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Background A dysregulated immune system is implicated in the development of psychotic disorders. Persons with schizophrenia have altered levels of circulating immune cell signaling molecules (cytokines), and elevation of specific cytokines predict conversion to psychosis in persons at clinical high risk. Whether these peripheral signals are a causal or a secondary phenomenon is unclear. But, subpopulations of circulating immune cells do regulate the brain from meningeal and perivascular locations influencing cognition, mood, and behavior, and thus may be relevant to schizophrenia vulnerability. Hematopoietic stem cells in the bone marrow differentiate into cascading subtypes depending on signals from other organs, especially the brain. For example, a monocyte subpopulation emerges with repeated social defeat that establish the persistence of anxiety-like behaviors; blocking their release or inhibiting their attachment to brain vascular endothelium prevents the emergence of anxiety-like behaviors. In humans, a similar monocyte subpopulation is associated with social isolation and other adversities including low SES, chronic stress, and bereavement. Methods The North American Prodrome Longitudinal Study (NAPLS2) is an eight-site observational study of predictors and mechanisms of conversion to psychosis The full cohort includes 763 at clinical high risk (CHR) based on the Criteria of Prodromal State (COPS) and 279 demographically similar unaffected comparison (UC) subjects. Methylation of whole blood DNA collected in PAXgene tubes at baseline was analyzed with the Illumina 450k array in a subgroup of 59 subjects who converted to psychosis (CHR-C), 84 CHR subjects followed for 2 years who did not develop psychosis (CHR-NC) and 67 unaffected subjects (UC). Our analyses focused on methylation of promoter regions of genes, associated with gene expression. Classifier construction used Coarse Approximation Linear Function (CALF) with bootstrapping of 1000 random 80% subsets with replacement to determine statistical likelihood. Results We found highly overlapping sets of differentially methylated promoter regions in CHR-C subjects compared to CHR-NC and to UC subjects. A set of 10 markers correctly classified CHR-C and CHR-NC subjects with high accuracy (AUC=0.94, 95% CI 0.89–0.98). Included was SIRT1, a gene that is upregulated with HSV reactivation. Discussion Circulating immune cells excerpt powerful influences on mood, cognition and behavior. An obvious example is the experience of most human with “sickness syndrome”, characterized by apathy, avolition, and withdrawal, and triggered by immune-cell-released cytokines producing an adaptive, resource conserving, behavioral response. While at an early stage, our findings further implicate immune system dysregulation as a mechanism in the development of psychosis.

Background Prominent etiological conceptions of psychosis implicate abnormal cortico-striatal circuits. Dysfunction in these critical systems, responsible for filtering information and modulating higher-order function, may account for heterogeneous presentations of symptoms and characteristics of psychosis. Collectively, a body of work from our group and from other teams indicates that evaluating select motor behaviors and abnormalities, which directly reflect function of these circuits, may be a useful method for understanding and predicting the neural underpinnings of psychosis. In the context of the psychosis risk period, partitioning clinical high-risk (CHR) youth based on objective behavior may help guide early detection and intervention efforts, and provide a novel perspective on different etiological pathways or patient subtypes. Methods Using an unsupervised machine learning approach, 69 CHR young adults were included in a K-means cluster analysis based on their performance on instrumental measures of psychomotor slowing, dyskinesia, and neurological soft signs (NSS)—distinct motor domains affected across the psychosis spectrum. We also recruited a group of 70 matched healthy controls (HC) for comparison. All participants were also assessed with a resting-state functional connectivity analysis (rcfMRI). The resulting CHR group clusters and HCs were then compared on positive and negative symptoms, multiple cognitive domains, and cortical-striatal seed based resting state analysis. Results Results of a 3-cluster solution suggest that there are subtypes of CHR individuals who show psychomotor slowing, average motor performance, and impairment on measures of dyskinesia as well as NSS domains for motor coordination, sequencing and sensory integration. The cluster of individuals showing dyskinesia and abnormal NSS also have more severe negative symptoms and impairment on a number of cognitive domains. Furthermore, the clusters of CHR individuals who show psychomotor slowing and the cluster showing dyskinesia and abnormal NSS have different cortical-striatal connectivity compared to UHR who show average motor behavior and healthy controls. Discussion These results provide evidence for etiological theories highlighting altered cortico-striatal networks and the importance of examining motor behavior prior to the onset of psychosis. Taken together, this approach may reflect a novel strategy for promoting tailored risk assessment as well as future research developing individualized medicine.

Background Adolescence is an age of heightened vulnerability to develop psychiatric disorders that involve alterations in prefrontal cortex circuitry and cognitive dysfunction. The maturation of prefrontal cortex function is linked to the establishment of dopamine connectivity in this region. Development of mesocortical dopamine is a gradual process that continues until early adulthood. Because of its extended maturational course, this system is particularly susceptible to environmental influences. Yet there is a significant gap in our knowledge about the cellular and molecular mechanisms underlying adolescent prefrontal cortex dopamine development and how they are influenced by experience. Methods We examined the role of the Netrin-1 guidance cue receptor, DCC, and its microRNA repressor, miR-218, on adolescent mouse prefrontal cortex development. We used axon-initiated recombination and cell-specific knock-down techniques to characterize the spatiotemporal growth of mesocortical dopamine axons and the role that DCC and miR-218 play in this process. Next, we assessed whether stimulant drugs in adolescence alter miR-218/DCC signaling, thereby disrupting mesocortical dopamine axon growth. Finally, we determined whether altered dopamine axon growth influences prefrontal cortex development by quantifying pyramidal neuron morphology and cognitive performance in adulthood. Results Here we show, for the first time, that dopamine axons continue to grow from the nucleus accumbens to the prefrontal cortex during adolescence. We discovered that DCC receptors control the extent of this protracted growth by determining where and when dopamine axons recognize their innervation target. Exposure to stimulant drugs or to stress leads to disruption of DCC-dependent adolescent targeting events, causing dopamine axons that should innervate the nucleus accumbens, to grow ectopically to the prefrontal cortex. This effect profoundly changes prefrontal cortex structural and functional development, producing alterations in cognitive processes known to be impaired across psychiatric conditions, including schizophrenia. Importantly, miR-218 controls DCC receptor expression in dopamine neurons across postnatal development and acts as a molecular mediator of the effects of stimulant drugs on prefrontal cortex development. Discussion The prolonged growth of dopamine axons during adolescence represents an extraordinary period for experience to influence their growth and predispose to or protect against psychopathology. MicroRNA control of DCC receptor in dopamine neurons is a molecular link where genetic and environmental factors seem to interact in adolescence to influence the development and function of the prefrontal cortex.

Overall Abstract: A major emerging issue in schizophrenia research is the degree to which the mechanisms underlying the disorder are specific to schizophrenia or are common to a number of disorders, potentially indicating common and distinct pathways to illness. Understanding this is important for diagnosis, biomarkers and the development of new treatments. This symposium will bring together new data to consider the latest findings from different genetic, imaging and clinical approaches. Dr. Owen, Wales, will present the latest genetic data from the largest genome-wide genetic analyses to date in psychotic disorders (schizophrenia and bipolar disorder) and neurodevelopmental disorders (autism, intellectual disability and ADHD), comprising samples from over 100,000 patients and controls. These data identify novel shared pathways involving neurodevelopmental genes, synaptic function and histone modification that are common across these disorders, but also identify differences in the degree of involvement of particular pathways. Dr. Howes, England, will present new data from neurochemical and structural imaging studies comparing patients across psychotic and neurodevelopmental disorders (including schizophrenia, bipolar disorder people at risk of autism), showing that there are common dopaminergic alterations linked to psychosis across disorders, as well as showing that structural and neurochemical brain heterogeneity is increased in most brain regions, but also identifying key cortical and sub-cortical regions with increased homogeneity. Dr. Clementz, USA, will present new EEG and cognitive data from over 400 patients with schizophrenia, and bipolar disorder. This shows differences in intrinsic neural activity that cuts across diagnoses, identifying sub-types that were linked to differences in cognitive functioning. Dr. Wichers, Netherlands, will present new data from a longitudinal study of adolescents using in-depth real-time phenotyping using experience sampling to investigate the relationship between the coherence of responses and the subsequent development of psychotic and other symptom domains one year later. Her novel application of complex systems theory identifies suspiciousness as a common predictor of the later development of a number of symptoms, but also that other responses, such as low mood, determine the specificity of later outcomes to psychosis. Overall this symposium will bring together researchers using different, complementary approaches to provide a comprehensive and multi-disciplinary analysis. By bringing researchers from different disciplines together it will enable common mechanisms to be considered, and new insights to be developed. Finally, Dr. DeLisi’s wide-reaching experience means she is well placed to lead the discussion of the implications of these findings for understanding the neurobiology of schizophrenia, and for biomarker development as well as considering their implications for the developing new treatments. The symposium includes gender diversity in presenters and chairs, speakers from multiple institutions across continents, and diversity in career levels with speakers from early, mid and established positions.

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.

Overall Abstract: Recently aerobic exercise training has begun to be systematically examined in randomized controlled trials (RCTs) in schizophrenia. This symposium will report and discuss the results of RCTs that examined the impact of aerobic exercise on physical health, cognition, and everyday functioning across first-episode and established illness phases of schizophrenia. In addition, data on neurotrophic and brain structural changes will be examined as promising mechanisms of action. Dr. Amal Abdel-Baki of the University of Montreal has focused on the physical health benefits of interval training in her RCT with first episode and multi-episode schizophrenia outpatients. She is demonstrating improved waist circumference, diastolic blood pressure, HDL cholesterol, and social functioning in first episode and multi-episode patients. Dr. David Kimhy of Icahn School of Medicine at Mount Sinai in New York has focused on the impact of aerobic exercise training on cardiovascular fitness, Brain-Derived Neurotrophic Factor (BDNF), cognition, and functional outcome in individuals with an established schizophrenic illness. He has demonstrated beneficial effects at each of these levels. Furthermore, relationships between fitness improvements and BDNF increases and the cognitive and functional gains suggest potential mechanisms of action. Dr. Berend Malchow of Ludwig Maximilian University of Munich has examined the impact of adding cognitive training to aerobic exercise in multi-episode schizophrenia patients. This combination led to increased verbal memory and improved global functioning. Increase in left temporal grey matter volume is a promising brain mechanism of action. Dr. Keith Nuechterlein from UCLA will present results from a recently completed RCT of first-episode schizophrenia patients in which aerobic exercise training was added to computerized cognitive training to determine the extent to which it could enhance the impact of cognitive training. He will show that this combination significantly enhances cognition and work/school functioning gains beyond the effect of cognitive training alone and leads to increases in prefrontal cortical thickness and functional connectivity. Furthermore, he will examine early BDNF increases in response to treatment as a predictor of later cognitive and functional improvements. Dr. Peter Falkai will lead the discussion of the promise of aerobic exercise as an intervention to improve physical health, cognition, and functional outcome in schizophrenia and consider the potential mechanisms of action.

Background The human dopamine (DA) transporter (hDAT) mediates clearance of DA. Genetic variants in hDAT are associated to neuropsychiatric disorders. We investigated the structural and behavioral bases of an in-frame deletion in hDAT at N336 (∆N336) associated with neuropsychiatric disorders. Methods This study bridges structural biology, molecular neuroscience and organism physiology culminating in a mechanistic model that relates precise alteration in a transport cycle with behavioral manifestations. Results We uncovered a previously unobserved conformation of the intracellular gate of the transporter promoted by ∆N336, representing likely the rate limiting step of the transport process. This state is defined by a “half-open and inward facing” state (HOIF) of the intracellular gate that leads to DA dysfunction. The HOIF state is regulated by a network of interactions conserved phylogenetically, as we observed it both in hDAT and in its bacterial homolog leucine transporter. We demonstrated these dysfunctions in brains of Drosophila melanogaster expressing hDAT ∆N336. These flies are hyperactive and display increased fear and impaired social interactions, traits associated with neuropsychiatric disorders. Discussion Here, we describe how a genetic variation causes DA dysfunction. In this study different techniques and discoveries came together to detail in a translational effort how rare variants in plasma membrane proteins affect complex behavior.

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 Several imaging and postmortem studies provide evidence that, in the brains of people with schizophrenia, there are alterations in glucose metabolism and energy utilization. However, it is difficult to determine whether altered excitatory transmission alters bioenergetics that then contributes to symptoms of the disorder. We have used a mouse model to begin to address these questions. GluN1 knockdown mice have a mutation that reduces NMDA receptor levels throughout development and maturity. Methods We affinity purified PSD95 protein complexes from GluN1KD and WT brains (n=3 per group) and ran each sample through our liquid chromatography tandem mass spectrometry (LC-MS/MS) protocol in singlicate. We performed pathway analysis with the EnRICHr suite of bioinformatic tools and compared WT to GluN1KD PSD95 interactomes using the top 20 differentially expressed proteins. We also studied how NMDA receptor hypofunction changes the expression of genes related to glucose metabolism and bioenergetics by quantitative PCR of brain cDNA from WT and GluN1 knockdown mice. Results Pathway analysis revealed that WT mice showed pathways relevant for synaptic plasticity (as expected), while GluN1KD analyses yielded proteins related to glucose metabolism and utilization. Gene expression analysis revealed that GluN1 knockdown mice have significant decreases in the expression of Slc16a3, Slc2a1, and Slc2a3, which are the genes for the monocarboxylate transporter (MCT4), and glucose transporters 1 and 3 (GLUT1 and GLUT3). Discussion Our results show that NMDA receptor dysfunction leads to expression changes that would reduce glucose and lactate transport into neurons. The synaptic proteome of NMDAR deficient mice shows an increase in glycolytic enzymes located at the synapse. These data suggest a profound shift in the composition of the cortical excitatory synaptic proteome in GluN1KD mice, with apparent increases in neuroenergetic substrates in neurons. At the same time, there were significant decreases in the levels of transporters that bring glucose and the primary energy substrate, lactate, into neurons. The MCT4 shuttles lactate from astrocytes to neurons, which can then be used for oxidative respiration in neurons. GLUT1 is responsible for transport of glucose across the blood-brain-barrier, and GLUT3 is expressed on neurons and is responsible for glucose uptake in those cells. Notably, we have identified that these transporter gene transcripts are reduced in postmortem brains of people with schizophrenia. Thus, this mouse may be a useful tool to model bioenergetic changes that are observed in schizophrenia, and study functional outcomes when glucose metabolism is improved.

Overall Abstract: Converging behavioural and neuroimaging evidence indicates that an inability to regulate behaviour by working memory (WM) is a core feature of people with schizophrenia (PSZ) which significantly influences their level of recovery. WM dysfunction has also gained interest as a target of cognitive enhancement interventions and as an intermediate phenotype in the study of the genetic architecture of schizophrenia. These translational strategies critically depend upon a clear understanding of the underlying cognitive and neurophysiological disturbances. The aim of the symposium is to highlight current approaches to identify the pathophysiological mechanisms underlying WM deficits on both the microcircuit and the systems level. M. Ichinose will report cognitive modelling data showing that PSZ have elevated internal noise during perceptual processing, which was inversely correlated with WM precision. This indicates that ‘noisy’ perception contribute to impairments in WM and other cognitive domains. R. Bittner will present behavioural data from PSZ and imaging genetics fMRI data from a large cohort of healthy participants. The results of these studies indicate, that specific impairments in bottom-up attentional processes associated with genetic risk contribute to the dysfunction of working memory encoding in schizophrenia. A. Anticevic will present computational microcircuit models, resting state fMRI data and fMRI data using ketamine which provide evidence for a disturbed excitation-inhibition (E-I) balance and resulting in large scale dysconnectivity in schizophrenia in the context of working memory and other cognitive processes. The research presented in this symposium integrates computational, neuroanatomical, electrophysiological, pharmacological, genetic, behavioural and neuroimaging methods to connect pathophysiological mechanisms at the microcircuit level such as increased neuronal noise and an abnormal E-I balance to disturbances in large scale brain networks at the systems level and to behavioral impairment. Such an integrative approach promises to yield new insights into the pathophysiology of cognitive dysfunction in schizophrenia.

Background Problems with cognitive function are found in many major psychiatric disorders. In schizophrenia and attention deficit hyperactivity disorder (ADHD), they are among the core symptoms. Based on a growing recognition that there is little diagnostic specificity for any single cognitive impairment, there is an increasing emphasis on investigating impairments across psychiatric disorders. This approach, which is consistent with the NIMH Research Domain Criteria initiative, is expected to lead to a better understanding of the neurobiological mechanisms involved in cognitive deficits. An increase in neuronal background noise has been identified as a neuronal correlate of inattention. Because the dopamine system has been found to play a critical role in modulating neuronal noise, dopamine dysfunction may play a substantial role in generating the excessive noise that has been found to characterize information processing in both schizophrenia and ADHD. This issue can be studied noninvasively via electrophysiological examination of the retina, a distinct neural network. Both basic research and human studies indicate that retinal information processing is under strong dopaminergic modulation (Bubl, Biol. Psychiatry, 2010; Bubl, Br J Psychiatry, 2012). We have previously demonstrated an elevated level of background noise at a very early stage in visual information processing in untreated patients with ADHD (Bubl, Plos One, 2015). Moreover, background noise was associated with inattention measures in these subjects. To further address the hypothesis that elevated retinal noise reflects dopaminergic dysfunction, we report here on a new study that compared retinal background noise in patients with ADHD both before and after therapy, as well as in patients with schizophrenia. Methods Neuronal noise was assessed using pattern electroretinogram (PERG), an objective electrophysiological measure for retinal network function from the photoreceptors to the retinal ganglion cells. A total of 20 patients diagnosed with ADHD were tested both before and after treatment with methylphenidate (MPH). The control group consisted of 21 healthy subjects. The PERGs were recorded in a steady state mode in response to checkerboard stimuli of 12 reversals/s. Data collection with people with schizophrenia is ongoing, and results will be reported at SIRS. Results Before treatment, the patients with ADHD presented with elevated background noise (higher by 127%) in comparison to the control group. After treatment, noise level did not differ from what was observed in the control group. Retinal background noise was found to be highly correlated with the severity of the ADHD symptoms. The results will be discussed in relationship to our findings in patients with schizophrenia. Discussion These data provide further evidence for the hypothesis that elevated background noise is linked to ADHD and cognitive deficits. The findings are of special relevance because ADHD is a disorder with a dedicated treatment option for cognitive symptoms. Interestingly, a similar pathophysiological mechanism for cognitive dysfunction has been proposed for both schizophrenia and ADHD. However, because ADHD medications, such as MPH, typically elevate dopamine levels, potentially leading to exacerbation of psychotic symptoms, different approaches for treating cognitive symptoms in schizophrenia need to be explored. On this basis, current approaches used to target neuronal noise and cognitive symptoms in patients with schizophrenia will be discussed and their relevance for future research will be addressed.

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 Fetal or prenatal programming, i.e. the process in which environmental events during pregnancy are shaping and determining the development of the embryo, can be embedded by epigenetic changes including DNA methylation. Apart from environment, also the genome plays an important role and a variety of studies which identified meQTLs (methylation quantitative trait loci, i.e. SNPs which are associated with methylation levels) have been published. Methods Focusing on variably methylated regions (VMRs), we investigated if genotype (G), prenatal environment (E) or the combination of both (GxE, G+E) best explain cordblood DNA methylation in sample of 817 Finnish neonates. Furthermore, we used an epigenetic clock predictor to evaluate if accelerated or decelerated epigenetic age was associated with prenatal environment or with childhood psychiatric problems at age 3. Results We found that SNP genotype alone best explained methylation status in 44%, SNP x environment in 32% and SNP and prenatal environment in 24% of all VMRs. While functionally relevant meQTLs were located in close proximity to the specific CpG-site, functionally relevant SNPs involved in interaction models showed much broader peaks. Concerning the epigenetic clock, lower gestational age was associated with maternal depression diagnosis and greater depressive symptoms throughout pregnancy. Epigenetic age deceleration was associated with pre-eclampsia. Furthermore, lower epigenetic gestational age was significantly associated with greater total and internalizing problems in boys. Discussion Not only environment but also genotype should be considered in epigenetic studies. Furthermore, our results suggest that long-distance effects are present in GxE interactions. The epigenetic clock which mirrors prenatal environment is partially predictive for future development of the child. Lower epigenetic gestational age seems to be developmentally disadvantageous for boys, who in early childhood show greater psychiatric problems.

Overall Abstract: This symposium has a translational approach. First, we present human post-mortem and in-vivo imaging studies on the pivotal role of oligedondrocyte loss and dysfunction with consecutive impairments of brain connectivity in schizophrenia. Natalya Uranova will show morphometric data on ultrastructural alterations of oligodendrocytes, myelin damage and degeneration and disturbed oligodendrocyte-axon interactions in post-mortem prefrontal white matter in schizophrenia. Adrienne Lahti will report diffusion tensor imaging data suggesting impaired axonal and myelin integrity. Because, MR Spectroscopy permits the non-invasive measurement of neurometabolites, such as N-acetylaspartate, a marker of neuronal integrity, and glutamate, which can be neurotoxic when overproduced, this technique provides further understanding of the relationship between white matter microstructure and neuronal function. Second, we present data from cell culture and animal models suggesting that restoration of oligodendrocyte function (in terms of energy metabolism, maturation and myelin production) is a promising target for the development of novel treatment strategies in schizophrenia. Proteomic studies in postmortem brain by Daniel Martins-de-Souza have suggested a schizophrenia-related energy metabolism dysfunction in oligodendrocytes. These findings have been followed up using oligodendroglia cell lines and induced pluripotent stem cell-derived cerebral organoids, supporting the notion that alterations in glycolysis in oligodendrocytes are pivotal to the overall energy dysfunction in schizophrenia brains. Lan Xiao′s lab has shown that oligodendrocyte dysfunction and impaired myelination in the prefrontal cortex is correlated with schizophrenia-like behavior in mice undergoing prolonged social isolation. Enhancing oligodendrocyte generation and myelin repair by FDA-approved compounds, like quetiapine (an APD) or clemastine (a histamine antagonist) successfully reversed the above phenotype.

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.

Background Parvalbumin inhibitory interneurons (PVIs) are crucial for maintaining proper excitatory/inhibitory balance and high-frequency neuronal synchronization. Their activity supports critical developmental trajectories, sensory and cognitive processing, and social behavior. Despite heterogeneity in the etiology across schizophrenia and autism spectrum disorder, PVI circuits are altered in these psychiatric disorders. Identifying mechanism(s) underlying PVI deficits is essential to establish treatments targeting in particular cognition. Based on our previous publications and new data, we propose oxidative stress as a common pathological mechanism leading to PVI impairment in schizophrenia and some forms of autism. Methods Using immunohistochemistry technique and confocal imaging analysis, we assessed the relationship between oxidative stress (as revealed by 8-oxo-DG immunolabeling) and PVI and their perineuronal net (PNN) in twelve established animal models relevant to autism (i.e., the fmr1 KO and CNV 15q13.3) and schizophrenia (CNV: 22q11, 15q13.3, 1q21, serine racemase (SR) KO, GRIN2A KO, Gclm KO) with or without additional insult (e.g., environmental: Gclm KO + GBR12909, GRIN2A KO + GBR12909, neonatal ventral hippocampal lesion (NVHL), methylazoxymethanol acetate developmental rodent model (MAM) and poly:IC). Results When PVI deficits in the anterior cingulate cortex were found in these animal models carrying genetic and/or environmental risks relevant to diverse etiological aspects of these disorders, oxidative stress was always present. Specifically, oxidative stress was negatively correlated with the integrity of PVIs and the extracellular perineuronal net enwrapping these interneurons. Oxidative stress may result from dysregulation of systems typically affected in schizophrenia, including glutamatergic, dopaminergic, immune, and antioxidant signaling. As convergent endpoint, redox dysregulation has successfully been targeted to protect PVIs with antioxidants/redox regulators across several animal models (e.g., Gclm KO, NVHL rats, GRIN2A KO and SR KO mice). D-serine, an allosteric modulator of brain NMDA receptor also protected PVIs and PNN against oxidative stress in SR KO mice. Discussion In view of the fact that the established pathophysiological processes dopamine excess, immune dysregulation and NMDA receptor hypofunction could all induce oxidative stress and are potentiated by additional oxidative insults, this mechanism could be central to damage of the highly metabolically active PVIs and the PNN surrounding them. Antioxidant systems are therefore potential therapeutic targets, assuming that redox regulators could be applied early, during environmental impacts, long before the clinical emergence of the disease.

Background While comparing the proteomes and subproteomes of 8 post-mortem brain regions and cerebrospinal fluid from schizophrenia patients to controls, we consistently observed alterations in energy metabolism, cell growth and maintenance, synaptic function, and myelinization processes. Considering the nature of these analyses, it was not possible to reveal which particular cell types display such alterations. This is essential information given increasing evidence of glia cells as pivotal players in schizophrenia. With this in mind, we analyzed the proteomes and phosphoproteomes of cultured astrocytes, oligodendrocytes and neurons treated with MK-801, a NMDA-receptor antagonist which impairs glutamatergic transmission as postulated in schizophrenia. We also analyzed biochemical pathways modulated by typical and atypical antipsychotics in human oligodendrocytes. Results led us to employ induced pluripotent stem cell-derived cerebral organoids to deepen our understanding of the data. The central aim of this study is to depict which cell type(s) present proteome changes similarly to those we found in our earlier analysis of human brain tissue as well as identify key pathways for an effective antipsychotic response. Methods Cell line cultures (astrocytes, oligodendrocytes and neurons) were treated with MK-801 and oligodendrocytes were also treated with a range of typical and atypical antipsychotics. In addition, human embryonic stem cells reprogramed from schizophrenia patients and controls fibroblasts were cultured in mTeSR1 media on Matrigel coated surface and then differentiated into cerebral organoids. All pre-clinical models here employed were submitted to state-of-the art large-scale proteomic analyses. In silico systems biology was employed to identify key pathways in the studied processes. Results MK-801-treated astrocytes, and especially MK-801-treated oligodendrocytes displayed several proteins differentially expressed which overlapped with previous findings of schizophrenia human brains. On the other hand, MK801-treated neurons displayed very few differences in their proteome, an overlap with previous findings in human brain tissue below 10%. More interestingly, the dysregulation of glycolytic enzymes in MK801-treated oligodendrocytes are very similar to our observations in schizophrenia brain tissue, corroborating with recent findings about of the importance of oligodendrocytes in the energy status of the brain. In oligodendrocytes, antipsychotics displayed differences in translational machinery and eIF2 signaling. Findings on cerebral organoids also showed overlaps with previous postmortem data, mainly on synaptic proteins and specially energy metabolism-associated pathways. Discussion These findings hold potential for the investigation of developmental and evolutionary features of schizophrenia brains and provides targets to be drug-screened as well as leads to the schizophrenia pathobiology.

Background The predominant neurodevelopmental theory of schizophrenia posits that there is a failure of normal synaptic loss believed to occur during normal adolescence. However, the most consistent neuropathology in the cortex of people with schizophrenia is a deficit in the γ–aminobutyric acid (GABA) inhibitory interneurons, not a reduction in presynaptic and postsynaptic elements. Thus, disruption to the normal development of cortical interneurons may lead to interneuron deficiency in schizophrenia. However, to understand if pathological changes in the brain of an adult with schizophrenia would be consistent with aberrant development, the known neuropathology must be placed in the context of normal human cortical development. Methods We examined the molecular changes that occur in the synapses, interneurons and the neurotransmitter systems during normal development of the human prefrontal cortex of 68 brains from healthy individuals (1 month - 49 years). Results Contrary to the prevailing view that synaptic pruning predominates during adolescent brain development, we found presynaptic mRNA and protein levels generally peak between 5–12 years of age and then remain stable through adolescence and into adulthood. Likewise, markers for dendritic spines peak in infancy and while mRNA levels then decline, protein levels are maintained throughout development. The various interneuron markers show three very distinct patterns of expression over development. Parvalbumin and cholecystokinin increase from infancy, whereas somatostatin, calretinin and neuropeptide Y decrease from infancy. Calbindin and vasoactive intestinal peptide peak in the toddlers and then decrease in adults in an inverted U shaped-pattern. Levels of mRNA for the GABA synthesizing enzymes GAD65 (GAD2) and GAD67 (GAD1) peak around 1 year of age and stay consistent through to adulthood. The postsynaptic GABAA receptor α1, β2 and γ subunits increase over the postnatal period to peak in adolescent/young adulthood whereas the α2 subunit shows the inverse pattern and decreases over the postnatal period. The dopamine receptor, D1, increase expression throughout the postnatal period to peak in early adulthood, whereas D2 and D5 show a continual decline throughout life. The NMDA receptors are highest in the first year of life and while subunits GRIN 2B, 2D and 3A all decrease throughout life, GRIN1 remains stable and GRIN 2A decreases after childhood. More recently data supporting the neuroinflammatory hypothesis of schizophrenia has merged with the neurodevelopmental hypothesis and posits that the strongest signal from GWAS studies in schizophrenia is in the C4 gene, which is a component of the complement cascade involved in normal synaptic development. We have initiated an examination of the various components of the complement cascade to determine if/when they are expressed in the human cortex and how they could be impacting the developing circuitry. Preliminary data shows C4 mRNA expressed at very low, but constant levels throughout postnatal life. In contrast, C3 mRNA is expressed at higher levels than C4, peaks in infancy and remains stable into adulthood. MAC protein (CD-59) mRNA which protects cells from complement mediated damage, is expressed at very low levels at birth but then increases significantly with age and is highest in adulthood, suggesting that significant changes in complement may occur after brain maturation is complete. Discussion Together these findings show very dynamic and complex patterns of expression from birth to adulthood, with the most active growth phase and dynamic changes occurring in the early years before adolescence. Thus, an insult during these early years could profoundly affect the developmental trajectory.

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 Evidence from postmortem CNS studies and a neuroimaging study suggest that, compared to controls, there are low levels of muscarinic receptors in a number of CNS regions from subjects with schizophrenia. Current data suggests the muscarinic M1 receptor is lower in the cortex of subjects with schizophrenia but other muscarinic receptors may be decreased in sub-cortical regions such as the striatum and hippocampus. In addition, it has been reported that ~25% of subjects with schizophrenia can be divided into a distinct sub-group because they have a marked decrease in cortical muscarinic M1 receptors (muscarinic receptor deficit schizophrenia (MRDS)). These findings have become of clinical significance because proof of principal data shows that treating subjects with schizophrenia with drugs that activate the muscarinic M1 receptor is effective in lessening the symptoms associated with the disorder. Methods Published and unpublished data will be reviewed to challenge the hypothesis that drugs that activate the muscarinic M1 receptor will be useful in treating schizophrenia. Results A proof of clinical trial has shown that treating subjects with treatment resistant schizophrenia with the muscarinic M1 and 4 receptor agonist, xanomeline, improves positive and negative symptoms as well as cognitive deficits. Moreover, it has more recently been reported that giving xanomeline on a transdermal patch with a peripheral muscarinic receptor antagonist can lessen the unwanted side effects of the drug to that of placebo. Relevant to these data is the finding that there is a sub-group of subjects with MRDS as the absence of cortical muscarinic M1 receptors in these receptors may make these subjects resistant to treatment with muscarinic M1 receptor agonists. However, novel studies using postmortem CNS from subjects with MRDS and non-MRDS has shown that whilst subjects with MRDS will likely be resistant to muscarinic M1 receptor orthosteric agonists (oxotremorine-M) they will, at least partially, respond to muscarinic M1 receptor allosteric agonists (AC-42) or positive allosteric modulators (BQCA). Discussion Muscarinic receptor agonism appears to be a promising new treatment for schizophrenia. However, some subjects with MRDS may only respond to activation of the allosteric site on the muscarinic M1 receptor. Evidence from a neuroimaging study suggests subjects with MRDS can be identified whilst living. Hence, establishing the muscarinic receptor status of subjects involved in trials of muscarinic M1 receptor agonists may help in explaining varying levels of treatment responsiveness in subjects with schizophrenia. These conclusions, being directed by data from studies using postmortem CNS, reflect the need for drug discovery and delivery to be based on a growing understanding of the pathophysiology(ies) of schizophrenia.

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.

Overall Abstract: In the past decade, rapid advances in the field of neuroscience resulted in a dramatic paradigm shift in the way we understand the role of glia in normal brain functions and brain disorder pathology. A growing body of evidence shows that diversified populations of astrocytes, microglia, oligodendrocyte precursors and mature oligodendrocytes play a critical role in the regulation of synaptic functions, blood-brain barrier, immune response regulation, myelination and axonal conduction, and in the synthesis of the extracellular matrix, a key regulator of neural plasticity. Building on this evidence, exciting new findings are beginning to emerge, shedding light on glia abnormalities in schizophrenia and their impact these functions. This symposium aims to discuss and integrate the current state of knowledge on direct evidence for glial abnormalities in schizophrenia and their underlying mechanisms. Dr. Juliana Nascimiento will present novel findings on the effects of NMDAr antagonists and antipsychotics influence glial cell lines and 3D cultures as neurospheres and cerebral organoids. Results from these studies point to the central role of glycolysis, EIF2 signaling and translational machinery in oligodendrocytes and astrocytes. Dr. Paul Klauser will report on elegant investigations on the implication of developmental redox imbalance inducing oxidative stress leading to impairments of oligodendrocytes, myelin formation and eventually to the disruption of white fibers integrity and conductivity, especially in brain regions where the metabolic demand is high. In patients, alterations of white matter were found to be inversely correlated with blood levels of GSH precursor cysteine and could be prevented by the early administration of the antioxidant N-acetyl cysteine. Dr. Sabina Berretta will discuss recent findings on novel modalities of interaction between glial cells, extracellular matrix and neurons, postulated to affect synaptic structural plasticity and axonal conductance. A growing body of evidence from her group shows disruption of such interactions in schizophrenia, potentially contributing to synaptic pathology and impacting neural connectivity. Dr. Dost Ongur will build on previous work showing abnormal diffusion of neuron-specific metabolite NAA in frontal white matter in patients with chronic schizophrenia in the absence of abnormalities in the diffusion of non-specific metabolites Cr and Cho. State-of-the-art recent studies on first episode psychosis patients and matched healthy controls show that NAA diffusion is normal in first episode patients but Cr and Cho diffusion is abnormal, suggesting that white matter abnormalities in non-neuronal elements in early phases of schizophrenia which are followed by neuronal damage in chronic disease.

Background One source of controversy in the emerging field of autoimmune psychiatry concerns varying prevalence estimates of neuronal surface autoantibodies (NSAbs) in psychiatric disorders, particularly psychotic disorders. Differences in assay methodology and patient selection may contribute to varying case-control estimates. I will argue that the field needs to move beyond small n prevalence studies, to address the question of the relevance of NSAbs in psychotic disorders, and namely the following questions: 1) Does the presence of NSAbs offer any aetiopathological insights into psychosis i.e. by associating with other disease-relevant biomarkers? 2) Do NSAbs shape the clinical phenotype of psychotic disorders? 3) Do NSAbs have a predictive role in psychotic disorders, in terms of treatment response or course of illness? Methods To address this issue, we have undertaken measurement of NSAbs using multiple immunoassays in a cohort of individuals at ultra-high risk for psychosis, and another first episode psychosis cohort. Associations between NSAb seropositivity and phenotype, outcome and biomarkers including structural MRI were explored. Results NSAbs were detected at rates of between 1% and 9% of cases in both cohorts, depending on assay used. Live CBAs detected significantly more NMDAR and GABA-AR IgG antibodies than did fixed CBAs. Rates in cases were not significantly different from controls, regardless of assay. Nevertheless in UHR subjects NSAbs, and NMDAR Abs in particular, showed clear aetiopathological and phenotypic relevance, associating with cognitive function (poorer verbal memory and IQ), more severe psychopathology and increased volumes of key limbic areas. Significant interactions with a marker of blood-brain barrier integrity offered further aetiopathological insights. NSAbs detected by both fixed and live CBAs demonstrated phenotypic associations and interactions with BBB status, suggesting both assays can detect phenotypically relevant antibodies in the UHR context. In FEP subjects, no such associations were noted. GABA-A receptor antibodies, which have been proposed as NSAbs with emerging disease-relevance, showed no phenotypic associations. Data on the predictive utility of NSAbs in UHR and FEP subjects will be presented. Discussion With appropriately fine-grained phenotyping and careful consideration of moderating biological factors and assay variation, clear disease-relevance of NSAbs could be established in UHR subjects but not in FEP subjects. In particular, NMDAR antibodies may have important biomarker potential in the at-risk mental state. The failure to establish clear disease-relevance in previous psychiatric cohorts may reflect a genuinely irrelevant antibody but could also be due any of the following: 1) Inadequately fine-grained phenotyping of subjects 2) Ignoring the important moderating role of BBB permeability 3) Choosing subjects at ‘too late’ a stage of illness 4) Inadequately sensitive antibody detection assays

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.

Overall Abstract: As expanding genetic studies increasingly demonstrate that both rare variants of large impact and common variants of small effect contribute to schizophrenia, it becomes increasingly critical that we unravel how these risk factors interact within and between the diverse cell types populating the brain. While mouse models are uniquely suited for demonstrating how aberrant function of single gene products contribute to aberrant neuronal function or behavior, genetic studies of penetrance and complex gene interactions are nearly impossible to address using inbred mouse lines. Similarly, the lack of human post-mortem tissue, coupled with the inability to conduct functional experiments in patient cells, has to date left us with a very limited understanding of how rare and common variants impact gene expression or cellular function. Our panelists have each developed human induced pluripotent stem cell (hiPSC)-based models for the study of predisposition to neuropsychiatric disease, establishing a new mechanism by which to systematically explore the impact of rare and common putative causal variants in human cells. Given the heterogeneity of schizophrenia and the limited cohort sizes feasible with hiPSC-based cohorts, our panelists will share their successes and struggles in developing cohorts defined by shared clinical or genetic features. They will discuss both the molecular and phenotypic insights they have uncovered, in neurons and glia, from case/control and genetically-edited isogenic cohorts. Our discussant will focus on integrating these findings into consortia-led datasets generated from recent genomic and post-mortem studies of large schizophrenia cohorts. Our overall objective is to consider the role of hiPSC-based studies in dissecting the genetic origins of schizophrenia, validating causal variants identified through ongoing genetic analyses, and serving as a personalized medicine approach to screen for novel therapeutics with which to prevent or reverse disease course.

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.

Overall Abstract: Advances in genomics and transcriptomics have yielded novel insights for the pathophysiology of schizophrenia, moving the field forward by providing new substrates for the development of treatment strategies. Interestingly, this has led to a large gap in knowledge in the field, as the impact of genomic variability or alterations in transcript expression is dependent on the next level of gene expression. While proteomics has lagged behind other disciplines in schizophrenia research, several groups are utilizing proteomics approaches to ask and answer the largest possible questions in translational schizophrenia research. Proteomics has evolved as a field very quickly, going beyond the characterization of expression levels of one or a few proteins. With precise quantification of protein expression and degradation, characterization of post-translational modifications as well as the detection of low abundant proteins as putative biomarkers, we will show several different state-of-the-art proteomics approaches applied to the schizophrenia substrate. James Meador-Woodruff (University of Alabama at Birmingham) will provide a brief overview of the field, and present new data showing abnormalities of lipid and carbohydrate modifications on receptor proteins in schizophrenia, as well as abnormal levels of key enzymes associated with these abnormal protein modifications. Robert McCullumsmith (University of Cincinnati, USA) will add pivotal information on the long-standing synaptic hypothesis of schizophrenia by depicting the PSD95 interactome in normal and schizophrenia brain, connecting the excitatory postsynaptic proteome to Big Data analytics. The other two speakers will show have translational proteomics data can be used to develop clinical biomarkers. Dr. Mariana Fioramonte will present how the use of the latest tools in proteomics can tell us more about brain proteomics and protein interactomics. Finally, David Cotter (Royal College of Surgeons, Ireland) will show that proteins associated to the complement system present in the blood plasma of adolescent subjects experiencing psychosis can be predictive broadly in the vulnerability of adult psychiatric disorders. This symposium provides relevant on the biological and biochemical aspects of schizophrenia and proposes potential applications that might be, after adjustments and validations, implemented in the clinic in the future, towards a personalized medicine concept.

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

Overall Abstract: Accumulating evidence suggests that bioenergetic function is impaired in the brain in schizophrenia. In normal brain, glucose is metabolized to lactate and pyruvate, which are monocarboxylate intermediates that serve as the primary energy source for neurons. Working memory and other cognitive domains are dependent on the shuttling of lactate from astrocytes to neurons. Defects in this complex pathway may underlie cognitive dysfunction in schizophrenia. The focus of this symposium is to present evidence of such defects, and to identify substrates that may be targeted for the development of new treatment strategies. Dr. Laura Rowland (University of Maryland, Baltimore, Maryland, USA) will present evidence of bioenergetic dysfunction in living subjects with schizophrenia. Increased levels of lactate (P < 0.05) were present in the ACC in schizophrenia (n = 27) compared to controls (n = 29). Higher lactate levels were associated with lowers scores on the MATRICS Consensus Cognitive Battery. These data establish a direct link between cognition and bioenergetic function in vivo in schizophrenia. Dr. Robert McCullumsmith (University of Cincinnati, Cincinnati, Ohio, USA) will present evidence of alterations in the lactate shuttle and glycolytic enzymes in postmortem samples from schizophrenia (n = 20) and control subjects (n = 20). Cell-subtype specific changes (P < 0.05) in transcripts include increased levels of the lactate transporter MCT4, decreased levels of the glycolytic enzymes PFK1 and hexokinase, and decreased levels of the glucose transporters Glut1 and Glut3. These data suggest attenuated glycolysis in pyramidal neurons, with a shift towards pathways that boost protection from oxidative stress. The last two speakers will present data that address mechanisms related to these findings, using animal models with behavioral endophenotypes of schizophrenia. Dr. Eduard Bentea (Free University of Brussels (VUB), Brussels, Belgium) will present data from the xCT knockout mouse showing that disruption of system xc-, which supports oxidative stress buffering mechanisms, leads to synaptic dysfunction. Specifically, electron microscopy studies indicate depletion of both pre-and post-synaptic glutamate, while electrophysiological studies show diminished excitatory postsynaptic potentials. These findings directly connect oxidative balance and extracellular glutamate levels with development of “broken” synapses, highlighting a potential mechanism for perturbation of bioenergetic coupling between astrocytes and neurons. Dr. Amy Ramsey (University of Toronto, Toronto, Canada) will present evidence from an animal model of synaptic dysfunction, the GluN1 knockdown mouse. These mice show a bioenergetic defect similar to schizophrenia, with decreased expression of glycolytic enzymes and glucose transporters. These translational findings indicate that genetic risk for schizophrenia may lead to an intermediate bioenergetic phenotype, where diminished supply of lactate and other energetic molecules to neurons could contribute to cognitive dysfunction. Taken together, the work presented by these speakers will provide a fresh look at the bioenergetic defects in schizophrenia, establishing that 1) metabolic perturbations in the brain are prominent and not just an effect antipsychotic treatment, 2) altered neuron-astrocyte coupling leads to synaptic dysfunction, and 3) genetic risk for “broken” synapses disrupts metabolic function.

Background The phytocannabinoid cannabidiol (CBD) attenuates the psychotomimetic effects produced by high doses of delta-9-tetrahydrocannabinol (THC), the main component of the Cannabis sativa plant. Corroborating this effect, several preclinical and clinical studies indicate that CBD has antipsychotic properties. The mechanisms responsible for these properties, however, remain unknown (Campos et al., Philos Trans R Soc Lond B Biol Sci 367:3364–782013). We have recently found that repeated CBD administration prevents the behavioral impairments, measured in the pre-pulse inhibition, social interaction and novel object recognition tests, induced in mice by repeated treatment (28 days) with the NMDA receptor antagonist MK-801. CBD also prevented the neural (measured by delta-FosB) and microglia activation, and the decrease in the number of parvalbumin-positive neurons, observed in the medial prefrontal cortex (Gomes et al., Int J Neuropsychopharmacol 18(5)2014, Schizophr Res 164:155–63, 2015). Currently, we are investigating if CBD could also reverse these changes once they have been established and the possible mechanisms of this effect. Methods Male C57BL/6J mice received intraperitoneal injections of MK-801 (0.25, 0.5 or 1 mg/kg, twice a day) for 7 or 14 days. To determine if these treatments regime would induce acute and long-term deficits, the social interaction (SI) test was performed 1 or 8 days after the end of the MK-801 treatment. Twenty-four hours after the SI, animals were submitted to the novel object recognition (NOR) test. Having established that 14 days of MK-801 induce both acute (24 h after) and long-term (8 days after) behavioral deficits in the SI and NOR tests, we investigated if repeated treatment with CBD (15, 30 or 60 mg/kg daily, i.p.) would reverse these changes. CBD treatment began 24h after the end of the MK-801 treatment and lasted for 7 days. Repeated clozapine (1 mg/kg) was used as a positive control. Forty-eight hours after the last injection, animals were submitted to SI and, 24-h later, to the NOR test. In a second experiment, independent groups of mice received, before each CBD injection, AM251 (a CB1 receptor inverse agonist, 0.1–0.3 mg/kg), AM630 (a CB2 receptor inverse agonist, 0.1–0.3 mg/kg), or the 5HT1A receptor antagonist WAY100635 (0.1–0.3 mg/kg). The data were analyzed by ANOVA followed by the Newman-Keuls test. Results MK-801 (0.5 mg/kg) administration for 14 days, but not for 7 days, impaired SI and NOR. Repeated CBD or clozapine treatment reversed these impairments. CB1 and CB2 antagonists (AM251 and AM630, respectively) failed to change CBD effect. However, its effect was blocked by pretreatment with the 5HT1A receptor antagonist WAY100635. Discussion Our findings show that a 2-week treatment with the NMDA receptor antagonist MK801 impairs social interaction and novel object recognition, which have been associated with negative and cognitive symptoms of schizophrenia, respectively. These behavioral deficits last for at least one week and are reversed by the atypical antipsychotic clozapine or CBD, reinforcing the proposal that this latter drug has antipsychotic-like properties. CBD effects seem to depend on facilitation of 5HT1A-mediated neurotransmission.

Background The human brain is comprised of billions of neurons that form networks of connections within and between brain regions. These connections facilitate neuroplastic events that underlie learning and memory, critical aspects of cognitive function often perturbed in neuropsychiatric illnesses. Neuronal signaling is mediated by fast and slow transmission events, encompassing receptors, ligands, ions, enzymes, and other substrates. These elements are spatially arranged in subcellular microdomains, facilitating juxtaposition of proteins that coordinate various biological processes. For example, synaptic transmission is modulated via release of neurotransmitter into the synaptic cleft, where receptors are activated and the postsynaptic cell modulated via electrical and chemical signals. The pre- and postsynaptic compartments include highly specialized protein clusters, with elegant and complex regulatory mechanisms that traffic proteins to and from these zones. In particular, postsynaptic densities are microdomains comprised of about 1000 unique proteins that are interacting with one another via specialized multipotent scaffolding molecule. Postsynaptic density-95 (PSD-95) is a multipotent scaffolding, trafficking, and clustering protein that links glutamate receptors, signaling molecules, and other structural proteins at postsynaptic sites. More than 95% of PSD-95 expression is localized to excitatory synapses, and it is the most abundant scaffolding protein within the postsynaptic density. Mounting genetic, proteomic, and pharmacological evidence converges on alterations in the postsynaptic density of excitatory synapses in subjects with schizophrenia. Cognitive and negative symptoms associated with dysfunction of limbic circuitry, including working memory and motivation, are particularly implicated by this mechanism. To investigate excitatory postsynaptic protein hubs in schizophrenia, we assessed the PSD-95 protein interactome from brain tissue of subjects with schizophrenia and controls. Methods Human brain tissue from fifteen subjects with schizophrenia and fifteen control subjects from the DLPFC was processed for affinity purification of PSD-95 protein complexes. We confirmed PSD-95 capture and enrichment from each sample using Western blot analyses. Samples were then pooled by region and assessed by mass spectrometry for a quality control step. Pooled samples were run in triplicate. Go versus nogo was based on finding more than 500 unique peptides in each pooled sample from each region. Next, individual samples were run through our mass spectrometry protocol in triplicate. We then subtracted any non-specifically captured peptides identified by our IgG control studies that were performed in parallel to PSD-95 affinity purification. Data were normalized within each of the mass spec runs to the most intense PSD-95 peptide. This PSD-95 peptide used for normalization was the same in every sample. Peptides that were present in at least 2 of 3 technical replicates were carried forward and subjected to quantile normalization. Peptides missing in a technical replicate were replaced by imputation, and the dataset subjected to unsupervised clustering. We also performed a semisupervised clustering protocol, non negative matrix factoring (NMF). Consensus signatures of 200 peptides were identified for each brain region, and subjected to traditional and alternative bioinformatics analyses to identify pathways, processes and compounds associated with the signatures for each brain region. Results Preliminary analyses indicate changes in the PSD-95 interactome consistent with diminished NMDA receptor signaling complex activity in schizophrenia, with lower levels of NMDA-subtype glutamate receptor subunits, as well as protein kinases associated with postsynaptic signaling in this complex. Specific biological pathways and processes identified include metabolic and inflammatory pathways. We will also present proteomic signatures generated from this dataset, and interrogate the iLINCS perturbagen database to identify drugs and genes that simulate or reverse this signature. Discussion Our preliminary data suggest that NMDA receptor function is compromised in schizophrenia. Additional work is needed to see if this is an effect of antipsychotic medications. Our proteomic findings extend the NMDA receptor hypothesis beyond the transcriptome, highlighting an important new approach for assessing abnormalities of synapses in postmortem brain.

Overall Abstract: Evidence continues to accumulate on heterogeneity in phenomenology, course and outcome of non-affective and affective psychotic disorders. Both DSM and ICD classification systems have evolved to include a large number of categories of psychosis. However, doubt remains about this categorical approach because of high comorbidity, common etiological factors and the absence of zones of relative rarity between categorical diagnoses. Some authors have nevertheless argued that categorical representations of psychosis may still be of clinical utility if used in combination with dimensional indicators. It is now widely accepted that psychotic symptoms partition into several symptom dimensions that would support the heterogeneity of psychotic disorders. However, there is no consensus on the exact number of these dimensions, with previous factor-analytic work pointing towards models with two to twelve specific symptom dimensions. However, recently, there has been evidence for a transdiagnostic dimension underlying affective and non-affective psychotic symptoms in schizophrenia, schizoaffective and bipolar disorder that challenges their classification as distinct diagnostic constructs. There is also considerable heterogeneity in clinical course and outcome of psychotic disorders, but how to best map and model this over time remains to be established. Taken together, this presents significant challenges for the classification of psychotic disorders as separate diagnostic entities. This symposium brings together international researchers at the forefront of research into the phenomenology, course and outcome of psychotic disorders. Roman Kotov will present novel data on symptom dimensions and examines the course of these dimensions in an epidemiologic cohort of 628 first-admission inpatients with psychosis interviewed 6 times over two decades in the Suffolk County Mental Health Project. Craig Morgan will report new findings from the 10-year follow-up of the Aetiology and Ethnicity in Schizophrenia and Other Psychoses (AESOP-10) study, an epidemiological cohort of 552 patients with a first episode psychosis, using a data driven approach to identify latent trajectory classes to account for heterogeneity in patterns of change in psychotic symptoms over time and characterize these trajectories with the WHO classification, baseline demographic characteristics and diagnoses. Ulrich Reininghaus will present novel data from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) consortium to investigate whether there is a transdiagnostic dimension cutting across symptoms of schizophrenia, schizoaffective disorder and psychotic bipolar I disorder. Diego Quattrone will report recent findings from EU-GEI Functional Enviromics Study on genetic and socio-environmental factors associated with transdiagnostic and specific symptom dimensions of non-affective and affective psychosis. Robin Murray will discuss these findings in the context of new challenges in the field and directions for future research.

Background Mobile health applications offer ecologically valid, data-rich methods of modeling daily symptoms and functioning, which could inform treatment delivery and facilitate early intervention in individuals with psychosis. To date, most studies evaluate adoption of technology independent of care providers. However, successful implementation and long-term adoption of mobile technology likely also requires integration into outpatient settings as an add-on tool to enhance treatment. We implemented a smartphone “app” plus clinician Dashboard as an add-on treatment tool in the UC Davis Early Psychosis (EP) Programs and tested feasibility, validity, and predictive utility of symptom tracking via the app as part of EP care. A subsequent pilot study examined barriers to implementation within two additional community outpatient settings in Northern California. Methods Study 1 implemented the platform within the UC Davis EP Programs. For up to 14 months, EP clients completed daily and weekly surveys examining mood, symptoms, and treatment relevant factors via the app, as well as monthly in-person clinical assessments using the BPRS. Clinicians discussed symptom ratings and surveys during treatment sessions using the Dashboard. We examined client enrollment and survey completion to determine feasibility, and relationships between BPRS and weekly symptom ratings to evaluate validity of self-report symptom data collected via the app. Analysis of predictive utility determined if weekly self-report symptoms predicted symptom exacerbations 2 weeks later. Study 2 expanded recruitment to 2 additional community-based EP outpatient clinics. EP clients and their clinicians used the platform as part of care for 5 months and filled out satisfaction surveys at study-end regarding usability of the platform. Rate of survey completion in the absence of financial incentives was examined to determine real-world implementation of the platform. Results For study 1, 76 clients enrolled and remained in the study for an average of 183 days (SD=88). Survey completion rates remained high over the course of the study (weekly surveys: 77%; daily surveys: 69%) and were not significantly impacted by baseline symptom severity or length of time in the study. Weekly survey positive and depression/anxiety symptoms were significantly associated with BPRS positive (p

Background Patients with first-onset psychosis have evidence of impaired glucose tolerance, but otherwise are metabolically healthy when traditional cardiovascular risk markers are used. After antipsychotic treatment is started, there is rapid weight gain and emergence of dyslipidemias. Weight gain and development of abdominal obesity is accompanied by worsening chronic low-grade inflammation. Activation of innate immunity is often present at the onset of disease. One unexplored mechanism possibly contributing to these problems is altered gut microbiota. Methods The Helsinki Early Psychosis Study recruited 97 patients with first-episode psychosis and 62 controls into a longitudinal study. Here, data on longitudinal changes in inflammation, weight gain and abdominal obesity during the first year of treatment in patients with first-episode psychosis is presented and compared with matched healthy controls. Three time points (baseline, 2 months, 12 months) are available for patients and two (baseline, 12 month) for controls. The possible contribution of different antipsychotics will be explored, and whether patients who were no longer using antipsychotics at the one-year follow-up have less problems in these measures. First results regarding the gut microbiome will be presented (Schwarz et al. 2017), and the possible contribution of gut microbiota to inflammation and weight gain in first-episode psychosis explored. Results Our previous findings from a subset of the study sample found most marked changes in innate immunity chemokines (Mäntylä et al. 2015), whereas full longitudinal data on 38 cyto- and chemokines will be available at the SIRS congress. As a preliminary result on the longitudinal course of inflammation, high-sensitivity C-reactive protein showed a significant increase during the first year of treatment in patients (median baseline 0.65 mg/l, 2 months 0.79 mg/l and 12 months 1.68 mg/l). Data on PBMC gene expression will also be presented, revealing notable differences related to different antipsychotic use. Discussion The findings will be discussed in the context of to what extent they may reflect underlying disease mechanisms and environmental contributions, including gut microbiota alterations, and to what extent inflammation is a secondary phenomenon related to antipsychotic use and weight gain. References 1) Mäntylä T, Mantere O, Raij TT, Kieseppä T, Laitinen H, Leiviskä J, Torniainen M, Tuominen L, Vaarala O, Suvisaari J. Altered activation of innate immunity associates with white matter volume and diffusion in first-episode psychosis. PLoS One. 2015 May 13;10(5):e0125112. 2)Schwarz E, Maukonen J, Hyytiäinen T, Kieseppä T, Orešič M, Sabunciyan S, Mantere O, Saarela M, Yolken R, Suvisaari J. Analysis of microbiota in first episode psychosis identifies preliminary associations with symptom severity and treatment response. Schizophr Res. 2017 [Epub ahead of print]

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 Language offers a privileged view into the mind; it is the basis by which we infer others’ thoughts. Subtle language disturbance is evident in schizophrenia prior to psychosis onset, including decreases in coherence and complexity, as measured using clinical ratings in familial and clinical high-risk (CHR) cohorts. Bearden et al previously used manual linguistic analysis of baseline speech transcripts in CHR to show that illogical and referential thinking, and poverty of content, predict later psychosis onset. Then, Bedi et al used automated natural language processing (NLP) of CHR transcripts to show that decreased semantic coherence and reduction in syntactic complexity predicted psychosis onset. To determine validity and reproducibility, we have applied automated NLP methods, with machine learning, to Bearden’s original CHR transcripts to identify a language profile predictive of psychosis. Methods Participants in the Bearden UCLA cohort include 59 CHR, of whom 19 developed psychosis (CHR+) within 2 years, whereas 40 did not (CHR-), as well as 16 recent-onset psychosis and 21 healthy individuals, similar in demographics; speech was elicited using Caplan’s “Story Game. Participants in the Bedi NYC cohort include 34 CHR (29 CHR+), with speech elicited using open-ended interview. Speech was audiotaped, transcribed, de-identified and then subjected to latent semantic analysis to determine coherence and part-of-speech tagging to characterize syntactic structure and complexity. A machine-learning speech classifier of psychosis onset was derived from the UCLA CHR cohort, and then applied both to the NYC CHR cohort and to the UCLA psychosis/control comparison, with convex hull (three-dimension depiction of model) and receiver operating characteristics analyses. Correlational analyses with demographics, symptoms and manual linguistic features were also done. Results A four-factor model language classifier derived from the UCLA CHR cohort that comprised three semantic coherence variables and one syntax (usage of possessive pronouns) predicted psychosis t with accuracy of 83% (intra-protocol) for UCLA CHR, 79% (cross-protocol) for NYC CHR, and 72% for discriminating psychosis from normal speech (UCLA psychosis/control). Convex hulls were defined as the smallest space containing all datapoints within a set for CHR- or healthy controls: these convex hulls showed substantial overlap, with CHR+ and psychosis speech datapoints largely outside these convex hulls. Coherence was associated with age, but speech variables did not vary by gender, race, or socioeconomic status in this study. While automated text features were unrelated to prodromal symptom severity, they were highly correlated with manual text features (r = 0.7, p < .000001). Discussion In this small preliminary study, we identified and cross-validated a robust language classifier of psychosis risk that comprised measures of semantic coherence (flow of meaning in language) and syntactic usage (usage of possessive pronouns). This classifier had utility in discriminating speech in individuals with recent-onset psychosis from the norm. It demonstrated concurrent validity in that it was highly correlated with manual linguistic features previously identified by Bearden et al, important as automated methods are fast and inexpensive. Automated language features were unrelated to sex, ethnicity or social class in these small samples, and semantic coherence increased with age, consistent with prior studies of normal language development. Of interest, overlapping convex hulls could be defined for groups of individuals without psychosis (UCLA CHR-, NYC CHR- and UCLA healthy), suggesting a constrained hull of normal language in respect to syntax and semantics, from which pre-psychosis and psychosis speech deviates. The RDoC linguistic corpus-based variables of semantic coherence and syntactic structure hold promise as biomarkers of psychosis risk and expression, with initial validation and reproducibility. Next steps in biomarker development include larger multisite studies with standardization of protocols for speech elicitation, test-retest, and attention to traction/feasibility, acceptability, cost, and utility. Mechanistic studies can also yield neural and physiological correlates of abnormal semantic coherence and syntax.

Background Recent work with a dopamine 2 receptor (D2R) over-expressing (D2R-OE) mouse has suggested that this receptor over-expression leads to a highly plastic increase in bridging collaterals from the associative striatum (AST) to the external segment of the globus pallidus (GPe). Because of the densely interconnected nature of basal ganglia-thalamo-cortical signaling circuitry, we hypothesized and demonstrated in a recent publication that the resting state functional connectivity (RSFC) of AST to multiple cortical and thalamic subregions is broadly disrupted in unmedicated patients with schizophrenia. In this talk, I will present novel simultaneous multi-slice (aka “multiband”) fMRI data that provides the spatial resolution necessary to image smaller basal ganglia substructures (such as the GPe/GPi), and show that unmedicated patients with schizophrenia exhibit specifically disrupted AST-GPe connectivity, as predicted directly from the D2R-OE mouse model findings. In addition, recent work with a 22q11 deletion mouse, which models a similar syndrome in humans that is strongly associated with schizophrenia, has shown that these mice exhibit a D2R-mediated reduction in the strength of excitatory post-synaptic potentials in primary auditory cortex in response to stimulation of the medial geniculate nucleus (MGN) of the thalamus. Consistent with this finding, I will present multiband fMRI data that employs both RSFC and an audio-visual localizer task to demonstrate a specific reduction in RSFC between the MGN and primary auditory cortex, consistent with these findings in the 22q11 mouse. Methods Partially-overlapping samples of 19 and 14 unmedicated patients with schizophrenia and 15 and 16 matched healthy participants participated in two sets of studies. For both studies, multiband fMRI images were acquired on a GE MR 750 system at the New York State Psychiatric Institute, with a multiband acceleration factor of 6, 2 mm isotropic voxel resolution, and 850 ms TR. Thirty minutes of RSFC data was collected in each participant, and participants in the auditory study also completed a 15 minute audio-visual localizer task that employed sparse temporal sampling with either auditory (9 seconds of a randomized and rapidly-varying musical stimulus) or visual (7.5 Hz alternating checkerboard) stimulation between each acquisition cluster. Basal ganglia subregions were identified via manual drawings conducted by an experienced rater, and the MGN and LGN were identified using the audio-visual localizer task. Results Unmedicated patients with schizophrenia showed a significant reduction in RSFC strength between the dorsal caudate and GPe (Cohen’s d = 0.87, P = 0.017), but no other striatal or pallidal subregion pairs, consistent with a specific alteration in anatomical projections between these two regions. In addition, patients with schizophrenia showed a reduction in RSFC between the MGN and primary auditory cortex, as well as between the LGN and primary visual cortex (P < 0.05, alphasim corrected for whole-brain analysis). Discussion These findings provide initial support for the existence of D2R-mediated alterations in functional neuroanatomy, first observed in animal models of schizophrenia, in a clinical sample of unmedicated patients. In addition to providing early evidence for potential mechanisms of psychotic phenomena, this work suggests that the use of non-invasive multiband RSFC is a promising approach to translating basic neuroscience findings in animal models back into a clinical setting. Altered circuitry was shown in the D2OE mice to underlie motivational deficits, and we propose that they may have a similar functional impact in patients.

Overall Abstract: The viral hypothesis of schizophrenia posits that viral infections disrupts cortical circuits that give rise to schizophrenia psychopathology. Prenatal viral exposure during key neurodevelopmental periods, either through direct effects on fetal brain or exposure to excessive maternal cytokines and other chemokines, have been implicated. In addition, abnormal activation of dormant neuro-viruses have been linked to the pathophysiology of schizophrenia. Activation of dormant viruses has potentially important treatment implication for therapies, such as valacyclovir, that suppress viral activity. Among the viruses that have been mostly frequently associated with schizophrenia include herpes simplex virus type 1 (HSV1) and Epstein-Barr virus (EBV). The purpose of this symposium is to focus on the role of viruses in the pathophysiology of schizophrenia and results of antiviral treatment trials in this illness. Diana Perkins will present data from the North American Prodrome Longitudinal Study (NAPLS2) which is an eight-site observational study of predictors and mechanism of conversion to psychosis and is comprised of a cohort of 763 individuals at clinical high risk for developing psychosis. This paper examines methylation of promoter regions of genes associated with gene expression and reports that 10 markers correctly classified individuals who converted to psychosis. The SIRT1 gene, that is upregulated with HSV, was among the predictive markers. Faith Dickerson will focus on the association between HSV1 exposure and cognitive impairment in schizophrenia and the potential link between EBV and this illness. In a large cohort of 828 individuals and 573 controls, a significant relationship between HSV1 exposure and cognitive impairment was found. The strongest linkage was in the domain of immediate memory. In 397 subjects with schizophrenia who were compared to 289 controls, significantly higher levels of antibodies to the EBV viral capsid antigens (VCA) was discovered in the schizophrenia cohort. Vishwajit Nimgaonkar will examine the relationship between HSV1 infection and cognitive performance in a mixed cohort of 226 individuals and present the results of a randomized clinical trial of the anti-viral agent valacyclovir. HSV1 infected participants had significantly lower scores on Emotion Identification and Discrimination (EMOD), spatial memory and spatial ability irrespective of schizophrenia diagnoses. Valacyclovir treatment (1.5 grams BID, 16-week trial) improved EMOD. Alan Breier will report the results of the VISTA study – 12-site, double-blind, placebo controlled, 16-week trial of the anti-viral medication valacyclovir (3 grams/day) in early phase schizophrenia. 170 subjects were randomized of whom 74 were HSV-1 seropositive and 96 were seronegative. Baseline working memory scores (letter number sequence) were significantly lower in HSV1 positive as compared to HSV1 negative subjects. Analysis of valacyclovir treatment outcomes have only recently commenced and are ongoing. The complete data set (cognitive domains, role function, symptoms and safety) will be presented in full at the meeting.

Background Recent neuroimaging studies have shown altered brain connectivity in patients with schizophrenia, associated with disturbed myelination in different fiber tracts and disruptions of white matter (WM) integrity, including prefrontal WM. We aimed to perform a qualitative and morphometric study of the ultrastructure of oligodendrocytes, myelin-forming cells, in prefrontal WM in schizophrenia and normal controls. Methods WM of the prefrontal cortex (Brodmann’s area 10) was studied by transmission electron microscopy and morphometry. Size, volume density (Vv) and the number (N) of organelles in oligodendrocytes were estimated in 21 patients with schizophrenia and 20 normal matched controls. Pearson correlation analysis was performed to assess possible correlations between the parameters measured and age, post-mortem interval, neuroleptic treatment and duration of the disease. ANCOVA tests were used for group comparisons. Results Qualitative study showed swelling, vacuolation, paucity of ribosomes and mitochondria and accumulation of lipofuscin granules in oligodendrocytes in schizophrenia as compared to controls. Morphometry detected lowered Vv and N of mitochondria and higher Vv and N of lipofuscin granules and vacuoles in oligodendrocytes in the schizophrenic group as compared to the control group (all p

Background Evidence-based medicine suggests that a subset of schizophrenia is associated with an inflammatory syndrome. To fully harness the potential of novel immunomodulatory therapeutics, it is critical to first determine the impact of antipsychotics on microglial function in vivo. Evidence suggests antipsychotics are anti-inflammatory; however, this is based on in vitro models and non-clinical doses of antipsychotics in vivo. It therefore remains unknown if antipsychotics promote detrimental neuroinflammation or beneficial, homeostatic changes in the brain. To address this question, we explored the effects of chronic haloperidol treatment on microglia in a rat maternal immune activation (MIA) model, representative of schizophrenia pathology. Methods Pregnant SD rat dams were exposed to poly (I:C) on GD15 (4 mg/kg, i.v.; n=5; POL) to induce MIA, or saline (n=5; CON) as a control. At 4 months of age, male offspring from CON and POL (n=2 per litter), were randomly allocated to treatment with either haloperidol (0.5 mg/kg/d s.c.) or vehicle for 28 days by osmotic minipumps, giving four groups: CON/vehicle; CON/haloperidol; POL/vehicle and POL/haloperidol (all n=10). After 28d treatment, animals were culled and perfused transcardially with 4% PFA. Fixed brain tissues were dissected, cryoprotected and microtome sectioned (1 in 12 series, 40 µm thick). Serial sections were stained for Iba1 as a marker of microglia using an immunoperoxidase protocol. The density and morphology (soma size) of Iba1+ microglia were then assessed in the corpus striatum (CS) and anterior cingulate cortex (ACC) using unbiased stereology. Data were analysed using 2x2 ANOVA in SPSS with main effects of prenatal, postnatal and pre x post-natal interactions. Results There were significant main effects of prenatal exposure to POL on Iba1+ microglia density in the CS (F(1,32)=18.09; p

Background Laboratory rodents and human studies have demonstrated that cannabidiol (CBD) presents antipsychotic effects. Several mechanisms of action have been associated to CBD effects. Most of the studies that have investigated these mechanisms have been performed in vitro and their relevance for the in vivo effects of this drug is still uncertain. Methods In spite of its low affinity for CB1 receptor (CB1R), CBD is capable of antagonizing CB1R agonists at reasonable low concentrations. CBD can also inhibit anandamide uptake and metabolism, enhancing endocannabinoid tonus. It is also possible to attribute the antipsychotic action of CBD to an antagonism of CB1R. This suggestion was reinforced by the observation that patients in the initial prodromal states of psychosis and patients with schizophrenia had higher levels of anandamide in CSF than health controls. Moreover, there would be a decrease in glutamatergic inputs from this area to the prefrontal cortex, impairing locomotor activity and working memory and endocannabinoids could regulate this system. CBD could facilitate endocannabinoids “on demand” synthesis in post-synaptic neurons, acting pre-synaptic terminals and negatively regulating the release of neurotransmitters, particularly GABA and glutamate. Results Also, an increase in anandamide levels induced by CBD could attenuate GABA release from ventral pallidum neurons, restoring the normal function of this system in psychotic patients. CBD can also increase adult neurogenesis in mice and that this effect has been shown to be dependent on the CB1 receptors. In addition to the mechanisms discussed above, CBD can produce several other effects that could also be involved to be responsible for its antipsychotic properties, including interaction with 5HT1A and TRPV1 receptors and anti-inflammatory/neuroprotective effects. CBD can act as a serotonin 1A receptor (5HT1A) agonist, although the role of 5-HT1A-mediated neurotransmission in schizophrenia is unclear, aripiprazole, an atypical antipsychotic, acts as a partial agonist at this receptor, an effect that could, together with its actions on D2 and 5-HT2A receptors, contribute to therapeutic effects of this drug. CBD can also activate Transient Receptor Vanilloid-1 (TRPV1) receptors that are expressed in several brain areas related to psychosis such as the prefrontal cortex, amygdala and hippocampus. Since CBD is also a potent anti-inflammatory, antioxidant and neuroprotective compound, it is possible that these effects are involved in its antipsychotic action. Discussion Since CBD is also a potent anti-inflammatory, antioxidant and neuroprotective compound, it is possible that these effects are involved in its antipsychotic action.

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.