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Background While there is a wide consensus regarding the potential benefits that early detection and intervention in clinical high-risk (CHR) states for psychosis might offer, application of this paradigm in current mental healthcare systems frequently involves concerns about the iatrogenic impact of stigma on patients, families, institutions, and the society at large. Based on examples from other areas in medicine (e.g., ‘high-risk pregnancy’ as opposed to ‘miscarriage risk syndrome’, or ‘hearing loss’ as opposed to ‘attenuated deafness’) we have recently hypothesized that restructuring CHR for psychosis states as high-risk states for universal functions (e.g., reality-testing) has the potential to reduce these concerns. The goal of this presentation is to introduce this notion and present pilot data that provide preliminary support for its validity. Methods In the first study, a sample of 125 adults from the general population read an experimental vignette describing a young adolescent experiencing either mild or severe prodromal symptoms who was randomly assigned a ‘psychosis-risk’ or ‘high-risk reality testing’ diagnostic label, and answered questions about stigma, hope, and need for care toward the individual in the vignette. In the second study, a sample of 254 mental health professionals read the same experimental vignette who this time was randomly assigned an ‘attenuated psychosis’ or ‘reality-testing loss’ diagnostic label, and answered questions about stigma, hope, and need for care toward the individual in the vignette. Results In the first study, the ‘high-risk reality testing’ label elicited significantly higher appraisals of self-image, hope, likelihood of seeking help, and need for care than the ‘psychosis risk’ label. Similarly, in the second study, the ‘reality-testing loss’ label elicited higher appraisals of self-image, hope, likelihood of seeking help, and importance of providing care than the ‘attenuated psychosis’ label. In both studies, no effects were found for symptom severity. Discussion These pilot results provide first empirical support for the social and clinical potential of ‘high-risk health’ formulations in minimizing the potential stigmatizing harms of ‘at-risk’ diagnostic labels and improving help-seeking behaviors. If addition, they lay the theoretical and methodological foundation for future studies that will replicate and extend the above findings using more ecologically valid manipulations (e.g., experimental intake meeting clips) among individuals at high risk and their families.

Background Although several studies have documented retinal cell dysfunction in schizophrenia (Silverstein & Rosen, Scz Res: Cogn, 2015), the extent to which these abnormalities contribute to, and/or result from, other features of the condition is unclear. Thus we sought to: 1) evaluate associations between retinal signaling anomalies as measured with flash electroretinography (fERG) and previously reported changes in visual evoked potentials (VEPs), contrast sensitivity, visual acuity, and contour integration in people with schizophrenia (Silverstein, Neb Symp Motiv, 2016); 2) determine whether fERG anomalies are related to retinal structural abnormalities as indicated by optical coherence tomography (OCT); 3) examine relationships between fERG changes and psychiatric symptoms; 4) determine relationships between fERG anomalies and frequent medical comorbidities in schizophrenia that are known to affect the retina (e.g., diabetes, hypertension); and 5) examine potential medication effects on these findings. Methods We have assessed 25 patients with schizophrenia and 25 controls who are free of medical comorbidity with fERG and measures of visual function and symptom severity, and data collection is ongoing with patients and controls with diabetes and/or hypertension using these same measures. In addition, we are in the process of completing data collection with two additional groups of patients and controls, one with fERG and OCT (n=12 to date), and another with fERG and VEPs (n=13 to date). fERG data are being collected under both light- and dark-adapted conditions, using a range of flash intensities, backgrounds, and temporal frequencies. The primary fERG variables of interest are a-wave and b-wave amplitudes, which reflect photoreceptor and bipolar cell responses, respectively, and the photopic negative response (PhNR), which reflects ganglion cell activity. Results On photopic fERG tests, patients with schizophrenia demonstrated significantly weaker photoreceptor response when a flash was presented against an unlit background (p

Background Exposure to childhood trauma (CT) is a global major public-health and social-welfare problem worldwide. CT increases the vulnerability to major psychiatric conditions including psychosis and is associated with poorer clinical outcome. CT affects the development of brain structures such as hippocampus, possibly through oxidative stress and neuroinflammation, two mechanisms linked to psychosis. We therefore hypothesized that there is an interplay between oxidative stress and CT in psychosis patients. We thus explored in early psychosis patients the relationships between CT and i) hippocampal volume, ii) antioxidant systems; and iii) clinical and cognitive outcomes. Methods We studied a cohort of 118 early psychosis patients, 36 were exposed to CT (experiences of physical, sexual, or emotional abuse/neglect before16 years old). In a subgroup of 48 patients (18 CT), hippocampal volume was determined by MRI. Antioxidant systems were quantified in blood for the whole cohort. Markers were: glutathione peroxidases (GPx) activity which appeared as a peripheral correlate of brain GSH levels (Xin &al, 2016); peroxiredoxine levels (Prx); Thioredoxine (Trx). Psychopathology (PANSS) and neuropsychology (MCCB) were assessed. The various groups were segregated by linear discriminant analysis. Results The previously observed decreased hippocampal volume in patients and association of small hippocampal volume with high blood GPx activity (reflecting high oxidative status) (Baumann &al, 2016) was due to the contribution of the traumatized group. Indeed, this association was absent in the no-trauma group, suggesting that the smaller hippocampus is linked to a redox dysregulation. To explore that point further, four groups were then formed, according to trauma and oxidative status: (i) noCT-lowGPx, (ii) noCT-highGPx, (iii) CT-lowGPx and (iv) CT-highGPx. Group CT-highGPx only had smaller hippocampi. In CT patients, small hippocampal volume was associated with high GPx activity, while hippocampal volume was similar in CT patients with low GPx activity (CT-lowGPx) and in patients not exposed to CT. Interestingly, other antioxidant defense systems such as Trx and oxidized Prx levels correlated negatively with GPx in CT-lowGPx group, suggesting that the Trx/Prx system is able to compensate for changes/decreases in GPx activity. Moreover, CT-lowGPx patients perform better than the other patients on speed of processing, verbal memory and attention tests. In contrast, hippocampal volume was decreased in CT patients with high GPx activity (CT-highGPx) compared with CT-lowGPx patients and patients not exposed to CT. There was no correlation between GPx and Trx/Prx system in this group. CT-highGPx patients had more severe positive, negative and disorganized symptoms than the other patients. Discussion We report that traumatized psychosis patients with high peripheral oxidation status (high GPx) had smaller hippocampal volumes and more severe clinical symptoms, while those with lower oxidation status (low GPx) had better cognition and appear to activate a compensatory antioxidant regulation by the Trx/Prx system. These results suggest that, in early psychosis patients, traumatic experiences during childhood interact with different redox systems and have long term neuroanatomical and clinical impacts. Therefore, redox pathways such as GPx, Trx and Prx systems represent important translational biomarkers for patient selection and stratification in order to aid in diagnostics and treatment decision at early stages of the disease.

Background Structural and functional brain alterations as well as cognitive deficits are well-documented findings in schizophrenia patients. Cognitive impairments affect the long-term outcome of schizophrenia and are the main contributors to disability. Aerobic endurance training has been shown to have effects on brain plasticity, gray and white matter volume as well as functional connectivity measures and on cognitive functioning in animal models and healthy humans. However, effects of physical exercise in combination in combination with cognitive remediation (CR) are unknown in schizophrenia. Methods 21 chronic schizophrenia patients and 21 age- and gender-matched healthy controls underwent 3 months of aerobic exercise (endurance training, 30 min, 3 times per week). 21 additionally recruited schizophrenia patients played table soccer (known as “foosball” in the USA) over the same period. After 6 weeks of endurance training or table soccer, all participants commenced standardized cognitive training with a computer-assisted training program. Clinical symptoms, thorough neuropsychological testing and multimodal neuroimaging with 3D-volumetric T1-weighted sequences, DTI and magnetic resonance spectroscopy (MRS) were performed on a 3T MR scanner at baseline and after the 3-month intervention and 3 additional training-free months. DNA from all subjects was genotyped with the Infinium PsychArray Chip (Illumina, San Diego, CA, USA). Polygenic risk scores were calculated and associated with hippocampal subfield volume change. Results In summary, a 3-month endurance training program combined with CR therapy for the last 6 weeks of the intervention period was feasible (Keller-Varady et al. 2016) and had positive effects on everyday functioning in multi-episode schizophrenia patients. Deficits improved from medium to mild as assessed with the GAF. Negative symptoms, short- and long-term verbal memory and cognitive flexibility also improved with endurance and cognitive training (Malchow et al. 2015). We could demonstrate grey matter volume increase in the left temporal lobe in schizophrenia patients undergoing endurance training. A non-endurance and coordinative training stimulus like playing table soccer led to a clearly distinct pattern of grey matter alterations in schizophrenia patients (Malchow et al. 2016). There were no effects of the intervention on structural and functional brain networks in schizophrenia patients as well as MRS measures (in preparation). No effects of PRSs were found on total hippocampal volume change. Subfield analyses showed that the volume changes between baseline and 3 months in the left CA4/DG were significantly influenced by PRSs in schizophrenia patients performing aerobic exercise. A larger genetic risk burden was associated with a less pronounced volume increase or a decrease in volume over the course of the exercise intervention. Results of exploratory enrichment analyses reinforced the notion of genetic risk factors modulating biological processes tightly related to synaptic ion channel activity, calcium signaling, glutamate signaling and regulation of cell morphogenesis (Papiol et al. 2017). Discussion Exercise interventions are feasible and effective interventions for people with schizophrenia and might also help to disentangle the underlying brain pathology of the disorder.

Background Specialized early intervention services have demonstrated improved outcomes in first episode psychosis (FEP); however, functional recovery lags behind symptomatic remission, and many FEP patients remain socially isolated with poor functional outcomes. Similarly, psychological and pharmacological treatments have been demonstrated to reduce rates of transition to psychosis in Ultra High Risk (UHR) patients. However, recent research shows that UHR patients have a poor functional outcome regardless of transition to psychosis. These findings have resulted in widespread calls for new treatments aimed at improving functioning in both FEP and UHR patients. The aim of these studies was to determine the safety, acceptability, feasibility and treatment effects of an advanced online social media based intervention specifically designed to enhance social functioning in FEP and UHR patients. Methods Our multi-disciplinary team of 35 researchers, software engineers, professional writers, clinical psychologists, comic developers, experts in human-computer interaction and young people has developed novel online social media platforms for young people with FEP (Horyzons), and UHR patients (Momentum). Our interventions integrate: i) peer-to-peer social networking, ii) tailored therapeutic interventions, iii) expert and peer-moderation, and iv) new models of psychological therapy (strengths-based models, self-compassion and mindfulness). The acceptability and safety of these platforms have been evaluated through 2 pilot studies in FEP (N=20; 1 month intervention), and UHR (N=15; 2 months intervention). In addition, the effectiveness of Horyzons is currently being evaluated in a large 5 year RCT in FEP (N=170; 18 months intervention). Results UHR pilot: System usage was high, with a total 270 logins (18/user), 749 posts (58/user), 170 therapy modules completed (12/user), and 67% of users being actively engaged over the trial. All participants reported a positive experience using Momentum and would recommend it to others. 93% considered Momentum to be helpful. Analysis revealed a significant increase in social functioning (p

Background Dr. Larry Seidman made numerous impactful contributions to our understanding of the roles of disrupted neurocognition and brain function in individuals with or at risk for schizophrenia. Based in part on Larry’s seminal work, many in the field have come to view schizophrenia as fundamentally a disorder of dysconnection within and between certain functional networks in the brain. However, what levels or patterns of dysconnection may be sufficient for overt psychosis remains unclear. Because schizophrenia is complexly determined, clinically heterogeneous, and (frequently) chronic and debilitating, neuroimaging studies comparing those with and without this condition cannot by themselves differentiate which neural changes contribute causally, which are epiphenomena, and which are secondary to factors associated with chronicity of illness or antipsychotic drug treatment. A crucial aim is thus isolation of the changes immediately preceding the onset of psychosis that, by virtue of their temporal priority, may represent primary mechanisms in the cascades of events leading to the emergence of psychosis. Methods Identifying such changes requires a paradigm for ascertaining at-risk individuals prior to psychosis onset and following them over time. Larry Seidman’s early work found that both patients and their first-degree relatives fail to disengage the default mode network and fail to engage task-positive networks under cognitive challenge. In the early 2000’s, in an effort to isolate changes in brain structure and function more proximal to the onset of psychosis, Larry joined with seven other investigators to launch the North American Prodrome Longitudinal Study (NAPLS). This talk will focus specifically on neuroimaging markers and on results examining baseline and longitudinal changes in brain structure and function among clinical high-risk (CHR) and control subjects, who were scanned at baseline and at 12-months or the point of conversion if it occurred earlier. Results Converters to psychosis showed a significantly steeper rate of gray matter thinning in right superior and medial prefrontal cortex (PFC) and greater ventricular expansion than non-converters and controls. These effects were significant controlling for multiple testing and independent of exposure to antipsychotic drugs. Higher levels of proinflammatory cytokines at baseline were predictive of steeper rates of gray matter reduction in superior and medial PFC, consistent with the notion that progressive gray matter change in this context is likely to reflect dendritic retraction and synaptic pruning driven by microglial activation. This interpretation is further supported by recent evidence of genetic susceptibility mechanisms involving complement signaling in schizophrenia, variations that appear to result in over-pruning of cortical synapses in animal models. In smaller subsamples using both task-based and resting-state fMRI, CHR subjects who converted to psychosis showed a progressive decrease in global efficiency and increase in network diversity from baseline to follow-up at the point of conversion. The identified network alterations were highly correlated with each other and with progressive gray matter changes in the prefrontal cortex in converters. Discussion These results are suggestive of a progressive loss of gray matter potentially triggered by altered immune signaling leading to over-pruning of synapses and provide preliminary evidence for longitudinal reconfiguration of resting-state and task-positive brain networks during psychosis development. The latter results appear to converge with Dr Seidman’s pioneering work on default mode and task-positive network function in individuals at genetic risk for schizophrenia.

Background The response to antipsychotic treatment in patients with psychosis is difficult to predict on the basis of the patient’s clinical features. As a result, patients are generally treated in a similar way, even though their response can vary dramatically. Recent neuroimaging studies suggest that the pattern of brain abnormalities in patients with psychosis may vary in relation to treatment response. However, in many of these studies, patients had already been treated, and it was unclear if this had contributed to the findings. Methods In Optimise we obtained a structural Magnetic Resonance Imaging data from n=203 minimally treated patients at their first presentation for a psychotic episode. All patients then started treatment with standard doses of amisulpride. After 4 weeks, 56% were in symptomatic remission. Results We identified brain neoplasms in 3 patients, but the most common radiological findings were non-specific white matter T2-weighted hyperintensities (n=48); cavum septi pelludici (n=34); and arachnoid cysts (n=9). Cortical thickness, surface area, and gyrification were measured using Freesurfer (). Preliminary analyses applying machine learning to these measures at baseline indicated that symptomatic remission at 4 weeks could be predicted with an accuracy of 64%. Discussion These findings suggest that radiological assessment can identify abnormalties that require an alternative to conventional treatment in a minority of patients. In most patients with psychosis, neuroimaging abnormalities may be better detected using statistical approaches, and these have greater potential for the stratification of patients according to future antipsychotic response.

Overall Abstract: Lawrence J. Seidman was born and grew up in New York City. He obtained a PhD from Boston University in Psychology and stayed in Massachusetts to work for many years in the Harvard affiliated Hospitals, such as the VA-Boston Healthcare System, Massachusetts General Hospital and at his untimely passing, he was Professor of Psychology in the Department of Psychiatry at Beth Israel-Deaconess Hospital and the Massachusetts Mental Health Center. He was about to move to a new phase in his career, assuming a position at Children’s Hospital, Boston. He was a pioneer in the fields of the neuropsychology of schizophrenia, ADHD and related disorders, of using the tools of cognitive assessments and brain imaging to understand the genetic predisposition for serious mental illness, and in the last several years—prediction of conversion to psychosis in individuals at high risk. He contributed to many multicenter collaborations and had several collaborators world-wide, playing an important role in their work. This symposium is conducted in his honor with contributions from key collaborators on different aspects of his work. Drs. Tyronne Cannon and Elaine Walker will both represent the North American Prodrome Longitudinal Study (NAPLS) consortium by reviewing its findings in brain imaging and cognition. Dr. David Braff will review the work of the Consortium on the Genetics of Schizophrenia (COGS) multicenter collaboration, in which Dr. Seidman led one of its sites, and Dr. TianHong Zhang from Shanghai will present current data from the Shanghai-Boston SHARP collaboration on early detection of psychosis. The symposium will be concluded by Dr. Keshavan from Beth Israel-Deaconess, who was a close colleague of Dr. Seidman for the last decade. Together they worked side by side exploring many aspects of early detection of schizophrenia and educating trainees and the public on their findings. He will sum up the legacy of Dr. Seidman to the field and how we can continue it into the future.

Background The validity of the classification of non-affective and affective psychoses as distinct entities has recently been disputed in light of calls for a dimensional and transdiagnostic approach to diagnostic classification and evidence on shared aetiological factors. Despite the shifts in view, there remains a dearth of empirical efforts to clarify and identify a transdiagnostic spectrum of psychosis. Our recent research has demonstrated evidence for a transdiagnostic psychosis spectrum as detailed in a bifactor model with one transdiagnostic symptom dimension and five specific symptom dimensions of positive symptoms, negative symptoms, disorganization, mania, and depression in patients with schizophrenia, schizoaffective and bipolar disorder. The aim of the current study was to investigate whether there is a transdiagnostic dimension cutting across symptoms of schizophrenia, schizoaffective disorder and psychotic bipolar I disorder using widely established measures for assessing psychosis, mania and depression in the large multi-centre Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) consortium in the United States. Methods This study analysed data from the B-SNIP Phenotyping Consortium, which included 933 patients with a diagnosis of schizophrenia (n=397), schizoaffective disorder (n=224), and bipolar disorder (n=312). Multidimensional item-response modelling was conducted on symptom ratings of the Positive and Negative Syndrome Scale (PANSS), the Young Mania Rating Scale (YMRS), and the Montgomery-Åsberg Depression Rating Scale (MADRS) using the mirt package of the R environment. Results A bifactor model with 1 transdiagnostic symptom dimension and 5 specific symptom dimensions of positive symptoms, negative symptoms, cognitive disorganization, mania, and depression best matched the B-SNIP sample data. The bifactor model with 1 transdiagnostic factor and 5 specific factors based on the PANSS 5-factor solution by Emsley et al. (2003) provided the best model fit (AIC=53209.8, BIC=53920.0, aBIC=53443.7), as compared with a unidimensional model (AIC=55583.1, BIC=56151.3, aBIC=55770.2), a pentagonal model based on the PANSS 5-factor solution by Emsley et al.3 (AIC=53452.6, BIC=54068.1, aBIC=53655.3) as well as pentagonal and bifactor models of other previously reported factor solutions. When we extended analyses to include YMRS and MADRS, again, the bifactor model with 1 transdiagnostic factor and 5 specific factors, again, provided the best model fit. Discussion Consistent with our previous findings, this study provides evidence on a transdiagnostic symptom dimension that cuts across traditional diagnostic boundaries of schizophrenia, schizoaffective disorder and psychotic bipolar disorder using three widely established measures for assessing psychosis, mania and depression. The best-fitting, bifactor model also included 5 specific symptom dimensions based on the PANSS 5-factor solution by Emsley et al. (2003), which reflects a direct replication of our previous findings on the dimensionality of the PANSS. Overall, our findings lend further support to a transdiagnostic psychosis spectrum encompassing schizophrenia, schizoaffective and bipolar disorder as we have previously proposed.

Background Widespread (Klauser et al., 2016) and progressive (Cropley et al., 2017) cerebral anomalies of white matter diffusion properties (i.e. fractional anisotropy, FA) have been observed in the Australian Schizophrenia Research Bank (ASRB), one of the largest samples of patients with schizophrenia. From a topological perspective, widespread alterations of white matter tend to concentrate into hub regions that interconnect brain areas over long-distances in a so-called “rich-club” (van den Heuvel et al., 2013; Klauser et al., 2016) in which the metabolic demand is high and thus are most likely to suffer from oxidative stress. Evidence from human and animal models suggests that redox dysregulation leading to oxidative stress during neurodevelopment is implicated in schizophrenia pathogenesis (Steullet et al., 2017). At the cellular level, the triad composed of NMDAR hypofunction, neuroinflammation and dopamine dysregulation interacts with redox imbalance and leads to oxidative stress, affecting oligodendrocytes precursor cells (OPC) and parvalbumine interneurons (Steullet et al., 2016). However, the links between redox imbalance, oligodendrocytes and gross alterations of white matter integrity are largely unexplored. Under oxidative stress induced in vitro by impairing the synthesis of glutathione (GSH), the key player in antioxidant defense, OPC showed a decreased proliferation mediated by an upregulation of Fyn kinase activity. In the prefrontal cortex of a mouse model with impaired GSH synthesis, mature oligodendrocyte numbers as well as myelin markers were decreased at peripuberty (Monin et al., 2014). FA was also reduced in fornix-fimbria and anterior commissure, a change accompanied by a reduced conduction velocity (Corcoba et al., 2015). Methods 49 patients with psychosis and 64 healthy controls were scanned with the same 3-Tesla scanner. The diffusion spectrum imaging (DSI) sequence included 128 diffusion-weighted images with a maximum b-value of 8000 s mm−2. White matter diffusion properties were estimated using generalized fractional anisotropy (gFA). Total blood cysteine (Cys, protein-bound form, free reduced and free oxidized form), the rate-limiting precursor of GSH, was measured by high performance liquid chromatography from plasma samples collected at the same time-point as MRI brain scans. Whole brain voxel-based analyses were performed using cluster-based non-parametric permutation testing on gFA maps. Cerebral levels of GSH were assessed by localized 1H-MRS measurements from a volume of interest in medial prefrontal cortex. Results As previously described in ASRB, we observed widespread abnormalities of white matter in patients. Interestingly, the degree of white matter alterations (i.e. decreased gFA) patients could be predicted by the levels of blood cysteine, a precursor of GSH, strongly suggesting the important role played by oxidative stress in the pathophysiological mechanism. Also, we found that white matter alterations could be reversed by 6 months of add-on treatment with the antioxidant and GSH precursor N-acetyl-cysteine (NAC). Most importantly, this improvement was positively correlated with an increase in prefrontal GSH levels. Discussion We propose that developmental redox imbalance inducing oxidative stress may lead to impairments of oligodendrocytes, myelin formation and eventually to the disruption of fibers integrity and conductivity, especially in brain regions having high metabolic demand. In patients, alterations of white matter are inversely correlated with blood levels of GSH precursor cysteine and could be prevented by the early administration of the antioxidant NAC.

Background Current approaches to stratify psychiatric patients into groups based on violence risk are limited by inconsistency, variable accuracy, and unscalability. Methods Based on a national cohort of 75 158 Swedish individuals aged 15–65 with a diagnosis of severe mental illness (schizophrenic-spectrum and bipolar disorders) with 574 018 patient episodes, we developed predictive models for violent offending through linkage of population-based registers. First, a derivation model was developed to determine strength of pre-specified criminal history, socio-demographic, and clinical risk factors, and tested it in external validation. We measured discrimination and calibration for prediction of violent offending at 1 year using specified risk cut-offs. Results A 16 item model was developed from criminal history, socio-demographic and clinical risk factors, which are mostly routinely collected. In external validation, the model showed good measures of discrimination (c-index 0.89) and calibration. For risk of violent offending at 1 year, using a 5% cut off, sensitivity was 64% and specificity was 94%. Positive and negative predictive values were 11% and 99%, respectively. The model was used to generate a simple web-based risk calculator (OxMIV). Discussion We have developed a prediction score in a national cohort of patients with psychosis that can be used as an adjunct to decision making in clinical practice by identifying those who are at low risk of violent offending

Overall Abstract: Research findings from the past two decades have opened new opportunities for ameliorating outcomes of psychosis through indicated primary prevention in individuals at clinical high risk for psychosis (CHR-P), which can result in delayed or prevented onset of first episode. To optimize these benefits, available research has mostly focused on improving the prognostic accuracy and the effectiveness of preventive treatments for individuals at CHR-P. However, research evidence published in the recent years indicates that despite the prominence of the CHR state, difficulty remains in identifying all individuals who may later develop psychosis. In particular, there is converging evidence indicating that most individuals who will develop a first episode are not currently benefiting from indicated prevention. There is thus a pressing and urgent need to enhance our ability to detect the individuals who are at risk. Identifying at-risk individuals who will later develop psychosis (true positives) is particularly challenging. This symposium acknowledges these challenges by reviewing the empirical validity of the CHR-P construct for detecting individuals at risk of psychosis. At the same time, the symposium suggests specific and differential strategies for overcoming these challenges in secondary mental health care, primary care, or the community. The first speaker (Dr. Shah) will discuss the relevance of the CHR-P construct for identifying individuals at risk for psychosis. Dr. Shah found that over half of the first episode cases in a catchment area had experienced CHR-P like features prior to their illness onset, while a substantial minority of first episode cases had not. This indicates that not all the first episode cases did pass through a CHR-P like stage, thereby providing an initial estimate of what proportion of first episode cases could be prevented through interventions at the CHR-P stage. The second speaker (Dr. Fusar-Poli) will discuss the effectiveness of current CHR-P detection strategies in secondary mental health care. Dr. Fusar-Poli found that only a tiny minority (5%) of first episode cases accessing secondary mental health were detected by the local CHR-P service that had been fully established in the Trust. This study developed and validated an individualised risk calculator that can improve the detection of individuals at risk of psychosis in secondary mental health care. The third speaker (Dr. Perez) will discuss how to improve detection of individuals at risk for psychosis within primary care. Dr. Perez will present a cluster-randomised controlled trial assessing whether increased specific liaison with primary care improves the clinical effectiveness and cost-effectiveness of detection of people at high risk of developing a first psychotic illness. This study showed that intensive outreach to improve liaison with primary care is clinically and cost effective for improving the detection of at risk cases. The fourth speaker (Dr. Calkins) will discuss the importance of investigating psychosis risk as a dynamic developmental process. Dr. Calkins will present a neurodevelopment prospective study evaluating subclinical symptoms in the community. This study showed that an integrated and multidimensional evaluation of youths with early psychotic-like experiences can enrich our ability to detect individuals at risk of psychosis in the general public. These findings will be then appraised and critically integrated by the discussant, prof. Craig Morgan.

Background Cognition is a major determinant of functioning in patients with schizophrenia. There is evidence that the endocannabinoid system influences cognition in human subjects, and participates in the pathophysiology of schizophrenia. In a previous study, we have shown that the expression of cannabinoid receptors (CB1R and CB2R) on peripheral lymphocytes is inversely correlated with performance in the Brief Assessment of Cognition in Schizophrenia (BACS), in patients with schizophrenia. Recently, CBRs polymorphisms have been associated with an increased risk for schizophrenia, structural changes in the central nervous systems and in cognitive performance of the patients. The aim of the present study was to investigate the association between CBRs polymorphisms and cognitive performance as assessed by the BACS. Methods A sample of 85 stable medicated patients (61% men; age = 41.6 ± 12.2 years; illness duration = 12.8 ± 10.7 years) was enrolled in this study. Two CB1R polymorphisms (rs1049353; rs12720071) and one CB2R polymorphism (rs2229579) were tested. Results We did not find any difference in general cognitive performance (BACS total score) regarding the three polymorphisms tested. However, when we analysed specific cognitive domains we have found a significant difference (p=0.002) regarding working memory (assessed by the Digit Span test) in patients with the rs12720071 polymorphism, where those with allele C performed better than those with T/T genotype. Since about a third of the patients (34%) had a history of past use of cannabis and 2.5% reported current use, we performed the rs12720071 polymorphism analysis excluding these patients. In this subgroup of patients, those with allele C also performed significantly better on Digit Span test (p=0.037). Discussion In this sample, the rs12720071 polymorphism of CB1R appears to influence performance on a working memory task that is sensitive to prefrontal cortex function.

Background Epidemiological, immunological, and microbiological studies indicate that infections with members of the family Herpesviridae may be associated with schizophrenia and with cognitive impairment. Herpesviruses are enveloped, double-stranded DNA viruses which are widely prevalent and which are capable of causing persistent infections. The most highly replicated association is that between the alpha herpesvirus Herpes Simplex Virus Type 1 (HSV-1) and cognitive impairment in schizophrenia. Acute HSV-1 infection results in oral lesions which usually resolve spontaneously. However, latency can occur in nerve root ganglia leading to cycles of reactivation in later life. Other herepsviruses may also be associated with schizophrenia. Epstein Barr virus (EBV) is a gamma herpesvirus usually acquired in childhood or adolescence. Acute EBV infection is often associated with fever and adenopathy leading to a vigorous immune response and the suppression of viral replication. However, latency can occur with long term consequences to the infected individual. Methods We examined the association between HSV-1 seropositivity and cognitive functioning in 828 individuals with schizophrenia from the Sheppard Pratt cohort and 573 control individuals. We also studied antibodies to EBV in a recently enrolled subset of the Sheppard Pratt cohort consisting of 397 individuals with schizophrenia and 289 without a psychiatric disorder. Antibodies to HSV-1 and EBV proteins were measured by immunoassay and confirmed by Western blot. Cognitive functioning was measured by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Regression models were employed to define the independent association between virus exposure and outcome. Results Serological evidence of exposure to HSV-1 was associated with significantly lower levels of cognitive functioning as measured by the RBANS Total score (coefficient =-3.84, 95% CI -5.60, -2.09, p

Background An association between low-grade inflammation and symptoms commonly shared between psychiatric disorders may explain the trans-diagnostic effects of inflammation, and lead to novel mechanistic hypotheses. Schizophrenia includes diverse symptoms, but the relationship between low-grade inflammation and specific psychotic symptoms has not been examined. Methods In the general population-based ALSPAC birth cohort, serum CRP levels were assessed around age 16 years. Ten positive and ten negative symptoms of psychosis were assessed using self-report questionnaires around age 17 years. Associations between CRP and psychotic symptoms were examined using regression analysis before and after controlling for concurrent depressive symptoms, substance use, and other confounders. In addition, we used factor analysis to create positive and negative symptom dimension scores, which were then correlated with CRP. Results About 13% of 5126 participants reported at least one positive symptom. Paranoid ideation (4.8%), visual (4.3%) and auditory hallucinations (3.5%) were the most common. Negative symptoms were correlated with concurrent depressive (P

Background The main attempt to prevent the development of psychosis has been through clinics for people at clinical high risk. Such an approach is useful for research but can never reach the majority of individuals who will become psychotic. Biological markers could be used to identify individuals with unusual vulnerabilities e.g. those with copy number variations such as VCFS. However, identifying the with such markers is unlikely to impact on the majority of cases, and as yet no useful interventions are available. How therefore to prevent psychosis? Methods Data will be presented from 3 studies of first onset psychosis (FEP) which used similar methods of ascertainment and assessment of cases and controls; AESOP and GAP from South London and the EU-GEI across 16 sites in 5 European countries. Results The identified risk factors for psychosis were the polygenic risk score for schizophrenia, childhood abuse, living in a city, being from an ethnic minority, drug abuse, adverse life events. Clearly, reducing some of these (e.g. urbanicity or migration) is not within the powers of psychiatrists. The GAP study showed that the polygenic risk score accounted for the greatest variance in caseness; those with scores in the highest quintile were 7 times more likely to be a psychotic case than those in those lowest quintile. The GAP study also gave estimates of the population attributable fraction (PAF): these indicated that if no one was exposed to child abuse and use of high potency cannabis, then 16% and 24% respectively of psychosis in South London could be prevented. The EU-GEI study showed striking differences in the incidence of psychosis between Northern and Southern Europe; data will be prevented concerning the contribution of risk factors, especially cannabis use, to this. Discussion The knowledge that schizophrenia is the extreme of a continuum of psychosis has important implications for prevention. Preventive approaches to hypertension or obesity do not focus on identifying individuals carrying biological markers; rather they encourage members of the general population to take exercise and reduce their calorie intake. A similar approach should be adopted for psychosis. In the long-term attempts to reduce risk factors should be made e.g. addressing psychotogenic aspects of city living or by decreasing discrimination of ethnic minorities. This will be difficult. However, an obvious place to start is by attempting to influence society’s patterns of consumption of high-potency cannabis. Unfortunately, public policy in the US and certain other countries appears to be moving in the opposite direction with increases in consumption and potency. Are these countries sleep-walking to more psychosis?

Background The patients included in RCTs represent a small atypical minority of the entire patient population, as up to 80–90% of patients are excluded because of mental or physical comorbidity, suicidal or antisocial behaviour, or substance abuse. Concerning clozapine, this means that those most severely ill patients having the greatest potential benefit from clozapine treatment are excluded from RCTs. Another major limitation of RCTs is that when very important but relatively infrequent phenomena, such as suicide or death is studied, exclusion of high risk patients and insufficient statistical power prevent obtaining statistically significant findings. Methods Observational studies can overcome these obstacles by using nation-wide electronic databases of hospitalization, mortality, and filled prescriptions. However, the main problem with these observational studies is selection bias. Although the most important covariates could be adjusted in the statistical analysis, there always remains residual confounding associated with the personal characteristics of each patient. One way to overcome this problem is to use within-individual analysis, in which each individual is his or her own control. In this approach, the exposure periods of each individual are compared with the non-exposure periods of the same individual. Results This far, 3 large observational studies using traditional between-subject analyses have found that when compared with other oral antipsychotics, clozapine is associated with the best outcome concerning risk of re-hospitalization, and 4 large cohort studies have shown that clozapine is associated with the lowest mortality. The only cohort study this far using within-individual analyses showed that in a nation-wide cohort of 29,823 patients, clozapine was associated with the lowest risk of treatment failure (defined as psychiatric re-hospitalization, suicide attempt, discontinuation or switch to other medication, or death). Discussion A large body of observational studies shows that clozapine has better real-world effectiveness than any other oral antipsychotic treatment.

Background The incidence of psychotic disorders varies across replicable social and environmental gradients at both an individual and a population level, such as higher rates of disorder in urban and migrant populations. However, the factors underpinning this are unclear. The EU-GEI study was established to investigate the incidence as well as the genetic and environmental determinants of first episode psychosis in a multi-national setting. The aim of the present study was to investigate the variance found in the incidence across the 17 catchment areas in the 6 countries (England, France, Italy, the Netherlands, Spain and Brazil) included in this study at both individual and population level, and identify putative predictors of psychosis risk. Methods We conducted a population-based study of the incidence of non-organic adult ICD-10 psychotic disorders (F20-F33). Demographic data (age, sex, ethnicity) and OPCRIT diagnoses were collected, and denominator data was estimated from government sources. Crude incidence rates were directly standardised to the 2011 England and Wales Census population to account for population differences in age, sex and ethnicity. Multilevel Poisson regression was carried out to investigate variance in incidence between catchment areas by latitude, population density, and percentage of unemployment, owner-occupied houses and single-person households as markers of catchment-area level social fragmentation, using official government statistics and data from the 2011 European Population and Housing Census. Results We identified a total of 2,774 cases over 12.94 million person-years at risk, leading to a crude incidence of 21.4 per 100,000 person-years (95%CI: 19.4–23.4). The age pattern of incidence differed between men and women: crude incidence peaked in men aged 18–24 (61.0 per 100,000 person-years, 95%CI: 59.0–63.1) and declined sharply thereafter, for women rates also peaked in the youngest age group (27.0 per 100,000 person-years, 95%CI: 24.9–29.1) but decline was more gradual and there was a small but robust secondary peak after age 45. By age 35, 68% of male cases had presented to services, compared to 51% of female cases. Age-sex-ethnicity standardised incidence of all psychotic disorders varied 8-fold across settings. Poisson regression revealed higher rates in minority groups (IRR: 1.6, 95%CI: 1.5–1.7), and an association between greater catchment area-level owner-occupancy and lower incidence (IRR for a 10% increase: 0.8, 95%CI: 0.7–0.8). No relationship was found for other putative environmental risk factors, including latitude and population density. Results were similar for non-affective and affective disorders. Discussion Variance in treated incidence was substantial and was only partially explained by standardisation for age, sex and ethnicity, and Poisson regression including catchment-area level risk factors. For the prevention of psychosis two main lessons can be learned: services focused on early intervention should not have an upper age limit as half of all female (and 32% of male) cases present after age 35, and future examinations of variance should focus on socioenvironmental and not geographical determinants.

Background In 2010, the “ShangHai At Risk for Psychosis (SHARP)” study was launched at the Shanghai Mental Health Center (SMHC), the largest outpatient mental health clinic in China. The Chinese SHARP research was led by Dr. Larry Seidman, who was also the PI of the Harvard site of the NAPLS project. He had implemented methods very similar to those used in NAPLS for the identification of clinical high risk (CHR) individuals in Mainland China in studies jointly funded by the United States National Institute of Mental Health and Chinese funding agencies. Methods Dr. Seidman began a collaboration with the SMHC by advising us in carrying out an epidemiological study and then received joint funding for an R21 MH093294 (Fogarty/NIH, “Broadening the Investigation of Psychosis Prodrome to Different Cultural Groups”) designed to implement a variety of clinical, neurocognitive and event related potential (ERP) measures in a preliminary study of CHR. That study, which began in April 2012 and ended in March 2015, aimed to build research capacity at the SMHC. He guide us provided 4 in-person research and clinical skills trainings (2 in SMHC, 2 in Boston), translated a widely used CHR diagnostic instrument (the Structured Interview for Prodromal Symptoms/SIPS), and trained China partners to conduct a preliminary study of 100 CHR individuals. Building upon the R21 project, and the North American Prodrome Longitudinal Studies (NAPLS) model, the same group of researchers led by Dr. Seidman is collaborating on an NIMH R01 101052-01 project (2013 to 2016) to examine biomarkers of CHR with 1 year follow-up. The R21 and R01 collaborations between Harvard Medical School (HMS), MIT, Florida A&M University (FAMU), and SMHC investigators have capitalized on the resources and experiences of the Harvard researchers as members of NAPLS, MIT researchers’ leading role in functional magnetic resonance imaging (fMRI), and FAMU researchers’ expertise in bridging western and Chinese cultures to enhance the existing capacity of Chinese researchers studying the biopsychosocial aspects of CHR. Finally, a stratified cohort of 300 CHR participants was recruited between 2012–2015, and followed up for at least 1 year. Results With the hope of Dr. Seidman, the SHARP project is ongoing and getting better, larger and stronger. Of the total 417 CHR participants (previous epidemiological survey [CHR, n = 117], R21 [CHR, n = 100], R01 [CHR, n =200]), 349 completed at least a year of follow-up (until August 30, 2017; the longest follow-up case was six and a half years), in which 83 converted to psychosis, and 68 were lost. Preliminary data showed about 20% CHR converted to a psychotic disorder over the course of follow-up, several clinical factors such as 1) functional decline; 2) selected positive symptoms(unusual thoughts and suspiciousness); 3) selected negative symptoms(social anhedonia, expression of emotion, and ideational richness); biological factors such as the P300 auditory ERP; fMRI: Reduced anti-correlation between the bilateral parietal lobule and left dorsolateral prefrontal cortex; Structural MRI: superior temporal gyrus. et al. are account for increasing the risk of conversion to full psychosis. Discussion This is the first, well-implemented, longitudinal study of CHR in a low and middle-income country to comprehensively investigate clinical and biological factors in predicting psychosis conversion and illness progression. Dr. Seidman provide a critical step in the implementation of CHR concept in China, just as an obvious need and urgency for prevention and early intervention for Chinese patients with schizophrenia.

Background People with schizophrenia die on average 15–20 years earlier than the general population, and the mortality gap has grown in recent years. Non-CNS, particularly cardio-metabolic, causes account for the majority of this premature mortality. Abnormalities in the cardio-metabolic and immune system are well established in patients with schizophrenia, but it is unknown if abnormalities are present in people at risk of psychosis and at illness onset prior to antipsychotic treatment, and how they compare to neurofunctional measures. To address this, we conducted a series of meta-analyses and meta-regressions to determine the magnitude and consistency of findings and influence of antipsychotic treatment, exercise and other factors across cardio-metabolic parameters at onset of psychosis. Methods We conducted a meta-analysis of peripheral gluco-regulatory, immune and lipid measures and comparison with brain neurofunctional outcomes (including N-acetyl aspartate, gray matter volume and auditory P300 measures) in studies of clinical high risk samples and first episode psychosis, focusing on drug naïve patients. The entire PubMed, EMBase and PsychInfo databases were searched to identify relevant studies. Then we conducted a meta-review statistical comparison of cardio-metabolic and immune function with neurofunctional measures. Results 35 studies (>1500 patients and controls) were included in the meta-analyses. Interleukin-6 (g=2.2, p=0.013), and TNF-alpha (g=0.94, p0.3). Moreover, the median effect size for immune alterations (g=1.3) was significantly greater than that for neurofunctional measures (p=0.002). Discussion We demonstrate that effect sizes for markers of cardio-metabolic and immune disturbance are comparable in magnitude to those for markers of neurofunctional CNS disturbances from the onset of psychosis, suggesting schizophrenia involves multiple organ systems from illness onset. The three main pathoetiological models by which CNS and non-CNS abnormalities may co-occur in schizophrenia will be discussed. The shared genetic and environmental risk architecture between schizophrenia and cardiometabolic disorders suggests common aspects of pathoetiology.

Background Heterogeneity of psychosis presents significant challenges for classification. Between two and 12 symptom dimensions have been proposed, and consensus is lacking. The present study sought to identify uniquely informative models by comparing the validity of these alternatives. A critical validator is future course, and we examined trajectory of each dimension. Methods We investigated this question in the first U.S. study to follow an epidemiological cohort with psychotic disorders for 20 years after first hospitalization. Participants were assessed in person 6 times over 2 decades on Global Assessment of Functioning (GAF), psychotic symptoms, and mood symptoms, and 373 completed 20-year follow-up (68% of survivors) including an electrophysiological assessment of error processing. We first analyzed a comprehensive set of 49 symptoms rated by interviewers at baseline, progressively extracting from one to 12 factors. Next, we compared the ability of resulting factor solutions to (a) account for concurrent neural dysfunction and (b) predict 20-year role, social, residential, and global functioning, and life satisfaction. Results A four-factor model showed incremental validity with all outcomes, and more complex models did not improve explanatory power. The four dimensions—reality distortion, disorganization, inexpressivity, and apathy/asociality—were replicable in 5 follow-ups, internally consistent, stable across assessments, and showed strong discriminant validity. On all of these measures schizophrenia exhibited a decline that began between years 5 and 10. Correspondingly, GAF scores dropped from 49 (Year 4) to 36 (Year 20). Neither aging nor changes in antipsychotic treatment accounted for the declines. Discussion These results reaffirm the value of separating disorganization and reality distortion, are consistent with recent findings distinguishing inexpressivity and apathy/asociality, and suggest that these four dimensions are fundamental to understanding neural abnormalities and long-term outcomes in psychosis. They also revealed a substantial symptom burden across psychotic disorders that increased with time and ultimately may undo initial treatment gains. Additional research is needed, but previous studies suggest sociocultural factors and different care models may preempt this decline.

Background Both preclinical and human research suggest that cannabidiol (CBD) has antipsychotic properties. This study assessed the safety and effectiveness of CBD in patients with schizophrenia. Methods Patients with schizophrenia (n=88) were randomized to receive CBD (1000 mg/day) or placebo alongside their existing antipsychotic medication for 6 weeks. Participants were assessed before and after treatment using the PANSS, BACS, GAF scales, and the CGI Improvement and Severity scales. Results Compared those given placebo, patients treated with CBD had lower levels of positive psychotic symptoms (PANSS; p=0.02), and were more likely to have been rated by clinicians as improved (CGI-I; p=0.02) and as not severely unwell (CGI-S; p=0.04). Patients who received CBD also showed trends for greater improvements in cognitive performance (BACS; p=0.07) and in overall functioning (GAF; p=0.08). There was no difference in the frequency of CBD of adverse events between CBD and placebo. Discussion These data suggest that CBD has beneficial effects in patients with schizophrenia and is not associated with significant adverse effects.

Background Little is known about patients with a first episode of psychosis (FEP) who had first presented to prodromal services with an “at risk mental state” (ARMS) before making the transition to psychosis. We set out to identify the proportion of patients with a FEP who had first presented to prodromal services in the ARMS state, and to compare these FEP patients with FEP patients who did not have prior contact with prodromal services. Methods In this study information on 338 patients aged ≤37 years who presented to mental health services between 2010 and 2012 with a FEP was examined. The data on pathways to care, clinical and socio-demographic characteristics were extracted from the Biomedical Research Council Case Register for the South London and Maudsley NHS Trust. Results Over 2 years, 14 (4.1% of n = 338) young adults presented with FEP and had been seen previously by the prodromal services. These ARMS patients were more likely to enter their pathway to psychiatric care via referral from General Practice, be born in the UK and to have had an insidious mode of illness onset than FEP patients without prior contact with the prodromal services. Conclusions In the current pathways to care configuration, prodromal services are likely to prevent only a few at-risk individuals from transitioning to psychosis even if effective preventative treatments become available.

Background Clozapine has long been considered the gold standard antipsychotic for treatment refractory schizophrenia (TRS). There have been a number of recent meta-analyses of efficacy of clozapine on psychotic symptoms and effectiveness in reducing hospitalisations that have sparked debate on the role of clozapine. Methods Current literature regarding the efficacy of clozapine for TRS, including pair-wise and network meta-analyses of RCTs with reported outcomes of total psychotic symptoms, positive symptoms and negative symptoms were reviewed. We also examined the results of a meta-analysis of the effectiveness of clozapine on reducing hospitalisations based in RCTs and observational studies. Results Two recent meta-analyses: Samara et al (2016), a network meta-analysis in JAMA Psychiatry; and Siskind et al (2016) a pairwise meta-analysis in BJPsych, found similar equivocal results for total psychotic symptoms. However, Siskind et al (2016) found clozapine to be superior to other anti-psychotics for positive symptoms. Factors influencing the difference in results included pair-wise vs network methodology and sensitivity analyses of pharmaceutical industry support. Of note, only 40% of people with TRS responded to clozapine. Clozapine’s effectiveness for reducing hospitalisations was significant, with a relative risk of 0.74 (95%CI 0.69–0.80). Discussion There are a lack of recent non-industry funded randomised control trials of clozapine compared to SGAs, which hinders an equivocal statement about the superiority of clozapine for total psychotic symptoms. However, there is evidence to suggest that clozapine is superior to other antipsychotics, including SGAs, for positive symptoms. In terms of effectiveness, initiation of clozapine can reduce the proportion of people hospitalised and reduce bed days. Use of clozapine needs to be balanced against its adverse drug reaction profile. There remains a need for more effective treatments for TRS, and biomarkers to identify TRS.

Background General practitioners are usually the first health professionals contacted by people with early signs of psychosis. It is unclear whether increasing the intensity of liaison between primary care and secondary care improves the clinical effectiveness and cost-effectiveness of detecting people with, or at clinical high-risk (CHR-P) of developing, a first-episode psychosis (FEP). This is important given political commitments to facilitate early intervention and decrease waiting times in mental health. We developed and tested a theory-based intervention to improve detection and referral of these mental states. Methods The LEGS study was a cluster randomised controlled trial (cRCT) involving primary care practices (clusters) in the county of Cambridgeshire and Peterborough, UK. Consenting practices were randomly allocated into two groups: (1) low-intensity liaison between primary care and secondary care, a postal campaign consisting of biannual guidelines to help in the identification and referral of individuals with early signs of psychosis and (2) the high-intensity intervention described in the previous section, which, in addition to the postal campaign, included a specialist mental health professional to liaise with each practice and support the theory-based educational package. Concealed randomisation involved a randomly permuted sequence in blocks, with 12 strata and 96 blocks. Practices that did not consent to be randomised constituted a practice-as-usual (PAU) group. The high- and low-intensity interventions were implemented over a period of 2 years for each practice during the study period April 2010 to October 2013. The primary outcome was the number of CHR-P referrals to Early Intervention in Psychosis Services per practice site predicated on an assumption that the intensive intervention would double them. New referrals were assessed clinically and stratified into those who met criteria for CHR-P or FEP (together: psychosis true positives) and those who did not fulfil such criteria for psychosis (false positives). Referrals from PAU practices were also analysed. An economic evaluation quantified the cost-effectiveness of the interventions and PAU, using decision-analytic modelling. Cost-effectiveness was expressed as the incremental cost per additional true positive identified. Results Of the 104 eligible practices, 54 consented to be randomised. Twenty-eight practices were randomised to low-intensity liaison and 26 practices were randomised to the high-intensity liaison. Two high-intensity practices withdrew. High-intensity practices referred more CHR-P (incidence rate ratio (IRR) 2.2, 95% CI 0.9 to 5.1; p = 0.08)), FEP (IRR 1.9, 95% CI 1.05 to 3.4; p = 0.04) and true positive (IRR 2.0, 95% CI 1.1 to 3.6; p = 0.02) cases. High-intensity practices also referred more false positives (IRR 2.6, 95% CI 1.3 to 5.0; p = 0.005); most (68%) of these were referred on to appropriate services. The total costs per true positive referral in high-intensity practices were lower than those in low-intensity or PAU practices; the high-intensity intervention was the most cost-effective strategy. Discussion Increasing the resources aimed at managing the primary–secondary care interface provides clinical and economic value in this setting. Early detection of CHR-P in primary care is clinically and cost-effective This talk will also introduce the continuation of this work; a 5-year research programme that will focus on the treatment of individuals with psychotic experiences in primary care settings.

Background Adult patients having schizophrenia, bipolar disorder or major depression display indicators of brain dysfunctions that may be detectable in healthy children-adolescents at genetic risk, such as those born to an affected parent (Maziade, New Eng J Med 2017; Schizophr Res 2013). For instance, cognitive deficits are displayed by both adult patients and children at risk (Maziade, Schizophr Bull 2011). We had reported that schizophrenia patients present diminished amplitudes and delayed latencies of rod and cone photoreceptor responses (Hébert, Schizophr Res, 2015) and we recently found that bipolar patients have similar ERG anomalies. We had also reported preliminary data in a small sample of 29 children born to an affected parent showing that young offspring had rod diminished amplitudes (Hébert, Biol Psychiatry 2010). The present objectives were i) under the hypothesis that offspring would display many of the ERG anomalies that schizophrenia or mood disorder patients carry (Hébert, Schizophr Res 2015; Prog Neuropsychopharmacol Biol Psychiatry 2017), to look for cone and rod response anomalies in a large sample of young high-risk offspring; ii) to describe the relationship between ERG anomalies and other risk endophenotypes in the offspring; and iii) look at the relationship between ERG anomalies and the risk clusters already shown to predict later transition to illness. Methods The sample consisted of 84 young offspring (aged 6 to 27) of a parent affected by schizophrenia or bipolar disorder, compared to 224 healthy controls balanced for age and sex. Full-field cone and rod ERG was measured in non-dilated eyes for all subjects. In the young offspring, we also collected measures of different cognitive domains, attenuated symptoms of psychosis, non-psychotic DSM diagnosis and/or an episode of poor GAF functioning in childhood-adolescence, childhood trauma, and cannabis use (Paccalet, Schizophr Res 2016). Results In comparison to controls the offspring displayed three ERG anomalies that were observed in adult patients: prolonged cone b-wave latency (p=0.04), diminished rod b-wave amplitude (p=0.04) and prolonged rod b-wave latency (p=0.006). These ERG anomalies were shared by offspring of a parent with schizophrenia or bipolar disorder, an observation of ERG commonality that we had made in adult patients. The three ERG amplitude and latency anomalies tended to aggregate in a child at risk, a trend we also observed in another endophenotype modality such as deficits in different cognitive domains. However, in these high-risk children and adolescents, the patterns of aggregation suggest that ERG anomalies would depict another risk pathway than that marked by cognitive deficits. Discussion First, ERG anomalies in high-risk children have neurobiological implications for future research on the illness neurodevelopment. Second, as found for other modalities of risk endophenotypes in children at genetic risk (Maziade, New Eng J Med 2017), multiple rod and cone ERG anomalies tended to cluster together in a child. Such an aggregation may be compatible with the multifactorial polygenic theory with a threshold. Remarkably, a clustering of risk indicators is also observed in children at risk of metabolic cardiovascular disorders and is presently considered in practice guidelines for these children. The clustering of risk indicators may provide an empirical basis for the staging of the risk status of children at genetic risk and has immediate implications for their longitudinal surveillance in the clinic.

Background Psychosis is seen in a number of disorders and treated with the same drugs. However, there is considerable variability in response to treatment and clinical course. Understanding the neurobiology underlying psychosis across diagnoses and in treatment response is important to help guide the development of new treatments and biomarkers for treatment response. Elevated dopamine synthesis and release capacity and structural brain changes have been consistently associated with schizophrenia, but it remains unknown how variable these are, or how they compare across psychotic disorders. Methods Two cohorts of first episode patients, one with a diagnosis of schizophrenia (n=16) and another with a diagnosis of bipolar affective disorder (n=22) received 18F-DOPA PET and [1H]-MR spectroscopy imaging and clinical measures. All patients had experienced a psychotic episode and received clinical follow-up over 18 months to determine diagnostic stability. We then conducted a meta-analysis using a novel meta-analytic approach to quantify variability in measures to investigate structural and neurochemical heterogeneity in schizophrenia and bipolar affective disorder. The entire PubMed, EMBase and PsychInfo databases were searched from inception to identify relevant studies and the natural log of the measures of dispersion and the coefficient of variance. Results Striatal dopamine synthesis capacity (Kicer) was significantly elevated in both bipolar (effect size=1.02; p0.4). Kicer was significantly positively correlated with positive psychotic symptom severity in the transdiagnostic group of people with psychosis (r=0.52, p4000 patients and >4000 controls. Variability ratio was significantly increased in patients relative to controls in gray matter volumes in temporal lobe (VR=1.1, p=0.004) and thalamus (VR=1.16, p

Background Several lines of evidence suggest that Herpes Simplex Virus type 1 (HSV-1) may contribute to cognitive impairment in schizophrenia. Herpes viruses are enveloped, double stranded DNA viruses that are capable of infecting human CNS resulting in life-long infection with over 40% of the population seropositive for this virus. Valacyclovir is an effective treatment for the suppression of herpes virus infections. A previous small clinical trial (N=24) assessed the efficacy of valacyclovir for cognitive impairment in patients with early phase schizophrenia who were seropositive for HSV-1 (Prasad et al 2013). Results indicate that adjunctive valacyclovir, as compared to placebo, showed improvement in working and visual memory. The current study was undertaken to confirm and extend these findings and determine if HSV-1 seropositive, as compared to those who were HSV-1 seronegative, derived cognitive improvement from adjunctive valacyclovir. We hypothesized that individuals who were HSV-1 positive, but not HSV-1 negative, would demonstrate significant valacyclovir efficacy for cognitive impairment. Methods An early psychosis network comprised of 12 US sites was established for the valacyclovir trial. Subjects had early phase schizophrenia (within 8 years since psychosis onset) and were randomized 1:1 to a 16-week trial of adjunctive valacyclovir (3 grams/day) or placebo. Assessments included cognitive domains (MATRICS), role functioning (UPSA-B, Q-LES-Q-SF, PSP), psychiatric symptoms (PANSS, NSA-16) and a range of inflammatory markers. The primary outcome was change in working (composite score of Spatial Span and Letter Number span) and visual (Brief Visuospatial Memory Test) as measured by the MATRICS. Results 170 subjects with early phase schizophrenia were stratified by HSV-1 status and randomized 1:1 to adjunctive valacyclovir or adjunctive placebo. Of those randomized, 74 were HSV-1 seropositive and 96 were seronegative. The valacyclovir vs. placebo groups, respectively, were well matched: age (28.4 vs. 27.5 years), gender (males: 69% vs. 77.9 %), race (white-caucasian: 28.6% vs. 33.7%) and duration of psychosis (3.7 vs. 4.0, years). Baseline working memory scores (Letter-Number Span) were significantly lower in HSV1 positive vs. negative subjects (mean/SD: vs. 35.1/9.0 vs 38.3/11.0, p=0.046). Treatment outcome analyses have only recently commenced and are ongoing. Full results of the cognitive, functioning, symptom and safety measures will be presented at the meeting. Discussion The current study included 170 patients with early phase schizophrenia randomized to valacyclovir or placebo and stratified by HSV1 sero-status. Baseline working memory scores (Letter-Number Span) were significantly lower in HSV1 positive compared to HSV1 negative subjects. As analyses of treatment effects are ongoing, detailed results of valacyclovir’s effects on cognitive domains, symptoms, functioning and safety will be presented at the meeting. Additional research is needed to determine the full therapeutic potential of valacyclovir and other medications targeting herpes viruses in the treatment of schizophrenia.

Background The endocannabinoid (EC) system comprises of fatty acid neurotransmitters such as anandamide and 2-acylglycerol, at least two specific cannabinoid (CB) receptor subtypes and enzyme machinery for synthesis and degradation of ECs. The EC system regulates a wide array of functions in central nervous system and peripheral tissues such as brain development, plasticity, reward and stress sensitivity as well as metabolic functions a such as energy/lipid metabolism including liver function and insulin resistance (1). One of the aims of the METSY project (www.metsy.eu) is to study the central and peripheral EC system in FEPs and their involvement in brain mechanisms in psychosis as well as related metabolic co-morbidities. The cannabinoid CB1 receptor (CB1R) is the most abundant cannabinoid receptor subtype in the human brain and is the predominant mediator of various EC effects. In this first series of METSY experiments we report in vivo brain CB1R binding characteristics in patients with first-episode psychosis (FEP) and controls. Methods Brain CB1R availability was measured using [18F]-FMPEP-d2 and 3D ECAT HRRT positron emission tomography (PET) using distribution volume (DVt) as a proxy for CB1R availability. Our studies in healthy volunteers revealed a marked sex difference in [18F]-FMPEP DVt with males having higher CB1R availability. The overall CB1R sex difference was widespread but also regionally different with most significant effects in the occipital cortex. Therefore, subsequent studies focused first on male patients with FEP and controls (n=18). Results The results indicate a significant and relatively widespread decrease in CB1R DVt in patients with FEP in fronto-temporal regions, putamen, posterior cingulate as well as parietal regions with large effect sizes. Largely similar results were seen in an independent sample of medication-free male patients with FEP (n=17, the other METSY PET site, King’s College, London, UK) (2). Those studies used another validated CB1R tracer, the [11C]-MePPEP. The reduced CB1R in patients was also state-dependent as [18F]-FMPEP DVt correlated negatively with psychotic symptoms (BPRS) in a highly significant manner. Discussion Epidemiological studies have convincingly shown that cannabis use is associated with an increased risk of both psychotic symptoms and schizophrenia-like psychoses. We now provide direct in vivo evidence for a robust and partly state-dependent dysregulation of the endocannabinoid system in first-episode psychosis. This is well in line with a recent PET study with CB1R tracer, [11C]-OMAR in patients with schizophrenia (3). Based on previous experimental data the reduced CB1R availability is indicative of an increased endocannabinoid drive in psychosis. Acknowledgements Funding from the EU’s 7th Framework Programme; METSY - Neuroimaging platform for characterization of metabolic co-morbidities in psychotic disorders (no. 602478). References 1) Eriksson O et al The Cannabinoid Receptor-1 Is an Imaging Biomarker of Brown Adipose Tissue. J Nucl Med. 2015 Dec;56(12):1937–41. 2) METSY: Endocannabinoid pathways in early psychosis – brain imaging studies (Hietala J, Howes O, Laurikainen H, Borgan F and the METSY PET Imaging group). 3) Ranganathan M et al Reduced Brain Cannabinoid Receptor Availability in Schizophrenia. Biol Psychiatry. 2016 Jun 15;79(12):997–1005.

Background The clinical high-risk state for psychosis syndrome (CHR) offers substantial potential benefits in terms of early identification and treatment for at-risk youth. Early treatment might lead to decreased symptoms, thus leading to reduced symptom-related stigma. However, stigma of the clinical high-risk state for psychosis designation might also initiate further stigma through the label of risk for psychosis. Identifying the effects of these sources of stigma is critical in order to best minimize stigma associated with CHR identification and to facilitate recovery. Methods Baseline stigma assessments were conducted with 170 clinical high risk state for psychosis individuals in a major, NIH-funded longitudinal study at Columbia University Medical Center, Harvard University Medical Center, and Maine Medical Center from 2012 to 2017. Labeling-related measures of stigma (e.g., “shame of being identified as at psychosis-risk”) adapted to the CHR group, and a parallel measure of symptom-related stigma (e.g., “shame of the symptoms associated with CHR”) were administered. These measures were examined in relation to outcomes of: a) self-esteem, b) quality of life, and c) social functioning, adjusting for sociodemographics and core CHR symptoms (e.g. attenuated psychotic symptoms). Results Results indicated that stigma related to symptoms was more strongly associated with all outcomes when compared with shame related to the risk-label. Stigma related to symptoms remained a significant predictor of self-esteem and quality of life even after accounting for stigma related to the risk-label and the effects of sociodemographics and CHR symptoms. Conversely, stigma related to the risk-label was no longer a significant predictor for outcomes after accounting for stigma related to symptoms. Discussion Overall, symptom-related stigma was a more salient correlate and was independently linked with self-esteem and quality of life even after accounting for the effects of stigma related to the risk-label. These results indicate that treating of symptoms through early identification and treatment may provide major benefit for CHR youth by also alleviating symptom-related stigma. These findings also indicate that CHR services should address stigma associated with symptoms immediately at first identification, as these have substantial effects on psychological and functional outcomes. These findings have implications for guiding implementation of specialized CHR services both in the United States and worldwide.

Background Patients with schizophrenia and other psychotic disorders have an increased likelihood of engaging in violent behavior. These increased risks of dangerous and aggressive behavior, in combination with a lack of insight in their own illness, relatively often make involuntary admission of acutely disturbed psychotic patients on locked psychiatric admissions wards often inevitable. On these locked psychiatric admissions wards, aggression from psychotic patients against staff and fellow patients is a prevalent phenomenon, with the mean in the Netherlands being about 18 aggressive incidents per bed per year on locked psychiatric admissions wards. Methods In the lecture, a model of what causes or triggers aggressive behavior on (locked) psychiatric wards is presented. In this model, patient, ward and staff variables are integrated to explain why, and in what specific situations, psychotic patients particularly run a high risk of engaging in aggressive behavior. Results Based on the presented model, a number of preventive measures can be formulated. On the patient level, the administration of anti-psychotic medication is used to reduce the negative cognitive schemes and delusional thoughts that are depicted in the center of the model. A more novel intervention at the patient level may be the additional administration of nutritional supplements with (among others) high levels of omega 3 fatty acids. The results of two Dutch studies on this topic will be briefly presented in the lecture, among which a RCT on the effects of the use of nutritional supplements on aggressiveness. On the staff level, the use of short-term (daily) risks assessments by the ward nursing staff, among others by means of the six item BrØset Violence Checklist (BVC), has been found to reduce aggressiveness and the use of coercive measures on psychiatric wards in two cluster randomized RCTs. On the ward level, studies indicate that aggression on psychiatric wards can be reduced by preventing overcrowding on psychiatric wards, and by providing more space and privacy to the patients. Discussion The proposed model elucidates how certain patient, staff and ward characteristics may interact in causing aggression. The model also emphasizes that repeated inpatient aggression may be the result of a vicious circle, i.e. inpatient violence is often followed by an increase in environmental and/or communication stress on the patient, thereby heightening the risk of a repeated outburst of violence.

Background Previous studies have found that patients with schizophrenia and bipolar disorder are more likely to be violent than the general population. The aim of this study was to investigate the association between schizophrenia and bipolar disorder and violent crime in the Israeli population. Methods Using the Israeli Psychiatric Hospitalization Case Registry we identified 3187 patients with a discharge diagnosis of schizophrenia and 506 patients with a discharge diagnosis of bipolar disorder. For each proband we identified parents and siblings, and gender- and age-matched controls for patients, parents and siblings. Information on violent crimes was obtained from police records. Results Patients with schizophrenia were at increased risk for violent crimes compared with controls [odds ratio (OR) 4.3, 95% confidence interval (CI) 3.8–4.9], especially women (OR 9.9, 95% CI 6.2–15.7). Risk for violent crimes was higher among patients with co-morbid substance misuse than in patients without such co-morbidity (OR 5.1, 95% CI 4.2–6.3). Patients with diagnosis of bipolar disorder were 2.5 times more likely to be convicted or released for mental reasons of violent crimes compared with controls and unaffected full siblings (OR=2.5, 95%CI 1.7–3.7, OR=2.5, 95%CI 1.6–4.0 respectively). Although men were more violent than women, diagnosis of bipolar disorder was a more significant risk factor for female patients than for male patients (OR=16.1 95%CI 1.8–144.6 vs. OR=2.4, 95%CI 1.5–3.7). Discussion The results of this study suggest that increased risk of violence is part of the clinical picture of schizophrenia and bipolar disorder and needs to be recognized as a legitimate, essential, aspect of clinical management.

Background In schizophrenia (SCH), proton MRS studies of the medial prefrontal cortex (MPFC) show elevated glutamine (Gln) or the combination of Glu and Gln (Glx) in unmedicated patients. Studies in healthy human subjects demonstrate ketamine-induced acute increases in MPFC Glu or Gln. Together, these findings raise the question of potential disturbances in excitation-inhibition balance in the illness, possibly arising from NMDA receptor deficits in GABAergic interneurons. We investigated these questions following acute ketamine administration by using repeated 15-minute MRS acquisitions of Glx and GABA with simultaneous EEG and comparing the results with the same modalities acquired in SCH. Methods We enrolled 11 healthy volunteers (age 18–55) who were given a constant i.v. infusion of ketamine 0.5 mg/kg over 40 min during a combined EEG and 1H MRS study. Glx and GABA were acquired in the pregenual MPFC using a 3T GE system and a J-edited PRESS sequence. Sequential MRS acquisitions each of 15 min duration (90 min total) were obtained before, during, and following the infusion. EEG was recorded using an MRI-compatible 64-channel system with direct current BrainAmp MR amplifiers (Brain Products GmbH). Post-ketamine EEG data were analyzed in frontal electrodes for gamma and delta alterations. EEG and MRS data were also acquired in 12 patients with SCH with these systems. Results Neurochemicals Glx and GABA showed acute increases within 15–30 minutes following the initiation of ketamine infusion, more pronounced for GABA (13% increase, p = .04 by paired t test). Gamma amplitude in left and right frontal electrodes increased in the first 15-minute average after initiation of ketamine (p < .05), with no evidence of earlier gamma decrease. Left delta amplitude decreased linearly following ketamine (p < .01). Peak GABA concentration correlated inversely with average left delta amplitude in the immediately subsequent 15-minute acquisition. Data in SCH showed similar elevations in GABA and gamma amplitude. Discussion These data show the feasibility of attaining time resolution of Glx and GABA changes in the several-minutes range with standard PRESS J-edited 1H MRS, and simultaneous sub-second resolution with EEG. There were no indications in these frontal electrodes of very early GABAergic inhibition leading to disinhibition of Glx, which may occur in other brain regions following ketamine administration. The GABA, Glx, and EEG alterations found here following ketamine administration are consistent with stable alterations reported in unmedicated patients with SCH and are compatible with an NMDA receptor deficit mechanism in the illness. They show homeostatic rebalancing at elevated levels as found in SCH itself. Excitation-inhibition rebalancing at abnormally elevated levels may pose a risk of neuronal damage that persists in untreated psychosis.

Background Very few prospective, sequential studies are available that could guide decisions which have to be made in every day clinical routine. Some of the simplest questions of clinicians remain unanswered. For example: If the first antipsychotic used has not worked, is switching to another drug effective? Or should we perhaps increase the dose? And when should we start clozapine, the most efficacious drug? These questions are most urgent for patients with a first episode of psychosis. Methods OPTiMiSE is an international clinical trial, conducted in 27 research centers located in 14 countries across Europe and Israel. Among other purposes, OPTiMiSE was designed to test a three-stage treatment algorithm. The 446 participants of OPTiMiSE were diagnosed with a first episode of schizophrenia, schizophreniform or schizoaffective disorder. Each participant started with a 4-week open label amisulpride treatment. After these 4 weeks, non-remitters are randomized to switch to another antipsychotic versus continuation of amisulpride for 6 weeks, in a double-blind fashion (phase 2). After these additional 6 weeks, non-remitters were switched to clozapine for another 12 weeks. Results Description of the sample: Mean age at inclusion was 26 years, 30% of the patient sample was female. The median duration of illness was 4 months and none of the participants had been using antipsychotic medication for more than 2 weeks. All patients were treated on a voluntarily basis. The patient sample was moderately ill at baseline, with a mean score on the Positive And Negative Syndrome Scale (PANSS) of 78 (sd 19). Phase 1 Patients started on 200–800 mg/day amisulpride treatment, with a target dose of 400 mg/day. Drop-out rate was 20%. Out of the 446 patients who were initiated on amisulpride, 56% met remission criteria, based on the eight remission items of the PANSS. Side effects were mild, with a mean weight increase of 2.7 kg (sd 3.3). Phase 2 At the end of phase 1, 121 patients did not meet remission criteria. Out of the 93 patients who continued into the double-blind treatment phase, 72 patients completed the 6-week treatment phase. Remission rate in phase 2 was 35%. There was no significant difference between the two treatment arms regarding remission rate, nor regarding the drop out rate. Patients randomized to olanzapine gained significantly more weight compared to amisulpride. Phase 3 At the end of phase 2, 40 patients did not meet remission criteria. Out of the 28 patients who continued into the open-label clozapine treatment phase, 18 patients completed this 12-week treatment from which only 5 patients met remission criteria, translating into a remission rate of only 18%. Non-remitters generally did improve to a great extent but failed to meet the stringent remission criteria. Discussion Amisulpride is confirmed to be a good option for initiating pharmacotherapy in first episode patients, resulting in a high remission rate. There was no advantage related to remission rates or drop out rates for switching non-responders after 4 week of treatment to another antipsychotic versus continuing the initiated antipsychotic for another 6 weeks; continuing the first antipsychotic may have the benefit of avoiding new side effects related to introducing a new antipsychotic. Despite a low remission rate following clozapine treatment, non-remitters generally did show a substantial reduction in symptoms, demonstrating that clozapine should be an option for non-responding psychotic patients early in the illness.

Background Cannabidiol is a component of herbal cannabis, studied for a number of potential pharmaceutical indications, more recently, its potential anti-psychotic effects with an extremely favorable side effect profile. Cannabidiol content of cannabis may also attenuate the psychotic and cognitive effects associated with cannabis use. Early psychosis is associated with alterations in the endocannabinoid system and is marked by limited engagement in treatment, reluctance to use traditional antipsychotics, sensitivity to medication side effects and heavy cannabis use. Cannabidiol may thus represent a more acceptable and tolerable antipsychotic medication in this phase of illness with a novel mechanism of action. Methods Data will be presented from an ongoing double blind, placebo controlled, within subject, crossover study examining the effects of Cannabidiol (800mg/day) versus placebo in individuals within the first 7 years of their psychotic illness. Subjects participate in two treatment periods, each four weeks long separated by at least 2 weeks of washout. Results Data will be presented on the effects of Cannabidiol on psychotic symptoms (measured on the Positive and Negative Syndrome Scale), cognitive deficits (MATRICS battery), electrophysiological biomarkers of information processing (Resting EEG and ERPs relevant to psychosis and cannabinoids), metabolic parameters and general functioning. Discussion Cannabidiol is a novel drug that has shown potential efficacy in the treatment of psychotic symptoms. Early psychosis is a critical treatment period during which treatment engagement and adherence is critical and duration of untreated psychosis is associated with long term negative consequences. Cannabidiol may thus represent a more acceptable and tolerable medication to target this vulnerable population.

Background There has been growing interest in the therapeutic potential of Cannabidiol (CBD) stemming from independent evidence that CBD has antipsychotic and anxiolytic properties in patients with mental health disorders. CBD has been found to be non-inferior to antipsychotic medication in a 4-week clinical trial in acute schizophrenia (Leweke et al 2012) and also has been found to reduce anxiety symptoms in social phobia and following public speaking. Human data also suggest that it attenuates the cognitive impairments associated with use of the main psychoactive ingredient in cannabis. However, whether CBD may be useful in relieving symptoms and distress in patients at clinical high-risk of psychosis (CHR) has never been tested. Furthermore, how the beneficial effect of CBD on psychotic and anxiety symptoms may be mediated in the brain remains unclear. The aim of the present study was to investigate whether short-term treatment with CBD was associated with preliminary evidence of therapeutic benefit and understand the neurocognitive mechanisms. Methods We investigated the effects of short-term (21 days) treatment with CBD on psychotic and anxiety symptoms in 33 CHR patients, using a placebo-controlled, double-blind, parallel-arm design (CBD arm- 16; placebo arm- 17). In the subjects who received 21 days of treatment, we used fMRI in conjunction with a verbal memory task to assess the effect of CBD relative to placebo treatment on medial temporal and striatal function. Results Of the 33 CHR patients recruited into the trial, 31 completed treatment for 21 days. Following 21-day treatment (intention-to-treat, last observation carried forward analysis), CBD-treated (n=16) CHR patients showed a significantly greater reduction in anxiety (p=0.02) and in distress associated with psychotic symptoms (p=0.03) and a trend (p=0.14) toward greater reduction in the severity of psychotic symptoms compared to those treated with placebo (n=17) CHR patients (Figure 4). In addition, CBD was tolerated as well as placebo. Consistent with our predictions, treatment with CBD (n=15) attenuated the engagement during verbal encoding of the parahippocampal cortex, but increased activation in the putamen in CHR patients. A similar pattern of activation was evident during verbal recall, with CBD treatment associated with increased engagement in the putamen. Discussion Results from our proof-of-concept study suggest that 3-week treatment with CBD has beneficial effects on anxiety, attenuated psychotic symptoms and the distress associated with psychotic symptoms. They also suggest that short-term treatment with CBD modulates both medial temporal and striatal function in CHR patients, regions that are critically implicated in the CHR state. Coupled with the absence of significant adverse effects associated with CBD, a particularly important issue in relation to the treatment of CHR individuals, not all of whom develop a full-blown psychotic disorder, these data indicate that long-term treatment with CBD is likely to be efficacious in CHR patients.

Overall Abstract: Even if there have been effective antipsychotic treatments for more than fifty years, the implementation of these treatments in clinical practice is still far from optimal, and a significant amount of patients with schizophrenia show poor outcomes. It is unquestionable that antipsychotics remain the first treatment option for patients with first-episode schizophrenia (FES). However, several questions still demand answer in the field. It is unclear how long we should wait before changing an antipsychotic that has not been fully effective, how long we have to wait before starting clozapine in FES, whether we can identify who will respond better to current treatments using biological markers including neuroimaging, and how to improve adherence and functional prognosis after clinical remission is achieved. OPTiMiSE (‘Optimisation of Treatment and Management of Schizophrenia in Europe’) is an European Consortium funded under the VII Framework Program that addressed these questions in a sample of nearly 500 patients with FES or schizophreniform psychosis and minimal prior exposure to antipsychotics recruited across Europe and Israel. Within an integrative framework, the Consortium aimed at combining clinical, neuroimaging, genetic and biochemical data in a large representative sample to provide answers to these clinically relevant questions and prepare the field for personalised medication strategies as drugs with novel mechanisms of action become available. Results from this study have not yet been published and most of them will be presented for the first time in a Congress. Based on previous results from the EUFEST study, all patients received amisulpride as a first step. For those not achieving remission after 4 weeks, OPTiMiSE compared in a randomised double-blind fashion the option of staying on amisulpride or moving to a drug with a different receptor-binding profile, olanzapine. In those not achieving remission after 6 weeks, clozapine was started. OPTiMiSE thus constitutes the first systematic, large-scale testing of the potential benefits of early switching to an antipsychotic with different characteristics in patients not achieving remission, and the application of clozapine in non-remitting patients within the first 10 weeks of treatment. OPTiMiSE also provides information on the added value of psychosocial interventions to improve treatment adherence, reduce relapses and improve functional outcomes after remission is achieved, through a 1-year follow-up randomised controlled trial testing a web-based program comprising a motivational intervention package, psychoeducation, and electronic medication alerts and updates. OPTiMiSE also collected blood samples for patients participating in the clinical trial and a systematic sample of more than 200 standardised, high-quality, magnetic resonance imaging (MRI) images. Based on this information, OPTiMiSE examined the clinical utility and cost-effectiveness of MRI for screening of underlying organic conditions in FES. In addition, OPTiMiSE also offers novel information on how MRI alterations, genetic and biochemical markers at first presentation of schizophrenia can predict the response to subsequent treatment. For this, OPTiMiSE used two broad strategies—a combination of technology-driven (pharmacogenetics, proteomics, and metabolomics) and hypothesis-driven (neuroimaging, neurochemical, and immune-related) markers. This symposium offers an overview of the main results obtained in the project in all these areas, with special focus on their clinical and research implications.

Overall Abstract: Interaction between genetic risks and environmental adversities such as childhood trauma may underlie the etiology of psychiatric disorders. Mechanisms underpinning these interactions are poorly understood. This panel will present new data supporting a model in which epigenetic modifications and increased oxidative stress lead to altered trajectories and patients’ stratification. Helen Fisher will introduce the field, how exposure to severe stress may have immediate as well as long-lasting damaging effects on learning, behaviour, and health, and has been implicated in the development of psychosis. She will present epigenome-wide analyses of poly-victimisation across childhood and adolescence, utilising data from the Environmental Risk (E-Risk) Longitudinal Twin Study, an epidemiological study of 2,232 children (1,116 twin pairs) born in 1994–1995 in England and Wales and followed to 18 years of age. Results related to associations with DNA methylation in peripheral blood at age 18 years, specific forms of victimization and candidate genes in the stress response will be discussed. Luis Alameda will show that childhood trauma (sexual, physical and emotional abuse) engages oxidative stress in a cohort of early psychosis patients (n=118). Patients with high peripheral oxidation status were found to have smaller hippocampal volumes and more severe clinical symptoms, while those with lower oxidation status evidenced a compensatory antioxidant regulation and better cognition. Linear discrimination analysis highlights blood oxidation status together with childhood trauma as markers for poorer psychopathological profile, allowing patients’ stratification. Oussama Kebir will present the first longitudinal prospective study of genomic DNA methylation during psychotic transition in help-seeking young individuals (14 converters, 25 non converters). Alterations in gene promoters and pathways relevant for psychosis, including oxidative stress regulation, axon guidance and inflammatory pathways were observed. In particularly, antioxidant defense gene GTSTM5 is differentially methylated through time and two other genes of GST family might be differentially methylated after conversion to psychosis. These findings suggest that conversion to psychosis may depend on the specific control of oxidative metabolism and regulation between these genes. Darina Czamara will report on how cord blood methylation is affected by genetic and prenatal environment. Analysis on SNP (G) and environmental (E) effects as well as on GxE and G+E were performed using Illumina’s Human Omni Express Exom as well as the 450k DNA methylation array in a cohort of 817 Finnish newborns. G and the combination of G and E explained DNA methylation best, environment alone was almost never the best predictor. Furthermore, epigenetic gestational age was associated with prenatal environment as well as with childhood psychiatric problem at age 3 indicating that it might be used as a potential biomarker. Overall, these new results suggest new biomarkers of environmental and genetic adversity that are related to pathogenic mechanisms, including epigenetic, oxidative stress and structural abnormalities, in epidemiological studies and psychiatric disorders. These biomarkers offer the potential for individualized early intervention and preventive strategies.

Background We hypothesised that a multi-modal psychosocial intervention (PSI) after first episodes of non-affective psychosis would increase antipsychotic adherence, improve functioning and prevent readmission in a multi-centre, blind-rated, randomised controlled trial. Methods Following treatment of first episode non-affective psychosis with amisulpride, olanzapine or clozapine (those remitting after phases 1–3 of the OPTIMISE program or dropping-out but willing to enter the adherence trial) patients with DSM-IV schizophreniform disorder, schizophrenia, or schizoaffective disorder were eligible for allocation to PSI or treatment as usual (TAU). PSI involved: i) e-learning via a psychoeducational website; ii) mHealth intervention with 3 months SMS medication reminders configured by participants; iii) motivational interviewing targeting adherence over 6 weeks. Primary outcome measures at 3 and 12 month follow-up were Compliance Rating Scale (score 1–7 worst to best), and Social and Occupational Function Assessment Scale (SOFAS; 0–100). Secondary outcomes included remission, Drug Attitudes Inventory (DAI), and EuroQoL quality of life scale. We present interim analyses of 3 month data with general linear and logistic regression models, clustered by centre and adjusted for baseline scores and demographics. Results Recruitment time, now finished, was extended to reach target sample size, so 12 month data are incomplete. 258 were allocated to PSI or TAU. 18 dropped-out before baseline assessment: 240 entered the modified intention to treat analysis (PSI 121, TAU 119). After PSI, 71% were followed-up at 3 months; after TAU, 80%. No baseline variable significantly predicted this attrition. Webpages covering illness and treatment had 244–290 hits each. Only 24% of the PSI group set up SMS text reminders. At least 70% attended motivational interviewing, 77% of these for all sessions. Mean California Patient Alliance Scale item score was 5.2 (95% Confidence Interval, CI, 5.0, 5.3; score 1–7 poor-good). Mean baseline SOFAS (SD) for the PSI group was 62 (14); for TAU 62 (15). General linear modelling of 12 week data included baseline CRS and drug attitudes: marginal mean SOFAS after PSI was 65.3 (CI 62.6, 68.0) and after TAU 61.4 (CI 59.3, 63.4; p0.025; standardised effect size Glass’ Δ=0.41). Median (IQR) compliance score was 6 (5,7) at baseline for PSI and 6 (6,7) for TAU; and 6 (5,7) at 3 months in both groups (ordinal logistic regression, p0.36). In secondary analyses 3 month DAI did not differ significantly between PSI and TAU (marginal means 13.5 v 11.5, bootstrapped p0.164). EuroQoL wellbeing score was significantly better after PSI (marginal means 76.0 v 69.1, bootstrapped p0.003) and remission was significantly commoner (72 v 54%, binary logistic regression p0.007). No analysis result was sensitive to probability weighted adjustment for drop out. Discussion Interim analyses indicate that immediately after PSI social function and wellbeing improved significantly and remission was commoner. Adherence and DAI did not differ significantly. Either PSI’s immediate benefits were non-specific or adherence measures failed to capture its effect. Longer term effects are unclear until definitive analyses planned before 2018.

Background Recent genomic studies have begun to reveal the genetic architecture of psychiatric disorder and to give important insights into the relationship between the psychiatric syndromes that form the basis of current taxonomy. These studies have demonstrated the highly polygenic nature of psychiatric disorders, and have indicated that many individual genetic associations are shared across multiple disorders in a way that points to extensive biological pleiotropy and challenges the biological validity of existing diagnostic approaches. Methods I will present genomic data, predominantly from the study of rare variants, that support the idea of a neurodevelopmental continuum, in which schizophrenia and bipolar disorder, together with childhood neurodevelopmental disorders, such as ID, ASD and ADHD represent the diverse range of outcomes that follow from disrupted or deviant brain development and furthermore that, within the neurodevelopmental continuum, severe mental illnesses occupy a gradient of decreasing neurodevelopmental impairment as follows: ID, ASD, schizophrenia and bipolar disorder. I will also present findings indicating that common genetic variation modifies the outcome of neurodevelopmental impairment explaining in part the diversity of psychiatric outcomes. Finally, I will explore how genetic data might be used to inform novel approaches to patient stratification which will be informative for prognosis and treatment response and facilitate the identification of novel drug targets. Results Finally, despite the undoubted complexity and the fact that much of the genetic risk remains unaccounted for at the DNA level, there are encouraging signs that the genes implicated in schizophrenia converge onto sets of plausible biological processes. In particular, the data point to synaptic function and histone modification and implicate mechanisms involved in brain plasticity that are important in development and in learning and cognition. While these are almost certainly not the only processes involved, they provide robust entry points for clinical and basic neuroscience research. Discussion N/A

Background Much anti-stigma work suggests that reducing stigma and improving mental health literacy could also improve access to care and support for people with psychotic disorders. This is important given that increasing help-seeking, especially during the early stages of psychosis could reduce the substantial delays to care experienced by people with psychotic disorders. Little is known about levels of personal stigma and mental health literacy among young people at-risk of psychotic disorders, whether there are differences between young people with and without elevated risk for psychosis and how this is associated with actual help-seeking for individuals at-risk of developing psychotic disorders. Methods We interviewed participants from two existing, ongoing prospective cohorts in the UK and in Brazil. Participants were initially recruited from primary schools. Both samples represent enriched community cohorts (including a greater than average proportion of young people at risk of developing psychotic disorders) in Greater London (n=407) and a similar cohort of young people in Brazil (n=1,500). Participants were presented a vignette depicting a young person with early psychosis symptoms and asked about: recognition of the disorder; intended help-seeking; beliefs about interventions and prevention, stigmatising attitudes and whether they knew someone with a similar problem. We also collected detailed clinical data on psychiatric symptoms (via SDQ [Strengths and Difficulties Questionnaire] in the UK and DAWBA [Development and Well-Being Assessment] in Brazil), presence of psychotic-like experiences, and use of mental health services and personal experiences of seeking support for a mental disorder. Results Findings on the relationship between personal stigma and mental health literacy in relation to psychotic disorders, intended help-seeking and actual mental health service use, will be presented among young people with and without risk of developing psychotic disorders in the UK and Brazil. Discussion Reducing personal stigma and improving mental health literacy among young people at risk of psychosis who do not yet use clinical services could be important for future help-seeking. Future research should investigate the impact of anti-stigma interventions among young people with and without risk of developing psychotic disorders and how this facilitates help-seeking and support for this vulnerable group.

Background For individuals who have a psychiatric disorder and have committed a major crime, the rate of re-offending is twice as high in the US compared to nine other countries for which there is comparable data. For such individuals the average five-year rearrest rate is approximately 40% for those released from psychiatric hospitals and 60% for those released from jails or prisons. The use of treatment modalities such as extended conditional release, Forensic Assertive Community Treatment (FACT) teams, and Psychiatric Security Review Boards can reduce the rearrest rate from 40–60% to 10% or less. Methods All 50 states were surveyed to assess how they were doing in providing follow-up treatment for such individuals. Results Sixteen states were found to be making a moderate effort to provide follow-up treatment, and another 13 states are making a minimal effort. However, the other 21 states, 42% of the total, are making virtually no effort, lending to an unnecessarily high rate of re-offending. Discussion Using proven treatment approaches the re-arrest rate of individuals with serious mental illness can be reduced from 40–60% to 10% or less.

Background Stigma and discrimination are proposed as critical factors contributing to the underuse of mental health services amongst young people, however these influences remain understudied. Existing research on stigma experienced by young people has focused on individuals in contact with mental health services or with a psychiatric diagnosis. Using a community sample, this study investigates subjective accounts of stigma during the early stages of mental health difficulties with regards to how disclosure and coping are considered, and how help-seeking is approached. Methods In-depth semi-structured individual interviews were conducted with young people from a Greater London, UK, community cohort. Purposive sampling criteria were used to recruit participants who reported early psychopathology of a persisting nature (emotional and/or behavioural difficulties at a clinical level, and psychotic-like symptoms), thus representing young people at-risk of developing psychiatric disorder. 29 young people aged 12-18 years took part in the study. Thematic analysis was used to analyse the interview data. Results In-depth semi-structured individual interviews were conducted with young people from a Greater London, UK, community cohort. Purposive sampling criteria were used to recruit participants who reported early psychopathology of a persisting nature (emotional and/or behavioural difficulties at a clinical level, and psychotic-like symptoms), thus representing young people at-risk of developing psychiatric disorder. 29 young people aged 12-18 years took part in the study. Thematic analysis was used to analyse the interview data. Discussion “Conditional disclosure” is central to how young people cope with their difficulties. Often stigma-related concerns in particular contributed to restricted disclosure, in this way delaying young people’s initial help-seeking when difficulties emerge.

Background Cognitive and functioning impairments are present early in the course of psychotic disorder and remain one of the greatest treatment challenges in this population. While Cognitive Adaptation Training (CAT) is found to improve a range of outcomes in chronic schizophrenia, it has received limited investigation in first-episode psychosis (FEP). CAT may be particularly useful for addressing vocational recovery in FEP because the cognitive impairments experienced by individuals with FEP predict poorer vocational outcomes and impede the effectiveness of vocational interventions such as supported employment. The aim of this presentation is to present the findings of a pilot study investigating the feasibility and acceptability of CAT in young people with FEP and to describe the clinical considerations and adaptations required when delivering CAT with this population. Preliminary findings on the potential value of CAT in improving vocational outcomes in FEP will also be presented. Methods This was a single-arm feasibility study of CAT conducted at the Early Psychosis Prevention and Intervention Centre (EPPIC), Melbourne, Australia. Five FEP participants received 9 months of manually-guided CAT. A range of feasibility and acceptability measures were recorded, including participant and case manager satisfaction ratings. Participants’ goals, functional needs and clinical observations and adaptations were also recorded. Formal measures of functioning, quality of life and motivation were independently administered pre- and post-intervention. Results All participants completed the CAT intervention and session attendance rates were very high (95.3%). Participants and their case managers indicated strong satisfaction with CAT as indicated by overall positive mean ratings on the satisfaction items. CAT did not negatively affect existing case management, with case managers reporting that it enhanced their treatment. Vocational recovery (education, employment) was found to be a primary functional goal of most participants. Accordingly, the CAT intervention had a strong focus on vocational functioning, including functional domains that are requisite for successful work or educational outcomes, including organisation and planning, transportation and activities of daily living. Being mindful of factors that may be common in young FEP patients included cognitive heterogeneity, family involvement, flexibility in compensatory and environmental supports used, and the experience of stigma. There were mean improvements from baseline to post-intervention on most formal outcome measures, with the largest effects in global functioning, planning and organisation, and quality of life. Discussion This study provides encouraging preliminary evidence that CAT is a highly feasible and acceptable intervention in FEP, which may be easily integrated within existing early intervention services. Vocational recovery is important to young people with FEP. CAT is an intervention that appears well suited to addressing this need. The effectiveness of CAT in improving functional outcomes, particularly vocational recovery in FEP warrants further investigation in a larger trial.

Background Current diagnostic models of psychosis have been questioned since Kraepelin’s original dichotomy of dementia praecox and manic depression. Indeed, increasing evidence has suggested that a dimensional approach might be a valid alternative platform for research. However, while an increasing number of studies have investigated how environmental risk factors for affective and non-affective psychosis map onto symptom dimensions, only a few have examined these dimensions in relation to genetic variants as summarised by Polygenic Risk Score (PRS). Furthermore, no studies have examined the putative effect of PRS for Schizophrenia (SZ), Bipolar Disorder (BP), and Major Depressive Disorder (MDD) on previously identified general and specific symptom dimensions. At the same time, only one study has investigated how symptoms vary according to epidemiological factors such as living in urban neighbourhoods. The objectives of this study were to: 1) test whether a bi-factor model statistically fits the conceptualization of psychosis as composed of general and specific dimensions; 2) examine the extent to which SZ, BP, and MDD PRSs explain the phenotypic variance due to general and specific dimensions; 3) test the hypothesis that the general psychosis dimension would be more severe in highly urban environments. Methods We used clinical and epidemiological data from the EUropean network of national schizophrenia networks studying Gene-Environment Interactions (EUGEI) study, including 2322 First Episode Psychosis (FEP) patients recruited in 17 sites across 6 countries. Genetic variants were collectively analyzed for 800 individuals. The following analysis steps were performed: 1) Psychopathology items were analysed using multidimensional item response modelling in MPlus to estimate unidimensional, multidimensional, and bi-factor models of psychosis. Model fit statistics included Log-Likelihood, and Akaike and Bayesian Information Criteria to compare these models. 2) SZ, BP, and MDD PRSs for general and specific dimensions were built using PRSice. Summary statistics from large case-control mega-analyses from the Psychiatric Genomics Consortium were used as base data sets and general and specific dimension scores were used as discovery data sets. Individuals’ number of risk alleles in the discovery sample was weighted by the log odds ratio from the base samples, accounting for population stratification, and summed into the three PRSs. 3) Multilevel regression analysis was used in STATA 14 to examine the variance in general dimension due to the population density levels across the sites. Results A bi-factor solution, composed of one general and five specific symptom dimensions, showed the best model fit statistics. Higher SZ PRS score was associated with higher scores on positive dimensions (β= 0.27, t=2.11, p

Overall Abstract: The immune pathogenesis story of schizophrenia is gathering momentum, with increasing evidence from animal models, genetic, circulating biomarker and neuropathological studies. Potentially ground breaking new treatment approaches are proposed. However, it is vital that basic science and is equally matched by deep understanding of the complexity of clinical samples and management of multiple confounding factors when moving from bench to bedside. This presentation will pull together key speakers from a variety of fields, demonstrating the need for continued dialogue in translational, and reverse translational, approach. We will present findings from preclinical studies, genetic insights, longitudinal modelling of immune markers from population-based samples and detailed analysis from clinical samples. Data will include evidence of a prenatal immune activation and the potential transgenerational transmission of behavioural and neuronal abnormalities, co-variation of gene sets associated with both increased risk of schizophrenia and immune function (eg CSMD1, DPP4) together with CRP and peripheral inflammatory cytokine association with symptom profiles in both larger population and clinical samples. Thus, evidence presented will move from large data to fine grain analysis, animals to man and from bench to bedside. We aim to provide insights into early pathophysiological processes and forward avenues of research to the ultimate aim of elucidating the immune dysfunction impact on psychosis and future avenues for effectiveness of treatment.

Background Knowledge about the long-term cognitive course in psychotic disorders is limited. In this 18-year follow-up of participants of the Suffolk County project we report on the longitudinal course of cognitive performance in individuals with schizophrenia spectrum disorders, affective psychoses and other psychoses. We investigate (i) change in functioning in 6 cognitive domains from 2-years to 20-years follow-up after first admission; (ii) 20-year performance and age-related differences in cognitive performance in patients relative to a never psychotic comparison group; and (iii) key predictors of clinically meaningful cognitive decline in patients. Methods Data came from the Suffolk County Mental Health Project, a prospective study of first-admission patients. Cognitive tests were administered 2 years (n = 399; schizophrenia spectrum: 285, affective psychoses: 226, other psychoses: 117) and 20 years (n = 240; 115, 92, and 34, respectively) after first admission, with 195 individuals completing cognitive tests at both time points. A never psychotic comparison group (N=260) was assessed at year 20. Results Individuals with schizophrenia spectrum disorders showed lower cognitive functioning than those with affective and other psychoses. Over time, patients declined in cognitive performance on almost all tests (d = 0.24 (range 0.12- 0.44)) with comparable magnitude across diagnoses. Longer duration of untreated psychosis and low childhood IQ were significantly associated with clinically relevant decline (>0.5SD) in general verbal ability and processing speed, but there were no robust predictors of cognitive decline across tests. Cross-sectional comparisons of patients to controls showed increasing impairments with age for general verbal ability, verbal fluency, and executive functioning. Discussion Our findings indicate that cognitive functioning in psychotic disorders continues to decline after the illness onset, that this decline is not specific to schizophrenia but present across psychotic disorders, and that, relative to never-psychotic individuals, impairments on some key-cognitive domains worsen with age. These results imply that cognitive treatment should not only include cognitive remediation but also prevention of age-related cognitive stagnation and/or decline.

Overall Abstract: The superiority of clozapine for treatment refractory schizophrenia was, until very recently, seen as one of the few unshakeable truths in psychiatry. But the pre-eminence of clozapine has recently been called into question by meta-analyses. What are we to make of the fact that meta-analyses of clinical trials, supposedly the pinnacle of evidence based medicine, fail to show an effect which seems clearly evident to most clinicians, and on which many of our guidelines are based? Have we believed in a fairytale for the past three decades? Or do biases in RCTs and methodological limitations of meta-analyses explain the results? These questions will be discussed by Dan Siskind. Another way to address the question of efficacy is to examine the pharmaco-epidemiological evidence using population-based registers. Jari Tiihonen will present data from his seminal studies of mortality and readmission rates under clozapine treatment versus other antipsychotics, as well as other data. These data seem to show powerful positive effects of clozapine at the population level. Furthermore, more recent evidence suggests a role for clozapine in reducing rates of violent offending, with new data presented for the first time by Vishal Bhavsar. Finally, despite clinical guidelines recommending the use of clozapine, the actual rates of clozapine use are much lower than expected, with large regional and international variations. There is evidence that the burden of blood monitoring deters physicians from prescribing clozapine. Yvonne van der Zalm will present new data from a cluster randomised trial testing the efficacy and safety of an intervention to increase rates of clozapine prescribing by employing nurse practitioners trained in the initiation and monitoring of clozapine. John Kane, author of the first, seminal RCT of clozapine in 1988, will lead the discussion.

Background Anti-neuronal antibodies are associated with psychosis although their clinical significance in first episode of psychosis (FEP) is undetermined. This study examined the prevalence of anti-neuronal antibodies in patients admitted to hospital for treatment of their first episode of psychosis and described clinical presentations and treatment outcomes of those who were antibody positive. Methods Between July 2013 and May 2015, all consenting patients aged between 12 and 50 admitted for their first episode of psychosis to three mental health hospitals in Queensland, Australia, were tested for anti-neuronal antibodies in serum. Antibody positive patients were referred for neurological and immunological consultation and treatment. Results During the study, 154 FEP patients were admitted with their first episode of psychosis and 113 consented to participate. Six patients were found to have anti-neuronal antibodies; (anti-NMDAR antibodies [n = 4], VGKC antibody [n = 1], antibody against uncharacterised antigen [n = 1]). Of these, five received immunotherapy, leading to complete resolution of psychosis in four. Discussion A small, but significant subgroup of patients with first episode psychosis have anti-neuronal antibodies detectable in serum and evidence of central nervous system autoimmune pathology. Early identification of these patients and referral for appropriate treatment is critical to optimise recovery.

Overall Abstract: Most patients with schizophrenia and bipolar disorders (severe mental illness, SMI) are not violent in their lifetimes, however, a minority of patients are violent at some points in the course of their illness. As the illness appears relatively early in life, and typically runs a chronic course, the number of violent incidents caused by patients can be considerable in some cases. Due to the stigma toward SMI, the media often emphasize reporting of these incidents, which fuel the stigma even more. Although violent behavior is a common cause of concern for patients, their families and clinicians, it is not often discussed in scientific meetings. The purpose of this symposium is to bring this relatively neglected, but very important topic into the spotlight in SIRS, in order to summarize the latest evidence for clinicians and researchers, and to foster new work on reducing these risks of violence. Dr. Weiser will present an overview of the prevalence of violent behavior in patients with SMI, and will present a population-based, case-control study from Israel, showing increased rates of violent crime in patients with SMI, particularly in female patients and patients who abuse drugs. Secondary analyses will show increased rates of violent behaviour in siblings of patients as well. Dr. Fazel will present a systematic review on the prognostic (or predictive) accuracy of structured ways to assess violence risk in patients with severe mental illness, and present new work on a scalable and potentially useful predictive model of violent behaviour based on 75,000 patients in Sweden. Dr. Nijman will present a model based on patient, ward and staff variables focused on the causes and triggers of aggressive behavior on (locked) psychiatric wards. Based on this model, a number of preventive measures can be formulated. At the patient level, the administration of anti-psychotic medication is used to reduce the negative cognitive schemes and delusional thoughts that are depicted in the center of the model. A more novel intervention at the patient level may be the additional administration of nutritional supplements with (among others) high levels of omega 3 fatty acids. The results of two Dutch studies on this topic will be briefly presented in the lecture, among which a RCT on the effects of the use of nutritional supplements on aggressiveness. On the staff level, the use of short-term (daily) risks assessments by the ward nursing staff, among others by means of the six item BrØset Violence Checklist (BVC), has been found to reduce aggressiveness as well as the use of coercive measures on psychiatric wards in two cluster randomized RCTs. On the ward level, studies indicate that aggression on psychiatric wards can be reduced by preventing overcrowding on psychiatric wards, and by providing more space and privacy to the patients. Dr. Torrey will present data on rates of re-arrest in patients with SMI, showing that the average five-year re-arrest rate is approximately 40% for those released from psychiatric hospitals and 60% for those released from jails or prisons, and will present comparison data from other countries. He will then present data on the effect of extended conditional release, Forensic Assertive Community Treatment (FACT) teams, and Psychiatric Security Review Boards on re-arrest rates.