera, Sony-DCR-SR52, was used to record the mice’s behaviour and behaviour in the final 4 minutes was analysed, blind to treatment. Two way ANOVA was used to assess the effects of sex and treatment (InVivoStat). Results: There was a significant effect of treatment with U50,488 on time spent immobile in the forced swim test in CD1 mice (F (3, 48) = 13.10, P<0.0001) but not C57BL/6J mice (F (3, 46) = 0.38, P=0.77). There was no significant effect of sex on immobility behaviour in the forced swim test in either mouse strain (F (1, 48) =0.21, P=0.65; F (1, 46) =0.36, P=0.55). Pairwise analysis of U50,488’s effects showed a significant increase in the time spent immobile in both male and female CD1 mice at 5mg/kg (P<0.001) but the 0.1 mg/kg dose only produced a significant effect in male mice (P<0.05). Conclusions: Taken together, the results show that KOP receptor activation by U50,488 causes a pro-depressant effect in both female and male CD1 mice, at doses that are without significant locomotor effects. There were no significant effects of sex in these studies although male CD1 mice may be more susceptible to the prodepressant effects of KOP activation than their female counterparts as lower doses of U50,488 produced a significant increase in the time spent immobile. There is clear evidence of a difference in responding to KOP receptor activation between strains, highlighting again the importance of strain specific differences in preclinical behavioural studies (Lucki et al. Psychopharmacology (Berl). 2001; 155; p315-322). No sponsorship was received for the study

I10 EFFECTS OF KAPPA OPIOID RECEPTOR AGONISTS AND ACUTE STRESS ON BRAIN REGIONS IMPLICATED IN THE RESPONSE TO STRESS AND DRUGS OF ABUSE Ma Q, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, BA2 7AY [email protected] Wonnacott S(1), Bailey SJ(2), Bailey CP(2) (1) Dept of Biology and Biochemistry, University of Bath, Bath BA2 7AY; (2) Dept of Pharmacy and Pharmacology, University of Bath, Bath BA2 7AY Introduction: Kappa opioid receptors (KOPrs) have been shown to play an important role in both stress responses and addiction-related behaviour (Bruchas et al., 2010, Brain Research 1314:44-55). We have previously shown that activation of KOPrs activates various brain regions (Ma et al., 2017, J Psychopharmacol, 31, 8). The aim of this study was to compare the brain regions activated by KOPr agonists with those activated by in vivo stressors. As sex differences in responses to KOPr activation have been reported, we conducted our study in both male and female mice (Bolea et al., 2018, J Psychopharmacol 32:125-133; Russell et al., 2014, Biol Psychiatry 76:213-222). Methods: Adult (8-12wks) male and female C57BL/6 cFos-GFP transgenic mice (Barth et al., 2004, Journal of Neuroscience 24:6466- 75) were injected (i.p 10ml/kg) with saline or KOPr antagonist norBNI (10mg/kg). After 24 hours, these mice were treated with either saline or KOPr agonist U50,488 (20mg/kg) or a 15-minute forced swim stress (FSS) (n=6 per treatment group). Two hours later, mice underwent transcardial perfusion fixation under terminal anaesthesia and brains were removed. Brain sections (40μm) were immunolabelled to assess cFos and cFos-driven GFP expression and quantified by fluorescence microscopy. Results: One-way ANOVA with Sidak’s post-hoc test showed that in male mice, both cFos and cFos-driven GFP expression in the nucleus accumbens (NAcc) and prelimbic area of the prefrontal cortex (PFC) were increased by both U50,488 (NAcc: P<0.001; PFC: P<0.01) and FSS (NAcc: P<0.01; PFC: P<0.01). In contrast, in female mice U50,488 did not increase cFos or cFos-driven GFP expression in either NAcc (P=0.08) or PFC (P=0.07). FSS increased ABSTRACTS A125 expression in NAcc (P<0.001) not PFC (P=0.25). cFos and GFP expression were also increased in central and basolateral amygdala following U50,488 in both sexes (male: P<0.001; female: P<0.01). In each case, the effects of U50,488 were significantly blocked by pre-administration of the KOPr antagonist norBNI, whereas norBNI was ineffective against FSS. Conclusions: These data suggest strong overlap between brain regions activated by KOPr agonists and FSS in male mice. In constrast, in female mice, a single injection of KOPr agonist and FSS induced different patterns of activation, particularly in the NAcc and PFC. These differences support previous evidence suggesting sex differences in the behavioural effects of KOPr agonists. KOPr activation had similar effects between male and females in the amygdala, a brain region implicated in the anxiogenic effects of KOPr activation. FSS increased cFos and GFP expression in NAcc after FSS in both sexes, which might suggest that NAcc plays an important role in responses to physical stressors. No sponsorship was received.

I11 THE SYNERGISTIC PHARMACOLOGICAL INTERACTION OF COMPOUNDS PRESENT IN AYAHUASCA: A SYSTEMATIC REVIEW Ruffell SGD, Lambeth Early Onset Psychosis, South London and the Maudsley NHS Foundation Trust, Lambeth Hospital, 108 Landor Road, London, SW9 9NU [email protected] Netzband ND(2), Young AH(1), Juruena MF(1) (1) Centre for Affective Disorders, Institute of Psychiatry, Psychology and Neuroscience, King’s College London PO72, De Crespigny Park, Denmark Hill, London SE5 8AF; (2) University of the West of England, Health and Social Sciences, Bristol Background: Ayahuasca is a South American psychoactive plant-brew used traditionally for religious or ceremonial purposes. Its use has been rapidly spreading into the West accompanied by claims of its therapeutic ability to treat an extraordinarily broad range of physical and psychological conditions. Studies have begun investigating some of the potential applications, yet it remains relatively under- researched. It is accepted that the experiential effects of ayahuasca are a result of combining two plants (typically P. Viridis and Banisteriopsis Caapi). Mechanistic data, in regards to synergy, usually focus on dimethyltryptamine (DMT) and the inhibitory effect on monoamine oxidase in the stomach by harmala alkaloids (MAOIs). Despite this, evidence suggests that there are at least 4 active chemicals within a typical ayahuasca brew. This review is designed to outline the current scientific understanding in regards to profiling the complete synergistic mechanisms that may be present within ayahuasca. Methods: Searches were performed using PubMed and PsycINFO databases using the primary terms ayahuasca, dimethyltryptamine, pharmacology, synergy, harmala alkaloids (including harmine, harmaline, tetrahyrdroharmine) and monoamine oxidase. The search is up-to-date through March 2018. Citation lists of relevant studies were checked for additional papers and secondary searches were performed using related keywords and complimentary search engines. Results: 2141 papers were initially returned, of which 202 were selected after title and abstract assessment. After further vetting 57 articles were selected for full-text analysis, only 16 of these discussed detailed pharmacological principle relating to synergy. As hypothesised, the primary narrative within existing research revolves around prevention of deamination of DMT by MAOI. Searches also identified several articles since 2012 that imply further synergistic mechanisms may be present than we currently understand pertaining to the effects of the brew immunologically as well as its effect on serotonin transporter sites, neurogenesis and the potential action of DMT as a neuromodulator. This is implied from mechanistic action derived from neurological and pharmacokinetic data. It is unclear at present whether these actions are of a true synergistic nature, or additive. Summary: It is clear based on this review that more extensive, multi-faceted, experiments are required if we are to acquire the level a level of pharmacological understanding necessary to compliment develops that are being seen relating to therapeutic potential. Such an approach would allow us to have a solid foundation to build upon in order to develop more refined experiments for the potential of future applications. No funding has been received for this study. A126 ABSTRACTS

I12 TRUE COLOURS MONITORING IN TREATMENT RESISTANT DEPRESSION: A QUALITATIVE STUDY OF PATIENTS’ PERSPECTIVES Taylor R, Centre for Affective Disorders, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, 16 De Crespigny Park, London, UK, SE5 8AB [email protected] Incecik E(1), Hutchinson J(4), DeAngel V(1), Opera E(1), Mather S(3), Nortey K(4), Geddes J(2), Cleare AJ(1), Marwood L(1) (1) As presenting author; (2) Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, OX3 7JL; (3) Research and Development Department, Warneford Hospital, Headington, Oxford, OX3 7JX; (4) Wolfson Research Centre, Institute of Neuroscience, Campus for Ageing and Vitality, Westgate Road, Newcastle Upon Tyne, NE4 5PL Background: Symptom monitoring is a key management strategy in affective disorders. True Colours is an online symptom monitoring programme developed by academic clinicians and software engineers at the University of Oxford. The usefulness of True Colours has been assessed by a number of studies in patients with bipolar disorder, who have commented positively on its ease of use, as well as its contribution to enhancing their clinical care and self-management. However, in order to fully assess the clinical usefulness of True Colours as a mood monitoring system, we must also explore its application to unipolar depressed patients. The aim of the current study was to examine whether patients with unipolar treatment resistant depression (TRD) find symptom monitoring via True Colours be a useful addition to their current treatment regimes, and to identify any potential barriers to use. Methods: Semi-structured qualitative interviews were conducted with patients who had engaged in True Colours monitoring as part of the Lithium versus Quetiapine in Depression study (across three NHS trusts). The interview schedule included five open ended questions relating to the participants’ experience of using True Colours. The sixth question asked participants to provide an overall star rating for the system on a scale from 1-5, with associated reason. Responses were then thematically analysed using an inductive (bottom-up) approach. Results: Six main themes emerged from the data: (1) insight, indicating that True Colours facilitated patient comprehension of their illness; (2) absence of behaviour change, whereby True Colours did not appear to influence depression management by patients; (3) improved clinical care, suggesting that patients consider True Colours a useful tool for improving their contact with clinicians; (4) prioritisation, indicating that some patients had difficulty in making time for True Colours; (5) categorisation concerns, indicating that there was some discrepancy between patient experience and their answers on the True Colours system; (6) interface issues, primarily relating to difficulties using the True Colours technology. The participants’ mean overall star rating for True Colours was 3.8. Conclusions: Our findings contribute to the growing body of research into True Colours as a method for monitoring patients’ symptoms. While the system has the potential to provide TRD patients with benefits such as insight into their disorder, and improved clinical care, we have identified some barriers to use which need to be overcome in order for the system to be used consistently and effectively by patients with unipolar TRD. Funding and support: The authors receive funding support from the National Institute for Health Research (NIHR) Maudsley Biomedical Research Centre (BRC) at South London and Maudsley NHS Foundation Trust and King’s College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. ABSTRACTS A127

I13 VALIDATING AN OBJECTIVE MEASURE OF MOTIVATION FOR REWARD USING A JOYSTICK-OPERATED RUNWAY TASK Slaney C, School of Physiology, Pharmacology & Neuroscience, University of Bristol, Biomedical Sciences Building, University Walk, BS8 1TD [email protected] Houghton CJ(1), Penton-Voak I(2), Munafo M(2), Robinson ESJ(3) (1) Dept of Computer Science, Univ of Bristol, Merchant Venturers Bldg, Woodland Road, Bristol, BS8 1UB; (2) School of Experimental Psychology, Univ of Bristol, Priory Road Complex, Priory Road, Bristol, BS8 1TU; (3) School of Physiology, Pharmacology & Neuroscience, Univ of Bristol, Medical Sciences Bldg, University Walk, Bristol, BS8 1TD Introduction: Motivational deficits are a common symptom of many psychiatric disorders including depression and schizophrenia. However, currently available treatments fail to successfully address this symptom (Salamone et al., 2018). Progress in developing new effective treatments is hindered by the reliance on subjective self-report questionnaires to diagnose and assess treatment efficacy. There is the need to develop objective measures of core symptoms of psychiatric disorders (Der-Avakian et al., 2013). This study addresses this by providing initial validation a novel behavioural task that objectively measures reward motivation. Methods: Twenty-five healthy volunteers completed a modified version of the Joystick- Operated Runway Task (JORT; see Perkins et al., 2009). In this task, participants were required to push a joystick to catch an onscreen target. Trials varied in the amount of physical effort required to win (50, 80, 100 or 120% of their maximum calibrated force) and reward magnitude (0, 10, 100 or 1000 points). Participants were informed that the total number of points earned directly corresponded to the amount of money they would win. The primary outcome was relative physical effort exerted. Data were analysed using a repeated-measures ANOVA. Results: There was a main effect of reward (p = .005) with participants exerting more physical effort for higher, compared to lower, reward magnitudes. There was also a main effect of effort (p < .0001), participants exerted more physical effort for higher, compared to lower, effort trials. There was no reward*effort interaction (p > .05), participants exerted more physical effort for higher reward magnitudes regardless of the effort required. Conclusions: These findings provide initial validation for the JORT as a novel behavioural measure of reward motivation in humans. Further work examining motivational impairments in patient populations using this task is warranted. In line with the Research Domain Criteria (RDoC), this may subsequently inform research on clinical diagnosis by taking a symptom-based approach. This work was funded by the Wellcome Trust Doctoral Training Programme in Neural Dynamics.

I14 EVALUATING THE ANXIOLYTIC POTENTIAL OF AMILORIDE IN THE 7.5% CARBON DIOXIDE EXPERIMENTAL MODEL OF ANXIETY Parker R, University of Southampton, University Department of Psychiatry, Academic Centre, College Keep, 4-12 Terminus Terrace, Southampton, SO14 3DT [email protected] Mahood F(1), Taylor ANW(1), Mills S(1), Hou R(1), Baldwin DS(1), Garner M(1) (1) As presenting author Introduction: Inhalation of 7.5% carbon dioxide (CO2) induces subjective, autonomic and neurocognitive features of anxiety in healthy subjects (Garner et al., 2011, Neuropsychopharmacology 36:1557–1562). CO2 challenge is considered a translational model of anxiety with potential for testing putative anxiolytic compounds (Bailey et al., 2011, J Psychopharmacol. 25(9):1199–1206). Acid-sensing ion channels (ASIC) are implicated in a number of health conditions including pain, neurological disease and anxiety. Studies in animals suggest that drugs that increase or decrease ASIC activity (particularly ASIC1) lead to corresponding increases and decreases in anxious behavior, however the effects in human anxiety are unknown. Amiloride is a non-specific ASIC blocker and potassium sparing diuretic that is currently licenced in the UK for hypertension and congestive heart failure. It has an acceptable side-effect profile and is well-tolerated in healthy and clinical samples. Amiloride has demonstrated anxiolytic effects in animal models of anxiety (Dwyer et al. 2009), however its anxiolytic potential in humans has not been A128 ABSTRACTS examined. We tested whether amiloride can reduce anxiety following 7.5% CO2 challenge in healthy adults compared to placebo. Methods: 60 healthy volunteers were recruited. On day 0 participants’ baseline responses to twenty minute 7.5% CO2 challenge (vs. normal air inhalation) were measured. On day 7 participants were randomised to receive a single dose of amiloride (20mg, titrated from 10mg the previous day) or pill placebo (double-blind). During each inhalation participants completed an eye-tracking antisaccade attention task (Garner et al., 2011). Subjective anxiety (modified GAD-7), heart ater and blood pressure were recorded at baseline and after each inhalation. Results: 51 participants completed the study. Mixed-design analysis of variance (ANOVA) tested the effect of drug and inhalation gas on subjective and autonomic outcome measures. CO2 significantly increased heart rate and blood pressure similarly in both drug and placebo groups. CO2-challenge increased subjective anxiety (vs. air) in both groups at baseline and on day 7. There was some evidence that post-CO2 anxiety was lower following the administration of amiloride (vs. baseline response to CO2 challenge, F(1, 49) = 3.128, p = .083. Response to CO2 was unaffected by placebo. There were no clear effects of drug on blood pressure and heart rate. Conclusions: Our results provide some initial evidence that amiloride has anxiolytic effects in an experimental medicine model of human anxiety. Our findings invite further research into the ASIC mechanisms that might target anxiety and associated mood disorders. The study was approved by the University of Southampton Research Ethics and Governance Office. The study was funded by MRC grant MR/N012712/1– awarded to Garner, Baldwin, Hou.

I15 EFFICACY OF AFFECTIVE BIAS MODIFICATION VIA SMARTPHONES IN A LARGE POPULATION SAMPLE Chelliah A, Institute of Cognitive Neuroscience, University College London, Alexandra House, 17-19 Queen Square, London, WC1N 3AZ [email protected] Robinson OJ(1) (1) As presenting author Introduction: Negative affective bias is the tendency to preferentially attend to negative stimuli and to interpret neutral or ambiguous stimuli in a negative manner (Mathews & MacLeod, 2005, Annu. Rev. Clin. Psychol., 1, 167-195.). These biases are thought to be crucial in developing and maintaining negative mood, suggesting that the ability to modify them could prevent onset of and/or improve negative mood. To study whether bias modification can be effectively delivered on a large scale and with wide scope we asked whether adults using a smartphone application would shift their bias toward positive over negative stimuli. Methods: Participants were 47,000+ users of a smartphone application developed in partnership with the online platform ‘Peak’ (www.peak.net), of whom 30,000+ completed at least 2 sessions experience. Sessions included test and training versions of ‘gamified’ dot-probe and facial search tasks, where participants were split into receiving bias modification and sham training on both tasks separately. The Dot-Probe test involved viewing 2 face stimuli (one with a positive and the other negative facial expression), followed by identifying how many ‘gems’ appeared on screen; in sham and test training, gems were behind the positive stimulus 50% of the time, and in modification training, gems were always behind the positive stimulus. The Facial Search test involved one block of selecting positive faces in an array of negative faces, and another selecting negative faces in an array of positive expressions; training involved selecting only positive faces (modification training) or five-petalled flowers in an array of seven-petalled flowers (sham training). Results: Across both tasks, participants were faster (Dot-Probe: F1,47771=6.95,p=0.008, Facial Search: F1,47299=8.541,p=0.003) and more accurate (Dot-Probe: F1,47771=403.5,p<.001, Facial Search: F1,47299=121.9,p<.001) when completing the modification than test/ sham versions. By the second session, participants receiving modification Dot-Probe training had improved speed on test significantly more than sham participants (t=-33.6,df=29870,p<0.001). There were no significant differences in accuracy improvements (t=1.79,df=30265,p=0.07). Critically, there was evidence of reduced negative mood state in training relative to sham conditions; participants who reported themselves as less Ashamed and more Interested were in the training Dot-Probe (Ashamed: F1,45780=11.26,p<.001, Interested: F1,45870=4.30,p=.037) and Facial Search groups (Ashamed: F1,45143=11.21,p<.001, Interested: F1,45143=26.26,p<.001). Conclusions: We provide evidence that bias modification can shift task ABSTRACTS A129 performance via cost-effective smartphone applications, and that this can shift mood state at a population level. Given waiting-lists and delays before any treatment is effective, such cost effective, easy to deliver training procedures might be considered valuable adjuncts to current treatments. Sources of financial sponsorship This work was supported through a consultancy agreement between UCL consultants and PEAK, as well as an MRC CDA (MR/K024280/1) awarded to OJR.

I16 EMOTION PROCESSING BIASES OF MENTAL IMAGERY IN MONOZYGOTIC TWINS WITH BIPOLAR DISORDER OR UNIPOLAR DEPRESSION. Taylor P, Centre for Psychiatry, Imperial College London (Hammersmith Campus) Du Cane Road London, W12 0NN [email protected] Meluken I(2), Miskowiak K(2), DiSimplicio M(1) (1) Centre for Psychiatry, Brain Sciences Division, Imperial College London (Hammersmith Campus), Du Cane Road, London W12 0NN; (2) Psychiatric Centre Copenhagen, University Hospital of Copenhagen, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen Introduction: Mental imagery acts as an ‘emotional amplifier’ in affective disorders such as bipolar disorder (BD) or unipolar depression (UD) enhancing depressive and or manic mood states (Di Simplicio et al., Bipolar Disord. 2016 Dec;18(8):669-683.). Previous literature has shown that identifying endophenotypes can improve: (i) understanding of disease aetiology, (ii) diagnostic accuracy, and (iii) treatment outcomes. Based on this, we aimed to investigate whether emotional processing biases, specifically enhanced mental imagery, existed in individuals with mood disorders compared to healthy individuals, and whether this would fulfil the endophenotype criteria. Methods: From a cohort of monozygotic twins, participants (N=204) (M:57, F:147) were: 40 low risk individuals (no co-twin history of BD or UD), 49 high risk individuals (co-twin history of BD or UD), and 115 individuals affected by a mood disorder. Initial assessment included: psychiatric diagnosis screening and premorbid IQ; and affective questionnaires to assess depression, mania, anxiety, and coping. Imagery questionnaires and experimental tasks assessed cognitive (non-emotional) stages of mental imagery via mental rotation and letter corner classification, and emotional mental imagery with particular focus on prospective imagery. Results: Comparison of groups found significant differences on measures of emotional prospective imagery. Affected twins reported a greater impact of emotional future images compared to high risk and low risk twins (F(1,51) = 4.53, p=0.038), in particular in the dimension of intrusive prospective imagery. Also a significant difference was found between groups on vividness (F(2,162) = 6.58, p=0.002) and sense of experiencing (F(2,164) = 10.27, p<0.001) of future images. In particular affected twins, compared to low and high risk twins, demonstrated: (i) stronger vividness of negative imagery, (ii) weaker vividness of positive imagery, and (iii) stronger experiencing of negative imagery. There were however no significant differences between groups in measures of cognitive (non-emotional) mental imagery. Conclusions: Compared to low risk and high risk twins, individuals with a mood disorder showed enhanced emotional mental imagery characteristic. However, as high risk individuals did not differ from low risk individuals, this suggests that imagery biases are secondary to the affective illness rather than an endophenotype. Interestingly twins with a mood disorder presented no deficits in cognitive (non-emotional) mental imagery tasks, which may indicate preserved processing of visual stimuli. Funding sources: The Lundbeck Foundation ( R108-A10015 ), Hørslev Foundation, The Capital Region of Denmark, the Augustinus Foundation, the Weimann Foundation and the Axel Thomsen´s Foundation. A130 ABSTRACTS

I17 AUTOBIOGRAPHICAL RECALL BEFORE VS AFTER PSILOCYBIN THERAPY FOR TREATMENT RESISTANT DEPRESSION Porffy LA, Psychosis Studies, IoPPN, King’s College London, 16 De Crespigny Park, London, SE5 8AB [email protected] Stroud JB(3), Oliver DAP(1), Ashton P(3), Lily Fitzgerald L(3), Freeman TP(2), Carhart-Harris RL(3) (1) As presenting author; (2) National Addiction Centre, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London SE5 8BB; (3) Psychedelic Research Group, Psychopharmacology Unit, Centre for Psychiatry, Department of Medicine, Imperial College London, London W12 0NN; Background: Individuals with depression struggle to recall specific autobiographical memories (AM). Disruptions in AM is a trait-like characteristic that contributes to the development and maintenance of depressive symptoms. Therefore, AM has the potential to be an important therapeutic target. Psilocybin, a 5-HT2A receptor agonist, has been found to reduce depressive symptoms, and enhance autobiographical recollection in healthy volunteers. In the present study, we tested whether psilocybin improves AM recall, as measured by the Autobiographical Memory Test (AMT), in patients with treatment-resistant depression (TRD). Methods: Nineteen patients with TRD completed the AMT (mean age = 44.1 ± 11.3 years, 6 females) at baseline and one week after administration of psilocybin (25mg). Eighteen healthy individuals (mean age = 32.7 ± 11.5 years, 6 females) also completed the task at two different time points separated by a month. Both groups were instructed to recall a specific AM, lasting for no longer than a day, in relation to 4 positive, 4 negative, 4 neutral cue words. Reponses were rated independently, on a scale from 0 (omission) to 5 (detailed specific), by two blinded researchers (intraclass correlation = .903, 95%CI = .887 – .917). Changes in AM recall were evaluated for each word valance separately using linear mixed models with time point (visit 1/2) included as a within-subject factor and group (patients/controls) as a between-subjects factor. Results: In response to positive cue words, there was a significant main effect of group (F1, 48.34 = 7.95, p = .007) and time point (F1, 37.97 = 6.60, p = .014), and trending time point x group interaction (F1, 36.37 = 3.47, p = .071). We found no effect of group or time point in response to negative or neutral cue words. These results were unchanged when age was added to the model as a covariate, due to significant mean age difference between the two groups (t35= 3.03, p = .005). Discussion: To our knowledge, this is the first study to explore the effects of psilocybin on AM in TRD. eW found that compared to controls, depressed patients struggled to recall specific memories, particularly in response to positive cue words. After psilocybin administration, however, their performance significantly improved. Our findings are in line with previous research showing greater overgenerality in response to positive cues in depression. Conversely, recovered patients were found to have increased specific recall to positive cues, highlighting a cognitive mechanism through which psilocybin may ameliorate depressive symptoms.

I18 ACUTE 5-HT4 RECEPTOR AGONISM ENHANCES LEARNING, MEMORY AND REWARD SENSITIVITY IN HEALTHY VOLUNTEERS Murphy SM, Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, OX3 7JX [email protected] Wright L(1), Browning M(1), Cowen PJ(1), Harmer CJ(1) (1) As presenting author Introduction: Stimulation of 5-HT4 receptors enhances learning and memory, and decreases depression- related behavior in rodent models. This preclinical evidence suggests that the 5-HT4 receptor might be a novel potential target for antidepressant and/or procognitive treatment. There has been a lack of experimental medicine work establishing these effects in human models. The current study investigated the effect of 5-HT4 receptor agonism on measures of learning and memory, emotional processing and reward sensitivity in healthy volunteers. Methods: 41 healthy volunteers were randomized to receive a single 1mg dose of prucalopride (partial agonist of the 5-HT4 receptor, licensed for the treatment of constipation) or placebo. 2 hours after drug administration, participants completed a battery of cognitive ABSTRACTS A131 tests measuring emotional processing (Emotional Test Battery), learning and memory (Auditory Verbal Learning Task (AVLT), N-Back task, Contextual Cueing) and reward sensitivity (Probabilistic Instrumental Learning task (PIL), analysed using a reinforcement model within a hierarchical Bayesian framework). Results: Prucalopride significantly enhanced memory performance on the VLTA (p=0.002) and Emotional Recall Task (p=0.01). Prucalopride also significantly enhanced reward sensitivity on the PIL task. There were no significant effects of prucalopride on facial expression recognition, working memory (N-back task) or implicit learning on the contextual cueing task. Conclusions: Consistent with preclinical studies, prucalopride had a pro-cognitive effect on learning and memory. These findings are an important translation of the preclinical effects of 5-HT 4 receptor agonism into human models and support the notion that this is a promising therapeutic target for the development of cognition enhancing agents. No financial sponsorship was received for this study.

I19 MOOD INSTABILITY AND REWARD PROCESSING: DAILY REMOTE MONITORING AS A MODERN PHENOTYPING TOOL FOR BIPOLAR DISORDER. Panchal P, Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, OX3 7JX priyanka. [email protected] Scholl J(2), Nelissen N(1), Saunders KEA(1), Darby D(3), Rushworth MFS(2), Harrison PJ(1), Nobre AC(2), Harmer CJ(1) (1) As presenting author; (2) Department of Experimental Psychology, University of Oxford, Oxford; (3) Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Victoria, Australia Introduction: Mood instability is a prominent feature of bipolar disorder (BD) and other affective disorders (Broome et al., 2015). Recent research has begun to highlight a strong association between mood instability and cognitive processing, particularly within the decision-making and reward-processing domain, suggesting the ability for mood to bias perception of reward and loss, and to induce risk-taking behaviour (Eldar et al., 2016; Eldar and Niv, 2015). However, research has failed to explore the complexities of this relationship over a longitudinal basis. Modern technologies, such as remote online platforms, can address this issue by using high frequency and prospective monitoring. This is particularly important given the dynamic nature of mood instability (Solhan et al., 2009). Aims: We aimed to assess whether remote monitoring can capture mood instability in individuals showing dimensions of BD as measured by the Mood Disorder Questionnaire (MDQ) screening tool, and whether such instability is reflected in risk taking behaviour in a longitudinal decision-making and reward-processing task. Methods: Remote mood and cognitive monitoring over 10 weeks, as part of the Cognition and Mood Evolution across Time (COMET) study. We analysed data from 37 participants scoring >7 on the MDQ (high MDQ group) and 35 matched controls (MDQ<5). Mood was assessed on a daily basis using the PANAS scale on an iPad. Participants also completed a “Wheel of Fortune” task, where they were asked to pick the best out of 2 gambling options, with the aim of winning as many bonus points as possible. Repeated measures ANOVAs were used to analyse mood and cognitive task data. Results: The high MDQ group showed greater variability in their PANAS positive affect, F(1)=10.56, p<0.001, and negative affect, F(1)=15.01, p<0.001, scores compared to the controls. They also reported greater average negative affect scores, F(1)=14.46, p<0.001, but were no different in their average positive affect scores. Whilst the high MDQ participants did not show a significant bias towards riskier decisions in the gambling task in these preliminary analyses, all participants appeared to make less risky choices, F(5.00)=7.42, p<0.001, and were less variable in their choices, F(4.81)=2.50, p<0.05, across time. Conclusions: Daily remote mood monitoring captures mood instability in individuals showing dimensions of BD. Concurrent monitoring of cognition, particularly within the reward processing domain, suggests a pattern of dynamic decision-making and warrants further sophisticated analyses to better elucidate the cognitive underpinnings of such instability. Nevertheless, findings add to the increasing evidence for mood instability as a marker for BD. This will aid in the search for biomarkers that can be used in determining the effectiveness of current treatments and in the development of novel therapeutic targets. Wellcome Trust funded. A132 ABSTRACTS

I20 REWARD AND MOTIVATION BIASES IN SELF-HARM Amaralingam J, The Centre for Psychiatry, Imperial College London, 7th Floor Commonwealth Building, Hammersmith Campus, Du Cane Road, London, W12 0NN [email protected] Sen K(1), Di Simplicio M(1) (1) As presenting author Introduction: Self-harm is defined as “any act of self‑poisoning or self‑injury carried out by a person, irrespective of their motivation”(NICE/2013). Self-harm is becoming increasingly common with annual incidence being as high as 37 and 12.3 per 10,000 in girls and boys respectively (Morgan et al/2017/BMJ/395/ j4351). Although this behaviour tends to subside spontaneously by early adulthood, in those who continue it becomes increasingly harmful with 3 in 100 people who continue to self-harm over 15 years taking their own lives. Research to date has highlighted abnormalities in emotion processing and impulsivity as a potential mechanism driving self-harm and treatments focus on emotion regulation techniques. However, current available interventions remain unsatisfactory. Some studies have proposed that reward and motivation biases also exist in individuals who self-harm, but no systematic review has been conducted in this specific field to date. The aim of our systematic review is to investigate if abnormalities are present in reward and motivation processing in individuals who self-harm. This will improve our understanding of the neurobiological and cognitive underpinnings of self-harm behaviour and can guide the development of novel effective treatments. Methods: We searched for human studies in English only, from input to March 2018. Search terms were divided into 6 groups: 1 = terms related to self-harm (e.g. ‘NSSI’), 2 = conditions frequently associated with self-harm (e.g. Borderline Personality Disorder, suicide), 3 = terms associated with reward (e.g. “positive reinforcement”), 4 = terms associated with motivation (e.g. “drive”, “approach behaviour”), 5 = related questionnaires and tasks (e.g. Monetary Incentive Delay task) and 6 = neurobiological correlates (e.g. basal ganglia, dopamine). Each term from Group 1 and 2 was searched with each term from Group 3, 4, 5, and 6 using PubMed, PsycINFO, PsycArticles and EMBASE with an outcome of 38,425 article titles in total. Results: So far, we selected 108 abstracts from the PubMed search: 19 reviews and 89 original studies. Of the original studies, 36 investigated neurobiological measures of reward or motivation, including measures of dopamine or opioids, and neuroimaging methods. Another 53 papers reported a variety of cognitive experimental tasks, behavioural analysis and self-report questionnaires. Conclusion: Preliminary findings from the literature reviewed so far suggest that abnormalities in the brain circuitry underpinning reward processing (such as striatal circuits and orbitofrontal cortex) are present in individuals who self-harm. In particular, reduction in reward anticipation may represent a mechanism wanting further investigation in this population. Acknowledgement: No sponsorship received

I21 THE FAKE IQ TEST: A NOVEL, DIRECT MEASURE OF SELF-PERCEPTION IN MAJOR DEPRESSION Marwood L, Centre for Affective Disorders, Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, 103 Denmark Hill, PO74, London, SE58AF [email protected] Wise T(2), Patrick F(1), Cleare A(1), Perkins A(1) (1) As presenting author; (2) Wellcome Trust Centre for Neuroimaging, University College London, London, UK Introduction: Negative self-perception is a common feature of psychiatric disorders, yet discerning whether it is a cause or effect of illness remains a challenge as the tools available for measuring self- reflection are limited largely to self-report questionnaires or reliance on invoking emotional states. Methods: Here we present an objective measure of self-perception, the Fake IQ Test. This computerised task presents participants with sets of items that are described to them as testing an intelligence construct known as “visual perception ability”. This construct is fictitious and after each set of items, participants are asked to estimate their total number of correct answers, whether their performance was better or worse than average, and whether they were satisfied with their performance. The design of the task’s items means there are no right or wrong answers and so perceived differences in performance between subjects reflect individual differences in self-perception. We piloted the Fake IQ test in patients with major depressive disorder and healthy controls as an fMRI and behavioural task. Results: Behaviourally, ABSTRACTS A133

30 patients and 20 healthy controls completed the task. We found elevated negative self-comparison to others (p<.001), higher self-dissatisfaction (p<.05), and lower perceived success (p<.05) in depressed patients relative to controls on the task. Importantly, the ‘fake’ nature of the task did not appear to have been perceived by participants in post-task questioning and was not revealed quantitatively. Thirty-five participants completed the Fake IQ test during MRI scanning (16 patients and 19 controls). A main effect of task was found with greater activation in self-perception versus control conditions bilaterally in the inferior cortex, insula, dorsolateral prefrontal cortex, motor cortex and dorsal anterior cingulate cortex, regions involved in self-reflection and error processing. These regions were significant at a cluster-defining threshold of p<.001 and cluster-wise threshold of p<.05 FDR corrected across the whole brain. However, there were no significant differences between patients versus controls in neural activation on the task, nor correlations between brain activity and self-report measures of global self-reflection. Conclusions: We therefore propose the FIQT as an alternative to traditional self-report measures of self-perception, with application to multiple patient groups associated with abnormal self-perception. Further work should explore the task’s relationship to self-blame and perfectionism: constructs that are likely to be involved with perception of task performance and in a variety of psychiatric disorders associated with aberrant self-perception. Financial Sponsorship: This work was funded by a Medical Research Council/Institute of Psychiatry, Psychology and Neuroscience Excellence studentship.

I22 EFFECT OF LURASIDONE ON COGNITION IN CHILDREN AND ADOLESCENTS WITH BIPOLAR DEPRESSION: INTERIM ANALYSIS OF A 2-YEAR OPEN-LABEL EXTENSION STUDY Tocco M, Medical Affairs, Sunovion Pharmaceuticals Inc., 84 Waterford Drive, Marlborough, MA, 01752 [email protected] Burdick KE(1), Goldman R(2), Deng L(3), Loebel A(3) (1) Department of Psychiatry, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA; (2) Sunovion Pharmaceuticals Inc., 84 Waterford Drive, Marlborough, MA 01752; (3) Sunovion Pharmaceuticals Inc., One Bridge Plaza, Suite 510, Fort Lee, NJ 07024 Introduction: Studies suggest that bipolar disorder is associated with cognitive impairment that is often underrecognised and may persist during euthymic periods. There is limited research on cognitive function in children and adolescents with bipolar disorder, and the effects of pharmacotherapy on cognition in this population. The aim of the current study was to evaluate the longer-term effects of lurasidone on cognition in children and adolescents with bipolar depression. Methods: Patients 10-17 years with a DSM-5 diagnosis of bipolar I depression were randomised to 6 weeks of double-blind (DB) treatment with flexibly-dosed lurasidone 18.5-74 mg/d. Patients who completed 6 weeks of DB treatment were eligible to enroll in a 2-year, open-label (OL) extension study in which patients were continued on lurasidone, or switched from placebo to lurasidone (all patients in the extension study were started on a dose of 37 mg/d). Cognitive function was assessed with the Brief CogState battery, which evaluates four cognitive domains: processing speed, attention/ vigilance, visual learning, and working memory. Based on normative data, an overall cognitive composite Z-score was calculated as the average of the standardised Z-scores for each of the four cognitive domains. The results presented here are based on an interim analysis of data at 1-year. Results: 223 patients completed the 6-week DB study and entered the extension study. At the time of the interim analysis, CogState data were available on 219 patients at OL baseline, 180 patients at week 12, 149 at week 28, and 92 at week 52. The cognitive composite Z-score showed impairment at DB baseline (-0.94). Mean change in Z-score, from DB baseline to OL weeks 0 (OL-baseline), 12, 28, and 52, respectively, were observed for the cognitive composite (+0.00, +0.16, +0.18, +0.23), and for the CogState domains processing speed (-0.15, +0.05, +0.07, +0.02), attention/vigilance (-0.02, +0.19, +0.22, +0.26), visual learning (-0.05, +0.10, +0.14, +0.25), working memory accuracy (-0.05, -0.11, +0.14, +0.07), working memory speed (+0.21, +0.30, +0.28, +0.36). Conclusions: Acute and long-term treatment with lurasidone did not have deleterious effects on cognition in children and adolescents with bipolar depression. Up to one year of treatment with lurasidone was associated with small improvements in cognitive function as measured by the Brief CogState battery. Sponsored by Sunovion Pharmaceuticals Inc. A134 ABSTRACTS

I23 SAFETY OF LONG-TERM TREATMENT WITH LURASIDONE IN CHILDREN AND ADOLESCENTS WITH BIPOLAR DEPRESSION: INTERIM ANALYSIS OF A 2-YEAR OPEN-LABEL EXTENSION STUDY Goldman R, Global Clinical Research and Medical Affairs, Sunovion Pharmaceuticals Inc., 84 Waterford Drive, Marlborough, MA, 01752 [email protected] Tocco M(1), Pikalov A(1), Deng L(2), Loebel A(2) (1) Sunovion Pharmaceuticals Inc., 84 Waterford Drive, Marlborough, MA 01752; (2) Sunovion Pharmaceuticals Inc., One Bridge Plaza, Suite 510, Fort Lee, NJ 07024 Introduction: Bipolar I disorder frequently has an early onset with a prevalence rate of 1.8% in pediatric populations; however, limited data are available on the long-term safety and tolerability of drug therapies in this age group. The aim of this 1-year interim analysis was to evaluate the long-term safety and tolerability of lurasidone in children and adolescents with bipolar depression. Methods: Patients 10-17 years with a DSM-5 diagnosis of bipolar I depression were randomised to 6 weeks of double-blind (DB) treatment with lurasidone or placebo. Study completers were eligible to enroll in a 2-year, open-label (OL) extension study in which patients were continued on flexibly-dosed lurasidone (18.5-74 mg/d), or switched from placebo to lurasidone. Results: In the short-term study, 347 patients were randomised to lurasidone or placebo (mean age, 14.3 years). A total of 223 patients entered the extension study. At the time of the interim analysis, 93 patients (41.7%) had completed 52 weeks of OL treatment, 36 patients were still ongoing, and 94 patients had discontinued prior to week 52 (withdrawal of consent, 14.8%; adverse event, 9.4%; lost to follow-up, 7.2%; protocol violation, 6.7%; lack of efficacy, 0.9%; other reasons, 3.1%). The mean dose of lurasidone during 52 weeks of treatment was 50.9 mg/d. The most frequent adverse events were headache (19.7%), nausea (14.3%), anxiety (9.9%), somnolence (8.5%), and vomiting (8.1%). Small median changes from DB baseline to weeks 28/52 were noted for total cholesterol (-4.5/-5.0 mg/dL), LDL cholesterol (-3.0/0.0 mg/dL), triglycerides (-2.0/-2.0 mg/dL), and hemoglobin A1c (0.0/+0.1 mg/dL); and mean changes in weight at weeks 28/52 were +3.0/+5.0 kg (vs. an expected weight gain of +2.3/+3.9 kg, based on normative CDC data). Median changes in prolactin, from DB baseline to week 28/52, were +2.0/+2.5 ng/mL for females and +1.6/+1.2 ng/mL for males. No patients had a QTcF ≥460, or an increase from DB baseline in QTcF of ≥60 milliseconds. During 52 weeks of treatment, 10 patients (4.5%) met criteria for treatment-emergent mania. There were no deaths in the study. A total of 4.5% of patients reported suicidal ideation as an adverse event, and 2.2% of patients made a suicide attempt. Conclusions: In children and adolescents with bipolar depression, up to 52 weeks of treatment with lurasidone was generally well-tolerated. The most common adverse events were headache, nausea and anxiety. Minimal effects were observed on weight, metabolic parameters, and prolactin levels. Sponsored by Sunovion Pharmaceuticals Inc.

I24 EFFECTIVENESS OF LONG-TERM TREATMENT WITH LURASIDONE IN CHILDREN AND ADOLESCENTS WITH BIPOLAR DEPRESSION: INTERIM ANALYSIS OF A 2-YEAR OPEN-LABEL EXTENSION STUDY Goldman R, Global Clinical Research and Medical Affairs, Sunovion Pharmaceuticals Inc, 84 Waterford Drive, Marlborough, MA, 01752 [email protected] Tocco M(1), Pikalov A(1), Deng L(2), Loebel L(2) (1) 84 Waterford Drive, Marlborough, MA 01752; (2) One Bridge Plaza, Suite 510, Fort Lee, NJ 07024 Introduction: Onset of bipolar disorder, prior to age 18, is relatively common, and is typically a chronic and disabling illness. Maintenance therapy is frequently required; however, few studies have been reported that evaluate the efficacy of long-term treatment of children and adolescents with this diagnosis.e W report here results of an interim analysis of a 2-year study of the effectiveness of lurasidone in pediatric patients with bipolar depression. Methods: Patients 10-17 years with a DSM-5 diagnosis of bipolar I depression were randomised to 6 weeks of double-blind (DB) treatment with lurasidone or placebo. The primary efficacy measure was the Children’s Depression Rating Scale, Revised (CDRS-R). Study completers were eligible to enroll in a 2-year, open-label (OL) extension study in which patients were continued on flexibly- dosed lurasidone (18.5-74 mg/d), or switched from placebo to lurasidone (all patients in the extension study ABSTRACTS A135 were started on a dose of 37 mg/d). Treatment response was defined as ≥50% reduction from DB baseline in the CDRS-R total score; remission was defined based on the following composite criteria: CDRS-R total score ≤28, a Young Mania Rating Scale (YMRS) total score ≤8, and a Clinical Global Severity, Bipolar (CGI- BP-S) depression score ≤3. Results: In the short-term study, 347 patients were randomised to lurasidone or placebo (mean age, 14.3 years). At Week 6 endpoint, treatment with lurasidone was associated with significant improvement vs. placebo in the CDRS-R total score (-21.0 vs. -15.3; P<0.0001; effect size, 0.45). A total of 223 patients entered the extension study; at the time of the interim analysis, data were available on 95 patients at 52 weeks. For the extension study population, the mean CDRS-R total scores at DB and OL baselines were 58.1 and 37.6, respectively; and the mean CGI-BP-S depression scores were 4.53 and 3.13, respectively. Mean change from OL baseline in the CDRS-R total scores at weeks 12, 28, 40, and 52 were -6.5, -10.0, -10.8, and -10.7, respectively; and mean change in the CGI-BP-S depression scores were -0.65, -1.11, -1.17, and -1.36, respectively. Responder rates at OL baseline, weeks 12, 28, 40, and 52 were 55.0%, 73.7%, 85.1%, 87.0%, and 92.6%, respectively. Remission rates at DB baseline, OL baseline, weeks 12, 28, 40, and 52 were 0.0%,26.6%, 45.7%, 57.8%, 64.1%, and 71.6%, respectively. Conclusions: In children and adolescents with bipolar depression, long-term treatment with lurasidone was associated with continued improvement in depressive symptoms. Sponsored by Sunovion Pharmaceuticals Inc.

I25 REVIEW OF PRESCRIBING AND MONITORING GUIDELINES FOR FIRST AND SECOND LINE PHARMACOLOGICAL AUGMENTATION THERAPIES IN TREATMENT RESISTANT DEPRESSION Oprea E, Centre for Affective Disorders, Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King’s College London and South London and Maudsley NHS Foundation Trust, London, UK, 103 Denmark Hill, PO74, IoPPN, London, SE5 8AF [email protected] Marwood L(1), DeAngel V(1), Valentini B(2), Mather S(3), Taylor R(1), Cleare A(1) (1) As presenting author; (2) Department of General Psychology, University of Padova, Padova, Italy; (3) Oxford Health NHS Foundation Trust, Oxford, UK Introduction: For patients with treatment resistant depression (TRD), in whom there has been at least a partial response to current antidepressant treatment, augmentation is usually recommended. However, there is evidence that these medications are underutilised in clinical practice and sub-optimal levels of dosing and safety monitoring have been reported in augmentation therapies such as lithium or atypical antipsychotics. One reason for this may be due to inconsistent recommendations provided by different guidelines. This may be particularly important to consider in augmentation as polypharmacy may present extra risks in terms of safety and balance of therapeutic effect versus burdens. This review compared guidance of different recommendations for pharmacological augmentation strategies in unipolar TRD to highlight consensus and recommend further research in this field. Methods: Current major guidelines for the treatment of major depression were reviewed. Recommendations for pharmacological augmentation strategies were extracted from guidelines by two independent researchers and where inconsistencies were noted consensus established by discussion with the wider group. Results: All included guidelines provided recommendations for pharmacological augmentation strategies in TRD, typically after failure to respond to one or more antidepressants. Lithium was recommended by all reviewed guidelines, though there was some variation in the therapeutic dose and regarding whether lithium should be considered a first or second-line option. Second-generation atypical antipsychotics were recommended by all guidelines, and most guidance tended to favour the following medications: aripiprazole, quetiapine and risperidone. Again variation existed in the recommended doses for each atypical antipsychotic. Thyroid hormones were recommended by all guidelines except one, however, some were unable to recommend specific doses. Bupropion and buspirone were also recommend by more than one guideline, though not by the majority. Safety information such as pre-prescription checks and monitoring recommendations were only available in a small number of guidelines. Conclusions: Though there appears to be some consensus regarding the type of add-on medications recommended in TRD, disparity surrounding adequate dose ranges and length of treatment continuation is apparent. This could be due to varying definitions of TRD, time of publication or different emphasis placed on studies included in constructing the recommendations. Often missing were safety recommendations. Although it could be argued that many guidelines did not seek to provide A136 ABSTRACTS this information, due to findings suggesting that this is often sub-optimal, this highlights a potential area of improvement for future guidance. Further research and guidance clarifying doses and duration of augmentation treatment is also required. Financial Sponsorship: None declared.

I26 MIGRATION AS A RISK FACTOR FOR DEVELOPING DEPRESSION: A SYSTEMATIC REVIEW Banafshei F, Centre for Affective Disorders, IoPPN, Room M3.24 PO72, De Crespigny Park, Denmark Hill, London, SE5 8AF [email protected] Young AH(1), Juruena MF(1) (1) As presenting author Introduction: An estimated 258 million people reside in countries other than their place of birth and this figure has increased by 49% since 2001. Meanwhile, depression has been characterised as a leading cause of disability, with over 320 million sufferers worldwide. Although researchers rely heavily on post-migration observations of mental health, and seldom have the opportunity to prospectively collect pre-migration data, studies have suggested an association between migration and the onset of depression, schizophrenia, anxiety and PTSD. Depressive symptoms within migrants has been suggested to be influenced through complex genetic and environmental interactions, including age, loss of cultural identity, migration status, fluency in language, forced migration, education and employment, trauma, genetic profile and gender. Mental health symptoms within second and third-generation migrants have also been documented. Alas, predictive factors of migration, aetiology, and the onset of depression amongst migrants remain unclear due to a shortage of clinical trials and studies. Aim: The study’s objective was to review the literature on migration as a risk factor for developing depression, and seek to identify whether there are effects between migration subtypes and the onset of depression and other comorbidities. Methods: We conducted a systematic literature review by searching in four main databases (Web of Science, PubMed, PsychINFO, and OvidSP) up until March 2018, using the key words “Migration”, “Migrants”, “Emigrating”, “Immigrating”, “Depression” and “Mental Health”. All studies were scrutinized to determine the methodological characteristics and screened for outcome-distorting biases. Results: Twenty-seven articles were selected that associated subtypes of migration with different symptomatic causes of affective disorders. Of these, 5 correlated ethnicity, age, gender, and genetic profile with depression, and 7 further associated employment, language proficiency and education with the disorder. Social isolation, loss of cultural identity, and lack of family ties were highly associated with the development of depression, anxiety, agoraphobia and adjustment disorder within 12 articles. 6 articles found forced migration and migration status to trigger the onset of PTSD, and 4 articles linked trauma and political violence to substance misuse disorder. Furthermore, 15 articles also demonstrated social isolation and integration as the main trigger for migrants developing disorders that impaired cognitive functioning. Conclusion: This systematic review found migration to be an evident risk factor for developing depression and other affective disorders that severely impact cognitive functioning. The process of migration, and social integration within new host countries, proved to be the main triggers of cognitive dysfunction. No sponsorship received.

I27 A SYSTEMATIC REVIEW OF THE EFFECTS OF CHINESE HERBAL MEDICINES WITH ANTI- INFLAMMATORY EFFECTS IN MOOD DISORDERS Hou M, Department of Psychiatry, Clinical and Experimental Sciences, Faculty of Medicine, 1.University of Southampton, College Keep, 4-12 Terminus Terrace,Southampton, SO14 3DT, UK; 2. Shandong Mental Health Centre, China, No.49 Wenhua East Road, Jinan, Shandong, People’s Republic of China, 250014 [email protected] Baldwin DS(1), Hou R(1) (1) Univ Dept of Psychiatry, University of Southampton, Southampton SO14 3DT Introduction: Inflammatory processes may be involved in the pathogenesis of mood disorders and medications with anti-inflammatory effects may provide new treatment approaches. We aimed to review ABSTRACTS A137 current evidence regarding the anti-inflammatory effects of Chinese herbal medicines in animal ‘models’ of depression and anxiety and in patients with mood disorders. Methods: Literature search performed in scientific databases including Pubmed, China National Knowledge Infrastructure (CNKI) Database, Scopus and Web of Science. Screening, data extraction and quality assessment were conducted. Primary outcome measures were pre- and post- treatment levels of peripheral inflammatory cytokines. Results: 112 studies were initially identified: after exclusion criteria were applied six studies could be included in this review (3 animal studies, 3 human studies). Soyo-san reduced IL-1β-ir neurons and depression-like responses in rats. Salvianolic acid B decreased expression of IL-1β and TNFα, and increased expression of anti-inflammatory cytokines IL-10 and TGFβ. Rhizoma drynariae reduced blood levels of IL-6 and increased levels of IL- 10, and reduced anxiety-like and depression-like behaviors in rats. Three randomised controlled trials (including 272 participants, with treatment duration varying between 4-8 weeks) used Chinese herbal medicine as an adjunctive treatment to treatment as usual (TAU) comparing to TAU. All three trials found a significant reduction in depressive symptom severity (P <0.05). Two CTsR included Chaihu Shugan powder combined with venlafaxine and modified Chaihu Decoction combined with paroxetine: symptoms assessed by Hamilton Depression Rating Scale reduced from32.24 to 7.20 (intervention group) compared to 32.68 to 12.49 (control group). After treatment serum levels of IL_2 and TNFα were significantly decreased in the two groups (P < 0. 05), significantly more so in the treatment group than in venlafaxine or paroxetine only group (P < 0.05). The third RCT investigated modified Chaihu-jia-longgu-muli-tang combined with paroxetine, and post-treatment serum levels of IL_ 1, TNFα and IL_ 6 significantly decreased in both groups (P < 0.05), significantly more so in the treatment group than in paroxetine only group (P < 0.05). Conclusion: Certain Chinese herbal medicines have anti-inflammatory effects in pre-clinical and clinical studies, suggesting potential benefits in patients with depressive and anxiety disorders. Further exploratory studies and placebo-controlled randomised trials are warranted to explore potential clinical applications. Funding: This study was funded by an academic exchange award from People’s Republic of China State Administration of Foreign Experts Affairs to Shandong Mental Health Centre and University of Southampton (2017/18: P172023007).

J01 CAN PERIPHERAL MEASUREMENTS OF BASELINE OXYTOCIN IN SALIVA AND PLASMA PROVIDE RELIABLE BIOMARKERS? Martins D, Neuroimaging, King’s College London, Department Of Neuroimaging (P089) King’s College London, De Crespigny Park Road, Denmark Hill, SE5 8AF [email protected] Gabay A(1), Mehta M(1), Paloyelis (1) (1) As presenting author Background: The oxytocin system has attracted remarkable attention over the last years as a promising therapeutic target for socio-emotional deficits in a range of neuropsychiatric disorders. A key question in the field is whether basal oxytocin concentrations in peripheral samples, such as plasma and saliva, can provide reliable biomarkers of the state of the oxytocin system that can be linked with and predict neuropsychiatric symptoms. Methods: Saliva and plasma oxytocin concentrations were measured at baseline and following the administration of exogenous intravenous or intranasal (115-120 min post-administration) oxytocin in a double-blind, triple dummy, placebo-controlled study, involving 17 healthy males tested across four weekly sessions at the same time of day. The reliability of baseline measurements across all four sessions was assessed in both fluids using intra-class correlation coefficient. An independent dataset (N = 20 males, two sessions) was used to replicate the estimated reliability of plasma measurements. To explore the extent to which oxytocin concentrations in saliva may index plasma concentrations, salivary oxytocin concentration following intravenous administration of exogenous oxytocin was assessed. Additionally, correlations between oxytocin levels measured in plasma and saliva samples collected concomitantly at baseline and after oxytocin administration (intravenous and intranasal) were determined using Pearson correlation. Oxytocin was assayed using radioimmunological analysis (RIAgnosis). Results: Both plasma and salivary oxytocin concentrations showed poor reliability across visits (ICC=0.29 – plasma; 0.23 – saliva). The low reliability of plasma measurements was replicated in an independent dataset (ICC=0.49). While intranasal oxytocin increased the concentration of oxytocin A138 ABSTRACTS in saliva, as expected, intravenous oxytocin administration did not (at 115-120 min post-administration, and while plasma concentrations of oxytocin were higher than physiological levels with both methods). Concentrations of oxytocin in saliva were not significantly correlated with plasma neither at baseline (R2=0.02, p=0.24) nor after exogenous intravenous or intranasal administrations (R2=3.20x10-5, p=0.96). Conclusions: Single measurements of basal oxytocin are unlikely to represent a valid marker of the state of an individual’s oxytocin system. Concentrations of saliva oxytocin are unlikely to accurately index its plasma levels and should be interpreted with caution. Further studies identifying conditions where peripheral oxytocin might be reliably measured are needed before its validity as biomarker might be disclosed. Disclosure: This study represents independent research funded by: (1) an Economic and Social Research Council fellowship to YP (grant number ES/K009400/1); (2) part funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London; (3) part funded by an unrestricted research grant by PARI GmbH to YP. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.’ AG was supported by an MRC studentship.

J02 EFFECTS OF POST-LEARNING REM SLEEP DEPRIVATION ON HIPPOCAMPAL ZIF268 AND MIR-124 EXPRESSION IN MICE Kilic E, Department of Physiology, Cumhuriyet University Faculty of Medicine, İmaret Köyü/Sivas Merkez/ Sivas, 58140 [email protected] Karabulut S(3), Kilic E(1), Bayramov KK(2), Golgeli A(4) (1) As presenting author; (2) Department of Medical Biology, Erciyes University, Kayseri, Turkey; (3) Department of Physiology, Cumhuriyet University Faculty of Medicine, Sivas, Turkey; (4) Department of Physiology, Erciyes University, Kayseri, Turkey The behavioral experiments have led to the conclusion that post-learning Rapid Eye Movement Sleep Deprivation (REM-SD) disrupts memory consolidation (MC) if this specific period of sleep is eliminated (Smith C, Rose GM. 1996/Physiol Behav/59/93-97). The transcription factor zinc finger protein-268 (Zif268) regulates the expression of many genes involved with synaptic plasticity and has a crucial role in MC. miR-124, an abundant brain-specific miRNA, reduces the expression of Zif268 and it is implicated in the MC (Yang Y, et al. 2012/Neuron/73/774-788.) Therefore, the current study aims to determine the effects of a specific time period of sleep, and sleep deprivation on hippocampal-dependent spatial MC and the changes of the expression of Zif268 and miR-124 in the hippocampus. Methods: 30 male BALB/c mice, aged 2 months, were grouped into three groups where each group consists of 10 mice. Group 1: after the last training session the mice were deprived of sleep for 3 hours immediately (SD1), Group 2: after the last training session the mice were deprived of sleep for 3 hours after 3 hours waiting period (SD2), and Group 3: control group - Non-sleep deprived (NSD). Spatial learning and memory were tested in the Morris Water Maze (MWM). REM sleep was eliminated by using the modified multiple platform method. Quantitative RT- PCR was used to measure the changes in the expression of mRNA and miRNA. Repeated-measures ANOVA was used to analyze the changes in Distance Moved (DM) and Escape Latency (EL). Probe trial, the time spent in the target quadrant to the ratio of the total time spent expressed as a percentage value (PT), was analyzed using one way ANOVA. Results: There was a significant increase in DM and EL in SD2 compared to control, while no difference was observed in SD1. In addition, PT was found to be significantly lower in SD2 compared to NSD. Hippocampal Zif268 gene expression was found lower in both SD groups compared to NSD, whereas a significantly decreased expression of in miR-124 was observed in SD1. Conclusion: Our findings indicate a specific 3 h of REM-SD period following learning impairs spatial memory. The downregulation of miR-124 in the SD1 group may be an adaptive response that to compensate for memory distortion. As potent regulators of mRNA translation, miRNAs may target critical components of MC and play central role in memory formation. Sponsorship: Erciyes University Scientific Research Projects Unit was supported this project by the project code TDK-2015-6077. ABSTRACTS A139

J03 AYAHUASCA BEVERAGE INDUCES CHANGES ON THE EXPRESSION OF GLUTAMATE RECEPTORS IN THE HIPPOCAMPUS OF WISTAR RATS Gervasio VP, FACISB, Street 10, number 337 - Ituiutaba, Minas Gerais - Brazil, 38300-060 nessa.paranaiba@ hotmail.com Bertequini RB(1), Calfi GS(1), Rosa MLNM(2) (1) Barretos School of Health Sciences Dr. Paulo Prata, FACISB, Barretos, Brazil; (2) Barretos School of Health Sciences Dr. Paulo Prata, FACISB, Barretos, Brazil; Institute of Neuroscience and Behavior, INeC-USP, Ribeirao Preto, Brazil Introduction: The consumption of Ayauhasca beverage is usual in several Brazilian syncretic religions that have expanded their activities to Europe and North America. Members of these religious groups ingest Ayahuasca at least 3 times a week. This beverage is made from an Amazonian psychoactive plant containing the 5-HT agonist N,N-dimethyltryptamine (DMT) and monoamine oxidase-inhibiting alkaloids (harmine, harmaline and tetrahydroharmine). Ayahuasca ingestion has been reported to affect learning and memory processes, which may involve interactions between serotonergic and glutamatergic systems in brain areas including hippocampus. This work aimed at investigating whether treatment with Ayahuasca might induce alterations in the expression of glutamate AMPA receptors (GluR1 and GluR2/3) in the hippocampus of rats. Methods: Twelve groups of male Wistar rats (230-250g, n=5-8/each) were used. Six groups received 0.2 or 0.4ml/g of Ayauhasca beverage, only once (acute), 3 times/day for 3 days (sub-chronic) or once/day for 15 days (chronic). Six control groups received water at the same conditions. Sixty minutes after the last Ayahuasca ingestion the animals were anaesthetized, perfused and their brains sectioned (40um) for immunohistochemistry detection of GluR1 or GluR2/3 subunits. The number of immunopositive cells (IC) was quantified in the hilus of dentate gyrus (HDG), CA3 and CA1, bilaterally. Comparisons between control and Ayahuasca groups for each treatment, separately, used Student t test for independent samples (p≤0.05). Results: The acute ingestion of Ayahuasca (0.2ml/g) induced a significant decrease in the number of GluR1 IC in CA1 (18%), while 0.4ml/g induced an increase in GluR1 IC in the HDG (30%) and CA1 (10%). Chronic ingestion of 0.4ml/g also induced an increase in GluR1 IC in the HDG (29%) and CA1 (23%). No difference was found in any hipocampal area with the sub-chronic treatment. Changes in the expression of GluR2/3 in the hippocampus were induced only by chronic ingestion of either 0.2ml/g or 0.4ml/g of Ayahuasca. Significant increase in the number of GluR2/3 IC was found in CA3 (25%) and CA1 (20%). Conclusion: These results suggest that acute or chronic ingestion of Ayahuasca beverage may trigger distinct mechanisms in the hippocampus involving the modulation of glutamate neurotransmission through the activation of 5-HT receptors. Support: FAPESP, FACISB

J04 MODULATORS OF GERANYLATION SHOW SELECTIVE TOXICITY ON NF2-NULL CELLS VIA PROMOTING NUCLEAR RAC1 CYTOTOXIC FUNCTION Zavyalov GA, RNRMU, Ostrovitianov str. 1, Moscow, Russia, 117997 [email protected] Stepanova DS(1), Shimanovskiy NL(1), Tyulganova DA(1), Chernoff JC(2) (1) As presenting author; (2) Fox Chase Cancer Center, Philadelphia, PA USA Introduction: Neurofibromatosis type II (NF2) is a rare autosomal dominant cancer syndrome characterized by the formation of multiple specific nervous system tumors, particularly schwannomas and meningiomas. The disease occurs due to inactivating mutations of the NF2 tumor suppressor gene. Clinical features of NF2 typically include nervous system tumors (vestibular schwannomas, intracranial meningiomas, spinal tumors, and peripheral nervous system tumors), and ocular abnormalities. The disease is often fatal due to formation of inexorable, inoperable, intracranial brain tumors. There’s no medical treatment for this condition; rather, patients must endure repeated neurosurgery to remove the tumors, often resulting in deafness and blindness. Methods: High through-put screening, FRET, xenografts Results and Conclusions: In order to probe the vulnerability of Nf2-null cells to small molecules, we performed a synthetic lethal screen using a library of small bioactive compound library in isogenic A140 ABSTRACTS

Nf2+/+ and Nf2-/- mouse embryo fibroblasts, seeking compounds that selectively kill Nf2-deficient cells. Nine compounds showed significant selectivity for NF2-deficient cells; of these, lovastatin proved to be the most effective. Further investigation revealed that the effect of lovastatin was due to inhibition of geranylation (by decreasing the geranyl-geraniol pool in the cell), and that a GGTase type I was involved. We proved that statins acted via geranyl-geraniol pool deprivation, thus promoting Rac1 to detach from the cell membrane. Tracing GFP-tagged Rac1 showed that being unable to anchor in the cell membrane it translocated to the nuclei in both knockout and wild-type cells. By measuring FRET (fluorescence resonance energy transfer) we showed significant activation of Rac1 in the nuclei of NF2-deficient cells in the presence of simvastatin, thus discovering a novel cytotoxic function of active Rac1 in the nucleus. In vivo, xenograft studies using RT4 (Nf2-deficient rat schwannoma) cells and SC4-9 (Nf2-deficient mouse schwannoma) revealed that lovastatin and zoledronic acid significantly slowed down tumor progression, indicating that these two FDA-approved agents might be useful in treating NF2-related schwannomas. Funding Support: 1) US Department of Defense CDMRP Neurofibromatosis Research Program Awards; 2) Donation from Galloway family; 3) Initiative research program, RNRMU, Russia

J05 PREDICTING RESPONSES TO PSYCHEDELICS: A PROSPECTIVE STUDY Haijen ECHM, Department of Medicine, Imperial College London, Burlington Danes Building, Hammersmith Hospital, Du Cane Road, London, W12 0NN [email protected] Kaelen M(1), Roseman L(1), Russ S(2), Nutt DJ(1), Daws R(1), Hampshire A(1), Lorenz R(1), Timmerman C(1), Carhart-Harris RL(1) (1) As presenting author; (2) Dept of Social Sciences, Dickinson State University, Dickinson ND 58601 Introduction : Responses to psychedelics are notoriously difficult to predict, yet significant work is currently underway to assess their therapeutic potential and the level of interest in psychedelics among the general public appears to be increasing. We aimed to collect prospective data in order to improve our ability to predict acute- and longer-term responses to psychedelics. Methods: Individuals who planned to take a psychedelic through their own initiative participated in an online survey (www.psychedelicsurvey. com). Traits and variables relating to set, setting and the acute experience were measured at five different time points before and after the experience. Principle component and regression methods were used to analyse the data. Sample sizes for the five time points included N= 611, N= 535, N= 379, N= 315, and N= 212 respectively. Results : Psychological well-being was increased two weeks after a psychedelic experience and remained at this level at four weeks after the experience. This increase was larger for individuals who scored higher for a ‘mystical-type’ experience, and smaller for those who scored higher for ‘challenging’ experience. Having clear intentions and expectations for the experience were conducive to mystical-type experiences. Having an experience with ‘recreation’ as intention and having a positive ‘set’ were both found to decrease the likelihood of having a challenging experience. The trait absorption and higher drug doses promoted both mystical-type and challenging experiences. Trait variables and having a ‘spiritual’ intention explained more variance in the change in well-being compared to acute experience measures. Conclusions: These results confirm the importance of extra-pharmacological factors in determining responses to a psychedelic. Whereas acute experience measures do have some influence on longer- term effects, trait variables showed to explain more variance, implying these might be more important to consider when predicting responses to psychedelics. We view this study as an early step towards the development of empirical guidelines that can evolve and improve iteratively with the ultimate purpose of guiding crucial clinical decisions about whether, when, where and how to dose with a psychedelic, thus helping to reduce risks while maximising potential benefits in an evidence-based manner. Funding The authors received no financial support for the research, authorship, and/or publication of this article. ABSTRACTS A141

J06 INTERGENERATIONAL TRANSMISSION OF PSYCHOPATHOLOGY: FROM ANTENATAL DEPRESSION TO CHILD SYMPTOMS IN THE PRAM-D COHORT Sawyer K, Psychological Medicine, IoPPN, KCL, Maurice Wohl Clinical Neuroscience Institute, 8 Cutcombe Road, London, SE5 9RX [email protected] Bind RH(1), Allegri B(1), Osborne S(1), Conroy S(2), Sethna V(2), Pawlby S(2), Pariante CM(1) (1) As presenting author; (2) IoPPN, De Crespigny Park, London, SE5 8AF Introduction: Maternal depression affects 10-15% of mothers in both pregnancy and the first year postpartum: the perinatal period. This can have a negative impact on the offspring’s development in early life, however less research has been conducted to understand how long-lasting these effects are, and what environmental factors may exacerbate or protect against them. The Psychiatry Research and Motherhood-Depression (PRAM-D) study aims to understand how maternal antenatal depression may lead to offspring showing increased symptoms of psychopathology. This research is important as it could inform practitioners on the most effective interventions to use to break this cycle of intergenerational transmission of psychopathology. Methods: We are conducting a follow-up study with the PRAM-D cohort, now that the children are aged 7-10 years. We are focusing on child mental health symptoms here, but are also collecting data on other aspects such as stress reactivity, cognition and attachment. We are primarily using mother reports of her own mental health (the Beck Depression Inventory: BDI) and that of her child using the Strengths and Difficulties Questionnaire (SDQ) and Development andell-Being W Assessment (DAWBA). We are also collecting child self-report questionnaires and a teacher-report version of the SDQ. We have conducted preliminary analyses in the first 22 children: 12 males and 10 females, with a mean age of 8.95 years (SD=0.31). Results: In this phase of the study, we have found that women who suffered with antenatal depression are still reporting significantly higher BDI depression scores [mean=9.25(SD=6.60)] when compared with controls [3.83(2.89), t(14)=-5.42, p=0.03]. In addition, we have found that the children of depressed mothers showed numerically higher scores for psychopathology using the DAWBA (although not reaching statistical significance) [mean=4.20(SD=4.92)], compared with controls [1.29(1.40)], t(20)=- 1.31, p=0.26]. Furthermore, these children tended to score higher on the emotion [3.80(3.90) vs. 2.41 (1.77), t(20)=-1.39, p=0.48] and conduct [3.40(2.79) vs. 1.65(1.32), t(20)=-1.75, p=0.24] scales of the SDQ. Conclusions: These data, although only in the preliminary stages, show that we are able to capture some of the previously-reported effects of intergenerational transmission of psychopathology in the offspring of antenatally depressed mothers as early as middle-childhood. As we collect data in the remaining 150 participants, we hope to ascertain what environmental factors present in the child’s upbringing have exacerbated or protected against these negative effects, so that practitioners can identify high-risk groups or make recommendations to ensure the best developmental environment for children. Sources of Financial Sponsorship Ms Sawyer is funded by an MRC Doctoral Training Programme Studentship, at King’s College London.

GL1 GENOMIC INSIGHTS ABOUT THE NEURODEVELOPMENTAL ORIGINS OF SCHIZOPHRENIA Weinberger D, Lieber Inst for Brain Development, Johns Hopkins Medical Campus , 855 N. Wolfe St. Baltimore, MD 21205 , USA [email protected] Compelling evidence from various approaches to identifying risk for schizophrenia implicates early development as playing a critical role. Epidemiological studies have long suggested that diverse complications during pregnancy increase risk upwards of two-fold. Pathway and gene ontology analyses of sets of genes in recent risk loci identified from large scale case control WASG studies implicate neuronal differentiation and early processes in brain developmental. Studies of gene expression across the human lifespan have shown that genes in GWAS risk associated loci are as a group more likely to be expressed during fetal life than during postnatal life, suggesting that they are dynamically regulated during fetal brain development (Birnbaum et al AJP 2012, Jaffee et al Nature Neurosci 2014). Moreover, studies of DNA methylation and of the 3D chromatin state, as epigenetic marks of environmental experience, have further shown that schizophrenia risk associated loci from recent GWAS studies implicate epigenetic variation A142 ABSTRACTS that distinguishes fetal from postnatal development (Jaffee et al Nat Neurosci 2016, ). These data argue that both genetic and epigenetic risk for schizophrenia involve early brain development, and surprisingly, not the period of time when the clinical diagnosis is first made. These data, however, are circumstantial and not definitive. Accordingly, we have recently shown that genetic risk for schizophrenia, as measured with polygene risk scores calculated from the most GWAS-significant loci, interact with serious prenatal and perinatal complications in affecting risk for schizophrenia, so that the liability of schizophrenia of genetic risk is five time higher in individual with a history of such complications compared with its absence (Ursini et al Nat Medicine 2018). Consistently, we have found that the genes mapping to the schizophrenia risk loci, and interacting with those complications, are highly expressed in placenta and differentially expressed in placentae from complicated in comparison with normal pregnancies; moreover, they are differentially up-regulated in placentae from male compared with female offspring. Such finding suggests a link between genetic risk for schizophrenia and placenta pathophysiology, together with a sex-biased role for the placenta in expressing genetic risk for schizophrenia. These data establish a time window of fetal life as a major component of the risk architecture of schizophrenia and suggest potentially new avenues for prevention based on placental health and high placental genetic risk. These studies and their implications are the subject of this lecture.

PD01 MIND YOUR CUES! - HOW THE COMT-MET MOUSE MODEL HELPS US UNDERSTAND THE CONNECTIONS BETWEEN CORTICAL DOPAMINE, CUE SALIENCE AND REINFORCEMENT LEARNING Huber A, Psychiatry, University of Oxford, Department of Psychiatry, Warneford Hospital, Warneford Ln, OX3 7JX [email protected] Oikonomidis L(2), Tunbridge EM(1), Walton ME(2) (1) As presenting author; (2) Department of Experimental Psychology, University of Oxford Using environmental cues to predict rewarding events is essential for adaptive behaviour in humans and animals alike. This process of learning by association depends on dopamine, specifically dopamine release in the ventral striatum. While much is known about striatal dopamine and reward prediction error, it is unclear whether dopamine in other brain regions, particularly the cortex, might play a role in mediating other factors influencing learning. To answer this question, I used a transgenic mouse model mimicking a polymorphism found in the human catechol-O-methyltransferase gene (COMT Val158Met). COMT plays an important role in the breakdown of dopamine in cortex, and its activity is reduced in Met-allele carriers. In this talk I will present a series of experiments revealing, surprisingly, that COMT genotype affects associative learning in a cue salience-dependent manner. I will then relate this effect to changes in phasic dopamine release in the striatum, recorded during learning through fast-scan cyclic voltammetry. Taken together, these data suggest that cortical-striatal dopamine circuitry may mediate salience effects in associative learning.

PD02 LOW ATTENTIVE AND HIGH IMPULSIVE RATS: BEHAVIOUR BASED MODELLING Hayward A, Center For Neuroplasticity and Pain, Aalborg University, Andrew James Hayward Fredrik Bajers Vej 7E1-203, Aalborg University, 9220 Aalborg E, Denmark, 9220 [email protected] Neill JC(1) (1) Manchester Pharmacy School, University of Manchester, Manchester M13 9PT, UK Many human conditions such as attention deficit hyperactivity disorder (ADHD), schizophrenia and drug abuse are characterised by deficits in attention and impulse control. Carefully validated animal models are required to enhance our understanding of the pathophysiology of these disorders, enabling development of improved pharmacotherapy. Recent models have attempted to recreate the psychopathology of these conditions using chemical lesions or genetic manipulations. In a diverse population, where the aetiology is not fully understood and is multifactorial, these methods are restricted in their ability to identify novel targets for drug discovery. Two tasks of visual attention and impulsive action typically used in ABSTRACTS A143 rodents and based on the human continuous performance task (CPT) include, the well-established 5 choice serial reaction time task (5C-SRTT) and the more recently validated, 5 choice continuous performance task (5C-CPT) which provides enhanced translational value. This talk will explore the idea of separating animals by behavioural performance into high and low attentive and impulsivity cohorts using established parameters in these tasks and how this offers a model with high translational value. Furthermore, methods to separate animals are compared and the results discussed to highlight advantages in comparison to other models.

PD03 DEVELOPMENT OF A HYPERVIGILANCE MODEL USING RODENT 22-KHZ ULTRASONIC VOCALISATIONS Cahill EN, Dept of Psychology, Univ of Cambridge, Downing Street, Cambridge, CB2 3EB [email protected] Hypervigilance, a state of heightened sensory sensitivity to threatening stimuli, is an attentional bias symptomatic of many anxiety disorders. The development of new therapeutics for anxiety disorders is highly dependent on the identification and characterisation of animal models of anxiety. Recent investigations of rodent 22-kHz ultrasonic vocalisations (USVs) have shown that these might be a valid behavioural measure of anxiety. The hypothesis of this study is that the emission of USVs in a Pavlovian conditioned-fear paradigm is associated with hypervigilant behaviour. As such, this research intends to develop and refine an animal model of hypervigilance that could be used to screen new therapeutics. Rats were trained in a fear-conditioning procedure, in which a tone (CS) predicted an unavoidable footshock (US). USVs and freezing were measured across a conditioning phase and a subsequent test phase in order to further elucidate the relationship between behaviour and the affective states induced by threatening stimuli. Additionally, the CS was modified at test to reduce its detectability and salience, in order to screen for hypervigilance. After fear-conditioning, a population of rats were screened in a traditional test of anxiety, the elevated plus maze, in order to examine inter-individual differences in anxiety-related behaviour. The results suggest that the nature of the anxiety experienced during a fear-conditioning procedure is qualitatively different to that elicited by the elevated plus maze and we will discuss the results on optimising the behavioural protocol.

PD04 ANXIETY AND ANHEDONIA: OVERACTIVITY IN THE MARMOSET SUBGENUAL ANTERIOR CINGULATE Gaskin PLR, PDN, University of Cambridge, Downing Street Cambridge, CB2 3DY [email protected] Alexander LA(1) (1) As presenting author The common marmoset Callithrix jacchus is an ideal species for studying the role of the prefrontal and anterior cingulate cortices in emotional regulation, owing to cortical structural comparability to humans, and the complex array of cognitive and emotional behaviours marmosets display. This presentation will consider anxiety and anhedonia in the common marmoset, what we have learned about the contribution of overactivity of subgenual anterior cingulate cortex (sgACC, Brodmann Area 25) to these symptoms, and their relevance to our understanding of mood and anxiety disorders. Anxiety and anhedonia are complex emotional constructs of behavioural and physiological changes that cannot be adequately examined using single experimental outputs. In the marmoset, we are able to study different behavioural components of these constructs experimentally, alongside autonomic cardiovascular monitoring via surgically implanted radiotelemeters, providing a more comprehensive analysis of evoked emotional responses. We can study uncertainty-induced anxiety by confronting marmosets with an unfamiliar human intruder in the home cage setting. This can be contrasted with conditioned fear, where contextual and auditory cues associated with the appearance of aversive outcomes (such as naturalistic snake stimuli or combined white-noise and darkness) induce marked cardiovascular and behavioural responses. Behavioural and autonomic correlates of anhedonia can also be examined in marmosets, including anticipatory, consummatory and motivational aspects. Using these methods we have examined the effects of overactivation of sgACC by intracerebral infusion of the GLT-1 glutamate transporter inhibitor dihydrokainic acid. SgACC/25 has been A144 ABSTRACTS implicated in cardiovascular regulation and elevated activity within sgACC/25 is associated with negative affective bias and depressive symptoms in patient groups. However, it still remains unclear whether elevated activity in sgACC/25 is causally related to these symptoms, or instead reflects a compensatory change. Building on our previous work which showed that sgACC/25 overactivation blunted anticipatory appetitive arousal we now show that such blunting extends into the motivational domain, reducing responding on an operant task with progressively increasing response demands. Reward consumption, however, is unaffected in two separate paradigms. In contrast to reduced reward sensitivity, sgACC/25 overactivation enhances the behavioural and cardiovascular correlates of conditioned fear and uncertainty-induced anxiety. Comparison of the sensitivity of these overactivation-induced symptoms to the antidepressant drug, ketamine, reveals that only the anhedonic symptoms are ameliorated. Thus, ongoing work utilising 18F-FDG PET imaging aims to elucidate the brain networks by which sgACC/25 overactivation influences negative and positive emotional experiences and determine how acute ketamine treatment differentially modulates these networks. This study was supported by a Wellcome Trust Investigator award (108089/Z/15/Z) to Angela C Roberts and performed within The Behavioural and Clinical Neuroscience Institute, jointly funded by the MRC and Wellcome Trust.

PD05 COMPUTATIONAL MODELS OF DYNAMIC LEARNING WITH IMPLICATIONS FOR UNDERSTANDING AFFECTIVE BIASES Pulcu E, Dept of Psychiatry, Univ of Oxford, Warneford Hospital Oxford, OX3 7JX erdem.pulcu@psych. ox.ac.uk Clinical research suggests a causal relationship between negative affective biases and depressive symptomatology. Therefore, understanding the mechanisms underlying formation and maintenance of affective biases is likely to be important for understanding why some people might be at high risk for developing major depressive disorder. Recently, we have shown that people adjust how they learn about positive and negative events in response to how changeable, or volatile, those events are. The volatility with which probabilistic events occur determines the level of “unexpected uncertainty” of the event. This is because, in volatile environments, previously learned associations can suddenly, and unexpectedly, change (e.g. rewarding choices become no longer rewarding). People estimate the “information content” of the events they observe and learn more from those events (such as volatile events) which they judge to be more informative. This finding may provide insight into why people display affective biases because, if negative events are judged to be more informative, developing a negative affective bias might be the optimal way of adapting to one’s environment. In the current talk, I will describe a study which builds on this previous work by testing the impact of different sources of environmental uncertainty (i.e. “expected” vs “unexpected”) on human reinforcement learning. Expected uncertainty arises when the association between events is less certain (e.g. events that are linked 60% of the time, rather than 100% of the time). In contrast to unexpected uncertainty, which requires increased learning rates, expected uncertainty should encourage low learning rates. Here, by using both well-established reinforcement learning (RL) and novel Bayesian Ideal Observer models, I will demonstrate, in a group of nonclinical participants (N=70), that unexpected uncertainty significantly increases learning rate (F(1,823)= 20.723, p<.001). In contrast, human learners displayed sub-optimal responses to changes in expected uncertainty and did not adjust their learning rate (F(1,823)= 0.037, p=.848). Furthermore, in a subgroup of participants (n=36) who underwent pupillometry recording, I will demonstrate evidence to suggest that the central norepinephrine system is engaged in tracking the trial-by-trial variation in different sources of environmental uncertainty. The lack of normative response to expected uncertainty demonstrated in this study is consistent with a general “noise blindness” in human learners. This suggests that affective biases may arise from, and be modified by, differential estimates of the volatility (unexpected uncertainty) of positive vs. negative events, but that such biases are unlikely to be caused or modified by differential responses to expected uncertainty. This study was funded by a Medical Research Council Clinician Scientist Fellowship awarded to Michael Browning (MR/N008103/1). ABSTRACTS A145

PD06 DISSECTING THE CONTRIBUTIONS OF REWARDS AND EFFORT ON MOTIVATION Valton V, Inst of Cognitive Neuroscience, University College London, Alexandra House, 17 Queen Street, London, WC1N 3AZ [email protected] Motivation is an essential component of neuro-economic decisions. It can be defined as the willingness to exert effort to attain a particular outcome, which is dependent on the magnitude of anticipated rewards and the effort costs required. Understanding motivation has wide ranging implications from being able to better gauge inter-individual variation in healthy decision-making, to dissecting symptoms such as anhedonia in depression and schizophrenia. Here we present a computational analysis of motivation, as assessed by the Apple Gathering Task (AGT). In the AGT, participants squeezed a hand-dynamometer to win points. Effort required (force) and potential reward (money) were manipulated on a trial-by-trial basis, and subjects could either accept the challenge and exert effort, or refuse and skip the trial. We analysed participants’ choices using models of trial-by-trial behaviour. We then compared the winning model parameters to four latent variables measuring low-mood/anxiety, anhedonia, apathy and dysfunctional attitudes. As expected participants’ willingness to accept an offer decreased significantly with increasing effort level, and increased significantly with increasing reward level. Subjects with higher effort sensitivity parameters scored higher on anhedonia (r=0.22, p=0.037) and dysfunctional attitudes (r=0.25, p=0.017), while those with lower reward sensitivity parameters scored higher on low-mood/anxiety (r=0.35, p<0.01). This analysis suggests that we may be able to dissect the individual contributions of reward and effort on motivation.

PD07 THE EFFECTS OF MIFEPRISTONE ON THE NEURAL CORRELATES OF WORKING MEMORY Yalin N, Centre for Affective Disorder, Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King’s College of London, 16 De Crespigny Park, PO 72, London, SE5 8AF [email protected] Young AH(1), Stokes PRA(1) (1) As presenting author Bipolar disorder is a severe mental health disorder and is an important cause of disability and death. A major unmet challenge in the treatment of bipolar disorder is the effective treatment of cognitive impairment, which is thought in part to be mediated by dysregulation of the hypothalamic-pituitary-adrenal (HPA) stress hormone axis (Young et al, 2004, Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 29(8): 1538-1545). Mifepristone is a glucocorticoid and progesterone receptor antagonist which may block the effects of stress hormones in the brain, and is currently clinically used to induce abortion and for emergency contraception. Experimental animal and preliminary clinical studies have indicated that mifepristone can improve spatial working memory performance in bipolar disorder but the neural mechanisms underlying is still unknown (Watson et al, 2012, Biological psychiatry 72(11): 943-949). This study aimed to examine the effects of mifepristone on working memory using functional magnetic resonance imaging (fMRI) in healthy male participants using a randomized, double blind and cross-over design. 20 right- handed healthy participants without past or current psychiatric disorders were recruited and were randomized to receive mifepristone (600mg) and an oral placebo. Participants completed an n-back working memory fMRI task on two separate imaging days using 3 Tesla MRI scanner in Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology and Neuroscience, King’s College of London. On each imaging day, participants received mifepristone or placebo 4 hours before each MRI scan. Each imaging session took place at around 2pm in the afternoon. Mifepristone, serum cortisol and dehydroepiandrosterone levels were measured before receiving medication and at the end of each scan. Mood and anxiety levels were measured at baseline and post-scan using the Quick Inventory of Depressive Symptomatology Self Report, Visual Analog Scale of subjective mood and experience and the Spielberger State Anxiety inventory. Repeated measures analysis of covariance will be used to explore the effect of mifepristone treatment on behavioural measures. All fMRI data will be analysed using SPM12. Data analysis is still ongoing and preliminary results for mifepristone related effects on N-Back fMRI task related brain activations will be presented during this presentation. This study was supported by the NIHR Maudsley Biomedical Research Centre and by grant funding from Corcept Therapeutics Inc A146 ABSTRACTS

PD08 COGNITIVE TRAINING OF EPISODIC MEMORY IN NEUROPSYCHIATRIC DISORDERS Savulich G, Dept of Psychiatry, University of Cambridge, Herchel Smith Building for Brain and Mind Sciences, Forvie Site, Robinson Way, CB2 0SZ [email protected] Introduction: Neuropsychiatric disorders are disorders of cognition, motivation and their interaction. In addition to impairments in cognitive domains including memory, patients with neuropsychiatric disorders also report a high incidence of apathetic and depressive symptoms, which represent complex barriers to treatment entry and engagement. Cognitive training is effective in patients with neuropsychiatric disorders, but does not typically address the motivational deficits associated with memory impairment. Method: We developed ‘Wizard’ (http://www.peak.net/advanced-training/) and ‘Game Show,’ two novel iPad-assisted memory games for cognitive training based on neuropsychological and neuroimaging evidence. In Study 1 (n=22), patients with schizophrenia were randomly assigned to either the cognitive training (eight hours of playing ‘Wizard’ over a duration of four weeks) or control (continuation of daily life as usual) groups. The same design was used in Study 2 (n=42; cognitive training compared with clinic visits as usual groups) in patients with mild cognitive impairment (MCI; often the prodromal stage of Alzheimer’s disease), but using the ‘Game Show’ memory game. All participants completed baseline and outcome measures of memory (e.g. CANTAB Paired Associates Learning task; www.cambridgecognition. com), global cognition and motivation. Results: In Study 1, the cognitive training group showed better episodic memory (p=.03) and global assessment of functioning (errors: p=0.04) compared with the control group at outcome. In Study 2, the cognitive training group showed better episodic memory (errors: p=.04, trials: p=.03), global cognition (p=.04) and visuospatial skills (p=.03) compared with the control group at outcome. Within-group comparisons revealed highly specific effects of cognitive training on episodic memory. Across all hours of gameplay in both studies, the cognitive training group maintained high levels of enjoyment and motivation to continue, with no participant dropping out. Conclusions: Cognitive training with a game robustly improved episodic memory in two patients groups. ‘Gamification’ maximizes engagement with cognitive training by increasing motivation and could complement existing pharmacological treatments for neuropsychiatric disorders. Gamification may also reduce some of the stigma associated with non-pharmacological interventions for memory. This work was was supported by Janssen Pharmaceutica/Johnson & Johnson and the NIHR Cambridge Biomedical Research Centre (BRC) Mental Health and Neurodegeneration themes. GS is funded by grants from Eton College and the Wallitt Foundation.

PW01 LEARNING WHAT TO EXPECT IN AUTISM SPECTRUM DISORDER: COMPUTATIONAL AND PHARMACOLOGICAL MECHANISMS OF SURPRISE. Lawson RP, Department of Psychology, University of Cambridge, Downing Street, Cambridge, CB2 3EB [email protected] Our perception of the sensory present depends strongly on prior expectations derived from the recent sensory past. Adaptive behaviour rests on the ability to dynamically adjust the balance of prior expectations against new sensory inputs in the face of uncertainty. An appealing new hypothesis is that cognitive features of autism can be understood terms of a failure of Bayesian inference, in which prior information is under-weighted and everyday experience is dominated by a disproportionate sensory drive (Pellicano & Burr, TiCS, 2012). Neurocomputationally, this amounts to problems with cortical gain control, where estimates of variability (e.g. uncertainty) scale the driving neural responses to sensory input via the action of neuromodulators (Friston, Phil. Trans. R. Soc. B, 2005). In this talk I will first introduce the framework by which adaptive gain control mechanisms are proposed to be aberrant in autism (Lawson, Friston & Rees, PNAS, 2016; Palmer, Lawson & Hohwy, Psych Bulletin, 2017). Then, I will go on to present the results of an experiment examining how individuals with autism learn about different kinds of uncertainty to build prior beliefs, and how these learning dynamics are related to pupil size; a proxy for noradrenergic function (Lawson, Mathys & Rees, Nature Neuroscience, 2017). Finally, I will present the results of a double-blind, placebo-controlled study that suggests a causal role for noradrenaline in ABSTRACTS A147 controlling the learning mechanisms by which prior expectations are formed (Lawson, Bisby, Burgess & Rees, in prep). These findings offer a roadmap towards a computationally-based neuropharmacological account of how prior expectations are balanced against sensory reality; a mechanism that may be vulnerable in many psychopathologies. RL is supported by a Royal Society Wellcome Trust Henry Dale Fellowship. This work was funded by the Wellcome Trust.

PW02 COMPUTATIONAL PSYCHOPHARMACOLOGY AS A TOOL FOR PSYCHIATRY Corlett P, Department of Psychiatry, Yale University, Ribicoff Research Facilities, Connecticut Mental Health Center, 34 Park Street, New Haven, 06519 [email protected] Psychopharmacology is concerned with the effects of drugs on the mind and behavior. My work has focused on bridging effects at a receptor level with the phenomenology of drug experiences with a computational framework. That framework, predictive coding, suggests that the brain contains an internal model of the world, organized hierarchically, with top-down predictions and bottom-up prediction errors. So-called psychotomimetic drugs alter the balance between top-down and bottom-up and different drugs do so in different ways. I will focus on the effects of ketamine, which, through functional neuroimaging during cognitive task performance, I suggest engenders aberrant prediction error signals. I find identical signals in first episode psychosis and there, as well as under ketamine aberrant error signals correlate with delusional beliefs. Further, biophysically plausible computational modeling suggests that the aberrant error signals are engendered through an alteration in excitatory/inhibitory balance and that this effect impacts the recurrent excitation critical for the maintenance of coherent cortical representations. Ketamine does not, however, typically engender hallucinations. The modeling work suggests why and predicts that hallucinations arise when the balance is tipped toward top-down prior beliefs. I will show evidence in favor of that prediction from human subjects and discuss its treatment implications. Armed with this computational understanding of psychotic symptoms we are better placed to deploy the treatments we have available and devise new, more targeted, approaches.

PW03 RELATIONSHIPS BETWEEN MESOLIMBIC DOPAMINE FUNCTION AND SALIENCE NETWORK CONNECTIVITY McCutcheon R, Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, Institute of Psychiatry, Psychology & Neuroscience, De Crespigny Park, London, SE5 8AF [email protected] The salience network, composed primarily of the anterior insula and dorsal anterior cingulate, and the mesolimbic dopamine system both play a role in identifying salient features of the environment. Dysfunction of both systems is associated with a range of neuropsychiatric illnesses. Despite overlap in function, the relationship between the two systems remains poorly understood, and has not been directly studied in humans. I will discuss a series of multimodal neuroimaging experiments that have used positron emission tomography to measure dopaminergic functioning within the limbic striatum, and resting state MRI to evaluate salience networks at rest. Specifically, I will show how a graph theoretical approach can be used to integrate PET and MRI data. Using these methods, we have identified dopamine- associated subnetworks within the salience network. In addition, we have defined brain regions as information processing hubs based on degree, betweenness centrality, participation coefficient. We have then shown that these hub regions overlap significantly with the dopamine-associated regions. Our findings highlight the interplay between systems that have frequently been studied in isolation, and are relevant to neuropsychiatric illnesses such as schizophrenia and Parkinson’s disease in which aberrant functioning of both the salience network and the mesolimbic dopamine system has been observed. Finally, I will discuss plans for future studies that will allow us to explore the functional relationship between localised neurochemical signalling, and distributed neuronal networks. A148 PRESENTING AUTHORS

Presenting Author Page Presenting Author Page Amaralingam, J A132 Godlewska, BR A111 Amaro, H A25 Goldman, R A134 Ashok, AH A115 Goldstone, AP A57 Badiani, A A17 Grayson, B A75, A89 Balasubramanium, B A51 Grigoriou, MG A49 Banafshei, F A136 Haan, N A99 Barber, LB A105 Haijen, ECHM A140 Barnes, TRE A44 Hales, CA A122 Bastlund, JF A18 Hayes, A A56 Beck, K A32 Hayward, A A142 Bell, C A10 Heneka, MTH A8 Bien, Z A76 Herane-Vives, A A94 Bind, RH A66 Herlinger, KE A59 Bisson, JI A11 Higgs, S A13 Bogdanova, A A31 Hindocha, C A28 Borgan, F A81, A144 Hobbs, M A64 Borsini, A A118 Hodgson, AR A24 Bourne, M A97 Hook, RW A72 Brennan, LJ A68 Hou, M A136 Brewin, CR A11 Hou, R A93, A110 Brian, EJG A58 Howes, O A1 Bristow, GC A102 Huber, A A142 Broome, M A3 Hughes, RB A40 Burgess, MA A37 Immonen, J A113 Cahill, EN A143 Iniguez, SD A121 Chelliah, A A128 Jauhar, S A104 Chinnasamy, M A47 Jelen, LA A110 Chu, KM A105 Jiang, W A41 Ciufolini, SC A103 Joels, M A4 Clark, L A17 Jones, APM A28 Clay, JM A54 Juruena, MF A5 Cleare, AJ A6 Kanen, JW A60 Cole, DM A71 Kelly, JP A39 Colgin, LL A19 Khandaker, G A9 Collins, DM A55 Kilic, E A138 Cooper, SJ A9, A12 King, MV A36 Corbet Burcher, G A97 Kirov, G A14 Corlett, P A2, A147 Kotecha, AN A48 Corsi-Zuelli, F A90, A91 Kouskou, M A79 Cunningham, MO A19 Kowalczyk, OS A43, A67 Dawson, N A15 Kowash, HM A43 Deakin, B A10 Kuter, BK A96 Enache, ED A95 Lalji, HM A123 Fachim, HA A33, A74 Lawn, WM A58 Farrow, LE A38 Lawson, RP A146 Fitzpatrick, CM A23, A83 Lingford-Hughes, AR A16 Gaskin, PLR A143 Livermore, JJA A73 Gervasio, VP A139 Lombardo, G A95 PRESENTING AUTHORS A149

Presenting Author Page Presenting Author Page Ma, Q A124 Roberts, AC A21, A101 Macare, CJ A25 Robinson, OJ A20 Mariani, NM A93 Ruffell, SGD A125 Martens, MAG A72 Sain, K A45 Martins, D A116, A137 Sami, MB A29 Marvar, PJ A23 Sarigiannidis, IS A27 Marwick, KF A48 Savulich, G A146 Marwood, L A132 Sawyer, K A141 McCabe, C A13, A112 Secchi, A A46 McCutcheon, R A52, A84, A108, A147 Selvaggi, P A107 McDonnell, CW A119 Sen, K A132 McLaughlin, AP A92 SerranodeHaroPerez, C A50 Merritt, K A103 Sethi, A A42 Mitchell , EJ A79 Slaney, C A127 Mkrtchian, A A68 Smith, S A61 Modaffar, M A106 Sokolowska, E A118 Mondelli, V A6 Sommer, WH A18 Morris, S A50 Srivastava, DP A30 Munni, STM A100 Strawbridge, R A87 Murphy, D A14 Stuart, SA A82 Murphy, SM A130 Taylor, MJ A46 Nabi, L A123 Taylor, P A129 Netherwood, BR A36 Taylor, R A126 Nettis, MA A85 Teodorini, RD A74 Nord, CL A66 Thomson, DM A78 Nutt, DJ A12 Tocco, M A133 Ogunbiyi, MO A109 Tofani, T A26 Oliver, D A53 Tomlinson, A A52 Oltean, BP A88 Treasure, J A12 Openshaw, RL A77 Trent, S A34 Oprea, E A135 Turkington, D A1 Osimo, EF A87 Uhlhaas, P A20 Paloyelis, Y A117 Upthegrove, RA A3 Panchal, P A131 Vaghi, MM A22 Parker, R A127 Valton, V A145 Payne, MEM A70 van Amelsvoort , T A4 Pepper, F A1, A39 van den Buuse, M A35 Perinpathasan, K A63 Verdi, S A63 Perry, B A8 Vernon, AC A98, A120 Pike, AC A69 Waldron, J A65 Porffy, LA A130 Walker, HR A108 Potter, HG A77 Walsh, KH A61 Pratt, JA A16 Watson, S A5 Priller, J A7 Weinberger, D A141 Przydzial, KM A54 Whittingham-Dowd, JK A40 Pulcu, E A144 Wijayaweera, SS A86 Reinecke, A A21 Wilkinson, MP A121 ReisMarques, T A7 Wise, T A27 A150 PRESENTING AUTHORS

Presenting Author Page Wootton, RE A31 Worrell, C A85 Yalin, N A145 Yamamori, Y A82 Yim, LL A80 Yung, AR A2 Zahn, R A112 Zajkowska, ZE A100 Zavyalov, GA A139 Zhou, K A62