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Preview: Schizophrenia Bulletin - current issue

Schizophrenia Bulletin Current Issue





Published: Sun, 01 Apr 2018 00:00:00 GMT

Last Build Date: Sat, 31 Mar 2018 20:47:15 GMT

 



1. CHANGING THE LENS ON MENTAL HEALTH

Sun, 01 Apr 2018 00:00:00 GMT

Abstract
Overall Abstract: Alastair Campbell, talking from personal and family experience, and based on years of campaigning and study, urges a rethink of how we view mental health and mental illness.



2. MICROCIRCUITS, MACROCIRCUITS, AND CORTICOL DYSFUNCTION IN SCHIZOPHRENIA: A COMPUTATIONAL AND TRANSLATIONAL NEUROSCIENCE PERSPECTIVE

Sun, 01 Apr 2018 00:00:00 GMT

Abstract
Overall Abstract: Computational neuroscience may be a critical component of the effort to understand how cortical micro- and macro-circuits support behavior and express the symptoms of neuropsychiatric disorders. This presentation will present an update on an ongoing interdisciplinary effort to understand the role of compromised glutamate synaptic signaling, particularly related to the NMDA glutamate receptor, for the pathophysiology of schizophrenia. This presentation will draw on studies in animal models, healthy humans, and schizophrenia patients. It will draw parallels between the effects of the NMDA receptor antagonist, ketamine, and working memory impairment and abnormalities in cortical functional connectivity in schizophrenia. In so doing, it will highlight examples where computational approaches have affirmed hypotheses arising from experimental work or contributed new predictions that could be tested experimentally. Lastly, it will illustrate a prediction about novel therapeutics for schizophrenia that are embedded in an emerging developmental model for this disorder.



3. EXCITATION-INHIBITION IMBALANCES IN SCHIZOPHRENIA: MECHANISMS AND INTERVENTIONS

Sun, 01 Apr 2018 00:00:00 GMT

Abstract
Overall Abstract: Evidence is accumulating that core features of schizophrenia (SCH) may arise from a fundamental disturbance in the cellular balance of excitation and inhibition (E-I balance) within neural circuitry. In the symposium, we will provide a comprehensive overview of E-I balance alterations in SCH with evidence from preclinical models and in vivo measurements investigating potential neurobiological mechanisms underlying these dysfunctions as well as interventions that remedy these disturbances.Takao Hensch will summarize findings on critical period plasticity and its potential role in vulnerability to schizophrenia. He will present new preclinical data on the destabilizing consequences of enhanced gamma oscillations, which reversibly prolong juvenile forms of brain plasticity by redox imbalance.Jan-Harry Cabungcal will address the role of redox dysregulation and oxidative stress in the pathophysiology of schizophrenia. He will present recent data on the relationship of deficits of the perineuronal net and oxidative stress in the anterior cingulate cortex, and evidence that redox dysregulation can be targeted with antioxidants/redox regulators across animal models.Lawrence Kegeles will present simultaneous EEG and proton MRS measurements of glutamate and GABA during ketamine administration in healthy young adults. These data will be compared with the same modalities acquired in individuals at clinical high risk and patients with SCH, showing disturbed delta and gamma band power and altered E-I balance despite homeostatic rebalancing of glutamate and GABA.Peter Uhlhaas will summarize evidence from EEG/MEG data examining the potential role of neural oscillations in the pathophysiology of schizophrenia. He will show that alterations in gamma-band oscillations are present prior to the onset of schizophrenia in at-risk individuals and related to aberrant E-I balance parameters revealed by MRS-measured levels of GABA and glutamate. Developmental data on the maturation of neural oscillations suggests that the transition from adolescence to adulthood is a sensitive period for modifications in neuronal dynamics that could potentially explain the manifestation of psychosis during this period.



3.1 ENHANCED PARVALBUMIN NETWORK ACTIVITY PROLONGS CRITICAL PERIOD PLASTICITY

Sun, 01 Apr 2018 00:00:00 GMT

Abstract
Background
Oscillations in neuronal activity tie the pathophysiology of schizophrenia to alterations in local processing and large-scale coordination, and these alterations in turn can lead to the cognitive and perceptual disturbances observed in schizophrenia. Here, we focus on the dual role of fast-spiking, parvalbumin (PV+) networks in the generation of gamma oscillations and critical periods of brain plasticity.
Methods
We generated a mouse model of reduced recurrent inhibition only within local PV+ cell networks by selective removal of GABAA receptor alpha1 subunits (PV-α1 KO mice). Electroencephalography (EEG), PV+ immunohistochemistry, perineuronal net (PNN) labeling and redox balance were compared to cortical measures of brain plasticity (loss of visual acuity, formation of preference behaviors) that are typically limited to a critical period early in life.
Results
PV-α1 KO mice exhibit chronically enhanced gamma-oscillations and extended juvenile forms of cortical plasticity into adulthood. Acute pharmacological suppression of excitatory input restored E-I balance onto these disinhibited PV+ cells and returned baseline EEG power to normal levels, preventing the extended plasticity. Enhanced gamma oscillations were further found to compromise the integrity of perineuronal nets (PNNs) surrounding PV+ cells, elevating oxidative stress and the turnover of metallopeptidases and structural components of the PNN. All of these aspects were also reversed by pharmacological dampening of excitation onto PV+ cells.
Discussion
Cortical gamma oscillations are associated with plasticity and cognition. Our results provide a cellular explanation of how elevated gamma oscillations may promote ectopic brain plasticity by regulating the extracellular matrix which normally stabilizes cortical circuitry. These results carry broad implications for subjects at-risk for schizophrenia who exhibit heightened gamma oscillations prior to psychosis onset (see talk by P Uhlhaas).



3.2 PARVALBUMIN INTERNEURON IMPAIRMENT INDUCED BY OXIDATIVE STRESS AS A COMMON PATHOLOGICAL MECHANISM IN ANIMAL MODELS OF SCHIZOPHRENIA

Sun, 01 Apr 2018 00:00:00 GMT

Abstract
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.



7. RETINAL FUNCTIONS EXPRESSED IN RETINAL IMAGING, CONTRAST PROCESSING AND ELECTRORETINOGRAPHY MAY DECRYPT EARLY RISK MECHANISMS AND PATHOPHYSIOLOGY OF SCHIZOPHRENIA AND MOOD DISORDERS AND ACCELERATE TRANSLATION TO THE CLINIC

Sun, 01 Apr 2018 00:00:00 GMT

Abstract
Overall Abstract: The rationale of this symposium is twofold. First, true understanding of the neurobiological and environmental causes of schizophrenia and mood disorders will require the investigation of the human neuronal tissue in function. As an external and accessible extension of the brain, the retina opens this avenue. Existing technologies such as retinal imaging, computerized psychophysical assessment, and electroretinography (ERG) have recently provided evidence that the microanatomy of the retina and strength of rod, cone, and bipolar cell responses to light stimuli can distinguish patients from healthy individuals (Adams & Nasrallah, Schizophr Res 2017; Silverstein & Rosen, Schizophr Res Cogn 2015; Bubl, Biol Psychiatry, 2010; Plos ONE, 2015, Meier, Am J Psychiatry 2014). Second, the search for indicators of brain dysfunction that are detectable both in adult patients and in children at genetic risk is the cornerstone of genetic high-risk research into the neurodevelopmental origins of serious mental disorders and prevention (Maziade, New Eng J Med 2017). In this regard, it has been shown that children at genetic risk show many of the retinal anomalies that adult patients display (Hébert et al., 2010, Biol Psychiatry). Studies of the retina can therefore contribute to clarifying illness pathophysiology and its developmental roots.This symposium objectives are to: 1) present findings from retinal imaging, visual processing and electroretinography in patients with schizophrenia or mood disorders, and in young healthy offspring of affected parents; 2) to discuss the data in terms of their implications for understanding psychotic and mood disorders; and 3) to clarify the similarities and differences between retinal findings in psychotic and mood disorders and their early developmental trajectories.Participating scientists: Professor Michel Maziade will be the chair, with Professor Steven Silverstein as the co-chair of the symposium. Professor Anne Giersh, INSERM Strasbourg, France, will act as the discussant.Professor Emanuel Bubl, Saarland University, Germany, will present findings on the potential of ERG measured retinal background noise as neurobiological correlate for cognitive deficits in ADHD and schizophrenia.Professor Maziade, Laval University, Canada, will present new ERG findings in young offspring of parents affected by schizophrenia or bipolar disorder and the implications for the illness developmental origin and later transition to illness.Professor Madeline Meier, Arizona State University, USA, will present results showing phenotypic and genetic associations between schizophrenia and retinal vessel diameter. Findings suggest that individuals with schizophrenia are at increased risk of microvascular complications.Professor Silverstein, Rutgers University, USA, will present new ERG findings in schizophrenia, and data on the relationships between ERG anomalies, symptoms, retinal structural abnormalities as measured with optical coherence tomography, and antipsychotic medication use.Based on empirical data, the symposium will offer an integrated view as to: i) how non-invasive measurements of retinal structure and function show consistent anomalies in schizophrenia, bipolar disorder, major depression and ADHD; ii) how findings from children and adolescents at high genetic risk not only indicate a neurodevelopmental process, but also suggest that retinal anomalies in patients are not due to medication use or degenerative effects; iii) how ERG can be administered to adults and children at low cost in clinical studies; iv) how to integrate findings in the staging of the risk status of children at genetic risk.



7.1 ELECTRORETINOGRAPHIC ANOMALIES IN SCHIZOPHRENIA AND THEIR RELATIONSHIPS WITH RETINAL STRUCTURE, VISUAL FUNCTIONS, CLINICAL SYMPTOMS, AND MEDICAL COMORBIDITIES

Sun, 01 Apr 2018 00:00:00 GMT

Abstract
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<.05), and during a steady-state flicker test (p<.005). On scotopic tests, the rate of response gain per unit of intensity increase was significantly weaker for patients than controls (p=.001). In both light- and dark-adapted conditions, patients demonstrated weaker signaling of bipolar cells (ps < .005). The schizophrenia group was also characterized by a weaker PhNR (p<.05). Weaker retinal cell responses were related to contrast sensitivity impairments in the schizophrenia group (ps < .05 and .001), but not to visual acuity or contour integration. Reduced responsiveness to low-intensity light was related to more severe negative symptoms, suggesting a reduced dynamic range within which environmental events (i.e., salience) are represented. Measures of retinal cell function were not related to antipsychotic medication dose. Preliminary findings indicate that attenuated fERG signals are not associated with weaker visual cortical responses (EEG-measured VEPs), presumably due to gain control mechanisms. We will report on the extent to which fERG anomalies are related to retinal structural changes and comorbid medical conditions.
Discussion
Reduced signaling of photoreceptor, bipolar, and ganglion cells are characteristics of schizophrenia, and are not related to extent of antipsychotic medication use. These changes are related to reduced contrast sensitivity and increased negative symptoms, and may reflect an attenuated ability to accurately represent changes in the intensity of environmental stimuli. Data collection is ongoing for studies examining relationships between ERG indices and VEPs and medical comorbidities.



O9.2. IDENTIFYING PSYCHOTIC SYMPTOMS AND PREDICTING RELAPSE THROUGH SOCIAL MEDIA

Sun, 01 Apr 2018 00:00:00 GMT

Abstract
Background
The internet and social media provide an unprecedented opportunity to transform early psychosis intervention services. This study aimed to capture concerning patterns of social media activity associated with the onset and persistence of psychotic symptoms.
Methods
Facebook and Twitter archives were extracted from over 150 participants with psychotic disorders, mood disorders and healthy controls. Machine learning was used to build classifiers aiming to identify patterns and distinguish between groups.
Results
Linguistic analysis of Twitter commentary identified significantly increased use of interpersonal pronouns (p < 0.001), decreased emphasis on friendship (p < 0.001) and increased emphasis on health (p < 0.001) in individuals with psychosis. Preliminary classifiers correctly recognized participants with psychotic disorders (n=62) from healthy controls (n=24) with an average accuracy of 80% and distinguished participants with psychosis from those with mood disorders (n=39) with an average accuracy of 70%. Further analysis identified shifts in language use of participants with psychosis who experience a relapse (n=18) including significant increases in the use of swearing (p<0.05), first-person pronouns (p<0.05) and negations (p<0.05). We additionally identified significant differences in the profile pictures (p<0.005) and structure of messages posted (p<0.005) by youth with psychosis who experienced a psychotic relapse.
Discussion
Identifying markers in social media activity associated with worsening psychotic symptoms offers the prospect that social media may be a clinically useful tool to identify patients in the earliest phases of relapse.



O9.3. PSYCHOTIC EXPERIENCES IN COMMON MENTAL DISORDERS AND AS CLINICAL MARKERS OF RISK FOR SUICIDAL BEHAVIOUR

Sun, 01 Apr 2018 00:00:00 GMT

Abstract
Background
A high risk for suicidal behaviour has long been recognized in psychotic disorders. More recently, research has demonstrated that subclinical psychotic experiences are strong markers of risk for suicidal behaviour. Whether PEs are specific risk markers for suicidal behaviour, beyond the indirect risk resulting from co-occurring psychopathology, remains unclear.
Methods
This study used a stratified, multi-stage probability sample of households in England to recruit a nationally representative sample aged 16 years and over (N=7,403). Participants were assessed for psychotic experiences, suicide attempts, common mental disorders and borderline personality disorder/traits.
Results
Psychotic experiences were reported by approximately 4% (n=323) of the total sample and were prevalent across the full range of mental disorders: the highest prevalence in non-psychotic disorders was in individuals with agoraphobia, nearly a quarter of whom reported psychotic experiences. Eighteen percent of individuals with social phobia reported hallucinations, as did 17% of individuals with OCD, 14% of individuals with depression, and 11% of individuals with generalised anxiety disorder. Psychotic experiences were risk markers for suicide attempts, regardless of whether they occurred in individuals with a common mental disorder (OR=2.47, 95%CI=1.37–4.43), individuals without a common mental disorder (OR=3.99, 95%CI=2.47–6.43), individuals with high borderline personality disorder traits (OR=2.23, 95%CI=1.03–4.85) or individuals without significant borderline personality disorder traits (OR=2.47, 95%CI=1.37–4.43).
Discussion
Psychotic experiences are prevalent across a wide range of (non-psychotic) mental disorders. They demonstrate a strong relationship with suicidal behaviour, beyond that explained by co-occurring mental disorder diagnoses.



O9.4. PREDICTING SCHIZOPHRENIA: IDENTIFICATION OF MULTIMODAL MARKERS OF DISEASE THROUGH A MACHINE LEARNING APPROACH

Sun, 01 Apr 2018 00:00:00 GMT

Abstract
Background
Diagnosis of schizophrenia is based on a collection of symptoms which are heterogeneous from one patient to the other. Therefore, improving the reliability of this diagnosis is a currently unmet need. Schizophrenia risk is associated with genetic variation and with environmental factors potentially affecting neurodevelopment. Moreover, among the symptoms, cognitive abnormalities are heritable and predate its clinical onset.Multivariate techniques can leverage the high dimensionality of data in order to study the combined effect of multiple risk factors and symptoms on clinical predictions. The aim of the current study is therefore to assess the predictability of schizophrenia diagnosis applying machine learning techniques to an ensemble of genetic, early environmental and cognitive deficits variables.
Methods
442 subjects (339 healthy controls – HC – and 103 patients with schizophrenia – SCZ) were recruited for the study. Participants underwent a full neuropsychological evaluation (Modality 1, assessment of working memory, verbal fluency, intelligence quotient, attention, speed of processing and cognitive control), a broad environmental assessment (Modality 2, investigation of urbanicity, obstetric complications, developmental anomalies, socio-economic parental status and age of parents at birth) and genome-wide genotyping (Modality 3). Following published procedures, we computed individual risk scores for each of the single nucleotide polymorphisms (SNPs) associated with risk for schizophrenia in the Psychiatric Genomics Consortium (PGC) study. Data from Modalities 1, 2 and 3 entered NeuroMiner v0.998 and underwent preprocessing procedures through scaling, pruning of non-informative variables and imputation of missing values through Euclidean distance-based nearest-neighbor search. Then, these three modalities were included in a Support Vector Machine HC vs. SCZ classification algorithm, which applied decision-based data fusion strategies to integrate the individual predictions of the three modalities in a nested cross-validation framework.
Results
Our cross-validated results revealed that Modality 1 (cognition) predicted schizophrenia diagnosis with the highest Balanced Accuracy (BAC, 87.3%) and that the most selected cognitive indices were intelligence quotient scores and attentional abilities. Modality 2 (environment) classified HC and SCZ with a BAC of 67.2%, and the most predictive environmental features were the parental socio-economic status, the presence of developmental anomalies during the first year of life and the age of father at birth. On the other hand, Modality 3 (genetics) predicted schizophrenia diagnosis with BAC=54,1%. The most informative SNPs were FUT9 rs117074560, TCF4 rs72934570 and STAG1 rs7432375. Decision-based fusion combining individual cognitive, environmental and genetic decision scores predicted the classification of SCZ from HC with a 78.9% BAC.
Discussion
Our results using a novel machine learning approach suggest that an ensemble of cognitive, early environmental and genetic features can predict schizophrenia with significant accuracy. Our results also give key information on cognitive and environmental factors that can be targeted in early identification programs and offer novel insights about genetic loci that may be prioritized in future investigations of the pathophysiology of the disease. However, the near chance-level predictive ability of the genetic modality alone calls for the implementation and testing of more complex models of interaction between multiple risk factors.



O9.5. ABERRANT DOPAMINE SYSTEM FUNCTION REVERSED BY THE OREXIN RECEPTOR ANTAGONIST TCS1102 IN A RODENT MODEL OF SCHIZOPHRENIA

Sun, 01 Apr 2018 00:00:00 GMT

Abstract
Background
Aberrant regulation of dopamine system function is thought to contribute to psychosis in schizophrenia patients; however, the brain regions associated with this dysregulation have not been conclusively demonstrated. We have recently demonstrated that medium spiny neurons in the nucleus accumbens (NAc) receive convergent input from the ventral hippocampus (vHipp) and paraventricular nucleus of the thalamus (PVT). Furthermore, inactivation of either the vHipp or PVT is sufficient to reverse aberrant dopamine system function in rodent models of schizophrenia. Using, chemogenetic experiments we now provide conclusive evidence that the thalamic input to the NAc plays a role in the regulation of dopamine neuron activity. These data demonstrate that the vHipp and thalamus (specifically the PVT) work in concert to regulate VTA dopamine neuron population activity. Such data are important as they provide evidence that thalamic abnormalities may contribute to the aberrant dopamine system function observed in schizophrenia and suggest that the PVT may be a novel site for intervention in psychosis. To examine this, we explored the orexin system, which is known to provide a dense innervation of the PVT.
Methods
Pregnant Sprague Dawley (SD) rats were treated on gestational day (GD) 17 with either methylazoxymethanol acetate (MAM; 22 mg/kg, i.p.) or saline. For Poly I:C, pregnant dams were treated on GD12 (7.5 mg/kg Poly I:C or saline). Male pups weaned on post-natal day 21 in groups of 2–3 until adulthood (>60 days). For chemogenetic experiments, normal SD rats were bilaterally micro-injected with AAV2 vectors (Addgene) expressing hm3D(Gq)(pAAV-h8yn-HA-hm3D(Gq)-mcherry; 0.5μL) into the PVT or mPFC. Control rats were administered the viral vector lacking the hm3D encoding gene. Prior to testing, CNO (0.75ul; 300uM) was injected into the nucleus accumbens. In vivo extracellular recordings were performed to measure dopamine neuron activity in the VTA. Spontaneously active VTA dopamine neurons were recorded using previously established electrophysiological criteria.
Results
NMDA activation of the PVT induces a significant increase in VTA dopamine neuron population activity. MAM- and Poly I:C-treated rats (both verified rodent models of schizophrenia) consistently display aberrant VTA dopamine neuron population activity, which is restored by pharmacological inactivation of the PVT with TTX. Chemogenetic activation of PVT neurons projecting to the mPFC do not affect VTA dopamine neuron activity; however, activation of PVT neurons projecting to the nucleus accumbens induces a significant increase in dopamine neuron population activity. This effect can be replicated in rats that receive microinjections of the endogenous orexin peptide A or B into the PVT. Consequently, dopamine neuron function can be restored in MAM-treated rats that received a systemic injection of the orexin peptide antagonist TCS 1102.
Discussion
We now demonstrate that orexin receptors are expressed on PVT neurons projecting to the NAc and may serve as a substrate for pharmacological manipulation of this pathway. Here, we provide evidence that both systemic and intracranial (PVT) administration of the orexin receptor antagonist, TCS1102, can normalize aberrant dopamine system function in a rodent model of schizophrenia. Collectively, these data suggest that targeting orexin signaling in the thalamus, specifically, the PVT, may represent a novel site of intervention for psychosis associated with schizophrenia.



O9.6. SPECIFIC SYMPTOMS IN ADOLESCENCE PREDICT PSYCHOSIS IN THE NORTHERN FINLAND BIRTH COHORT 1986

Sun, 01 Apr 2018 00:00:00 GMT

Abstract
Background
A number of psychological symptoms have been found to predict psychosis. Many studies have found no specificity to separate symptoms predicting non-psychotic psychiatric disorders from those predicting psychotic disorders. We were able to conduct prospective study comparing adolescent symptoms predicting non-psychotic psychiatric disorders and psychotic psychiatric disorders.
Methods
Members of the of the Northern Finland Birth Cohort 1986 were asked to fill in PROD-screen questionnaire at age 15–16 years. PROD-screen includes 21 items both measuring positive prodromal symptoms, negative prodromal symptoms and general symptoms.We were able to follow 6,514 participants using Finnish Hospital Discharge Register detecting new hospital treated mental disorders till 23 years.
Results
The highest prevalence of positive symptoms in the PROD-screen were in the group of subjects who developed psychotic disorder (65% over the cut off) compared to subjects who developed non-psychotic disorder (36%; OR 5.7; 95%CI 2.1–15.4, p<0.001, adjusted for parents’ psychiatric disorder, family structure, family SES, adolescent’s cannabis use and gender), and to subjects without any disorder (27%; adjusted OR 6.5; 2.8–15.0, p<0.001). Respective figures for negative symptoms were 55% in the group of psychotic subjects compared to 30% in subjects with non-psychotic disorder (3.3; 1.4–7.7, p=0.01) and 24% in the ‘healthy’ (4.1; 1.9–8.6, p<0.001).When comparing separate symptoms in those having psychiatric hospital treatments, we found four positive symptoms and one negative symptom predicting specifically psychotic disorders.
Discussion
In this large prospective population sample both positive and negative symptoms in adolescence associated specifically with development of first episode psychosis.



O9.7. INDIVIDUALIZED LONG-TERM OUTCOME PREDICTION OF PSYCHOSIS IN AN OBSERVATIONAL STUDY: A MACHINE LEARNING APPROACH

Sun, 01 Apr 2018 00:00:00 GMT

AbstractBackgroundSchizophrenia and related disorders have heterogeneous outcomes. Predicting long-term psychosis outcome may be helpful in improving treatment decision making. The aim of our study was to develop and validate a long-term outcome prediction model of psychosis in individual patients. Many studies have shown that outcome is related to symptoms, demographic, clinical, cognitive, genetic and environmental data – at the level of correlations. We hypothesized that, using machine learning (ML), it is possible to predict individual long-term outcome based on patterns that are present in these data at baseline. Second, we test if variables that were recently found to be predictive of short-term outcome (European First Episode Schizophrenia Trial (EUFEST), Koutsouleris et al, 2016) can yield accurate long-term outcome predictions in our sample.MethodsThis study included 523 patients (mean (SD) age = 27.6 (7.4) year) from the Genetic Risk and Outcome of Psychosis study. The study extensively assessed patients at baseline, 3- and 6-year follow-up. Outcome was defined in two ways: 1) Symptomatic: being in remission (good outcome) or not in remission (poor outcome), according to the Remission Tool (i.e. a consensus definition which defines remission as maintaining core DSM symptoms, based on Positive and Negative Symptom Scale [PANSS] on a low level during ≥6 months); and 2) Functional, using Global Assessment of Functioning (GAF) scale, divided into good (GAF≥65) and poor (GAF <65) outcome. A support vector machine was trained to predict outcome based on (combinations of) the following sets of baseline data: PANSS, clinical and demographic variables, substance use, neurocognitive/ social cognitive tasks, premorbid adjustment, need of care items (CANSAS), extrapyramidal symptoms, genetic features, environmental variables; and the sets of predictors from 4- and 52-week GAF-based outcome prediction models from the EUFEST study. We trained full and leaner models, using recursive feature elimination (RFE). We tested performance of outcome prediction models using nested cross-validation, i.e., predicting outcome in patients not part of the training set.Results6-year functional outcome (i.e. GAF status) was best predicted by a multi-modal model based on baseline PANSS, CANSAS, clinical and demographic variables, using RFE: 75% of the patients was correctly predicted. Significant predictions using single-modal models were obtained for baseline PANSS (62.7%), clinical (60.9%) and CANSAS predictors (58.0%). For functional outcome (GAF) at 6 years, also baseline PANSS, clinical and CANSAS related features produced highest accuracies (61.1%, 63.1% and 59.3% resp.). Classification of symptomatic and functional outcome at 3 years yielded comparable results. Replication using the best scoring predictors of 4 and 52 weeks outcome in the EUFEST study resulted in accuracies of 61.5% and 56.5% for remission 3-year outcome; 61.6% and 61.0% for remission 6-year outcome; 60.1% and 57.7% for GAF 3-year outcome; 62.3% and 64.6% for GAF 6-year outcome.DiscussionOur results show that predicting long-term symptomatic and functional outcome can be done with reasonable accuracies of up to 75%. Training a ML algorithm revealed that PANSS, clinical and need of care features predicted our multiple endpoints best. Interestingly, EUFEST predictors included these three types of data as a main part of best performing predictors. We showed that these short-term outcome predictors are, to certain extent (up to 65%), also predictive of long-term outcome. Our study is a promising step in pursuit of personalized medicine applicability in mental care institutes. However, our model needs replication in independent samples.[...]



O9.8. STRESS AND COGNITIVE FUNCTION AMONG INDIVIDUALS AT CLINICAL HIGH-RISK FOR PSYCHOSIS: FINDINGS FROM THE NAPLS COHORT

Sun, 01 Apr 2018 00:00:00 GMT

Abstract
Background
Accumulated evidence from non-human animal studies suggests that the prominent deficits in memory and executive function that characterise individuals with psychosis may, at least in part, be due to the effects of stress on the brain regions that support these functions. However, studies of patients with established psychosis have yielded inconsistent findings with regards to the relationship between stress and cognition, and research in high-risk populations is notably lacking. Utilising data from the North American Prodrome Longitudinal Study 2 (NAPLS 2), we aimed to further elucidate the relationship between stress (daily stressors, life events, and childhood trauma) and cognitive function in clinical high-risk (CHR) individuals and healthy controls (HC). We additionally explored the role of potential mediators [hypothalamic-pituitary-adrenal (HPA) axis function] and moderators (group status, sex, family history of illness).
Methods
The sample comprised 885 participants (CHR=646; HC=239) who completed measures of stress and cognitive function at the NAPLS 2 baseline assessment. Stress measures included the Daily Stress Inventory and a modified version of the Psychiatric Epidemiology Research Interview Life Events Scale, both of which provided continuous measures of stress exposure (number of events) and distress (subjective feelings of distress). Participants were also interviewed using the Childhood Trauma and Abuse Scale to determine any exposure to childhood trauma (abuse, neglect, and bullying occurring prior to age 16 years). Basal HPA axis activity was determined via salivary cortisol samples obtained at the baseline assessment and standardised scores from selected subtests from the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) were used to derive two cognitive domain scores (memory and executive function). To examine relationships between stress and cognitive domain scores, linear regression analyses were performed on standardised variables.
Results
Daily stressor exposure, daily stressor distress, and life event exposure exhibited negative quadratic (i.e., inverted U-shaped) associations with both memory and executive function (P < 0.01 for all). In contrast, the reverse pattern (i.e., a negative linear relationship and a positive quadratic relationship) was shown in the model for life event distress and memory domain scores (P < 0.01) whilst trauma history showed only a trend-level association with poorer memory performance (P = 0.084). These relationships, which did not differ across CHR and healthy control groups, were largely unchanged after adjusting for demographic factors and salivary cortisol. Exploratory analyses suggested that trauma exposure and a family history of psychosis may moderate the relationship between daily stressors/life events and cognitive function.
Discussion
In this large sample of predominately CHR individuals, we observed that the association between stress and cognition is complex and differs across stressor types. The negative quadratic associations that we observed for daily stressor exposure, daily stressor distress, and life event exposure imply that whist lower levels of stress may facilitate memory and executive function, there may be a negative impact on cognition when these stressors become more frequent and distressing. Interventions aiming to minimise stress exposure and promote effective coping strategies might feasibly improve cognition in CHR individuals.



O10.1. DISORGANIZED GYRIFICATION NETWORK PROPERTIES DURING THE TRANSITION TO PSYCHOSIS

Sun, 01 Apr 2018 00:00:00 GMT

Abstract
Background
There is urgent need to improve the limited prognostic accuracy of psychopathology-based classifications to predict the onset of psychosis in clinical high-risk (CHR) subjects for psychosis. However, as yet no reliable biological marker has been established to differentiate CHR subjects who will develop psychosis from those who will not. This study investigated abnormalities in graph-based gyrification connectome in CHR subjects and patients with first-episode psychosis (FEP) and tested the accuracy of this systems-based approach to predict the transition to psychosis among CHR individuals.
Methods
44 healthy controls (HC), 63 at-risk mental state (ARMS) subjects without later transition to psychosis (ARMS-NT), 16 ARMS subjects with later transition (ARMS-T), and 38 antipsychotic-free patients with FEP were recruited from the specialized clinic for the early detection of psychosis at the Department of Psychiatry, University of Basel, Basel, Switzerland. Gyrification-based structural covariance networks (connectomes) were constructed to quantify global integration, segregation and small-worldness. Extremely randomized trees with repeated, nested cross-validation was performed to differentiate ARMS-T from ARMS-NT individuals. Permutation testing was used to assess the significance of classification performance measures.
Results
Small-worldness is reduced in both ARMS-T and FEP patients, secondary to reduced integration and increased segregation in both groups. In addition, we also found that transitivity (segregation) was significantly higher in ARMS-T and FEP groups compared to both ARMS-NT and healthy controls. Using the connectome properties as features, we obtained a high classification accuracy of 90% (balanced accuracy: 81%, positive predictive value: 85%, negative predictive value: 92%.) All performance measures were highly significant as indicated by permutation tests (all p < 0.01).
Discussion
Our findings suggest that there is poor integration in the coordinated development of cortical folding in patients who develop psychosis. This study further indicates that gyrification-based connectomes might be a promising means to generate systems-based measures from anatomical data that improves individual prediction of psychosis transition in CHR subjects.



O10.2. PSYCHOTIC EXPERIENCES ARE ASSOCIATED WITH HEALTH ANXIETY AND FUNCTIONAL SOMATIC SYMPTOMS IN PRE-ADOLESCENCE

Sun, 01 Apr 2018 00:00:00 GMT

Abstract
Background
Psychotic experiences (PE) in children and adolescents include hallucinations, delusions and thought-disturbances in the absence of psychotic disorders. Psychosis can be viewed on a continuum ranging from subclinical PE throughout the life span, to clinical psychosis syndromes. Psychosis and PE often co-occur with anxiety and depression, and several studies point towards an affective pathway to psychosis.Health anxiety (HA) is a relatively new concept in child and adolescent psychiatry, characterized by obsessive rumination, with thoughts about suffering from a disease and misinterpretation of benign bodily sensations and changes. HA at age 11–12 years are associated with emotional disorders and functional somatic symptoms (FSS). In adolescence extensive physical changes occur, and it has been suggested that increased bodily awareness in some cases is accompanied aberrantly by anxiety regarding somatic sensations and somatic health.We hypothesized that PE would be associated with HA and FSS, and that the associations would remain significant after adjustment for general psychopathology, suggesting a particularly strong specific link between these specific psychopathologies over and above the general multidimensionality of psychopathology.
Methods
The study population consists of 1572 children from the general population who participated in the 11–12 year follow-up of the Copenhagen Child Cohort 2000 (CCC2000). PE were assessed face-to-face by the Kiddie Schedule for Affective Disorders and Schizophrenia present and life-time version, and were rated dichotomously as either present (likely or definitely) or not present. HA was self-reported using the Childhood Illness Attitude Scale and FSS were self-reported using the Children’s Somatization Inventory, Child Report Form, revised. HA and FSS were scored dichotomously into high (high 10%) and low (bottom 90%) scores. The associations between PE and HA + FSS were adjusted for i) general psychopathology, rated by parents, using the Strengths and Difficulties Questionnaire total score, ii) chronic physical conditions assessed by parent report, iii) onset of puberty onset defined by Tanner-stage I vs II-IV and iv) sex.
Results
PE were associated with HA (OR 2.91 (CI95% 1.86–4.57)) and FSS (OR 4.61 (CI95% 3.08–6.89)) in univariate analyses. In a mutually adjusted multivariate model which was further adjusted for general psychopathology, puberty, chronic physical conditions and sex, the associations still held significance for both HA (OR 1.73 (CI95% 1.03–2.90)) and FSS (OR 3.39 (CI95% 2.15–5.35)).
Discussion
Our study is, to our knowledge, the first to estimate the role of HA and FSS with regard to PE. Our hypothesis, that PE are associated with HA and FSS in pre-adolescence, was confirmed. The statistical effects were reduced, but remained significant after mutual adjustment and adjustment for general psychopathology. This shows that part of the association is confounded by a general load of psychopathology, but also indicates that HA and FSS contribute to PE over and above general psychopathology. Our study warrants further longitudinal studies, exploring if HA and FSS might constitute a specific pathway in psychosis development.



O10.3. EARLY BRAIN AND COGNITIVE DEVELOPMENT IN CHILDREN AT RISK FOR SCHIZOPHRENIA

Sun, 01 Apr 2018 00:00:00 GMT

Abstract
Background
Currently, most attempts at early identification and intervention for individuals at risk for schizophrenia focus on the prodromal phase of the illness during adolescence. However, cognitive and other deficits likely arise well before the prodromal phase. Many risk genes for schizophrenia play a role in early brain development, and recent studies indicate that the basic structural and functional networks of the brain are in place by the second year of life. This suggests that schizophrenia likely has origins in prenatal and early childhood brain development, and that early identification and intervention may need to be shifted to this developmental period to have a real impact on the incidence and severity of schizophrenia.
Methods
We studied early childhood brain development 25 children of mothers with schizophrenia and 178 control children. Children had a 3T MRI after birth and at 1 and 2 years of age, and global tissue volumes (gray matter, white matter, CSF), ventricle volumes, and cortical thickness and surface area were determined. Children were also assessed with the Mullen Scales of Early Learning at 1 and 2 years.
Results
Children at risk for schizophrenia had significantly lower Mullen Composite scores at both age 1 (p=0.0078) and 2 years (p=0.0001) compared to control children. Reductions were present in fine motor, expressive and receptive language scales at both ages. Overall, high-risk children did not differ from controls in global tissue volumes, though there was evidence of a gender effect. Female high-risk children tended to have reduced gray matter volumes after birth and at age 1 year (significant reduction after birth, p =0.018), while males tended have increased gray matter volumes at age 1 and 2 years (significant at 1 year, p = 0.037). Cortical thickness and surface area results tended to reflect the gray matter volume findings. Females had regions of significant cortical surface area reduction after birth, while males had several regions of significant of cortical surface area expansion at 1 year. Males had a few regions of significant changes of cortical thickness after birth.
Discussion
In the context of its limitations, this study confirms previous studies that find alterations of very early childhood development in children at risk for schizophrenia. It also indicates that alterations of cortical gray matter are evident in very early childhood, and that there is a gender difference in these alterations, with females having reduced gray matter volumes and males having increased gray matter volumes. Brain structure and cognitive abnormalities associated with risk for schizophrenia are present shortly after birth; future studies may be able to identify very early biomarkers of risk that will not only improve our understanding of how brain abnormalities associated with schizophrenia develop, but also define periods of childhood development that can be targeted with early intervention.



O10.4. INCREASED RISKS FOR NON-AFFECTIVE PSYCHOTIC DISORDER AND BIPOLAR DISORDER IN AUTISM SPECTRUM DISORDER

Sun, 01 Apr 2018 00:00:00 GMT

Abstract
Background
Young adults with autism spectrum disorder (ASD) appear to be at increased risk for non-affective psychotic disorder (NAPD) and bipolar disorder (BD). However, previous studies have mostly examined the co-occurrence of ASD with NAPD and BD, which is problematic given substantial overlap in symptoms between these disorders. As such, previous risk estimates may have been influenced by diagnostic bias (i.e. NAPD/BD symptoms being mistakenly diagnosed as ASD) or selection bias (i.e. individuals being recognized and/or registered with ASD due to the development of NAPD/BD). In the present study, we used longitudinal data from two Dutch psychiatric case registers to obtain more reliable risk estimates for NAPD and BD among young adults with ASD.
Methods
ASD cases were followed between ages 16 and 35 (n = 17,234). Kaplan-Meier estimates were used to calculate risks for NAPD and BD. We conducted separate analyses to reduce possible bias, taking into account the age of ASD diagnosis (ASD diagnosed before or after age 16) and sequence of diagnoses (ASD before or after NAPD/BD). We conducted prognostic analyses using Cox regression to examine possible risk factors for NAPD and BD in ASD.
Results
ASD cases were at an increased risk for NAPD and BD compared to previously-reported risks in the general population, even when ASD had already been diagnosed at an early age, before a diagnosis of NAPD or BD. Among cases who were diagnosed with ASD at least one year before a diagnosis of NAPD or BD, an estimated 7.90% (95% CI, 6.70–9.31) developed NAPD, whereas 1.35% (95% CI, 0.89–2.04) developed BD, prior to age 36. Prognostic analyses showed that men with ASD were at a relatively greater risk for NAPD, whereas women with ASD were at a greater risk for BD.
Discussion
Young adults with ASD are at an increased risk to develop NAPD and BD, which is not only the result of diagnostic or selection bias. More research is necessary to examine possible mechanisms underlying these risks.



O10.5. ABNORMAL MODULAR ORGANIZATION OF THE FUNCTIONAL CONNECTOME PREDICTS CONVERSION TO PSYCHOSIS IN CLINICAL HIGH-RISK YOUTH

Sun, 01 Apr 2018 00:00:00 GMT

AbstractBackgroundThe first episode of schizophrenia is typically preceded by a prodromal phase characterized by sub-threshold symptoms and declining functioning. Elucidating the neurobiological substrate of prodromal symptoms that progress into overt psychotic illness is crucial to the development of early detection and intervention strategies for schizophrenia. In this study, we performed a functional connectome analysis in a large group of adolescents and young adults at Clinical High Risk (CHR) for schizophrenia. We aim to assess whether, and if so how, baseline connectome organization distinguishes CHR youth that go on to develop psychosis.MethodsThis study comprises a total of 251 subjects, including 158 psychotropically-naïve CHR subjects (CHRs) and 93 healthy controls (HCs), who were matched to CHRs on age, gender, and level of education. Prodromal symptoms and cognition were assessed using the SIPS structured interview and MATRICS cognitive battery. Anatomical T1 MRI and resting-state fMRI scans were collected at baseline and processed using Freesurfer v6.0 and CONN v17.d software. For each subject, a functional connectome map was reconstructed consisting of 162 nodes representing 148 cortical regions from the Destrieux atlas and 14 subcortical structures. Functional connectomes were analyzed in terms of modular topology using the Louvain community detection method. Modular network partitions of individual CHRs were compared to a group-averaged HC network using the rand similarity coefficient (SR), providing a measure of the level of (ab)normality of the CHRs’ modular partitions. Analysis of covariance (correcting for age- and gender) was used to compare SR levels between CHRs who developed psychosis during follow-up (CHR+; N = 23) as compared to CHRs who did not develop psychosis (CHR-; N = 135). Kaplan-Meier analysis was used to estimate psychosis-free survival functions for CHRs with below- versus above-average SR, which were compared using log-rank tests. Cox regression analysis was used to assess how baseline connectome organization and clinical measures (i.e., demographics, symptoms, IQ) predicted time to conversion.ResultsModular community detection in HCs yielded five major modules including a posterior ‘visual’, central ‘sensorimotor’, medial frontoparietal ‘default-mode’, lateral frontoparietal ‘central-executive’, and inferior ‘limbic’ module. Modular connectome organization of CHR+ was significantly less similar to HCs than CHR- (F(1,154) = 7.14, p = 0.008). A region-specific analysis to identify which regions contributed most to aberrant modular connectome organization in CHR+ showed that superior temporal (including STG), medial temporal (including amygdala), and ventromedial prefrontal regions were most abnormal in terms of their modular assignment. Psychosis-free survival functions of CHRs with low versus high SR were significantly different (z = 2.5, p = 0.013), with a Hazard ratio of 3.3 indicating an over 3-fold relative event rate (i.e., conversion to psychosis) in CHRs with abnormal baseline connectome organization. Cox regression analysis indicated that baseline connectome organization (z = -2.3, p = 0.019), IQ (z = -2.7, p = 0.007), and gender (z = 2.0, p = 0.048) predicted time to conversion.DiscussionThis study indicates that abnormalities in functional connectome organization precede the first psychotic episode. Conversion to psychosis was found to be over three times more likely in CHRs with abnormal modular organization of the functional connectome at baseline. Our results sugges[...]



O10.6. OLANZAPINE IMPAIRS CENTRAL INSULIN ACTION: EFFECTS ON BODY FUEL PREFERENCE IN RATS

Sun, 01 Apr 2018 00:00:00 GMT

Abstract
Background
Antipsychotics (APs) remain the cornerstone of treatment in schizophrenia, with increasing use on- and off- label. Olanzapine (OLZ) is a highly prescribed, high metabolic liability AP. Olanzapine has also been found to shift major fuel preference from carbohydrates to fats (while impairing fat breakdown and decreasing availability of fat as a substrate). The shift toward fat utilization is demonstrated by decreases in respiratory exchange ratio (RER). Notably, APs may alter signaling pathways in insulin-sensitive brain areas, particularly in the hypothalamus, that play a role glucose regulation and energy expenditure.
Methods
We investigated the effects of intracerebroventricular (ICV) insulin administration on OLZ-induced disruptions in energy homeostasis. Male Sprague Dawley rats were assigned to 4 treatment groups (ICV-peripheral): Vehicle (VEH)-VEH (n = 5), Insulin (INS)-VEH (n = 7), INS-OLZ (n = 6), VEH-OLZ (n = 5). Following acclimatization to the metabolic cages, rats received injections of INS (10mU) or VEH into the 3rd ventricle, and OLA (3mg/kg) or VEH subcutaneously at the beginning of the light (7AM, t=0) and dark (7PM, t=12h) cycle. Dose of OLZ was chosen based on clinically relevant >65% dopamine (D2) brain occupancy. Dose of ICV insulin was chosen based on established decreases in food intake. Indirect calorimetry was used to calculate RER, and heat production. Cumulative food intake was measured at 12-hour intervals (t=12h and 24 h).
Results
Treatment with OLZ reproduced the previously established downward shift in RER during the dark phase (p=0.016), which occurred independently of changes in food intake or heat production. Central insulin also decreased RER (p=0.013), an unexpected finding as insulin has been associated with increased carbohydrate oxidation. This may have been secondary to decreased food intake associated with central INS (p=0.011), leading to a shift towards fat-oxidation characteristic of fasting. Co-administration of OLZ with central INS (INS-OLZ) abolished the treatment effect seen in the INS-VEH group relative to VEH-OLZ, shifting the RER profile to become similar to the VEH-OLZ group. Similarly, when OLZ was co-administered with ICV-INS, the effect of central INS to reduce food-intake was lost. An interaction effect (p=0.007) was observed between central insulin and subcutaneous OLZ treatments on RER, supporting the notion that these compounds may work through independent mechanisms to influence fuel preference.
Discussion
Taken together, these findings suggest that: 1) central insulin stimulation alters metabolism but is unable to modulate OLZ-specific associated changes in RER; 2) this is likely occurring due to rapid induction of central insulin resistance by OLZ. Our data thus warrants further investigation into the effects of APs on central insulin sensing, and mitigation strategies (i.e. use of central insulin sensitizers) with the goal of mitigating the metabolic burden of these compounds.



O10.7. INVESTIGATING THE MECHANISMS UNDERLYING THE BENEFICIAL EFFECTS OF ESTROGENS IN SCHIZOPHRENIA

Sun, 01 Apr 2018 00:00:00 GMT

AbstractBackgroundEstrogens, in particular 17β-estradiol (estradiol) have repeatedly been shown to exert powerful influences over cognitive function, and in particular, on a range of cognitive behaviours associated with neurodevelopmental disorders. This includes depressive and anxious behaviours as well as learning and memory (including working memory). These cognitive enhancing effects have been shown to be dependent on increases in the number of dendritic spines as well as alterations in glutamate receptor transmission and regulation of synaptic protein expression. Modulation of these synaptic functions can result in long-term increases in synaptic connectivity.Interestingly, there is growing evidence that estrogenic-based compounds may have a positive effect in the treatment of a number of neuropsychiatric disorders, including schizophrenia. Importantly, recent clinical studies have demonstrated that adjunct treatment with estradiol or the selective estrogen receptor modulator (SERM) raloxifene, ameliorates positive and negative symptoms and improves working memory and attention deficits in male and female schizophrenic patients. However, it has been argued that estrogenic-based compounds are not an effective treatment option owing to potential serve side effects associated with long-term administration. It is, however, of note that the precise mechanisms that underlie the positive effects of estradiol, or estrogenic-based compounds, in this disease are currently unclear. Therefore, determining how estradiol exerts its positive effects in health as well as in disease, will aid in the development of safer and more effective estrogenic-based compounds.MethodsHere, we have used human induced pluripotent stem cell (iPSC)-derived from healthy or patients diagnosed schizophrenic but with no common genetic background to study the potential mechanism that may underlie estrogens beneficial effects in disease. iPSCs were differentiated into young, developing, cortical neurons using well established methods. First, we assessed the ability of estrogens to modulate key neuronal and synaptic structures as well as synaptic and inflammatory genes. Next, we assessed the expression and distribution of synaptic proteins were determined in both healthy iPSC-neurons and patient iPSC-neurons (from 3–6 individuals from each group). Subsequently, using a pharmacological approach, we have explored the ability of estrogens to rescue cellular and molecular deficits in iPSC-neurons derived from schizophrenic patients.ResultsBoth healthy and patient iPSC differentiated into neuroepithelium, neural progenitors cells and finally into TBR1- and EMX1-positive neurons efficiently. Assessment of synaptic protein expression revealed reduced expression of key synaptic proteins involved in excitatory transmission compared to control lines. When healthy iPSC-neurons were treated with a range of estrogenic compounds, we observed a robust increase in the expression of key synaptic protein including GRIN1 and DGL4. Consistent with previous reports, patient iPSC-neurons displayed reduced synaptic protein expression compared with healthy iPSC-neurons. Critically, when patient iPSC-neurons were treated with 17β-estradiol or raloxifene, we observed an increase in synaptic protein expression to a level similar to that observed in untreated healthy iPSC-neurons.DiscussionThese data are the first to demonstrate that estrogens are capable of regulating synaptic proteins in human neurons taken from patients diagnosed with schi[...]



O10.8. A PLURIPOTENTIAL AT RISK MENTAL STATE: INITIAL RESULTS

Sun, 01 Apr 2018 00:00:00 GMT

Abstract
Background
The development of the ultra-high risk (UHR) criteria for psychosis over 20 years ago created a new framework for research into subthreshold states in psychiatry. Since (i) early clinical phenotypes are overlapping and non-specific, and (ii) prevention research faces the challenge of achieving adequate statistical power when focusing on low incidence syndromes such as schizophrenia, we introduce an extension of the UHR approach in order to encompass trans-diagnostic targets. The ‘CHARMS’ (Clinical High at Risk Mental State) study aims to validate a set of pluripotential criteria to prospectively identify help-seeking young people at risk of developing a range of serious mental disorders.
Methods
The CHARMS study is a cohort study of help-seeking young people aged 12–25 attending youth mental health services in Melbourne, Australia. New referrals meeting the CHARMS criteria are allocated to the CHARMS+ group; referrals under CHARMS threshold are allocated to CHARMS- (control) group. Transition status and clinical/functional outcomes are re-assessed at 6 and 12 months. The CHARMS criteria consist of subthreshold states for psychosis, mania, severe depression and borderline personality disorder. A range of clinical predictors, including anxiety, stress, sleep/circadian disturbance, and cognitive biases are being assessed as well.
Results
To date, a sample of N=73 participants have been recruited: N=49 (67%) met CHARMS criteria (CHARMS+) at baseline with N=24 (33%) allocations to the control group (CHARMS-). Of these, N=48 participants have been followed up to 6 months and a sample of N=35 has been followed up to 12 months. At 6 months, 32% of the CHARMS+ group have transitioned to a full-threshold mental disorder which increased to 37% at 12 month follow-up. 0% of the CHARMS- control group has transitioned.
Discussion
Our initial results indicate that the CHARMS criteria can be applied in the context of a youth mental health service and validly identify help-seeking young people at substantial risk of progressing to serious mental disorder over a short time frame (within 12 months). This study is the first to introduce and validate a set of clinical criteria to identify a broader ‘at risk’ patient population, and represents an important advance from the UHR for psychosis approach. It will foster understanding of risk factors and pathogenic mechanisms that drive the onset of severe mental disorder transdiagnostically and introduce a new case identification paradigm for the next generation of preventive intervention trials.



O11.1. A RANDOMISED CONTROLLED TRIAL OF SMARTPHONE ACTIVE SYMPTOM MONITORING IN PSYCHOSIS

Sun, 01 Apr 2018 00:00:00 GMT

AbstractBackgroundWe developed a smartphone-based personalised technology to monitor symptoms in real time and showed good acceptability, reliability and validity for active remote monitoring of symptoms in previous published studies (www.clintouch.com). We report a randomised trial testing its efficacy in improving psychotic symptom control, and its potential as an early warning system for relapse when embedded into the ICT systems of mental health provider organisations, and as a tool for identifying new phenotypes for precision medicine.MethodsParticipants with SMI receive a semi-random beep 2–4 times per day on their smartphone app and answer 14 key symptom rating items using a touchscreen slider. Responses are uploaded wirelessly in real time to a central server and build into a graphical readout on the handset, allowing active symptom monitoring and attempts at self-management. We built this into an end-to-end system in two NHS Hospital Trusts (Manchester and South London) to stream data into electronic care records and enable detection by the clinical team of early signs of relapse in people with SMI when key symptoms exceeded a personalised severity threshold. We conducted an open randomised controlled trial of this active symptom monitoring (ASM) using the smartphone app compared to usual management with the aim of assessing: (i) acceptability of continuous monitoring over 3 months; (ii) impact of active self-monitoring on PANSS positive symptoms and Empowerment Rating Scale score assessed at 6 and 12 weeks; (iii) efficiency of detecting early warning signs of relapse. Eligible participants with a DSM5 diagnosis of schizophrenia and related disorders and a history of relapse within the previous two years were included from an early intervention team (early psychosis group) and a community team (chronic psychosis group).ResultsOf 181 eligible, 81 were randomised to either active symptom monitoring or management as usual. 90% stayed in the trial for 12 weeks. Of the 38 in the ASM arm who completed 12-week follow up, adherence defined as responding to >33% of alerts was 84%, >50% of alerts was 60%. At 12 weeks, ASM compared to usual management was associated with no difference on empowerment scale. PANSS positive subscale score showed a significant mean reduction in the ASM group over 12 weeks in the early psychosis group (n= 22, planned ANCOVA p<0.02), but no effect in the chronic psychosis group (n=19). Early warning sign alerts generated by the system occurred in 92% of cases and blind comparison with electronic case record data suggested good sensitivity and lower specificity, but with clear indications of how to adjust the gain of the system to improve future event-detection efficiency. Multivariate analyses pointed to the ability of the system to identify clinical subtypes.DiscussionThe active smartphone monitoring system is feasible and acceptable over three months in people with schizophrenia and related disorders. It was associated with psychotic symptom improvement in recent onset participants, supporting the notion of improved self-management. When built into clinical management workflows to enable personalised alerts of symptom deterioration, it was shown to have potential use in promoting earlier intervention for relapse.[...]



O11.2. CHANGES IN PSYCHOPATHOLOGY PREDICT CHANGES IN WORKING ALLIANCE IN FIRST EPISODE PSYCHOSIS

Sun, 01 Apr 2018 00:00:00 GMT

Abstract
Background
The cooperative and dynamic relationship between patients and therapist known as Working Alliance, has in two meta-analysis shown to be an important factor for positive outcome in psychotherapy regardless the modality of therapy. Studies investigating the association between working alliance and outcome conducted in cohorts of patients with mental illness treated in a case manager setting has reported an association between a strong working alliance and reduced symptom severity, better social function, adherence to psycho-social treatment.For this study, we used data from a trial testing the effect of five years of specialized early intervention (SEI) compared to two years of SEI for patients diagnosed with first episode of schizophrenia spectrum disorder. We aimed to study the effect of the intervention on the working alliance and the change in working alliance as a dynamic factor in the two treatment conditions from baseline to follow-up.When extending specialized early intervention from two to five years’ vs transferring to treatment as usual, we hypothesized a change in working alliance and psychopathology favoring the patient in the extended SEI group.
Methods
Participants were recruited from SEI teams (OPUS) in Denmark. All newly diagnosed within the schizophrenia spectrum (ICD-10, F2), age between 18 and 35. Participants were included 1 ½ year after initiation of SEI treatment (baseline) and followed up 5 years after initiation of treatment. At both assessments participants were examined with a comprehensive assessment battery including working alliance, psychopathology, social function, cognitive function, adherence to medication and client satisfaction. Assessors were blind to treatment allocation. The primary outcome, working alliance inventory (WAI), was assessed by self-assessment.A change score was calculated by subtracting the baseline score from the follow-up score. Multivariable linear regression analyses were conducted, corrected for the baseline value of the independent and dependent variable.
Results
Of the 289 participants who attended the follow-up interview 258 (89%) had completed the WAI at baseline and follow-up. Participants who were randomized to prolonged SEI had a stable WA from baseline to follow-up, while participants who were randomized to TAU had a mean drop in WA over the same period.Change in WA was associated with change in negative-, psychotic-, and disorganized symptoms dimension, and social function in the extended OPUS group. In the TAU group, we found that change in WA were negatively associated with change in cognitive function measured with BACS. In both groups, there were an association between the change in WA and change in client satisfaction.
Discussion
This indicates that those participants’ who continued the extended SEI treatment maintained their experiences of a strong WA with their case manager, while those participants who were transferred to TAU experiences a lower degree of WA with their case manager compared to their time in SEI treatment. Furthermore, the participants who increased on their cognitive functioning were less likely to assess WA positively if they were transferred to TAU.



O11.3. A LONGITUDINAL ANALYSIS OF THE EFFECTS OF NEUROTICISM AND EXTRAVERSION ON SUBJECTIVE WELL-BEING IN PATIENTS WITH SCHIZOPHRENIA

Sun, 01 Apr 2018 00:00:00 GMT

AbstractBackgroundOne in five patients with a psychotic disorder has a persistent low subjective well-being over three years. This group has a poorer prognosis for social functioning. This presentation reports on the first longitudinal study evaluating whether neuroticism and extraversion influence subjective well-being (SWB) in patients with a schizophrenia spectrum disorder. SWB is generally defined as ‘the subjective experience, as constituting aspects of mental or physical state, which patients report regardless of etiological attributions’. It is an independent determinant for recovery in patients with a psychotic disorder. Two cross-sectional studies on quality of life in schizophrenia suggest that personality traits are associated with the way patients value life. If personality traits predict the trajectories of subjective well-being, our results would provide a clinical reference point for patients at risk for a persistent low subjective well-being.MethodsWe included 186 patients and 126 healthy control subjects from the Dutch Genetic Risk and Risk and Outcome of Psychosis cohort. SWB was measured with the Subjective Well-being under Neuroleptics-20 (SWN) scale. Assessments took place at baseline, three years and six years follow-up. We used the Five-Factor Inventory to assess neuroticism and extraversion. Positive, negative and depressive symptoms in patients were assessed by the Positive and Negative Symptoms Scale. For controls we used the Community Assessment of Psychic Experiences for investigating subclinical symptoms. By using linear mixed model analyses we investigated the relation between SWB and the personality traits, including the moderating associations of positive, negative, depressive symptoms and a range of psychosocial indicators (among which antipsychotic use and smoking cannabis). An exploratory analysis in the patient sample, investigated the predictive values of personality traits and symptoms at baseline on the course of SWB over 3 and 6 years. Patients were accounted to one of three SWB-trajectories ‘stable low’, ‘low start and improving’ and ‘stable high’.ResultsMixed model analyses revealed that in patients, high scores of neuroticism and low scores of extraversion were associated with lower SWN-scores: at 3 years: t = - 3.07 and t = 4.34 for p < 0.05 and at 6 years: t = -2.62, p = 0.009 and t = 3.51, p = 0.001. We found no interaction effect of time and personality traits. Neuroticism and extraversion were related to SWB to the same extent in the control group.Regarding trajectories over time, we found a stable low SWB in 15.1% of the patients, forming the ‘stable low’ trajectory group. This group scored highest on neuroticism and lowest on extraversion compared to patients with an increase in SWB or a stable high SWB: neuroticism scores showed post hoc compared mean differences (MD) of 4.25, p = 0.03 for the ‘low start increasing’-group and MD 10.75, p <0.001 for the ‘stable high’-group).DiscussionWe found an association between personality traits and subjective well-being regardless of (subclinical) psychotic or depressive symptoms. Extraversion can be regarded as a resilience factor, whereas neuroticism is associated with a persistent low well-being. In patient with a schizophrenia spectrum disorder, neuroticism could be a focus for therapeutic interventions that diminish negative affectivity. Additionally,[...]



O11.4. EDUCATION, EMPLOYMENT AND DISABILITY AMONG YOUNG PERSONS WITH EARLY PSYCHOSIS PARTICIPATING IN A COORDINATED SPECIALTY CARE PROGRAM

Sun, 01 Apr 2018 00:00:00 GMT

AbstractBackgroundComprehensive early treatment programs for individuals with early psychosis have demonstrated success internationally, spurring rapid expansion of the model in the United States. Between 2014–2016, U.S. federal funding to states to support Coordinated Specialty Care (CSC) for individuals with early psychosis increased to $50 million annually (Dixon, 2017). New York State (NYS) was an early adopter and has rapidly expanded CSC across the state. This study prospectively evaluated education and employment outcomes over time within NYS’s CSC program, OnTrackNY.MethodsEmployment and education trajectories were assessed for individuals with early psychosis who had at least one three-month follow-up assessment, from the program’s inception in October 2013, through September 2016 (N=325). Rates of Social Security Administration (SSA) disability enrollment were assessed for individuals enrolled from October 2013 to June 2017 (n=679).Education and employment status was estimated using longitudinal logistic models utilizing generalized estimating equations with an autoregressive covariance structure to account for within-subject correlations over time. To test how education/employment changed over time, pre-specified contrasts were tested from the longitudinal model for the mean change in sequential follow-up visits. A Kaplan-Meier estimator with discrete time to event and censoring at last observed follow-up month with no event was used to estimate the probability of any education/employment by one year after admission and to estimate the risk of disability by two years after admission.ResultsApproximately 40% of individuals with early psychosis were engaged in school or work upon enrollment in a CSC program; engagement increased to 80% after 6 months of care. The estimated probability of being employed or in school at some time during the year after admission was 87.9% (95% Confidence Interval (CI)= [82.9, 92.0]). Relative to women, men had significantly lower odds of education/employment. Relative to non-Hispanic whites, individuals who were Asian, Hispanic or Black had lower odds of education/ employment. Relative to individuals who had not yet completed high school, individuals whose highest educational attainment was High School (HS) or GED had lower odds of educational/employment.At admission, 2.5% (17/679) clients were receiving SSA disability benefits. The Kaplan-Meier estimates that 18.3% (95% CI= [13.9, 23.9]) of clients followed for two years obtained disability benefits. In bivariate cox regression analyses, individuals with lower (worse) occupational and social functioning scores have significantly greater risk of disability enrollment than individuals with higher scores (in multivariate analysis, only lower occupational functioning remains significant). Age, gender, race, ethnicity, and symptom scores were not significantly associated with disability enrollment.DiscussionThis study demonstrates that individuals with early psychosis who receive CSC in non-research community settings achieve significant improvements in education and employment. Gender, race/ethnicity, and baseline education predicted education and employment outcomes, while poorer functioning was associated with risk of SSA disability benefits. CSC teams should make particular efforts to support the work and school goals of individuals who may be more likely [...]



O11.5. EFFECTIVENESS OF COORDINATED SPECIALTY CARE FOR EARLY PSYCHOSIS

Sun, 01 Apr 2018 00:00:00 GMT

Abstract
Background
The value of early intervention in psychosis and allocation of public resources has long been debated since outcomes in people with schizophrenia-spectrum disorders have remained suboptimal. Several research programs for early psychosis yielded promising results for team-based, multi-element coordinated specialty care (CSC).
Methods
Systematic literature search of PubMed/PsycInfo/Embase/clinicaltrials.gov without language restrictions until 06/06/2017. Random effects meta-analysis of randomized trials comparing CSC versus Treatment as Usual (TAU) in in first episode psychosis or early-phase schizophrenia-spectrum disorders (schizophrenia, psychotic disorder not otherwise specified, schizoaffective disorder, schizophreniform disorder, delusional disorder), calculating standardized mean differences (SMDs) and risk ratios (RRs) for continuous and categorical outcomes as well as prespecified subgroup and meta-regression analyses.Co-primary outcomes were all-cause treatment discontinuation and ≥1 psychiatric hospitalization during the treatment period. Key secondary outcomes were total symptom improvement, functioning, and work or school involvement.
Results
Across 10 trials (n=2,176; age=27.5 ± 4.6 years; male=62.3%; trial duration=16.2 ± 7.4 (range=9–24) months), CSC outperformed TAU at the end of treatment regarding all meta-analyzable outcomes. This included all-cause discontinuation (studies=10, n=2,173, RR=0.70, 95% confidence interval (CI)=0.61–0.80, p<0.001; number-needed-to-treat (NNT)=12.4), ≥1 hospitalization (studies=10, n=2,105, RR=0.74, 95%CI=0.61–0.90, p=0.003; NNT=10.1), total symptom severity (studies=8, n=1,179, SMD=-0.32, 95%CI=-0.47, -0.17, p<0.001), positive symptoms (studies=10, n=1,532, SMD=-0.22, 95%CI=-0.32, -0.13, p<0.001), negative symptoms (studies=10, n=1,432, SMD=-0.28, 95%CI=-0.42, -0.14, p<0.001), general symptoms (studies=8, n=1,118, SMD=-0.30, 95%CI=-0.47, -0.13, p=0.001), depressive symptoms (studies=5, n=874, SMD=-0.19, 95%CI=-0.35, -0.03, p=0.017), functioning (studies=7, n=1,005, SMD=0.21, 95%CI=0.09–0.34, p=0.001), involvement in school/work (studies=6, n=1,743, RR=1.13, 95%CI=1.03–1.24, p=0.012; NNT=17.8), and quality of life (studies=4, n=505, SMD=0.23, 95%CI=0.004–0.456, p=0.046). Superiority of CSC regarding all outcomes was also evident at 6, 9–12, and 18–24 months of treatment (except general symptoms and depression at 18–24 months).
Discussion
In early psychosis, CSC is superior to TAU across all meta-analyzable, highly relevant outcomes with small-to-medium effect sizes. These results support the need for funding and utilization of CSC in patients with early-phase psychosis.



O11.6. WHO GETS IN TO EARLY PSYCHOSIS INTERVENTION SERVICES? A COMPARISON OF SERVICE USERS AND NON-USERS IN HEALTH ADMINISTRATIVE DATA

Sun, 01 Apr 2018 00:00:00 GMT

Abstract
Background
There is a dearth of information on people with first-episode psychosis who do not access specialized early psychosis intervention (EPI) services. With this notable gap in knowledge comes the implicit assumption that nearly all cases of first-episode psychosis are detected and treated by EPI services. We sought to estimate the proportion of incident cases of non-affective psychosis who do not access these services, and to examine factors associated with EPI admission.
Methods
Using health administrative data, we constructed a retrospective cohort of incident cases of non-affective psychosis in the catchment area of the Prevention and Early Intervention Program for Psychoses (PEPP) in London, Ontario between 1997 and 2013. This cohort was linked to primary data from PEPP to identify EPI-users. We used multivariate logistic regression to model socio-demographic and service factors associated with EPI admission.
Results
Over 50% of suspected cases of non-affective psychosis did not have contact with the EPI program for screening or admission. Our findings suggest a clear gradient by age, with a decreasing likelihood of being treated in the EPI program with increasing age strata (age 46–50 years vs. age 16–20 years: OR=0.03, 95%CI=0.01–0.05). EPI-users are more likely to be male (OR=1.58, 95%CI=1.24–2.01), and less likely to live in areas of socioeconomic deprivation (OR=0.51, 95%CI=0.36–0.73). EPI-users also had a higher odds of psychiatrist involvement at the index diagnosis (OR=7.35, 95%CI=5.43–10.00), had a lower odds of receiving the index diagnosis in an outpatient setting (OR=0.50, 95%CI=0.38–0.65), and had a lower odds of prior alcohol-related (OR=0.42, 95%CI=0.28–0.63) and substance-related (OR=0.68, 95%CI=0.50–0.93) disorders.
Discussion
Much of the prior research on EPI services is predicated on the belief that nearly all patients with first-episode psychosis are represented in these services, with little discussion or consideration of people who may be receiving care elsewhere in the health system. We need greater consideration of patients with first-episode psychosis who are not accessing EPI services – our findings suggest this group is sizable, and there may be socio-demographic and clinical disparities in access. Non-psychiatric health professionals could be targeted with interventions aimed at increasing detection and referral rates.



O11.7. DISCHARGE PLANNING PRACTICES AND FAMILY INVOLVEMENT IN TRANSITIONS TO OUTPATIENT CARE FOLLOWING DISCHARGE FROM HOSPITAL PSYCHIATRIC UNITS

Sun, 01 Apr 2018 00:00:00 GMT

Abstract
Background
Individuals with mood and psychotic disorders treated in hospital psychiatric units have high rates of discontinuing treatment following discharge, a time that poses substantial risks of serious and even life threatening adverse outcomes. Hospital provider care transition practices believed to improve transitions include communication with outpatient providers, scheduling timely appointments for outpatient follow-up care, forwarding case summaries to aftercare providers, and involving family or support persons in discharge planning. While these are standards of care, little is known about how often they are adequately delivered and their impact on post-discharge aftercare adherence.
Methods
As part of a larger project looking at over 30,000 hospital admissions of Medicaid patients with serious mental illness, this study examined hospital medical records for 217 admissions at two urban US hospitals. Trained raters reviewed records for evidence of inpatient providers completing discharge planning practices. Medicaid data were used to measure demographics and attendance of seven- and 30-day outpatient appointments.
Results
The sample of 217 admissions was 51% male and 82% were adults, with discharge diagnoses including schizophrenia and related disorders (45%), bipolar disorders (28%) and depressive disorders (17%). The average length of stay was 14 ± 13 days with a median of nine days. The medical records showed evidence of inpatient providers communicating with outpatient providers 64% (n=139) of the time. There was evidence of an outpatient appointment scheduled within seven days of discharge for 81% (n=176) of the sample. A case summary was made available to the aftercare provider within one day of discharge for 66% (n=144) of the sample. Records showed that the inpatient team communicated with family members or support persons about the patient’s post-discharge treatment plan for 53% (n=114) of the sample, and 36% (n=79) attended a family meeting or therapy session. Rates of attending an aftercare behavioral health appointment were 55% (n=120) at seven days post-discharge and 80% (n=174) for 30 days.
Discussion
This study found varying rates of providers completing care transition practices. Only half of the sample had attended an aftercare appointment in the seven days post discharge, however the majority had attended an appointment by 30 days. Planned analyses will present demographic and clinical differences among those who received discharge planning activities and had family involvement. We will examine predictors of attending follow-up care and report the effectiveness of discharge planning practices. Findings will help inform strategies to improve care-coordination and discharge planning for individuals with serious mental illnesses treated in psychiatric hospitals.



O11.8. PREVALENCE AND PREDICTORS OF INTERVIEW-ASSESSED CLINICAL HIGH-RISK SYMPTOMS IN THE GENERAL POPULATION

Sun, 01 Apr 2018 00:00:00 GMT

Abstract
Background
In clinical samples, symptomatic ultra-high risk criteria and the basic symptom criterion “cognitive disturbances” perform well in predicting psychosis, and best when both approaches are combined. However, little-to-nothing is known about the prevalence, clinical relevance, and moderators of these clinical high risk (CHR) criteria and their constituent symptoms in the community.
Methods
Regression analyses involved 2683 community participants (age 16–40 years; response rate: 63.4%). Semi-structured telephone interviews were performed by well-trained psychologists.
Results
Lifetime and current CHR symptoms were reported by 21.1% and 13.8% of interviewees. Frequency of symptoms was mostly low, only 2.4% met any CHR criterion. A stepwise relationship underlay the association of the two types of CHR symptoms and criteria with the presence of mental disorders and functional deficits, with odds ratios being highest (7.4–31.8) when ultra-high risk and basic symptoms occurred together. Report of a family history of mental disorder generally increased risk for CHR symptoms. While younger age increased risk for basic symptoms, lifetime substance misuse and trauma increased risk for ultra-high risk symptoms.
Discussion
Prevalence of CHR criteria was within the range to be expected from the prevalence rates of psychoses. Clinical relevance of both CHR symptoms and criteria increased in a stepwise manner from basic symptoms via ultra-high risk symptoms to their combined presence, reinforcing the clinical utility of their combined use. The risk factors selectively associated with basic and ultra-high risk symptoms seem to support developmental models relating basic symptoms to neurobiological and ultra-high risk symptoms to psychological factors.



O12.1. EXAMINING THE NEUROBIOLOGICAL IMPACT OF CHILDHOOD TRAUMA: AN IMPORTANT ROLE FOR FRONTAL AND INSULAR REGIONS

Sun, 01 Apr 2018 00:00:00 GMT

Abstract
Background
Childhood trauma may increase the risk for psychiatric illness by its negative impact on brain development. Studies investigating the association between childhood trauma and deviations in gray matter volume have shown inconsistent findings, often restricted by a region-of interest approach with a sole focus on the amygdala and hippocampus and without controlling for the presence of psychiatric illness.
Methods
First, using a whole-brain approach in a large cross-diagnostic sample (n=554) of healthy individuals and patients with a bipolar type-I or psychotic disorder, we investigated the neurobiological correlates of childhood trauma by evaluating gray matter volume. Follow-up analyses were conducted to evaluate the effect of psychiatric illness. Second, we investigated to what extent these trauma-related structural correlates could be observed in both groups separately (healthy individuals versus patients). Participants were recruited as part of three different studies, all conducted in the University Medical Center Utrecht (the Netherlands) between 2007 and 2016. We included 554 participants: 220 healthy individuals without a psychiatric history, 250 patients with a bipolar-I disorder and 84 patients with a psychotic disorder. Childhood trauma was evaluated with the Childhood Trauma Questionnaire (CTQ-SF). Anatomical T1 MRI scans were acquired at 3T. FreeSurfer was used to assess regional brain morphology.
Results
In the total sample, childhood trauma severity was associated with bilateral reductions in frontal and insular gray matter volumes. In the right hemisphere, medial orbitofrontal and superior frontal volume reductions were related to childhood trauma. These associations remained when adjusting for psychiatric illness, with the exception of the right superior frontal subregion. However, when evaluating both groups separately, these structural correlates of childhood trauma were mainly observed in patients. Healthy controls did show trauma related reductions in right medial orbitofrontal region, while this association was not significant in the patient group.
Discussion
Our results suggest that gray matter reductions in the frontal and insular regions are important neurobiological correlates of childhood trauma. For future research, a whole brain approach should be applied, as cortical rather than subcortical areas may be the main correlate of childhood trauma contributing to the development of psychopathology.



O12.2. STICKS AND STONES MAY BREAK MY BONES BUT WORDS INCREASE THE RISK OF PSYCHOTIC EXPERIENCES

Sun, 01 Apr 2018 00:00:00 GMT

AbstractBackgroundThere has been a surge of interest into the relationship between psychotic experiences (PEs) and bullying. However, the methods of bullying and impact of bullying varies across individuals and the prevalence may also vary by respondent (parent or children). For this reason, a thorough investigation into this relationship is warranted.MethodsA longitudinal analysis was conducted on waves 1 and 2 (ages 9 and 13) of the nationally representative Growing Up in Ireland study. Data from n=7163 families were included in this study. Information regarding bullying, being a bully, bullying type, reasons for the bullying, the impact of the bullying was collected from the participating child and their primary care giver (PCG) at both waves. Psychotic experiences were reported by the child at the second wave using the Adolescent Psychotic Symptoms Screener.Results13.12% of children met validated criteria for psychotic experiences. Based on the PCG’s account, 32.89% of those with PEs at age 13 were bullied at age 9 and this was independently associated with PEs even after accounting for bullying at 13 (OR: 1.40, CI: 1.19–1.65). Physical, verbal, electronic bullying and bullying by exclusion were associated with an increased risk of PE. However, in a multivariate analysis only verbal bullying was independently associated with an increased risk of psychotic experiences (OR: 1.56, CI: 1.27–1.93; adjusted for bullying at 13: OR: 1.47, CI: 1.19–1.82). There was a linear relationship between the number of different methods of bullying experienced at 9 and the risk of PEs at 13 (continuous OR: 1.24, CI: 1.14–1.34). Of the reasons for bullying given by the PCG, only ethnicity (OR: 2.36, CI: 1.46–3.80), being a teacher’s pet (OR: 2.09, CI: 1.17–3.73) and jealously (OR: 2.28, CI: 1.5–3.39) were significantly associated with PEs. Persistent bullying was associated with a higher risk of PEs relative to their peers (never bullied OR: 2.31, CI: 1.73–3.08; and bullied at one-time point: OR: 1.49, CI: 1.10–2.03).Based on the child’s account, the vast majority of those who report being a bully (13.87%) at age 9 were also bullied (76.48%, OR: 7.04, 5.97–8.31). Both being a bully and being bullied at age 9 were associated with an increased risk of PEs (16.91%, OR: 1.34, CI: 1.09–1.64; and 50.48% OR: 1.71, CI: 1.48–1.98, respectively). In a multivariate analysis only being bullied was independently associated with PEs (OR: 1.68, CI: 1.44–1.96; adjusted for bullying at 13: OR: 1.57, CI: 1.34–1.83). Verbally bullying another was the only method of bullying associated with an increased risk of PEs at 13 (OR: 1.59, CI: 1.06–2.39). Of those reporting being bullied, verbal and written bullying at age 9 were associated with an increased risk of PEs at age 13 (OR: 1.25, CI: 0.97–1.6; and OR: 1.44, CI: 1.05–1.97, respectively). In a multivariate analysis only written bullying was associated with an increased risk of PEs (OR: 1.47, CI: 1.05–2.06; adjusted for bullying at 13: OR: 1.41, CI: 1.01–1.99). The impact of the bullying on well-being was also associated with an increased risk of PEs at 13 (OR: 1.36, CI: 1.09–1.72; adjusted for bullying at 13: OR: 1.30, CI: 1.04–[...]



7.2 ELECTRORETINOGRAPHIC ANOMALIES SEEN IN PATIENTS AFFECTED BY SCHIZOPHRENIA OR BIPOLAR DISORDER ARE DETECTABLE EARLY IN CHILDREN BORN TO AN AFFECTED PARENT: IMPLICATIONS FOR THE STAGING OF RISK STATUS IN CHILDHOOD-ADOLESCENCE

Sun, 01 Apr 2018 00:00:00 GMT

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



7.3 EVALUATING THE NEUROBIOLOGICAL CORRELATES AND IMPACT OF TREATMENT ON COGNITIVE DYSFUNCTION IN ADHD AND SCHIZOPHRENIA BY MEANS OF THE PATTERN ELECTRORETINOGRAM

Sun, 01 Apr 2018 00:00:00 GMT

AbstractBackgroundProblems 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.MethodsNeuronal 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.ResultsBefore 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.DiscussionThese 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[...]



O12.3. PROTECTIVE FACTORS FOR PSYCHOTIC EXPERIENCES AMONGST ADOLESCENTS EXPOSED TO MULTIPLE FORMS OF VICTIMIZATION

Sun, 01 Apr 2018 00:00:00 GMT

Abstract
Background
Experiencing multiple types of victimization (poly-victimization) during adolescence is associated with onset of psychotic experiences. However, many poly-victimized adolescents will not develop such subclinical phenomena and the factors that protect them are unknown. This study investigated whether individual, family, or community-level characteristics were associated with an absence of psychotic experiences amongst poly-victimized adolescents.
Methods
Participants were from the Environmental Risk (E-Risk) Longitudinal Twin Study, a nationally-representative cohort of 2232 UK-born twins. Exposure to seven different types of victimization between ages 12–18 was ascertained using a modified Juvenile Victimization Questionnaire at age 18. Adolescents were also interviewed about psychotic experiences at age 18. Protective factors were measured at ages 12 and 18.
Results
Exposure to poly-victimization during adolescence was associated with age-18 psychotic experiences (OR=4.62, 95% CI 3.59–5.94, P<0.001), but more than a third of the poly-victimized adolescents reported having no psychotic experiences (40.1%). Greater social support was found to be protective against adolescent psychotic experiences amongst those exposed to poly-victimization. Notably, social support was also generally associated with a reduced likelihood of age-18 psychotic experiences in the whole sample (along with engaging in physical activity and greater neighborhood social cohesion).
Discussion
Increasing social support from friends and family appears to be an important area for preventive interventions targeting adolescent psychotic experiences. Such prevention efforts would be most effectively targeted at poly-victimized adolescents who are at high-risk of developing psychotic phenomena.



O12.4. SOME OF THE INDIVIDUAL DIFFERENCES IN RISK TO DEVELOP PSYCHOSIS AMONG CANNABIS USERS CAN BE EXPLAINED BY WHERE THEY LIVE AND BY THEIR AGE AT FIRST USE

Sun, 01 Apr 2018 00:00:00 GMT

Abstract
Background
Cannabis use remains the most widely used recreational drug worldwide. Following from several USA states legalisation policies, European countries are reconsidering their cannabis laws. While a significant amount of Epidemiological evidence has reported that cannabis use increases the risk of psychosis it is still unclear: 1) what underpins individual differences in developing a psychotic disorder following cannabis use; 2) if variations in availability of cannabis have affected rate of Psychotic disorders across Europe.
Methods
Using detailed data on lifetime pattern of cannabis use from the EUGEI first episode case-control study (N=2300) and the available Incidence rates of Psychosis calculated for each European site of the same study, we aim 1) to estimate if differences in age at first use, especially of high potency cannabis among cannabis users resulted in differences in their probability to develop psychosis across the study sites; 2) to calculate the proportion of new cases of psychosis attributable to early adolescence-high Potency cannabis in the 5 countries; 3) to relate data on prevalence of cannabis use in each study site with the corresponding Incidence rates for psychotic disorders.
Results
Cannabis users starting using cannabis at age 15 and younger who live in those EU countries where high potency cannabis is available have the highest probability to develop psychosis, compared to never users (Adj ORs from 2.6–5.9; p<0.01). Moreover, the proportion of new cases of Psychosis attributable to heavy use started in adolescence was between 20% and 37%.Finally, the correlation between lifetime use of cannabis in population controls from the study sites was significantly correlated with the corresponding incidence rates for Psychosis (r=0.6; p<0.001)
Discussion
Before Europe rushes into the USA legalisation “moda” more public education effort might need to be invested in reducing the use of high potency type of cannabis among young adolescents. The latter could lead to a significant reduction in the proportion of new cases of psychosis across Europe.



O12.5. GENETIC AND ENVIRONMENTAL PREDICTORS OF MAIN OUTCOMES IN THE DANISH HIGH RISK AND RESILIENCE STUDY - VIA 7. A STUDY OF 522 7-YEAR-OLD CHILDREN OF PARENTS WITH SCHIZOPHRENIA, BIPOLAR DISORDER OR NEITHER OF THESE DISORDERS

Sun, 01 Apr 2018 00:00:00 GMT

Abstract
Background
Studies of children born to parents with schizophrenia and affective disorders can allow us to study the processes preceding the manifestation of the disease, and thereby provide a possibility for identifying early amendable risk factors such as poor parenting, deviances in cognitive functioning, and early, subtle signs of psychopathology at a point where preventive intervention can be applied.
Methods
The Danish High Risk and Resilience Study - VIA7 is a representative nationwide cohort study of 522 7-year-old children of parents with schizophrenia, bipolar disorder or neither of these disorders recruited during 2013–2015. The sample consists of: 202 children with a parent diagnosed with schizophrenia spectrum psychosis, 120 children with a parent diagnosed with bipolar disorder, and 200 children with neither of the parents treated in mental health services for the above diagnoses.We have collected blood and saliva samples from the children and their parents and polygenic risk scores were calculated. We have thoroughly assessed the home environment with the instrument HOME. We have assessed main outcomes such as psychopathology, PLIKS, neurocognition and social cognition.We will analyse the influence of genetic and environmental exposures and their interaction.
Results
Generally, the children with a familial risk of schizophrenia had lower neurocognitive, social cognitive and neuromotor functioning, more child psychiatric diagnoses, and more severe symptoms compared to control children. In most comparisons, children of parents with bipolar disorder were not different from controls, but in some tests they performed poorer or had more symptoms compared to than control children.We will present data on genetic and environmental risk factors for these outcomes
Discussion
This is the largest high-risk study ever conducted. It is unique that we have access to detailed phenotyping and extensive information on environmental and genetic risk factors. Studies like this can inform about patogenesis and possibilities for future preventive interventions



O12.6. Submission Withdrawn

Sun, 01 Apr 2018 00:00:00 GMT




O12.7. RISK OF PSYCHOSIS IN OFFSPRING OF PARENTS WITH A HISTORY OF HOMELESSNESS DURING CHILDHOOD AND ADOLESCENCE: A NATIONWIDE, REGISTER-BASED, COHORT STUDY

Sun, 01 Apr 2018 00:00:00 GMT

AbstractBackgroundChildren and adolescents with deprived backgrounds have high rates of psychiatric problems. Parental and social factors are regarded crucial for children’s healthy and positive development but whether children’s risk of psychosis in an early age is associated with parental social marginalisation is unknown. We aimed to analyse the association between mothers’ and fathers’ history of homelessness and the offspring’s risk of psychiatric disorders during childhood and adolescence with attention to the specific child and adolescent psychiatric diagnosis: psychosis, as well as to the combined effect of mother’s and father’s schizophrenia and bipolar disorder and homelessness experiences according to the child’s risk of any psychiatric disorder.MethodsWe conducted a nationwide, register-based cohort study of 1,072,882 children aged 0−16 years living or being born in Denmark between Jan 1, 1999 and Dec 31, 2015. Parental homelessness was the primary exposure and offspring’s risk of psychosis and other psychiatric disorders the outcome. We analysed the association by survival analysis using Poisson regression and incidence rate ratios (IRRs), adjusted for year and offspring characteristics, and additionally adjusted for parental factors (age at offspring’s birth and parental psychiatric disorders).ResultsIn total, 17,238 (2%) offspring had either one or two parents with a history of homelessness, and 56330 (5%) offspring were diagnosed with any psychiatric diagnosis during the study period. Of these, 850 (1.5%) had a diagnosis of psychosis before their 16th birthday. The incidence rate of any psychiatric disorder was 28.2 cases per 1000 person-years (20.7–38.4) in offspring with at least one parent with a history of homelessness and a mother with a schizophrenia or bipolar disorder, compared with 18.3 cases per 1000 person-years (16.8–20.0) in those whose parents had no history of homelessness.The IRR of psychosis in offspring born to a mother with a history of homelessness was 3.1 (95% CI 1.9–5.0) compared with those whose parents had no history of homelessness. A similar risk was found if both parents had a history of homelessness (IRR 5.4, 95% CI 2.7-1.9), whereas no association was found when only the father had experiences of homelessness. Also after full adjustment including parental psychiatric disorders, an increased risk of psychosis was found in offspring if the mother (IRR 1.8, 95% CI 1.1–3.0) or both parents (IRR 2.9, 95% CI 1.4–5.9) had a history of homelessness. Highest risk was found for attachment disorder when both parents had a history of homelessness (IRR 32.5, 95% CI 24.6−42.9) and substance use disorder when only the mother experienced homelessness (6.9, 95% CI 4.9−9.7). In offspring whose mother had a history of homelessness and a psychiatric disorder, 36% (95% CI 27%−45%) had received a psychiatric diagnosis themselves by the age of 15. If the mother or father had a schizophrenia or bipolar disorder, homelessness experiences did not [...]



O12.8. LOWER FAMILY INCOME PREDICTS PSYCHOTIC EXPERIENCES IN A COMMUNITY SAMPLE OF YOUTHS IN BRAZIL: RESULTS FROM A 3-YEAR FOLLOW-UP STUDY

Sun, 01 Apr 2018 00:00:00 GMT

AbstractBackgroundUp to 17% of community youths, from 9 to 12 years old, report subthreshold psychotic experiences (PE). Besides increasing conversion risk to psychotic disorders, PE also predicted suicide attempts and were associated with more severe general psychopathology. Understanding predisposing factors to PE during development can inform on risk to mental disorders, a crucial step to future prevention interventions. Adversity in early life has been associated with psychotic symptoms, and low socioeconomic status (SES) is an established environmental risk factor for several mental disorders. However, few studies investigated the effect of low SES on PE risk in youths, prospectively. This topic is highly relevant in underprivileged countries like Brazil, where large populations are exposed to poverty. We hypothesized that low income at baseline would predict later report of PEs.MethodsWe analyzed data from the Brazilian High Risk Cohort Study for Psychiatric Disorders (HRC), in which 2,512 youths (6–12 years old, mean age at baseline 9.7 years, SD = 1.92; 53,1% male) completed the baseline assessment and 2,012, the 3-year follow-up (T1). PE were assessed at each time-point through two sources of information: parental report, using the Child Behavior Checklist (CBCL), and youth self-report, using the positive dimension of the Community Assessment of Psychic Experiences (CAPE). A single latent variable for each time-point was created to encompass both sources of information using Confirmatory Factor Analysis, yielding good model fit. Total family income (T0) was correlated to the psychotic latent variable (T1), controlling for age, gender and baseline report of PE. Then, we investigated how any mental disorder diagnosis and exposure to trauma, two possible confounding factors, affected the results. The Development and Well-Being Assessment (DAWBA) was used to investigate mental disorders diagnoses. No conversion to psychotic disorder was observed at the follow-up. A latent variable encompassing parental and youths reports, measured by Childhood Trauma Questionnaire (CTQ), was used as trauma exposure.ResultsThe mean family income reported was approximately US$ 394 per month (p25 = US$ 195, p50 = US$ 307, p75 = US$ 516). Income (baseline) and PE (T1) had a negative significant correlation (pcorr = -0.064; df = 2004; p = 0.004). Subjects with any mental disorder reported PE more frequently, either at baseline or at the follow-up. Low income inversely correlated with trauma, whereas trauma was strongly associated with PE and having any mental disorder at both time points. The correlation between income and PE did not remain significant, after controlling for any mental disorder (T1) (pcorr = -0.049; df = 1597; p = 0.050) or trauma exposure (T0) (pcorr = -0.043; df = 2003; p = 0.053).DiscussionOther studies have previously reported a positive correlation between adversity and PE, but few have described a specific association between family income and psychotic experiences. Ou[...]



T1. STRESSFUL LIFE EVENTS AND PERCEIVED STRESS IN THE SAMPLE OF PATIENTS WITH FIRST-EPISODE PSYCHOSIS AND HEALTHY CONTROLS: PRELIMINARY RESULTS

Sun, 01 Apr 2018 00:00:00 GMT

Abstract
Background
Despite the evidence related to the role of major life events and childhood trauma in the development of first-episode psychosis (FEP; Varese et al., 2012; Morgan & Fisher, 2007), there are few studies on environmental exposure to stressful life events (SLEs) and how SLEs might influence the onset of a psychotic disorder, and the role of perceived stress in this population. The proposed analyses will investigate the association between the categories of SLEs (education, work, partner, family, home, legal, finances, social and health) and perceived stress between patients with FEP and healthy controls (HC).
Methods
Participants were patients with FEP (n=15) and HC (n=21). This research was part of a longitudinal observational study called the ‘PROFEP group’ in Catalonia. Stressful life events were assessed with the Questionnaire of stressful life events (QSLE) (Butjosa et al., 2017). We analysed the frequency of the categories of SLEs. Perceived stress was assessed with the Perceived Stress Scale (PSS; Cohen & Williams, 1988).
Results
There are more frequency of SLEs in the education (p<0.05) and health (p<0.05) categories, and perceived stress (p<0.05) in FEP sample than HC.
Discussion
Results show the relevance of the presence of SLEs (e.g. education and health) and a potent source of perceived stress in FEP sample. Therefore, more studies are needed to evaluate these stressors to apply future psychological interventions in relation to stress management in FEP population. In addition, it would add protective variables in the analyses such as resilience, coping and social support.



T2. DO ADVERSE LIFE EVENTS AT FIRST ONSET OF AUDITORY VERBAL HALLUCINATIONS INFLUENCE SUBSEQUENT VOICE-CHARACTERISTICS? RESULTS FROM AN EPIDEMIOLOGICAL STUDY

Sun, 01 Apr 2018 00:00:00 GMT

Abstract
Background
Understanding what happens at first onset of auditory verbal hallucinations (AVHs) is important at both a clinical and theoretical level. Previous studies have focused on age with regard to first onset of AVHs. In the current epidemiological study, we investigated the role of adverse life events (e.g. accidents, divorce, bullying, unemployment) at the time of first onset of AVHs regarding symptom severity and general mental health later in life.
Methods
Using data from the Launay-Slade Hallucination Scale (LSHS), we compared participants who reported having experienced at least one adverse life events at first onset of AHVs (Trigger group; N = 76) to those who did not report any specific events at first onset of AVHs (No-trigger group; N = 59) on a large array of variables using Fisher’s exact test.
Results
Results revealed that the Trigger group experienced the AVHs as more emotional and they were also more troubled by the AVHs compared to the No-trigger group (all p < 0.01). Also, the Trigger group more often reported hallucinations in other (non-auditory) sensory modalities (e.g. visual, p = 0.012) compared to the No-trigger group. Furthermore, the Trigger group reported poorer mental health in general, and having had more frequent contact with mental health professionals, and also reported more frequently taking medication for mental problems in general (all p < 0.01).
Discussion
Adverse life events at first onset of AVHs appear to have a negative influence on subsequent voice-characteristics and general mental health, suggesting their presence to be an important factor to take into account when determining the risk for psychosis or other mental disorders. However, future longitudinal studies are needed in order to corroborate these findings.



T3. METACOGNITIVE BELIEFS IN SEVERE MENTAL DISORDERS

Sun, 01 Apr 2018 00:00:00 GMT

AbstractBackgroundAffective dysregulation and psychotic experiences or symptoms often co-occur in the general population as well as in bipolar and psychotic disorders, suggesting a complex interplay. Early trauma is hypothesised to be important for the aetiology of both, and individuals with early traumatic experiences often develop disorders characterised by an admixture of affective and psychotic symptoms. Early emotional abuse seems to be particularly relevant for both disorders. Studies of common factors associated with affective dysregulation and psychosis in bipolar and psychotic disorders could help further theoretical understanding and tailor therapeutic interventions. Metacognitive beliefs – beliefs that outline the importance or consequence of thoughts – have been proposed as one possible common factor. Compared to healthy controls, patients with affective or psychotic disorders hold higher levels of metacognitive beliefs that could be maladaptive. Metacognitive beliefs have been linked to affective and/or psychotic diagnoses and symptoms in these disorders, and to early trauma in general. However, little is known about the specific relationships between symptoms of bipolar/psychotic disorders, early emotional abuse, and metacognitive beliefs.This project had three objectives: (1) to examine the prevalence of metacognitive beliefs in bipolar and psychotic disorders, compared to controls; (2) explore whether illness-related factors were linked to metacognitive beliefs; (3) examine if symptomatic responses (depression or positive symptoms) to early emotional abuse were mediated by metacognitive beliefs.MethodsPatients with a bipolar or psychotic disorder, and healthy controls, were included through the on-going Thematically Organised Psychosis (TOP) Study in Oslo, Norway. Analyses included t-tests for group comparisons, regression analyses, and regression based mediation pathway analyses where the indirect effects were tested with bootstrapped confidence intervals.ResultsPatients with bipolar or psychotic disorders reported higher levels of metacognitive beliefs compared to controls. Metacognitive beliefs were significantly related to depression for all patients. Higher levels of metacognitive beliefs were also related to illness-factors related to a poorer long-term outcome, specifically an earlier age at onset of affective disorder in bipolar disorders, and poorer premorbid social adjustment in psychotic disorders. Metacognitive beliefs significantly mediated the relationship between early emotional abuse and depression. The combination of metacognitive beliefs and depression significantly mediated the relationship between early emotional abuse and positive symptoms. The mediation models explained a moderate amount of the variance in symptoms (R2 = .21 and .29) compared to direct models of early emotional abuse impacting on symptomatic responses directly (R2 = .04 and .03)Discussion[...]



T4. IDENTIFICATION OF NEUROANATOMICAL SURROGATE MARKERS OF CHILDHOOD TRAUMA

Sun, 01 Apr 2018 00:00:00 GMT

AbstractBackgroundChildhood trauma (CT) plays an important role in psychiatric disorders. It is associated with an increased risk for psychiatric disorders like major depression, anxiety disorders, dependency, post-traumatic stress disorders and even psychosis. There is a high incidence of CT in patients with psychosis, especially for physical and sexual abuse. Already in UHR-individuals increased CT could be observed. A study of Thompson and colleagues showed that 97% of their UHR sample reported a trauma in the past. 83% of the cases were physical abuse, 67% emotional abuse and 27% sexual abuse. Our aim was to investigate if there are neurobiological surrogate markers of trauma existing which can be detected by a multi pattern analysis.MethodsPRONIA (‘Personalized Prognostic Tools for Early Psychosis Management’) is a prospective collaboration project funded by the European Union under the 7th Framework Programme (grant agreement n° 602152). Considering a broad set of variables (sMRI, rsMRI, DTI, psychopathological, life event related and sociobiographic data, neurocognition, genomics and other blood derived parameters) as well as advanced statistical methods, PRONIA aims at developing an innovative multivariate prognostic tool enabling an individualized prediction of illness trajectories and outcome. Seven clinical centers in five European countries and in Australia participate in the evaluation of three clinical groups (subjects clinically at high risk of developing a psychosis [CHR], patients with a recent onset psychosis [ROP] and patients with a recent onset depression [ROD]) as well as healthy controls; planned sample size is n=1680. CT was assessed by the Childhood Trauma Questionnaire (CTQ). To identify neuroanatomical and functional surrogate markers of CT, a multi pattern analysis via Neurominer (NM) was conducted. An additional VBM analysis was performed to evaluate the results of the NM analysis.ResultsWe found that patients and HC could be separated very well by the CTQ pattern. Moreover, the classification among the patient groups yielded results that were not much better than a random classification. This finding underlines that CT is an overarching risk factor for mental diseases and not specific for single clinical entities. Furthermore, the decision scores that were conducted in the first NM analysis revealed highly significant negative correlations with grey matter changes in frontotemporal cortical areas, the anterior cingulate and the insular cortex. These areas are already discussed for CT in the literature.DiscussionCT seems to be a global risk factor for psychiatric disorders. Moreover, we could re-examine the results of our multi variate analysis successfully in a VBM procedure.[...]



T5. LURASIDONE AND RISK FOR METABOLIC SYNDROME IN PATIENTS WITH SCHIZOPHRENIA: A COMPREHENSIVE DATABASE ANALYSIS

Sun, 01 Apr 2018 00:00:00 GMT

Abstract
Background
Patients with schizophrenia are at increased risk for developing metabolic syndrome, with an estimated prevalence of approximately 35–50% (Correll et al. Psychiatr Serv 2010;61:892–98; Vancampfort et al. World Psychiatry 2015;14:339–47). Treatment with atypical antipsychotic medications have been shown to increase rates of metabolic syndrome, with differences observed among antipsychotic agents, most notably in propensity for weight gain: higher for olanzapine, clozapine, and iloperidone; intermediate for quetiapine, risperidone, and paliperidone; and lower for amisulpride, aripiprazole, asenapine, lurasidone, and ziprasidone (Leucht et al. Lancet 2013;382:951–62). Independent of weight gain, atypical antipsychotics also appear to have direct effects on lipid metabolism and glucose regulation. The aim of this safety analysis was to assess the effects of treatment with lurasidone on metabolic syndrome risk in patients with schizophrenia.
Methods
Changes in the rate of metabolic syndrome during treatment with lurasidone (40–160 mg/d) versus active comparators (olanzapine, quetiapine, risperidone) were analyzed using pooled short-term data from 3 randomized, double-blind, placebo-controlled studies; long-term data from 2 active-controlled studies; and switch data from 2 open-label extension studies. Metabolic syndrome was defined based on the National Cholesterol Education Program criteria (NCEP ATP III; 2005 revision).
Results
In short-term studies, risk of treatment-emergent metabolic syndrome was similar for patients in the lurasidone and placebo groups (odds ratio [OR]=0.97; week 6 LOCF-endpoint); and was significantly greater for patients in the olanzapine (OR=2.68; P<0.001) and quetiapine (OR=3.70; P<0.001) groups compared to placebo. In long-term studies, risk of treatment-emergent metabolic syndrome after 12 months was significantly lower for lurasidone compared with risperidone (OR=0.374; 95% CI, 0.180–0.774; P<0.01) and non-significantly lower for lurasidone compared with quetiapine XR (OR=0.267; 95% CI, 0.040–1.806; P>0.05). In open-label switch studies, the rate of metabolic syndrome decreased in patients switched to lurasidone after 6 weeks of treatment with olanzapine or 12 months of treatment with risperidone.
Discussion
In this comprehensive analysis of the lurasidone clinical trial data base, treatment with lurasidone (40–160 mg/d) was not associated with the development of metabolic syndrome in patients with schizophrenia. Rates of metabolic syndrome increased in patients treated with olanzapine, risperidone, and quetiapine XR.



T6. SECOND GENERATION ANTIPSYCHOTIC DRUGS AND MORTALITY: A META-ANALYSIS OF PLACEBO-CONTROLLED RANDOMISED CONTROLLED TRIALS

Sun, 01 Apr 2018 00:00:00 GMT

AbstractBackgroundDespite intensive research it is unknown if treatment with antipsychotic drugs contributes to the reduced life-expectancy observed in patients with schizophrenia and other severe mental disorders. As randomized controlled trials (RCT) are considered the best evidence to examine causal relationship, we aimed to analyze mortality related to antipsychotics based on all placebo-controlled RCTs conducted so far.MethodsWe evaluated mortality in pair-wise meta-analysis of RCTs comparing second-generation-antipsychotics versus placebo across all diagnostic fields.Information about deaths was extracted from summary data of clinical trials as identified by two searches (last 01/28/2017) in several electronic databases. Furthermore, manufacturing companies and regulatory authorities were contacted, and their websites were searched for trial reports and supplemental information about fatal events. We examined mortality due to any reason (primary outcome), due to natural causes, suicide, and other unnatural causes. We synthesized the results with odds ratios (OR) in a common-effect meta-analysis. We addressed the effects of age, diagnostic field, gender, study duration, antipsychotic drug used, drug dose and polypharmacy with subgroup- and meta-regression-analyses. We used the GRADE framework to evaluate the confidence in the evidence.ResultsWe included 596 randomized trials that reported 207 deaths in 53804 patients on placebo (0.38%) and 99 deaths in 31184 patients on drug (0.32%). There was no evidence of significant difference between antipsychotics and placebo regarding mortality due to any reason (OR 1.19; 95% CI 0.93, 1.53), natural causes (OR 1.29; 95% CI 0.85, 1.94), suicide (OR 1.15; 95% CI 0.47, 2.81) and other unnatural causes (OR 1.55; 95% CI 0.66, 3.63). The number-needed-to-harm for all-cause mortality was 6 more deaths in 10 000 drug-treated patients compared to placebo, with a 95% CI ranging from 2 helped to 14 harmed. Most deaths occurred in patients with dementia and these patients also had the highest drug-related mortality in subgroup analysis (OR 1.56; 95% CI 1 .10, 2.21). The OR for patients with schizophrenia (based on 32807 patients) was 0.69 (95 CI 0.35, 1,35).DiscussionWe found no evidence of increased mortality related to treatment with second generation antipsychotic drugs, neither in the overall sample nor in the subgroup of patients with schizophrenia. Results of subgroup analyses indicated however that mortality of patients with dementia might be increased when they are exposed to antipsychotics. Strength of the analysis are the use of data from RCTs and the comprehensive search, which aimed to identify all placebo-controlled RCTs of second generation antipsychotics conducted so far. Limitations of our analysis are the remaining imprecision of the results with a 95% confidence in[...]



T7. PHARMACOGENETIC OF TARDIVE DYSKINESIA -- A FOLLOW-UP ON THE VALBENAZINE TARGET VMAT2/SLC18A2

Sun, 01 Apr 2018 00:00:00 GMT

Abstract
Background
Tardive dyskinesia (TD) is a motor side effect that may arise after long-term treatment of antipsychotic drugs. Its etiology is not well understood, but a number of risk factors have been associated with TD. TD occurrence appears to be familial, thus suggesting a genetic component. We previously reported on an association between the SLC18A2 gene that codes for the vesicular monoamine transporter 2 (VMAT2) that packages monoamines including dopamine from the cytoplasm into synaptic vesicles (Zai et al, 2013). In the present study, we examined the dopamine transporter gene SLC6A3 by itself and in conjunction with SLC18A2 for possible association with TD.
Methods
We genotyped and analyzed the variable-number tandem repeat (VNTR) polymorphism in the 3’ untranslated region of the SLC6A3 gene in our European sample of 187 schizophrenia/schizoaffective disorder patients assessed for TD occurrence based on the Abnormal Involuntary Movement Scale (AIMS). We also explored the interaction between the VNTR and the TD-associated SLC18A2 marker rs363224.
Results
Our preliminary analysis did not show the SLC6A3 VNTR to be associated with TD occurrence or severity. There also appeared to be no significant interaction between SLC6A3 VNTR and SLC18A2 rs363224 in TD occurrence or severity (p>0.05).
Discussion
Our findings did not support a major role of the dopamine transporter gene in TD risk or severity, but we will examine additional putative functional markers in this gene.



T8. NEUROLOGICAL SOFT SIGNS (NSS) IN SCHIZOPHRENIA: AN UPDATE ON THE STATE- VERSUS TRAIT-PERSPECTIVE

Sun, 01 Apr 2018 00:00:00 GMT

Abstract
Background
Neurological soft signs (NSS) represent minor neurological signs which indicate non-specific cerebral dysfunction. Numerous studies have confirmed their presence in schizophrenia across all stages of the disease. NSS have been looked at as an endophenotype or a trait phenomenon for many decades. However, during the past years studies increasingly reported on fluctuations of the NSS scores. To shade further light on the question whether NSS represent a state or a trait component or both, a review of longitudinal studies on schizophrenia patients was performed, because only measurements at two or more points in time can answer the question at hand.
Methods
A search of studies which had assessed NSS in adult schizophrenia patients and included at least one follow-up examination was undertaken. Studies which had been published between January 1966 and June 2017 and listed in relevant databases were included. Due to the fact, that ongoing brain maturation lasts until adulthood and is paralleled by a loss of those NSS which are present in childhood, studies on teenagers were excluded.
Results
Twenty-nine follow-up studies were identified which overall used well-known instruments for the investigation of NSS. Patients were at different disease stages. All expressed abnormally increased NSS, however to different extents. An NSS reduction during the course was detected in most first episode patients and those with a remitting course whereas chronically ill patients exhibited stable or increasing NSS scores. The change over time could for the most part be attributed to changes in the motor system subscales and to a lesser amount to sensory integration scales. As opposed to the earlier notion that medication evokes or worsens NSS, studies largely agreed on a positive interrelation between medication response and improvement of NSS. The type of antipsychotic was of small importance and when side-effects were commented on there was a weak relationship with NSS. On the other hand, studies gave some hints at relationships between NSS and symptoms, i.e. negative and cognitive symptoms.
Discussion
The reviewed studies confirmed the presence of abnormal, i.e. elevated NSS in patients diagnosed with schizophrenia. Studies disagreed on the amount of abnormalities in NSS. However, subgroups emerged with either stable or fluctuating properties of NSS. The latter speaks very much in favor of a state-trait dichotomy being present in NSS and thus challenges the view that NSS depict an endophenotype.



T10. HERITABILITY OF AMYGDALA ACTIVITY AND ITS GENOME WIDE ASSOCIATION WITH THE SCHIZOPHRENIA RISK LOCUS OF MIR137

Sun, 01 Apr 2018 00:00:00 GMT

AbstractBackgroundIt is well known that heritability plays a prominent role in risk for schizophrenia, and that this brain disorder is crucially characterized by emotional symptoms. Less known is how heritability shapes brain activity during emotion processing and whether this brain phenotype is also associated with genetic variation increasing risk for schizophrenia. Here, we implemented a multi-step, data-driven approach in order to assess the relevance of the link between heritability, genetic variation, and schizophrenia for brain activity during emotion processing.MethodsWe investigated three samples of healthy individuals and one sample of schizophrenia (SCZ) patients: i) 28 healthy twin pairs (16 monozygotic and 12 dizygotic twin pairs); ii) 289 unrelated healthy participants (genome-wide association study - GWAS -discovery sample); iii) 90 unrelated healthy participants (replication sample); iv) 40 SCZ patients. During fMRI, participants approached or avoided threatening angry faces (explicit emotion processing). Intra-class correlations (ICC) between twin pairs and ACE models (A: additive genetics; C: common environment; E: unique environment) were used to identify regions of interest (ROIs) with heritable functional activity. Then, we extracted BOLD signal from these ROIs and conducted a GWAS on 565,137 single nucleotide polymorphisms (SNPs) (selected with the following criteria: minor allele frequency>0.15, Hardy–Weinberg equilibrium<0.001, linkage disequilibrium pruning r2>0.9) using robust linear models of allelic dosage corrected for multiple comparisons (Gao et al. 2008 Genetic Epidemiology). Finally, we assessed the effect of surviving SNPs in the replication sample of healthy individuals as well as in the sample of SCZ patients.ResultsIn healthy twins, we identified bilateral amygdala as the brain region with the highest heritability during explicit emotion processing as evaluated with our task (ICC=.79; h2=0.54; p<.001). The subsequent GWAS in healthy non-twins indicated that bilateral amygdala activity during the task was associated with a polymorphism close to miR-137 (rs1198575) (p=1.5 × 10–7), with the C allele corresponding to lower activity than the t allele. A similar effect was found in the replication sample (p=.01) and in patients with SCZ (p=.03).DiscussionOur data-driven approach revealed that amygdala activity as evaluated with our task is heritable. Furthermore, our results indicate that a polymorphism in miR-137 has genome wide association with amygdala response during emotion processing which is also replicated in two independent samples of healthy subjects and of patients with schizophrenia. Previous findings indicated that this polymorphism has genome-wide association with schizophre[...]



T9. CROSS-SECTIONAL ASSOCIATION OF MEMBRANE FATTY ACID COMPOSITION AND PSYCHOPATHOLOGY IN THE NEURAPRO-E STUDY

Sun, 01 Apr 2018 00:00:00 GMT

Abstract
Background
Converging evidence suggests that people at ultra-high risk (UHR) for psychosis have depleted levels of several fatty acids (FAs), and that changes in omega-3 (n-3) FA levels may indicate a higher risk for transition to psychosis. However, limited information is available on how FA deficiencies relate to psychopathology in individuals with UHR phenotypes. Here, we report the relationship between membrane FA levels and symptom severity in a study of individuals at UHR for psychosis.
Methods
Data from 280 of 304 (92%) of participants of the NEURAPRO study, a multi-centre randomized-controlled trial of omega-3 fatty acids versus placebo, were used for the present analysis. All participants were aged between 13 and 40 years and met criteria for UHR for psychosis. Blood samples were collected at study baseline and month 6 (end-of-intervention). Membrane fatty acids were analysed using mass spectrometry as percentage of total fatty acids in erythrocytes. Pearson correlation coefficients were calculated between baseline erythrocyte fatty acid levels and scores on the Scale for the Assessment of Negative Symptoms (SANS) and Brief Psychiatric Rating Scale (BPRS).
Results
Negative symptoms were positively correlated with one saturated FA (Tetracosanoic acid [24:0], R=0.272, p<0.0001), one n-3 FA (Eicosapentaenoic acid [20:5], R=0.142, p=0.017) and one n-9 FA (Nervonic acid [24:1], R=0.274, p<0.0001), and negatively correlated with one saturated FA (Palmitic acid [16:0], R=-0.224, p<0.0001), two n-6 FAs (Dihomo-y-linolenc acid [20:3], R=-0.201, p<0.001 and Linolelaidic acid [18:2], R=-0.333, p<0.0001), and one n-7 FA (Vaccenic acid [18:1], R=-0.172, p=0.004). BPRS scores were positively correlated with one saturated FA (Tetracosanoic acid [24:0], R=0.363, p<0.0001) and one n-9 fatty acid (Nervonic acid [24:1], R=-0.346, p<0.0001), and negatively correlated with two n-3 FAs (Dihomo-y-linolenc acid [20:3], R=-0.153, p=0.010 and Docosahexaenoic acid [22:6], R=-0.193, p<0.001), and two n-6 FAs (Arachidonic acid [20:4], R=-0.125, p=0.037 and Linoleic acid [18:2], R=-0.340, p<0.0001).
Discussion
Consistent with a previous study, negative symptoms and general psychopathology were associated with levels of several classes of FAs in the present study. These findings support the relevance of membrane fatty acids for the onset of psychotic symptoms and indicate that FAs should be further evaluated as biomarkers in people at UHR for psychosis.



T11. CEREBROSPINAL FLUID (CSF) MARKERS OF INFLAMMATION AND INFECTIONS IN SCHIZOPHRENIA AND AFFECTIVE DISORDERS: A SYSTEMATIC REVIEW AND META-ANALYSIS

Sun, 01 Apr 2018 00:00:00 GMT

AbstractBackgroundInfections and inflammatory processes have been associated with the development of schizophrenia and affective disorders; however, no study has yet synthesized all the available data on cerebrospinal fluid (CSF) immune-alterations. We conducted the first systematic review of the immunological findings from CSF studies among patients with schizophrenia or affective disorders.MethodsAll studies investigating CSF inflammatory markers in persons with schizophrenia or affective disorders published prior to March 23, 2017 were identified searching PubMed, CENTRAL, EMBASE, Psychinfo, and LILACS. The literature search, data extraction and assessment of risk of bias were performed by two independent reviewers. Meta-analyses with standardized mean difference (SMD) including 95% confidence intervals (CI) were performed on studies including healthy controls.ResultsWe identified 112 CSF studies published between 1942–2016, of which 32 were included in meta-analyses; however, only few studies investigated identical biomarkers. The CSF/serum albumin ratio was increased in both schizophrenia (54 patients; SMD=0.62; 95%CI=0.24–1.00) and affective disorders (302 patients; SMD=0.43; 95%CI=0.25–0.61, I2=0%), compared to healthy controls. Total CSF protein was elevated in both schizophrenia (97 patients; SMD=0.38; 95%CI=0.12–0.65, I2=0%) and affective disorders (53 patients; SMD=0.77; 95%CI=0.36–1.18, I2=0%). The IgG ratio was increased in schizophrenia (54 patients; SMD=0.60; 95%CI=0.23–0.98), whereas the IgG Albumin ratio was decreased (32 patients; SMD= -0.62; 95%CI= -1.13 to -0.12). Interleukin-8 (IL-8) (95 patients; SMD=0.46; 95%CI=0.17–0.75, I2=0%) and IL-6 levels (230 patients; SMD=0.38; 95%CI=0.02–0.74; I2=64%) were increased among individuals with schizophrenia but not significantly increased in affective disorders. None of the remaining inflammatory markers were significantly different compared to healthy controls in the meta-analyses. However, in the studies which did not include healthy controls, CSF abnormalities were more common, and CSF dependent re-diagnosis occurred in 3.2–6% in the two studies investigating this.DiscussionOur findings suggests that schizophrenia spectrum and affective disorders are associated with CSF abnormalities including signs of blood-brain barrier impairment and inflammation, supporting a role of the immune system in mental disorders. However, only few studies investigated the same parameters with healthy controls and high quality longitudinal CSF studies are lacking, including impact of psychotropic medications and potential benefits of anti-inflammatory treatment in subgroups with abnormal CSF inflammatory markers[...]



T12. VITAMIN D STATUS AND PSYCHOTIC DISORDER: ASSOCIATIONS WITH CLINICAL VARIABLES AND RISK FACTORS

Sun, 01 Apr 2018 00:00:00 GMT

Abstract
Background
The association between schizophrenia and decreased vitamin D levels is well documented. Low maternal and postnatal vitamin D levels suggest a possible etiological mechanism. Vitamin D deficiency in patients diagnosed with schizophrenia is presumably (also) the result of disease-related factors.Furthermore, certain demographic risk factors such as urbanicity may be associated with vitamin D.
Methods
In a large study population of 347 patients with psychotic disorder and 282 controls, associations between vitamin D levels in blood and clinical variables and risk factors were investigated.Regression analyses were conducted correcting for gender, age, ethnicity, body mass index (BMI), smoking and sampling season. Group × symptomatology and group × urbanicity interactions were investigated. Both current urbanicity and urbanicity at birth were assessed.
Results
Vitamin D concentrations were significantly lower in patients (B= -8.05; 95% confidence interval (CI) -13.68 to -2.42; p=0.005). There were (trend) significant interactions between group and vitamin D for symptomatology (positive symptoms: χ2=2.81 and p=0.094; negative symptoms: χ2=5.63 and p=0.018). A small but significant effect was detected: higher vitamin D concentration was associated with lower positive (B= -0.02; 95% CI -0.04 to 0.00; p=0.049) and negative symptom levels (B= -0.03; 95% CI -0.05 to -0.01; p=0.008) in patients. The group × current urbanicity interaction was not significant. However, the group × urbanicity at birth was significant when corrected for current urbanicity (χ2=11.26 and p=0.001).
Discussion
Vitamin D levels in patients with psychotic disorder were lower than in controls, with an interaction between group and urbanicity at birth. In the patient group, symptom levels were lower when vitamin D concentration was higher.



T13. PROGRESSIVE SPONTANEOUS AND SYNCHRONY GAMMA-BAND OSCILLATION DEFICITS IN FIRST EPISODE SCHIZOPHRENIA

Sun, 01 Apr 2018 00:00:00 GMT

AbstractBackgroundDeficits in the gamma-band (30–100 Hz) auditory steady-state response (ASSR) and progressive volumetric decreases in the primary auditory cortex have been detected shortly after the onset of schizophrenia (SZ), and may be associated with symptoms such as auditory hallucinations. Disruption of gamma-band oscillation has received considerable interest, as the basic mechanisms underlying these oscillations are understood and are conserved across species. Despite the importance of abnormal gamma-band oscillations in SZ, it remains unclear whether the gamma-band ASSR deficit shows progressive change over time during the early stages of the disease. Moreover, animal models based on NMDA receptor hypofunction demonstrate an increase in spontaneous gamma power, which has been reported in chronic SZ (Hirano et al., JAMA Psychiatry 2015), yet it still remains unclear in first-episode schizophrenia (FESZ). Hence, a longitudinal electroencephalogram study of the spontaneous and synchrony gamma-band oscillation in FESZ is important to better understand the pathophysiology and trajectory of early-stage schizophrenia.MethodsSubjects were 23 FESZ (14 treated and 9 untreated with antipsychotics), and 39 matched healthy controls (HC). Dipole source localization of dense electrode EEG data was used to examine oscillatory activities in auditory cortices during auditory steady-state stimulation (20/30/40-Hz rates). ICA was used to remove artifacts. Phase locking factor (PLF) and induced power (not phase-locked) were calculated from artifact-free single trial source estimates. Clinical symptoms were assessed by SAPS and SANS. Subjects were recruited as part of the Boston CIDAR Center (www.bostoncidar.org). Test sessions (Time-1/Time-2) were 11.9 months apart.ResultsCompared to HC, FESZ showed reduced 40-Hz ASSR PLF (synchrony gamma) and increased induced gamma power (spontaneous gamma) during continuous auditory stimuli at time-1. Longitudinally, FESZ showed overall progressive reductions in 40-Hz ASSR PLF and progressive increases in induced gamma power, especially within the left auditory cortex. These progressive deficits were not related to antipsychotic medication. Progressive increase of induced gamma power was correlated with increased positive symptoms.DiscussionWe found coincide disruptions of auditory gamma-band oscillation, which showed progressive increase in spontaneous gamma (cortical excitability) and progressive decrease in synchrony gamma (cortical synchrony failure) during continuous auditory stimuli in FESZ. These two apparently distinctive circuit progressive abnormalities already occurred in the very early sta[...]



T14. ASSESSING DIFFERENCES IN INFLAMMATORY MARKERS BETWEEN FIRST EPISODE PSYCHOSIS PATIENTS AND HEALTHY CONTROLS: THE IMPORTANCE OF CONTROLLING FOR CONFOUNDING FACTORS

Sun, 01 Apr 2018 00:00:00 GMT

AbstractBackgroundAlthough there is a cumulative evidence for increased level of markers of inflammation in psychosis, it has not been conclusively proven yet whether this is due to the disorder in itself or to other factors. One reason for this is the lack of studies that have controlled for major confounding factors such as obesity, smoking, antipsychotic use and stress. The BMI, as an indirect measure of body fat level, and tobacco smoking are known to play a role in modulating the immune system, but little research has been done in this area in patients with psychosis. The aim of this study was to investigate the differences in markers of inflammation and neuroplasticity between FEP patients and HC while controlling for a priori confounding factors, such as BMI and tobacco smoking.MethodsNineteen First Episode Psychosis (FEP) patients and 21 healthy controls (HC) matched for age, gender, ethnicity and marital status were recruited in South London (UK). Blood samples were collected to measure High Sensitivity C-Reactive Protein (hs-CRP), Interleukin (IL)-6, IL-8 and Brain-Derived Neurotrophic Factor (BDNF). Body Mass Index (BMI) was also assessed. Moreover, patients were asked whether they were tobacco smokers. Differences in continuous variables were analysed using independent samples t-tests. Categorical variables were assessed using the chi-square (χ2) test. One-way ANCOVAs were conducted to assess difference between FEP patients and HC in markers of inflammation and BDNF while controlling for the effect of BMI and tobacco smoking. All analyses were conducted using IBM SPSS statistical software version 23. The significance value for all tests was set at α = 0.05.ResultsFEP patients had higher serum level of hs-CRP compared to controls (N = 19, M = 2.29 mg/L, SD = 2.76; N = 21, M = 0.56 mg/L, SD = 0.41; respectively, t(27.79)=-2.41, p=0.02), suggestive of a hyperactivation of the immune system. There was no significant difference in IL-6, IL-8 and BDNF serum levels between the two groups. BMI was significantly higher in patients than controls (N = 19, M = 27.67, SD = 4.91; N = 21, M = 23.55, SD = 3.31; respectively, t(38)=-3.14, p=0.003) and there was a significantly higher number of smokers in the FEP patient group than in the HC group (smokers= 57.9% of FEP patients; smokers=14.3% of HC; χ2(1)=8.34, p=0.004). The one-way ANCOVAs showed that there was not significant effect of group on hs-CRP, IL-6, IL-8 and BDNF values when controlling for BMI and tobacco smoking. In fact, BMI was significantly related to the hs-CRP level, F(1,36) = 7.20, p = 0.01.DiscussionWe found that BMI and tobacco smok[...]



T15. LONGITUDINAL ASSOCIATIONS BETWEEN CHILDHOOD SALIVARY CORTISOL LEVELS AND PRODROMAL SYMPTOMS IN LATE ADOLESCENCE: FINDINGS FROM A HIGH-RISK COHORT

Sun, 01 Apr 2018 00:00:00 GMT

AbstractBackgroundIndividuals with established psychosis are characterised by a distinct pattern of hypothalamic-pituitary-adrenal (HPA) axis dysfunctions which include both elevated daytime cortisol levels and a blunted cortisol awakening response (CAR). Whilst these patterns of dysfunction have also been observed among those at elevated risk for the disorder, longitudinal studies are scarce. As such, the relevance of these HPA axis abnormalities for the progression of psychopathology in high-risk populations is unknown. Utilising data from a well-characterised, longitudinal cohort of youth at elevated risk for schizophrenia and their typically-developing peers (The Child Health and Development Study), we aimed to investigate the extent to which HPA axis function determined in childhood is a significant predictor of putative prodromal status and psychopathology in late adolescence/early adulthood.MethodsThe sample comprised high-risk individuals who presented either multiple antecedents of schizophrenia (developmental delays, psychopathology, and psychotic-like experiences: ASz=21) or a family history of illness (FHx=13), and typically-developing youth with neither antecedents nor a family history (TD=36). Participants were recruited at age 9–12 years using a community screening method and assessed biennially throughout adolescence. At the age 11–14 years assessment phase, participants collected salivary cortisol samples in their home environment which were used to determine diurnal cortisol secretion and the CAR. At the age 17–21 years assessment phase, participants completed measures of prodromal symptoms (Prodromal Questionnaire: PQ), depression (Quick Inventory of Depressive Symptomatology questionnaire: QIDS), and anxiety (Social Interaction Anxiety Scale: SIAS). Established PQ thresholds were used to identify participants who met probable prodromal status. Logistic and linear regression analyses were used to examine the extent to which salivary cortisol measures at age 11–14 years predicted probable prodromal status and continuous psychopathology measures at 17–21 years, respectively.ResultsRelative to the TD group, ASz youth were characterised by higher depression (B=0.24, p=0.05) and disorganised symptoms (B=0.36, p=0.007) at 17–21 years whilst FHx youth obtained higher scores on the PQ general symptoms scale (B=0.24, p=0.048). Analyses performed in the total sample indicated that the CAR was negatively associated with depression symptoms (B=-0.28, p=0.006) and PQ negative symptoms (B=-0.30, p=0.004) at age 17–21 years. Positive associations were obser[...]



T16. GLUTAMATERGIC CHANGES IN UHR

Sun, 01 Apr 2018 00:00:00 GMT

Abstract
Background
The search for biomarkers may prove significant for short-term identification of UHR individuals (remission/non-remission). On a long-term basis, biomarkers might give the opportunity to delay or prevent psychotic episodes. Disturbances of the neurotransmitters glutamate and GABA have long been suspected to be involved in the pathophysiology of psychosis. These disorders have also found been found in people at UHR, making it a promising area for early detection.Cognitive deficits in schizophrenia are present prior to the onset of psychosis, and may be linked to perturbed glutamate and GABA function. Data suggest that this link is already present in UHR states.
Methods
Participants: UHR individuals who meet the CAARMS criteria recruited from Mental Health Services in the Capital Region of Denmark and matching healthy controls.
Examinations
1H-MRS of the ACC and thalamus. Diagnostic and psychopathological tests: CAARMS, SCID, SOFAS, PSP, Cornblatt, SANS, BPRS, MADRS, YMRS, CGI, PAS, SPI-A, AQoL Cognitive tests as part of collaborative studies.
Results
So far 116 UHR individuals and 42 healthy controls have been scanned (December 2017) Very early preliminary analysis of the baseline data finds no significant difference in glutamate levels (in ACC and thalamus) in UHR patients compared to matched healthy controls. Baseline data remains to be analysed in relation to relevant subgroups of patients e.g. based on clinical outcome. GABA analysis and analysis of follow-up data are also yet to be performed. Data will be ready for the meeting, and will be presented.
Discussion
More studies are needed in this field, since results so far have been diverging.Baseline data remains to be analysed in relation to relevant subgroups of patients e.g. based on clinical outcome. GABA analysis and analysis of follow-up data are also yet to be performed. Glutamate data will be presented at the meeting.



T17. OXIDATIVE STRESS BIOMARKERS AND NEGATIVE DIMENSION IN THE FIRST TEN YEARS OF SCHIZOPHRENIA: A 1-YEAR FOLLOW-UP STUDY

Sun, 01 Apr 2018 00:00:00 GMT

AbstractBackgroundSeveral studies have documented changes in oxidative parameters and antioxidant enzymes in patients with schizophrenia (1, 2). However, their relation to negative symptoms and the longitudinal clinical course is still unclear.The objectives of the present study are to: 1) analyze the association between oxidative stress biomarkers and negative dimension; 2) identify if these biomarkers could predict clinical outcomes in stable patients with schizophrenia at 1-year follow-up.MethodsA 1-year follow-up study of 57 stable outpatients with schizophrenia (≤10 years of illness) (mean age=31.5 ± 6.5; 63.2% males).AssessmentPANSS, Clinical Assessment Interview of Negative Symptoms (CAINS) -Motivation/Pleasure (MAP) & Expression (EXP) domains-, Brief Negative Symptom Scale (BNSS). Oxidative stress biomarkers: homocysteine, hemolysis test (% hemolysis), lipid peroxidation subproducts (LPO), catalase activity in erythrocytes (CAT).Pearson correlations were performed to determine associations between biomarkers and clinical scores at baseline, and they were included in stepwise multiple linear regression analyses, considering potential confounding factors.The clinical course for each psychopathological domain was determined using the formula: [follow-up-baseline scores]. Positive values were interpreted as worsening, while negative improvement. Pearson correlation and multiple linear regression analyses were performed to determine if baseline levels of oxidative stress parameters were predictors of clinical changes at follow-up.Results1) Baseline associations: Final regression models identified that LPO level was a significant predictor of lower scores in PANSS-N, BNSS total, Avolition and Blunted Affect subscale of BNSS and CAINS-EXP (β= -0.408; -0.290, -0.254, -0.296, -0.247, respectively).2) Longitudinal course: At 1-year follow-up, patients only improved significantly (p<0.05) in PANSS-Total [59.4 ± 16.4 - 54.5 ± 16.0 (t=3.362)], PANSS-General [29.7 ± 8.9 - 26.9 ± 7.9 (t=3.362)], Blunted Affect subscale [6.9 ± 5.0 - 5.9 ± 4.7 (t=2.489)], and almost significant (p<0.069) in CAINS-EXP and BNSS total score. No significant changes in BMI, waist circumference, smoking or antipsychotic equivalent doses were detected, but they were also considered in regression analyses. A higher percentage of hemolysis at baseline, with a decrease in equivalent doses of antipsychotics, both significantly predict an improvement in scores of PANSS-N (R2=0.140, F=7.166), BNSS (R2=0.246, F=6.193) and CAINS-EXP (R2=0.18[...]



T18. MULTIVARIATE BRAIN ANATOMICAL DIFFERENCES IN POSITIVE AND NEGATIVE SCHIZOTYPY: PRELIMINARY RESULTS FROM THE TYPIA STUDY

Sun, 01 Apr 2018 00:00:00 GMT

AbstractBackgroundIn schizotypy, a factor structure similar to the one observed in schizophrenia has been unraveled, being the positive and negative the most consistently replicated dimensions. Despite this fact, most of the studies on brain volume patterns in schizotypy consider it as an unitary rather than a multidimensional construct. Hence, based on previous results showing that schizophrenia and schizotypal personality traits share common neurodevelopmental patterns, it is hypothesized that brain volumetric patterns in individuals with high positive schizotypy are intrinsically different to those observed in persons reporting high negative schizotypy and to individuals with overall low schizotypal traits. The present study aims to evaluate this hypothesis using novel machine learning techniques to address the multivariate nature of psychotic diseases and the brain itself.MethodsData from the TYPIA Study, an ongoing project conducted at the Ludwig-Maximilian University of Munich and the University of Bonn in Germany, was used to investigate whether brain volumetric patterns are distinct in healthy individuals with high positive (HPS) and high negative schizotypy (HNS) when compared to one another (HPS vs HNS) and to individuals with self-reported low schizotypy (LS vs HNS and LS vs HPS). A preliminary analysis on grey matter volumetric patterns from 29 LS (19 f., mean age: 24.6 y.), 28 HNS (20 f., mean age: 26.8 y.) and 23 HPS (17 f., mean age: 26.4 years) individuals from the general population without any current psychiatric diagnosis was performed. Group divisions were based on the introvertive anhedonia and unusual experiences subscales from the Oxford-Liverpool Inventory of Feelings and Experiences (O-LIFE). Structural images were preprocessed with a standard voxel based morphometry pipeline using the SPM-based CAT12 toolbox in Matlab. After age, sex and grey matter intracranial volume and center corrections, a linear support vector classification (SVC) algorithm was used to assess separability between the groups.ResultsOur preliminary cross-validated results showed that LS and HNS can be separated with 56.0 % balanced accuracy (BAC), whereas LS vs HPS and HNS vs HPS allowed for only 42.87% and 48.8% BAC respectively. Interestingly, a post-hoc analysis comparing LS vs both high schizotypy groups merged together showed the highest BAC (59.2%). As expected, the brain differences between groups are rather small, since the sample consists fully of healthy controls. However, these results i[...]



7.4 PHENOTYPIC AND GENETIC ASSOCIATIONS BETWEEN SCHIZOPHRENIA AND RETINAL VESSEL DIAMETER

Sun, 01 Apr 2018 00:00:00 GMT

AbstractBackgroundIndividuals with schizophrenia are at increased risk for cardiovascular diseases, and this risk cannot be fully explained by antipsychotic medications or lifestyle factors. Retinal imaging offers a non-invasive means of visualizing the microvasculature in living individuals with schizophrenia. Here we test whether individuals with schizophrenia exhibit retinal microvascular abnormality (Meier et al., AJP, 2013), and test for overlap in the genetic variants associated with schizophrenia and retinal microvascular abnormality.MethodsTo test whether individuals diagnosed with schizophrenia showed microvascular abnormality, we used data from the Dunedin Study, a representative cohort of 1,000 New Zealanders followed from birth to age 38. The cohort underwent retinal imaging at age 38, and retinal venular (small veins) and arteriolar (small arteries) diameters were obtained. Analyses compared individuals with schizophrenia (n=27), healthy individuals (n=412), and individuals with medical or psychiatric conditions (ns ranged from 110–210) on retinal vessel diameter. To test for overlap in the genetic variants associated with schizophrenia and retinal vessel diameter, we used linkage disequilibrium-score regression (LD regression) to obtain the genetic correlation between schizophrenia and retinal vessel diameter. This method requires only GWAS (genome wide associate studies) summary statistics rather than actual genotypes. Summary statistics for schizophrenia and retinal vessel diameter came from published meta-analyses.ResultsAdults diagnosed with schizophrenia had wider retinal venules (standardized mean=0.59) compared with same-age healthy adults (standardized mean=-0.20) and compared with individuals diagnosed with hypertension, diabetes, and tobacco dependence. Findings could not be explained by antipsychotic medication, as venular diameter was similar in the subset of individuals diagnosed with schizophrenia who had not taken antipsychotic medication in the year prior to retinal imaging (n=22; standardized mean=0.69). There were no differences in arteriolar diameter between individuals diagnosed with schizophrenia and all other groups. Results from LD regression showed a small genetic correlation between schizophrenia and venular diameter (r=0.05, p=.31) and a slightly larger genetic correlation between schizophrenia and arteriolar diameter (r=0.17, p=.02).DiscussionWider venular diameter is a distinguishing feature of schizophrenia, but genetic var[...]



8. DECREASING CARDIOVASCULAR RISK IN PERSONS WITH SCHIZOPHRENIA: INTERVENTIONS AND FUTURE DIRECTIONS

Sun, 01 Apr 2018 00:00:00 GMT

Abstract
Overall Abstract: Persons with schizophrenia experience two to three times higher mortality than the overall population. This premature death is due in large part to cardiovascular disease and is potentially preventable. All cardiovascular risk factors are elevated in persons with schizophrenia. This presentation will describe the evidence for interventions to reduce cardiovascular risk factors in this vulnerable population, including obesity and tobacco smoking, and will describe models of integrated physical and mental health care. Ongoing research on interventions to decrease cardiovascular risk in schizophrenia will be presented, and future research needs will be discussed including implementation strategies to scale-up interventions to reduce cardiovascular disease risk in community settings.



9. DOES BIOLOGY READ THE DSM? TRANSDIAGNOSTIC FINDINGS IN PSYCHOSIS AND IMPLICATIONS FOR TREATMENT

Sun, 01 Apr 2018 00:00:00 GMT

AbstractOverall 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 researc[...]



T19. MULTIMODAL IMAGING IN FIRST EPISODE PSYCHOSIS: MAGNETOENCEPHALOGRAPHY, 7T FMRI STROOP, AND 7T MRS SPECTROSCOPY

Sun, 01 Apr 2018 00:00:00 GMT

AbstractBackgroundSchizophrenia (SZ) is an illness whose heterogeneity has impeded understanding the underlying pathophysiology. In order to better understand this heterogeneity, here we used magnetoencephalography (MEG), 7T Magnetic Resonance Spectroscopy (MRS), and 7T fMRI during the Stroop task, on the same set of patients with first episode psychosis (SZ).Methods22 minimally treated first episode SZ and 24 healthy controls (HC) matched for age, gender, and family socio-economic status were recruited. Neurometabolite levels were obtained from the bilateral anterior cingulate cortex using 7T proton MRS with an ultra-short echo time (5 ms) STEAM sequence, and referenced to water. MEG was performed in a 4D systems 148 channel magnetometer, and both the auditory evoked potential to 40 Hz tone clicks, and the resting state (eyes closed) were recorded. The fMRI BOLD response to the Stroop task was also recorded in a 7T scanner.ResultsThe magnitude of the audio-evoked MEG responses to 40 Hz tone clicks was not significantly different between SZ and HC. However, many SZ showed high levels of theta-band activity during the resting state. The ratio of theta to alpha band activity in the anterior MEG sensors significantly differentiated SZ from HC, P<0.05 by t-test. MRS levels of glutamate and total NAA (tNAA), also separated HC from SZ, P<0.05, t-test. An across-groups whole brain analysis of the Stroop fMRI BOLD response to incongruent trials relative to congruent trials was performed (p < .01, FDR-corrected). The strongest signal came from a region in the left parietal (MNI, -30, -58.5, 48), and between-group analysis of the BOLD signal from a 4mm sphere surrounding this location revealed that the activation was greater for SZ than HC by t-test, P<0.05. The MEG theta/alpha ratio, and the left parietal fMRI Stroop effect, were significantly correlated, r=0.45, P=0.005. However, the fMRI Stroop was uncorrelated with the MRS tNAA (r = -0.11, P=0.491) and also uncorrelated with the MRS glutamate levels (r = -0.16, P=0.334).DiscussionWe speculate that the MEG and fMRI data, and the MRS neurometabolite levels, may reflect two relatively independent underlying pathological mechanisms in SZ. Possibly the MEG and fMRI results are indicative of dysfunction in long-range cortical-cortical networks, while the MRS data is more indicative of local neurometabolic dysfunction. Further exploration[...]



T20. SEARCHING FOR NOVEL AUTOANTIBODIES WITH CLINICAL RELEVANCE IN PSYCHIATRIC DISORDERS

Sun, 01 Apr 2018 00:00:00 GMT

AbstractBackgroundImmunological reactions may have a role in subgroups of patients suffering from psychiatric disorders. Possible markers for such subgroups may be autoantibodies of currently unknown nature. If identified, they could indicate which patients that would benefit from immunomodulatory treatment in addition to standard interventions. Modern proteomic methods allow analyses of antibody binding to thousands of different human proteins, facilitating the identification of currently undiscovered autoantibodies.MethodsWe have explored the association between any seroreactivity in plasma samples from first episode psychosis patients against more than 2000 randomly chosen protein fragments derived from human proteins, and the development of disorders characterized by chronic or relapsing psychotic symptoms. Plasma from 53 patients and 41 non-psychotic controls were assessed; the clinical course of the patients were followed for a mean duration of 7 years. The plasma samples were analyzed for IgG reactivity to 2304 fragments (approx 100 a.a. residues in length) of human proteins using a multiplexed affinity proteomic technique, and positive hits validated for binding in two additional assays.ResultsThirty patients were diagnosed with schizophrenia, delusional disorder, schizoaffective disorder, bipolar disorder or a long-term unspecified nonorganic psychosis during follow-up, while 23 patients achieved complete remission. Eight patient samples showed autoreactivity to the N-terminal fragment of the PAGE protein family (PAGE2B/PAGE2/PAGE5), whereas no such autoreactivity was seen among the controls. PAGE autoreactivity was associated with a significantly increased risk of being diagnosed with schizophrenia during follow-up (odds ratio 6.7). An antisera raised against the N-terminal fragment stained an unknown extracellular target in human cortical brain tissue (Zandian et al., Transl Psychiatry 7: e1177; doi:10.1038/tp.2017.160).We are currently investigating the identity of this target. In addition, two other putative new autoantibodies found primarily among the patients, and rarely in the controls, will be discussed at the meeting.DiscussionOur findings suggest that autoreactivity to the N-terminal portion of the PAGE protein family is associated with schizophrenia in a subset of patients with first-episode psychosis. In addition, we propose that sear[...]



T21. ALTERATIONS OF CRY2 AND PER3 GENE EXPRESSION ARE ASSOCIATED WITH GRAY MATTER ABNORMALITIES OF THALAMIC-LIMBIC NETWORK IN UNIPOLAR DEPRESSION AND BIPOLAR DEPRESSION

Sun, 01 Apr 2018 00:00:00 GMT

Abstract
Background
The current study aimed to identify shared and distinct brain structure abnormalities and their relationships with circadian gene expression in patients with bipolar depression and unipolar major depression.
Methods
A total of 103 subjects participated in this study, including 32 patients with bipolar depression (BDP), 26 patients with unipolar depression (UDP) and age, sex-matched 35 healthy controls were conducted brain structural magnetic resonance imaging scans and then used optimized voxel-based morphometry to explore group differences in regional gray matter volume (GMV). Circadian gene mRNA expressions in peripheral blood were measured on a subset of 12 patients with BDP, 19 patients with UDP and 33 control subjects using reverse transcription quantitative real-time polymerase chain reaction.
Results
The GMV of the thalamus-limbic pathways had significantly increased in BDP cases relative to comparison subjects, while in UDP the increased GMV focused on the thalamus. The circadian-related gene mRNA expressions have significantly decreased in the patients with BDP, however with higher expression levels in the UDP cases. In addition, the GMV of right thalamus in the UDP was positively associated mRNA level of CRY2 gene, while the GMV of right hippocampus in the UDP was negatively associated mRNA level of PER3 gene.
Discussion
Our study identified the relationship between abnormalities of thalamic-limbic network and alterations of circadian gene pathway in BDP and UDP. The shared GMV abnormality was the right thalamus. PER3 might be critical to hippocampus dysfunction in UDP, and CRY2 might be critical to thalamus dysfunction at a right-hemisphere function in BDP.



T22. PITUITARY GLAND VOLUME DIFFERENCES IN INDIVIDUALS WITH PSYCHOSIS: RESULTS FROM THE BIPOLAR-SCHIZOPHRENIA NETWORK ON INTERMEDIATE PHENOTYPES (B-SNIP) STUDY

Sun, 01 Apr 2018 00:00:00 GMT

AbstractBackgroundWhen exposed to stress, the hypothalamic-pituitary-adrenal axis is hyperactivated, which can cause the enlargement of the pituitary gland. Hence, pituitary gland volume could be a biomarker of stress present in psychosis. However, it remains unclear if individuals with psychosis have larger pituitary gland than healthy people. Previous studies investigating this question used small samples and reported inconsistent results. In the current study, we used an automated multi-atlas segmentation method to investigate the differences between pituitary gland volumes in a large sample of individuals on the psychosis spectrum.MethodsData collection was completed across six sites in the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) consortium with a total of 755 participants included in the study - 174 individuals with schizophrenia (SZ), 115 with schizoaffective disorder (SZA), 167 with psychotic bipolar disorder (PBD), and 299 healthy controls (HC). Structural magnetic resonance images were acquired and pituitary gland volumes were obtained using the automated MAGeT-Brain algorithm. General linear model and post-hoc independent t-tests were used to analysis the differences between subgroups of patients using clinical diagnosis and agnostic Biotype classification (Biotype 1 being the most cognitively impaired). We also explored potential effect of antipsychotic intake, symptoms severity and duration of illness. In all analyses, we used Bonferroni correction for multiple comparisons and entered confounds as covariates (age, sex, race, intracranial volume, and site).ResultsOverall, the pituitary gland volumes were not significantly different between patients and HC. No significant main effect of diagnosis was observed, but SZ patients had trending larger pituitary volume compared to HC (p=.033, uncorrected). We observed a significant main effect of Biotype (p=.003), with Biotype 1 having significantly larger pituitary gland than HC and Biotype 2 (p=.004 and p=.013). In the patients group, no significant relationship between the pituitary gland and the amount of antipsychotic intake was observed (r=.02, p=.68). Significant correlations with the pituitary gland volume were observed with symptoms severity (r=.22, p=.000), and with the duration of illness (r=-.18, p=.002). Importantly[...]



T23. DYNAMICS OF NEURONAL METABOLISM AFTER THE ACUTE ONSET OF PSYCHOSIS – A TWO YEARS FOLLOW-UP 1H/31P-MR-SPECTROSCOPY STUDY IN NEUROLEPTIC NAïVE UHR TRANSITION PATIENTS

Sun, 01 Apr 2018 00:00:00 GMT

AbstractBackgroundGlutamatergic dysfunction, deregulated mitochondrial metabolism and alterations of membrane phospholipids are considered as core pathology of psychosis, and have been studied in schizophrenic illness using magnetic resonance spectroscopy (MRS). Combining 1H- and 31P-MRS, this study investigates these aspects in Ultra-high risk (UHR-T) patients right after transition to psychosis (T0) and after a two years interval (T1) in a naturalistic longitudinal design, including treatment as usual by cognitive-behavioral therapy (CBT) and pharmacotherapy with second generation antipsychotics.MethodsWe applied 3 T chemical shift imaging (3D 31P-MRS, 2D 1H-MRS) and hippocampal single-voxel 1H-MRS in 29 neuroleptic-naïve UHR-T patients and 27 healthy controls matched for age and gender. Glutamate (Glu) and N-acetyl-aspartate (NAA) reflect neuronal functioning, phosphocreatine (PCr), adenosine triphosphate (ATP) and NAA indicate mitochondrial function and energy metabolism, and phosphomono- and diester indicate the balance of phospholipid synthesis (PME) and -breakdown (PDE). Psychopathology was assessed using the CAARMS, BPRS-E and SCL-90-R. Generalized linear mixed models were used to examine case-control differences in metabolite changes over time, and associations with clinical improvement.ResultsAt T0, cross-sectional analysis revealed decreased NAA, Glu and PME levels in the left dorsolateral prefrontal cortex (DLPFC) and thalamus of UHR-T patients as well as higher PCr and lower PDE levels in the right hippocampus. (ii) Follow-up analysis (T1) showed in patients a significant increase of Glu in the bilateral DLPFC and the right thalamus, while a decrease of PCr was observed in the right hippocampus.DiscussionThe observed metabolite pattern at T0 likely reflects a hypofunction of glutamatergic neurons and a disturbance of membrane phospholipid turnover in fronto-thalamo-hippocampal networks during the first acute onset phase of psychotic illness. The pattern of changes at T1 is suggestive for an improvement of neuronal functioning in these networks that is caused by therapy, and presumably underlies the observed clinical improvement in terms of negative symptoms and cognitive impairment.[...]



T24. REDOX REGULATORS AND OXIDATIVE STRESS IN SCHIZOPHRENIA

Sun, 01 Apr 2018 00:00:00 GMT

AbstractBackgroundElevated levels of oxidative stress have been reported in schizophrenia and may play a role in the underlying psychopathology. The antioxidant defense system may be disrupted in schizophrenia. We have earlier shown how levels of membrane polyunsaturated fatty acids (PUFA) change during the course of schizophrenia, increasing from a low level in a subgroup, remaining stable in another. Here, we aimed at comparing levels of redox regulators, oxidative stress, and related genotypes in schizophrenia patients and healthy controls, and at identifying how these biomarkers are related to membrane fatty acids and clinical characteristics in acute and chronic phase of schizophrenia.MethodsPatients with schizophrenia spectrum disorders (n=55) examined during an acute phase and five years later during a chronic phase, and healthy controls (n=51) were included. We assessed blood levels of redox regulators [(alpha-tocopherol, bilirubin, uric acid, glutathione (GSH), glutathione peroxidase (GPx)], glutathione reductase (GR), markers of oxidative stress [F2-isoprostane, reactive oxygen metabolites (D-ROMs)] and PUFA. We examined genotypes and gene expression related to glutamate cysteine ligase (GCL), the rate-limiting enzyme of GSH synthesis, and its catalytic (GCLC) and modulator (GCLM) subunits. Links between redox measures and Positive and Negative Syndrome Scale (PANSS) were studied.ResultsIn the chronic phase, levels of alpha-tocopherol (p=0.03) and bilirubin (p<0.001) were lower, while uric acid (p=0.02) was higher in patients than in controls. In patients, the levels of alpha-tocopherol were higher in the acute phase than in the chronic phase (p=0.001). However, the changes depended on the PUFA levels in the acute phase. In the low PUFA group, alpha-tocopherol levels remained stable, whereas in the high PUFA group, they decreased to those of the low PUFA group. Levels of D-ROMs were linked to PUFA (r=0.39, p=0.007) and long-chain PUFA (r=0.42, p=0.003) in controls but not in patients.There was no significant difference in the distribution of GCLC genotypes between patients and controls. Compared to other GAG trinucleotide-repeat (TNR) genotypes, 7/9 GAG genotype was linked to higher gene expression of GCL (mRNA GCLC, p=0.049; mRNA GCLM, p=0[...]



T25. ALTERATIONS OF PLASMA PHOSPHOLIPID FATTY ACID PROFILES ARE ASSOCIATED WITH LOCAL BRAIN STRUCTURAL ABNORMALITIES IN NEUROLEPTIC NAïVE FIRST-EPISODE PSYCHOSIS PATIENTS

Sun, 01 Apr 2018 00:00:00 GMT

AbstractBackgroundAlterations in brain structure are among the most robust biological findings in schizophrenia. Also changes in fatty acid profiles including reduced levels of polyunsaturated fatty acids (PUFA) are well replicated in schizophrenia. Being essential for neurodevelopmental processes and structural plasticity and remodeling, alterations of PUFA metabolism might be also associated with the occurrence of brain structural abnormalities. To investigate this assumption in vivo we examined the interrelation of PUFA profiles and brain structure in neuroleptic naïve first-episode psychosis (FEP) patients and healthy controls (HC) matched for age and gender.MethodsHigh-resolution T1-weighted 3T MRI were acquired from 29 FEP patients (age 26.4 ± 5.3y; 13 females/16 males) and 31 HC (age 25.1 ± 4.7y; 14 f/17 m). Fatty acid profiles were analyzed using gas chromatography in the plasma phospholipid (PL) fraction that is rather independent of recent fat consumption, and that potentially indicates PUFA availability in phospholipid structural components essential in the brain. To investigate brain structural abnormalities in FEP and effects of illness on interactions between fatty acid profiles and local grey (GM) or white (WM) matter density, voxel-based morphometry (VBM) with the computational anatomy toolbox (CAT12) was used.ResultsVBM analyses revealed a reduction of GM in FEP in left frontal operculum, left middle frontal gyrus, left superior frontal gyrus and bilateral temporal gyrus (TFCE, FWE<0.05). The group comparisons of fatty acid profiles in the PL fraction showed reduced omega-6 PUFA and MCFA (C10-C14) levels in FEP patients. Interaction analyses revealed an influence of illness on the association between omega-6 PUFA and GM density at the left supramarginal gyrus/left postcentral gyrus and left superior temporal gyrus (TFCE, FWE<0.05) with a regression slope FEP patients > HC. For MCFA interaction analyses revealed effects of illness on associations with GM density in the bilateral superior medial frontal gyrus and left anterior cingulate gyrus with a regression slope HC > FEP patients.DiscussionOur results support the notion that the availability of PUFA and MCFA potentially affects brain structura[...]



T26. PERINATAL STRESS AND PSYCHOSIS: RESULTS FROM THE BOLOGNA FIRST EPISODE PSYCHOSIS (BO-FEP) STUDY

Sun, 01 Apr 2018 00:00:00 GMT

Abstract
Background
According to the gene-environment interaction model the pathogenesis of psychosis relies on an adverse neuro-socio-developmental pathway. Perinatal stress represents an important risk factor for the development of psychosis because it could interfere with socio-neuro-development early in life. We aim to investigate the correlation of perinatal risk factors with the onset of psychosis.
Methods
Case-control – incidence study. Patients (and their mothers) were eligible if they presented for the first time with first episode psychosis at the Bo West CMHC between 2002 and 2012. The Bo West CMHC serves a catchment area of about 200,000 people. The controls were recruited in the same catchment area and study period.
Results
42 patients and 26 controls and their mothers were included. Adjusted logistic regression showed that psychosis onset was significantly associated with: stressful situations during pregnancy; lower level of maternal physical health before or during pregnancy; use of anti-inflammatory drugs during pregnancy; low level of maternal education.
Discussion
The results of our study suggest that stress during perinatal period increases the risk of developing psychosis. More attention should be given to the containment of perinatal stress and the prevention of its adverse effects on mother and child mental health.Tarricone I, Mimmi S, et al.. First-episode psychosis at the West Bologna Community Mental Health Centre: results of an 8-year prospective study. Psychol Med. 2012 Nov;42(11):2255–64. PubMed PMID: 22404368



T27. DYSFUNCTIONAL ATTITUDES IN ADOLESCENTS WITH EARLY-ONSET PSYCHOSIS: PRELIMINARY RESULTS

Sun, 01 Apr 2018 00:00:00 GMT

AbstractBackgroundDysfunctional attitudes such as defeatist performance beliefs (DPB) and asocial beliefs (AB) have been linked to negative symptoms and functional outcome in chronic schizophrenia (Campellone et al., 2016; Grant and Beck, 2010) and in adults with recent onset schizophrenia (Ventura et al., 2014). Adolescents with early-onset psychosis (EOP) are at major risk of having persistent negative symptoms (Puig et al., 2017) but no previous study has examined dysfunctional attitudes in this population. We aimed: (1) to examine if more DPB and AB were present in adolescents with EOP compared with normal controls, and (2) to study the relationships between DPB and AB with symptoms and functioning.MethodsSample: 15 adolescents with EOP (11♀, age=15.33 ± 1.23) and 10 healthy controls (8♀, age=15.60 ± 1.51), participants in a trial about cognitive and behavioral social skills treatment in EOP developing in Hospital Clínic of Barcelona (baseline data). Patients were under antipsychotic meds. Inclusion criteria: having an early-onset schizophrenia spectrum disorder diagnosed between 9–18 years-old (schizophrenia, schizoaffective disorder, psychosis n.o.s.); being within the 5 first years after the disease onset; clinical stability. Exclusion criteria: IQ<70; comorbid substance dependence disorder; neurological disorders. Instruments: PANSS (Kay et al., 1987), Calgary Depression Scale (CDS, Addington et al., 1990), Children’s Global Assessment Scale (C-GAS, Shaffer et al., 1983), Social and Role Functioning Scales (GF:S, GF:R, Cornblatt et al., 2007), Life Skills Profile - Adolescent version (Puig et al., 2013), Dysfunctional Attitudes Scale - Spanish version (DAS, Sanz et al., 1993); Asocial Beliefs Scale (Grant and Beck, 2010). DPB was extracted from the DAS scale following Beck et al. (2013). Groups were compared with T-test or Chi-square tests. Pearson correlations were computed for examining relationships between variables.ResultsEOP and control groups were homogeneous in age (t=-0.49, p=0.632) and sex (X2=0.15, p=0.702). All subjects were living with their parents. Family SES was lower in EOP group (X2=10.69, p=0.030). All subjects but one patient were [...]



T28. QUALITY OF PARENTAL BONDING AMONG INDIVIDUALS WITH ULTRA-HIGH RISK OF PSYCHOSIS AND SCHIZOPHRENIA PATIENTS

Sun, 01 Apr 2018 00:00:00 GMT

AbstractBackgroundA child’s parental bonding, measured using the Parental Bonding Instrument (PBI), has been found to be associated with psychiatric illnesses. In particular, a significantly higher proportion of patients with schizophrenia tend to report affectionless-controlling mothers as compared to healthy controls.This study aims to (i) investigate the applicability of the PBI tool in Singapore, using exploratory factor analysis, and (ii) explore the association between parental bonding, symptom severity and functioning across schizophrenia patients, individuals at ultra-high risk of psychosis (UHR), and healthy controls.MethodsData from 59 schizophrenia patients, 164 UHR, and 510 healthy controls (N = 733) were collected. The Structured Clinical Interview for DSM-IV (SCID) was used to ascertain any psychiatric diagnoses. Positive and Negative Symptoms of Schizophrenia (PANSS) and Global Assessment of Functioning (GAF) were administered on UHR and patients. Social and Occupational Functioning Assessment Scale (SOFAS) was administered on HC and UHR. Calgary Depression Scale for Schizophrenia (CDSS) was administered on UHR only.Two exploratory factor analyses of the PBI were conducted on maternal items and paternal items (oblimin rotation). PBI factor scores were calculated for each individual and compared across groups using one-way ANOVA. Multivariate backward regressions were conducted to elucidate the association(s) between parental bonding factors and the clinical scales.ResultsFactor analyses revealed three-factor solutions for both maternal and paternal items, with factors ‘care’, ‘autonomy’, and ‘overprotection’. All the original ‘care’ items loaded onto the ‘care’ factor for maternal and paternal analyses. The original ‘control’ items were split into ‘autonomy’ (the degree to which children were allowed to make their own decisions, e.g. ‘gave me as much freedom as I wanted’) and ‘overprotection’ (e.g. ‘felt I could not look after myself’). Fit statistics suggested a good fit for both maternal items and paternal items (CFI > 0.9, TLI > 0.9). UHR were 1.61 times as likely to report affecti[...]



T29. ELECTRORETINOGRAPHIC RESPONSE IN YOUTHS AT GENETIC RISK OF SCHIZOPHRENIA AND BIPOLAR DISORDER AND IN NORMAL CONTROLS: TRANSVERSAL AND LONGITUDINAL DIFFERENCES AND IMPLICATIONS FOR THE RISK TRAJECTORY

Sun, 01 Apr 2018 00:00:00 GMT

AbstractBackgroundVisual defects have been widely reported in major psychosis. This includes altered eye tracking, retinal thinning and electrophysiological anomalies.1 One of the most replicated alterations is decreased electroretinographic (ERG) responses that are observed in both bipolar disorder and schizophrenia. Our previous study showed a diminished rod b-wave amplitude in a small sample of children born to an affected parent.2 The fact that an anomaly found in patients would also be observed in children at genetic risk suggests a neurodevelopmental origin and may represent a vulnerability marker. Little data exists on the stability of ERG measures in childhood and adolescence. We wanted to evaluate rod and cone ERG response in larger samples of young offspring of an affected parent (HR) and age and gender balanced controls. By comparing a subsample of 33 offspring to controls, we were able to evaluate the stability and change of ERG over time.MethodsERGs of 71 offspring (mean age of 19 y.o.) and 224 healthy controls (mean age of 20 y.o.) was recorded. From this sample, 33 HR and 26 healthy controls had ERG recordings at 2 different moments (mean interval of 4 years). We then compared the amplitudes obtained at Time 1 and Time 2 in order to assess whether the ERG amplitudes remained stable or varied over time.ResultsCongruent with our 2010 report, this larger HR sample showed a reduced rod b-wave amplitude (p<.05). Probably due to higher statistical power, two other differences were found: an increased cone b-wave latency (p<.05) as well as a diminished mixed rod/cone ERG amplitude (p <.05). None of the ERG amplitudes of the healthy controls changed over time. In contrast, 12 out of 33 HR participant showed a variation of more than one standard deviation (either increase or decrease) on the rod b-wave amplitude which was significantly more frequent than in healthy controls (2/26; p<.05). Change in offspring occurred in both directions: some of them had an increased ERG amplitude response that was sufficient to end up in the confidence interval of the controls whereas others experienced a decreased of [...]



T30. TIPPING POINTS – PREDICTING TRANSITIONS TO PSYCHOSIS IN AT-RISK YOUNG PEOPLE

Sun, 01 Apr 2018 00:00:00 GMT

Abstract
Background
In traditional psychosis prediction research, the assumption is that a single “snapshot” of clinical disturbance at time point one (i.e. baseline) can reliably predict the future emergence of psychosis over time (i.e., follow-up). This is a linear, static approach to psychosis prediction. However, the field increasingly recognizes that mental health behaves as a non-linear, dynamic system, common to other complex structures such as ecosystems, financial markets or the climate.
Methods
Increasing evidence points toward the existence of generic “tipping points” in these complex dynamic systems. A tipping point refers to a critical threshold whereby a system shifts from one state into another. Evidence suggests there are universal early warning signals/resilience indicators (such as a phenomenon called ‘critical slowing down’), which predict close proximity to a critical tipping point.
Results
There is growing evidence for the presence of these early warning signals in psychopathology. This presentation will introduce theoretical concepts of tipping points and resilience indicators in the context of transitioning from at-risk mental state to frank psychosis.
Discussion
This new framework may represent a paradigm shift from static prediction approaches to dynamic, individualized models of psychosis prediction and may inform the development of new clinical identification tools and early and individualized interventions to prevent such transitions.



T31. TEN YEAR CLINICAL FOLLOW-UP OF YOUTH WITH EARLY ONSET PSYCHOSIS

Sun, 01 Apr 2018 00:00:00 GMT

AbstractBackgroundEarly onset psychosis (onset prior to age 18) may be associated with poorer long-term outcomes than when onset takes place in adulthood. Studies so far prospectively following youth with early onset psychosis have suggested that only 20% of patients experienced a “good” outcome, and that nearly 50% experience a “poor” outcome. However, the major body of evidence so far has focused on cohorts recruited over 20 years ago, while a recent review (Clemmensen 2012) has noted that outcomes may be more favourable in more recent studies.We set out to update the evidence by prospectively assessing youth with a first episode of early onset psychosis after a 10 year follow-up period with clinical and functional measures.MethodsPatients were recruited from a child and adolescent psychiatry unit at a university hospital in Barcelona, Spain between 2003 and 2008. Inclusion criteria were: age 7 to 17 years and presence of positive psychotic symptoms of less than 6 months duration. Exclusion criteria: presence of a concomitant Axis I disorder that could account for the psychotic symptoms (e.g., substance abuse, autistic spectrum disorders, post-traumatic stress disorder, or acute stress disorder); learning disability according to DSM-IV criteria; neurological disorders. Occasional substance use was not an exclusion criterion. A sample of age matched healthy controls was recruited from the same geographical area. Controls had the same exclusion criteria in addition to no family history of psychotic disorders in first degree relatives. All participants were assessed with clinical (K-SADS, PANSS, GAF, CGI) measures by a psychologist and psychiatrist with experience with child and adolescent population at baseline and 10 year follow-up.ResultsSixty-nine patients and thirty-one controls were assessed at baseline; 36 patients (52%) and 24 controls (77%) were re-assessed at ten year follow-up. There were no differences in age (M=26.4 SD=1.4 vs. M=26.0 SD=2.0; t=.84; p=.41) or gender (47% vs. 46% females, Chi square=.011; p=.92). We were unable to locate 9 patients[...]



T32. USING PSYCHOSOCIAL INTERVENTION TO ENHANCE KNOWLEDGE OF ATTENUATED PSYCHOSIS SYMPTOMS AND HELP SEEKING BEHAVIORS AMONG AFRICAN AMERICAN YOUNG ADULTS

Sun, 01 Apr 2018 00:00:00 GMT

AbstractBackgroundThe lack in knowledge of mental illnesses is of primary concern with regard to help-seeking and treatment outcomes, especially when faced with chronic and severe illnesses such as psychotic disorders. Where mental health knowledge lacks, so does the ability to recognize the signs and symptoms, risk factors, and causes of mental disorders; as well as the appropriate routes of care for these illnesses. Psychotic disorders and attenuated/subclinical psychotic symptoms are often the target of stigma due to the distinctive symptoms, disruptive behavior and perceived dangerousness of both. Furthermore, the social stigma and discrimination historically faced by African Americans in the United States magnifies the disparity in treatment outcomes among this population. The enrollment of minority college students has increased from 15 percent to 33 percent over the past three decades; cases of students with mental illnesses have also increased. It is becoming more important to explore psychosocial intervention strategies geared to promote knowledge of attenuated psychotic symptoms and help-seeking behavior among African Americans young adults.MethodsThe sample consists of 177 students from a Historically Black College and University (HBCU) in the Southeast region of the United States. The participants ranged in age from 18–25. A within group test-retest design was used to conduct the study. The participants received a pretest, participated in a psychosocial training on attenuated psychosis syndrome, and a posttest.ResultsThe results suggest that the training was effective in enhancing the participants’ knowledge of early warning signs of psychosis and improving their help-seeking behavior. However, stigma unexpectedly increased after the training.DiscussionDiscussion: Enhancing mental health literacy has implications for influencing the effects of stigma and discrimination. Colleges and universities are optimal settings for improving mental health literacy because of the high-risk age groups served at these institutions. Mental[...]



T33. EARLY INTERVENTION FOR EARLY PSYCHOSIS IN FRANCE, MAPPING OF PROGRAMS

Sun, 01 Apr 2018 00:00:00 GMT

AbstractBackgroundEarly intervention programs (EIP) have been developed in many countries (United States, Europe, Canada, Australia) and are now widely considered effective in the treatment of early psychosis.In France, current national policies in the field of mental health promote the development of early intervention but France has not yet met national standards of care for EIP.A recent report from the London School of Economics (2016) comparing different European countries even mentioned the delay of France in this area, referring to only one EIP in the country.However, different early intervention initiatives have emerged in France during the last decade without such information being centralized and therefore with no visibility on the current situation over the whole territory.The aims of this study were to draw up a comprehensive inventory of existing or planned programs (in metropolitan France and in the overseas territories) in 2017 and to describe how they operate in 2016.MethodsThis was a two-phase study; phase one was to identify and create an inventory of existing initiatives, and phase two was to describe and conduct an analysis of each initiative.To be included, identified initiatives had to offer an early, intensive and multidisciplinary approach with at least 0.5 dedicated full-time equivalent staff. A secondary inclusion criterion concerned the out-patient setting of the initiative.Inventory was achieved through many contacts across the country, among physicians/psychiatrists, healthcare facilities (hospitals, clinics, adolescent centers…) or administrative institutions (Health Regional Agencies…) which may either provide this kind of care or know of such initiatives.An online declarative survey was administered between March and July 2017 to the identified psychiatrists with questions that covered administrative and clinical topics: structure of attachment, dedicated team, funding, targeted population, activity in 2016, partners of the program, difficulties encountered and prospects.Results[...]



T34. Submission Withdrawn

Sun, 01 Apr 2018 00:00:00 GMT




T35. DIFFUSION MEASURES OF EXTRACELLULAR FREE WATER IN A NON-HUMAN PRIMATE MODEL OF MATERNAL IMMUNE ACTIVATION: EXPLORING NEUROIMMUNE MECHANISMS OF PSYCHIATRIC DISORDERS

Sun, 01 Apr 2018 00:00:00 GMT

AbstractBackgroundEvidence has been accumulating for an immune-based component of psychiatric disorder etiology, particularly schizophrenia. Early epidemiological studies found an increased incidence of schizophrenia in offspring of mothers who had an infection during pregnancy. Recent work has identified genetic links to the MHC complex, pro-inflammatory cytokine elevations in cerebrospinal fluid and plasma. We have developed a non-human primate (NHP) model of maternal immune activation (MIA) using a modified form of the viral mimic polyIC (polyICLC) examine the relationship between altered neuorimmune function may contribute to psychosis risk through effects on the developing brain and behavior of NHP offspring. In a previous cohort of MIA-exposed offspring, our group observed evidence for increased pre-synaptic dopamine levels in the striatum using 6-[18F]fluoro-L-m-tyrosine (FMT) positron emission tomography, in addition to pubertal-onset behavioral abnormalities, which may model part of the neurodevelopmental pathway towards psychosis. This study builds on this model and examines the effect of maternal immune activation on in vivo--extracellular free water--a diffusion magnetic resonance imaging measure obtained with a multi-shell acquisition. We sought to test the hypothesis that offspring of pregnant monkeys who received polyICLC injections at the end of the first trimester would show increased extracellular free water compared to control offspring.MethodsFourteen pregnant rhesus monkeys (Macaca mulatta) receiving polyICLC at the end of the first trimester were compared to 14 controls. The offspring from both groups underwent a multi-shell diffusion MRI scan at 3 Tesla. Diffusion data was collected when the offspring were one month, 6 months, and 12 months of age. Six month preliminary findings are currently presented. Diffusion images were aligned to individual subject MPRAGE scans. Individual subject structural scans were then nonlinearly aligned to [...]



T36. THE ANTIPSYCHOTIC-LIKE PROPERTIES OF EVENAMIDE (NW-3509) REFLECT THE MODULATION OF GLUTAMATERGIC DYSREGULATION

Sun, 01 Apr 2018 00:00:00 GMT

AbstractBackgroundThe lack of adequate benefit with current 5HT2 / D2 antipsychotics in large proportions of schizophrenic patients suggests it is essential to modulate other mechanisms for improving symptoms of schizophrenia (SCZ). Increasing evidence implicates NMDAr hypofunction, and hippocampal hyperactivity, in the dysregulation not only of mesolimbic DA neurons but also of Glu neurons, leading to increasing synaptic activity of Glu in the PFC. Injection of NMDAr antagonists (PCP, ketamine) at doses that produce psychotomimetic effects lead to a downstream increase of Glu neurotransmission at non-NMDAr. The excessive firing and the hyper-glutamatergic tone represent alternative targets of treatment for SCZ ultimately affecting positive, negative, cognitive symptoms. The addition of Glu release inhibitors may augment the benefits of the antipsychotics in patients showing inadequate response.Evenamide uniquely does not interact with monoaminergic (DA, 5-HT, NA, H) pathways affected by current antipsychotics, or with more than 130 different targets that are involved in CNS activity, except sodium channels. Preclinical data suggests that by the modulation of the firing abnormalities, evenamide normalizes the aberrant spread of Glu excitatory transmission that occurs in the brains of patients with SCZ. Evenamide showed efficacy in animal models relevant to SCZ (sensory motor gating, mania, psychosis, depression, impulse control, cognition, social interaction), in monotherapy and as an add on to first or second generation antipsychotics irrespective of whether impairment was either spontaneous, induced by amphetamine or NMDAr antagonists or stress. Evenamide, has also shown significant benefit in a p.c phase 2 trial as an add-on to risperidone and aripiprazole in patients worsening on dopaminergic/serotoninergic antagonist medication, suggesting it acts through other mechanisms. New animal data further confirm evenamide’s activity [...]



T37. THE LONELY MOUSE: A MODEL FOR STUDYING MATERNAL PSYCHOLOGICAL STRESS AND ITS CONSEQUENCES IN THE OFFSPRING

Sun, 01 Apr 2018 00:00:00 GMT

AbstractBackgroundIt is well established that antenatal psychopathology affects obstetric outcomes and maternal behavior, and that it has long-term consequences on the offspring’s wellbeing and mental health, which are relevant for multiple psychiatric disorders. Against this background, it is of pivotal importance to investigate the precise mechanisms that underlie such association, and evaluate the potential beneficial and/or detrimental impact of pharmacological treatment during pregnancy and the postpartum period. To date, rodent models rely mainly on exposure to chronic or acute unpredictable stress during pregnancy, which is mainly based on physical stressors characterized by medium translational value. Therefore, we propose the use of a social isolation-rearing paradigm to investigate the effects of antenatal maternal stress on the offspring. This model has the advantage of implementing psychological stressors, as opposed to physical stressors, to induce depressive-like behaviours in female mice. Moreover, the depressive-like state can be induced and assessed before pregnancy, thus eliminating possible confounding factors that arise from physical stressful manipulations applied during pregnancy.MethodsC57BL/6 female mice were socially isolated, or group housed, from weaning (PND21) to adulthood (PND91). After 5 weeks of social isolation, the animals were tested to confirm the development of a depressive-like phenotype. At PND91, both group housed and socially isolated mice were bred and left undisturbed during pregnancy. The offspring were subjected to cognitive and behavioral testing in adulthood. A subgroup of socially isolated and grouped females were treated with the antidepressant Fluoxetine (10mg/kg) for the last 3 weeks of social isolation, pregnancy and weaning, and the offspring were once again subjected to cognitive and behavioral testing in adulthood.ResultsSocial isolation rearing ind[...]



T38. Submission Withdrawn

Sun, 01 Apr 2018 00:00:00 GMT




T39. NEURAL MECHANISMS OF METABOTROPIC GLUTAMATE RECEPTOR 3 MEDIATED ENHANCEMENT OF SYNAPTIC PLASTICITY AND COGNITION

Sun, 01 Apr 2018 00:00:00 GMT

AbstractBackgroundThe group II metabotropic glutamate receptor 3 (mGlu3) is an emerging therapeutic target for schizophrenia, as research has demonstrated a link between mutations in the human gene encoding for mGlu3, GRM3, and clinical diagnosis of schizophrenia. Schizophrenia is known to be accompanied by debilitating cognitive impairments that negatively impact the overall quality of life of the patient. While current pharmacological therapeutics mainly target the positive symptoms, cognitive symptoms are often not effectively treated. Our recent discovery that mGlu3 and mGlu5 can act as signaling partners to modulate synaptic plasticity in the prefrontal cortex led us to hypothesize that mGlu3 may subserve similar functions to those of mGlu5 during hippocampal synaptic plasticity and hippocampal-dependent behaviors.MethodsWe directly tested this hypothesis using acute slice electrophysiology to investigate basal synaptic transmission as well as long-term plasticity in hippocampal slices. To test cognition, the associative fear learning behavioral assay, termed trace-fear conditioning, was used. C57bl/6 mice or CaMKII-cre;mGlu5-/- mice were used in all studies.ResultsWe report that mGlu2/3 activation enhances hippocampal theta-burst (TBS)-induced LTP but was without effect on group I mGlu agonist-induced LTD The group II mGlu agonist enhancement of TBS-LTP was blocked by antagonists of mGlu3 or mGlu5.We next tested downstream mechanisms of group II mGlu induced LTP by chemically activating LTP with the group II agonist LY379268 in combination with selective antagonists. We verified the LTP was induced by mGlu3 activation but not mGlu2 using selective negative allosteric modulators of each subtype. Furthermore, mGlu5 negative allosteric modulation with MTEP blocked mGlu3-LTP, and conversely the mGlu5 positive allosteric modulator, VU0092273, enhanced[...]



T40. GPR52 AGONISTS REPRESENT A NOVEL APPROACH TO TREAT UNMET MEDICAL NEED IN SCHIZOPHRENIA

Sun, 01 Apr 2018 00:00:00 GMT

AbstractBackgroundThere are currently no treatment options for key symptom domains in certain psychiatric and neurological diseases. For example, antipsychotics effectively treat the positive symptoms of schizophrenia, however both the cognitive impairments associated with schizophrenia (CIAS) and negative symptoms, both key predictors of functional outcome, are not treated by current therapies. Additionally, psychotic symptoms associated with neurological diseases such as Alzheimer’s Disease (AD) are not adequately treated with current antipsychotics. Therefore, novel mechanisms to address these unmet medical needs are urgently required and are under investigation.GPR52 is a Gs-coupled orphan g-protein coupled receptor which has an intriguing pattern of brain expression. In cortex, GPR52 is expressed primarily on glutamatergic neurons and co-localized with the Gs-coupled D1 receptor (D1R). Deficiencies in D1R activation are associated with both cognitive deficit and negative symptoms of schizophrenia. In contrast, in the striatum, GPR52 is almost exclusively co-expressed with the Gi-coupled D2 receptor (D2R), which mediates the reduction in positive symptoms by antipsychotics. Based on GPR52’s functional coupling and co-localization, agonists may be predicted to resemble D1R agonists in cortical regions, thus treating cognitive or negative symptoms, while resembling D2R antagonists in striatal regions. Thus, GPR52 agonists have the potential to provide a novel therapeutic strategy for the currently untreated CIAS and negative symptom domains in addition to the psychotic symptoms of AD.MethodsTo assess the antipsychotic potential of GPR52 agonists, they were tested for their ability to decrease psychostimulant-induced hyperlocomotion. The efficacy of GPR52 agonists for CIAS and sociability, an aspect of negative symptoms[...]



T41. MODIFIED COGNITIVE BEHAVIORAL THERAPY FOR ELDERLY PATIENTS WITH SCHIZOPHRENIA: A RANDOMIZED, CONTROLLED PILOT TRIAL

Sun, 01 Apr 2018 00:00:00 GMT

AbstractBackgroundAn European society growing older sets the need to explore treatment options for elderly patients. Here we aimed to gather evidence on the effectiveness of a modified cognitive behavioural therapy (mCBT) in elderly schizophrenia patients as compared to treatment as usual (TAU).Methods43 schizophrenia patients > 55y (mean 60 y), were assessed in a randomized, single blind controlled pilot trial with parallel groups: TAU+mCBT vs. TAU and intention to treat (ITT) last observation carried forward (LOCF) analysis. Subjects were recruited in Germany among in- and outpatients. MCBT comprised 30 sessions in 9 month, and a 6 month follow-up including a) physical and social activation, b) problem solving c) social skills. Primary outcomes were pre/post change in either PANSS total score, UPSA-brief score or Calgary Depression Scale for Schizophrenia.ResultsFrom 43 patients, 40 were randomized. 15 mCBT and 16 TAU-patients comprised the ITT sample. None of the primary outcome measures reached significance. When assessing effect sizes we found little pre-/post change in PANSS total score (d=0.14) and the UPSA-brief (d=0.14). Depression symptoms however improved with treatment (pre/post d=0.75 and pre/FU d=0.52). Among secondary outcomes, global assessment of functioning significantly improved in the mCBT-group pre/post (d=.074) and pre/follow-up (d=.080).DiscussionOur results provide evidence for the feasibility of a sufficiently powered phase-III study targeting depressive symptoms and global functioning in long-term treated elderly schizophrenia patients. A history of about twenty years of pharmacological treatment does not imply there is no room for improvement in depression and global functioning following a modified cognitive behavioral therapy in this specific patient group. Supported[...]



T42. WHEN SHOULD EARLY INTERVENTION START, AND FOR HOW LONG SHOULD IT LAST?

Sun, 01 Apr 2018 00:00:00 GMT

AbstractBackgroundEarly intervention in psychosis facilities have often failed to integrate the two main elements of early intervention. While some facilities have focused on early, and have had Duration of Untreated Psychosis (DUP) as their main target, others have focused on the intervention and the treatment provided when patients were diagnosed. As both DUP reduction and specialized early intervention (SEI) has proved to have an effect on the treatment of patients with first-episode psychosis one could hope of a synergetic effect if the two strategies were integrated. In this study, we use data from a randomized clinical trial testing the effect of prolonged early intervention (5 years) compared to standard specialized early intervention (2 years). Overall the study found that both treatment groups remained stable or improved in psychopathology, functioning and cognition and that there was no further beneficial effect of the prolonged the treatment. Participants had a long DUP (median 52 weeks). For this specific sub-study we hypothesized that patients who were treated early in their course of illness would have a beneficial effect of the prolonged treatment compared to those who only received 2 years of specialized treatment.Methods296 participants with a psychotic diagnosis within the schizophrenia spectrum (ICD 10 – F2x, excluding F21) were included. DUP start was assessed from first psychotic symptom equivalent to 3 or above on a global SAPS item. DUP stop was when patients started antipsychotic treatment or specialized early intervention treatment. To assess if there were a delay within the mental health referral system we used the national register to identify when participants first were diagnosed with a schizophrenia spectrum diagnosis and calculated the tim[...]



T43. TRANSCRANIAL DIRECT-CURRENT STIMULATION (TDCS) IN PATIENTS WITH ULTRA-TREATMENT-REFRACTORY AUDITORY HALLUCINATIONS

Sun, 01 Apr 2018 00:00:00 GMT

AbstractBackgroundTranscranial direct-current stimulation (tDCS), a noninvasive neurostimulation treatment, has been reported to show improvements in treatment-resistant auditory hallucinations in patients with schizophrenia. tDCS administered over a limited number of sessions effectively produced lasting attenuation of auditory hallucinations in otherwise stable outpatients. It has also been shown that tDCS may be a useful intervention for ameliorating cognitive deficits in patients with chronic schizophrenia. The purpose of this study was to test tDCS for auditory hallucinations in ultra-treatment resistant schizophrenia to assess if this form of neurostimulation can alleviate treatment-refractory auditory hallucination symptoms up to 4 weeks after the final treatment. In addition, we also wanted to examine the effects of tDCS on cognitive functions.Methods28 inpatients with DSM-V schizophrenia and long-standing treatment resistance and persistent auditory verbal hallucinations were recruited. Each individual participated in behavioral assessments at baseline, endpoint and follow-up [PANSS and Auditory Hallucinations Rating Scale (AHRS) and MCCB cognitive battery] and were randomized to receive active vs. sham tDCS treatments. For active treatment, patients had the inhibitory (cathodal) tDCS electrode placed over left auditory cortex relative to an excitatory (anodal) electrode placed over frontal cortex on the right side. tDCS treatments took place for 20 min twice daily for 5 consecutive days. Assessment batteries were repeated following the 4 weeks of treatment. The Chattanooga, dual channel CHA-1335 stimulator with two 7 × 5 cm (35 cm2) sponge electrodes soaked in a saline solution (0.9% NaCl) was used for the delivery of 2 mA current.Re[...]



9.1 GENOMICS AND PSYCHIATRIC DIAGNOSIS

Sun, 01 Apr 2018 00:00:00 GMT

AbstractBackgroundRecent genomic studies have begun to reveal the genetic architecture of psychiatric disorder and to give important insights into the relationship between the psychiatric syndromes that form the basis of current taxonomy. These studies have demonstrated the highly polygenic nature of psychiatric disorders, and have indicated that many individual genetic associations are shared across multiple disorders in a way that points to extensive biological pleiotropy and challenges the biological validity of existing diagnostic approaches.MethodsI will present genomic data, predominantly from the study of rare variants, that support the idea of a neurodevelopmental continuum, in which schizophrenia and bipolar disorder, together with childhood neurodevelopmental disorders, such as ID, ASD and ADHD represent the diverse range of outcomes that follow from disrupted or deviant brain development and furthermore that, within the neurodevelopmental continuum, severe mental illnesses occupy a gradient of decreasing neurodevelopmental impairment as follows: ID, ASD, schizophrenia and bipolar disorder. I will also present findings indicating that common genetic variation modifies the outcome of neurodevelopmental impairment explaining in part the diversity of psychiatric outcomes. Finally, I will explore how genetic data might be used to inform novel approaches to patient stratification which will be informative for prognosis and treatment response and facilitate the identification of novel drug targets.ResultsFinally, despite the undoubted complexity and the fact that much of the genetic risk remains unaccounted for at the DNA level, there are encouraging signs that the genes implicated in schizophrenia converge onto s[...]



9.2 BRAIN STRUCTURAL AND NEUROCHEMICAL HETEROGENEITY AND HOMOGENEITY IN PSYCHOTIC DISORDERS: TRANSDIAGNOSTIC PET AND MRI IMAGING FINDINGS IN SCHIZOPHRENIA AND BIPOLAR AFFECTIVE DISORDER

Sun, 01 Apr 2018 00:00:00 GMT

AbstractBackgroundPsychosis is seen in a number of disorders and treated with the same drugs. However, there is considerable variability in response to treatment and clinical course. Understanding the neurobiology underlying psychosis across diagnoses and in treatment response is important to help guide the development of new treatments and biomarkers for treatment response. Elevated dopamine synthesis and release capacity and structural brain changes have been consistently associated with schizophrenia, but it remains unknown how variable these are, or how they compare across psychotic disorders.MethodsTwo cohorts of first episode patients, one with a diagnosis of schizophrenia (n=16) and another with a diagnosis of bipolar affective disorder (n=22) received 18F-DOPA PET and [1H]-MR spectroscopy imaging and clinical measures. All patients had experienced a psychotic episode and received clinical follow-up over 18 months to determine diagnostic stability. We then conducted a meta-analysis using a novel meta-analytic approach to quantify variability in measures to investigate structural and neurochemical heterogeneity in schizophrenia and bipolar affective disorder. The entire PubMed, EMBase and PsychInfo databases were searched from inception to identify relevant studies and the natural log of the measures of dispersion and the coefficient of variance.ResultsStriatal dopamine synthesis capacity (Kicer) was significantly elevated in both bipolar (effect size=1.02; p<0.003) and schizophrenia (effect size=0.9; p<0.05) groups, compared to controls. There was no significant difference in dopamine synthesis capacity between bipolar and schizophrenia groups (p>0.4). Kicer was significantly[...]



T44. A RANDOMISED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL OF THE EFFECTS OF VITAMIN B12, B6 AND FOLIC ACID ON COGNITION AND SYMPTOMS IN FIRST-EPISODE PSYCHOSIS: THE VITAMINS IN PSYCHOSIS STUDY

Sun, 01 Apr 2018 00:00:00 GMT

AbstractBackgroundVitamin B12, vitamin B6 and folic acid are homocysteine-reducing agents. People with schizophrenia have been found to have increased homocysteine levels. Elevated homocysteine has been associated with impaired cognition. Previous research in chronic schizophrenia has shown that supplementation with folate plus vitamin B12 can improve cognition and clinical symptoms. Whether homocysteine lowering agents are effective in first-episode psychosis is unknown. The aim of this study was to investigate if adjunctive vitamin B12, B6 and folic acid can lower homocysteine and improve symptomatology and cognition in people with first-episode psychosis.MethodsThis was a randomised, double-blind, placebo-controlled trial conducted at the Early Psychosis Prevention and Intervention Centre (EPPIC) in Melbourne, Australia. One hundred and twenty patients aged 15–26 years with first-episode psychosis consented and were randomised to receive folic acid 5mg, vitamin B12 0.4mg, and vitamin B6 50mg or placebo, each taken once-daily for 12 weeks as an adjunct to antipsychotic medication. Co-primary measures were change in cognition as measured by a composite score from a battery of 11 tests and total symptomatology (PANSS) over 12 weeks. Secondary outcomes included additional cognitive, symptom, functioning, tolerability and safety measures.ResultsOf the 120 participants randomised in the study, 20 dropped out with no follow-up assessments and were excluded from analysis. Of the remaining 100 participants, 52 were in the vitamins group and 48 the placebo group. At baseline, the two treatment groups had lower levels of folate and vitamin B12 intake than healthy control[...]



T45. A COMPARISON OF SCHIZOPHRENIA RELAPSE RATES OF 3 PALIPERIDONE FORMULATIONS, ONCE-DAILY, ONCE-MONTHLY AND ONCE EVERY-3-MONTH: POST-HOC ANALYSIS FROM 3 RANDOMIZED CONTROLLED TRIALS

Sun, 01 Apr 2018 00:00:00 GMT

AbstractBackgroundPoor adherence to antipsychotic treatment in patients with schizophrenia can result in recurrent relapses, worsening disease, functional impairment and reduction in treatment responsiveness. Long-acting antipsychotic formulations can maintain therapeutic plasma levels for longer durations, reducing dosing frequency and delaying time to relapse compared to oral formulations. Consequently, relatively lower rates of relapse can be expected in patients on long-acting injectables (LAIs) who have discontinued treatment versus those discontinuing oral medications of the same antipsychotic. However, there is no available evidence to support this association. In this post hoc analysis, the percentage of patients who relapsed and the time to relapse for three different formulations of the same molecule (oral paliperidone extended release [ER]; paliperidone palmitate once monthly [PP1M] LAI, and paliperidone palmitate three monthly [PP3M] LAI) were evaluated in adults with schizophrenia, comparing the active and placebo arms.MethodsData from three similarly designed, randomized, double-blind, placebo-controlled relapse prevention studies in adult patients with schizophrenia (DSM-IV-TR criteria) with similar inclusion/exclusion and relapse criteria were analyzed. Patients stabilized during an open-label stabilization phase with either paliperidone ER, PP1M or PP3M were then randomized to receive either placebo (analogous to non-adherent patients in the real-world) or the same active treatment used during stabilization phase (analogous to adherent patients). The primary outcome in each study was the time to relapse after entering th[...]



T46. TARGETING THE IMMUNE SYSTEM TO TREAT DEPRESSION AND NEGATIVE SYMPTOMS IN SCHIZOPHRENIA

Sun, 01 Apr 2018 00:00:00 GMT

AbstractBackgroundNegative symptoms consist of impaired quality of life, social isolation, reduced emotional responsiveness, self-neglect and anhedonia, which have been categorised into avolition-apathy and expressive deficits sub-domains. The treatment of negative symptoms remains a challenge. Depression is commonly seen in schizophrenia and previous findings have suggested a relationship between depression and negative symptoms via the avolition-apathy sub-domain, (Barnes et al., 2016). It is possible this is the result of a common aetiology, distinct from expressive deficit or other symptoms of schizophrenia. Immune dysfunction has been implicated in both psychotic and depressive illnesses; increased circulating pro-inflammatory markers (such as IL-6, TNF-α & CRP). This suggests a novel target for treatments. A putative neuroprotective role of minocycline has been suggested via reducing microglial activation, and decrease in the production of cytokines including IL-6. Minocycline has been shown to be effective in the treatment of negative symptoms (Xiang et al., 2017) and depression (Soczynska et al., 2012). Within schizophrenia, we predict that that minocycline will lead to a longitudinal improvement in depression and the avolition-apathy sub-domain of negative symptomsMethodsData from the BeneMin study will be presented. BeneMin recruited 207 patients with a current research diagnosis of schizophrenia within 5 years of onset and randomised to minocycline (300mg/day) or matching placebo for 12 months adjunctive to antipsychotic medication. For this analysis the primary outcome variable is the negative [...]



T47. IS THERE A DIURNAL VARIATION IN PSYCHIATRIC SYMPTOMS IN SCHIZOPHRENIA?

Sun, 01 Apr 2018 00:00:00 GMT

AbstractBackgroundAnecdotally we have observed subgroups of schizophrenic patients who experienced a diurnal variation in a wide range of psychiatric symptomology. Such a pattern could have substantial ramifications in both clinical care and clinical trials. For example, two commonly used measures of symptom severity in clinical trials, the Positive and Negative Symptom Scale (PANSS) and the Negative Symptom Assessment Scale (NSA-16) contain numerous items that are rated based entirely or in part on observations of the subject during the interview. We hypothesized that inconsistency in the time of day of assessment in subjects whose symptoms were influenced by circadian rhythms could introduce an erratic “noise” element in the longitudinal measure of their symptoms.To investigate this hypothesis we compared the change in PANSS total score and individual PANSS items across consecutive visits by whether the assessments had been conducted at consistent vs. inconsistent times of day.Methods2109 individual subject visits from multiple schizophrenia clinical trials for which PANSS interview start time was available were included in the analysis. 1,764 pairs of consecutive PANSS interviews within individual subjects were identified and the time difference between the start times of the interviews were calculated. The absolute time difference was divided into quartiles and the first quartile (assessments least disparate in time) and the fourth quartile (assessments most disparate in time) were compared in the analyses. The mean absolute change in PANSS total and PANSS individual items bet[...]



T48. ANTIPSYCHOTIC EFFICACY OF EVENAMIDE (NW-3509) IS DUE TO MODULATION OF GLUTAMATERGIC DYSREGULATION

Sun, 01 Apr 2018 00:00:00 GMT

AbstractBackgroundOver 70% of schizophrenic patients discontinue treatment with first (F)- or second-generation antipsychotics (SGA) due to dissatisfaction with their therapeutic effects; median time to discontinuation ranges from 3–7 months (1). Switching to another antipsychotic, except clozapine, did not yield better results (2). These results indicate it is essential to modulate mechanisms other than dopaminergic (DA)/serotoninergic (5-HT) systems to improve symptoms of schizophrenia (SCZ). Increasingly, NMDA receptor (NMDAr) hypofunction (3) and hippocampal hyperactivity (4) are implicated in the dysregulation of mesolimbic DA and glutamate (Glu) neurons, leading to increasing synaptic activity of Glu in the PFC (5). Augmenting the effects of current antipsychotics with Glu release inhibitors may improve symptoms of psychosis in patients with SCZ.Evenamide does not interact with monoaminergic (DA, 5-HT, NA, H) pathways affected by current antipsychotics, or with >130 different targets involved in CNS activity, except for sodium channels, leading to modulation of Glu release. Evenamide shows efficacy in animal models of SCZ as monotherapy and as an add-on to FGA or SGA, irrespective of whether impairment was spontaneous, or induced by amphetamine, NMDAr antagonists or stress.MethodsIn a pilot, proof of mechanism, randomized, double-blind, placebo-controlled, parallel group, 4-week trial, evenamide (n=50; 15–25 mg bid) or placebo (n=39) was added to patients with SCZ worsening on their current antipsychotic doses of risperidone (RIS; ≥2 mg/day) [...]



T49. THE NEURAPRO STUDY: ADHERENCE TO STUDY MEDICATION

Sun, 01 Apr 2018 00:00:00 GMT

AbstractBackgroundAdherence to a medication is generally defined as the extent to which patients take medications as prescribed by their health care providers. Poor adherence to study medication is not uncommon posing a major challenge to treatment trails. However, poor adherence may not be randomly distributed but rather be associated with demographic or illness factors. The aim of the present study was to identify factors associated with adherence to study medication in young people at ultrahigh risk of psychosis who participated in the NEURAPRO study.MethodsSecondary analysis of data collected in a multi-centre, double-blind, placebo-controlled, randomized clinical trial to prevent or delay the onset of psychosis in participants at ultrahigh risk of psychosis testing omega-3 polyunsaturated fatty acids (omega-3 PUFAs) vs. placebo, in combination with cognitive behavioural case management (NEURAPRO) were included in this analysis. Measures included the Brief Psychiatric Rating Scale (BPRS), the Scale for the Assessment of Negative Symptoms (SANS), the Montgomery Asberg Depression Rating Scale (MADRS), the Young Mania Rating Scale (YMRS), the Social and Occupational Functioning Assessment Scale (SOFAS), and the Global Functioning: Social and Role scales. Adherence to the study medication was assessed monthly for each participant based on capsule count. The mean adherence rating over the 6-month intervention period was then computed and categorized as either adherent (≤25% of capsules returned) or non-adherent (>25% of capsul[...]



T50. SYMPTOMATIC AND FUNCTIONAL RESPONSE TO BREXPIP RAZOLE TREATMENT IN PATIENTS WITH ACUTE SCHIZOPHRENIA BY AGE

Sun, 01 Apr 2018 00:00:00 GMT

AbstractBackgroundAtypical antipsychotics are the mainstay of treatment for schizophrenia, and have a meaningful effect on positive symptoms and agitation/aggression. More recently, treatment goals have shifted to target functioning; a cycle of deterioration often occurs in early schizophrenia in which recurring relapse results in decreased functioning.Brexpiprazole is a serotonin-dopamine activity modulator that is a partial agonist at 5-HT1A and dopamine D2 receptors, and an antagonist at 5-HT2A and noradrenaline alpha1B/2C receptors, all at subnanomolar potency. The efficacy of brexpiprazole has been shown in both short- and long-term studies. In this post-hoc analysis from three short-term studies, the proportion of patients achieving symptomatic and functional response was assessed, grouped by age at baseline.MethodsEfficacy and functioning data were pooled from three 6-week, double-blind, placebo-controlled studies in hospitalized patients with acute exacerbation of schizophrenia (Vector [NCT01396421]; Beacon [NCT01393613]; and Lighthouse [NCT01810380]), and stratified according to age at baseline (18–35 years; and 36–65 years). For the current analyses, response was defined as reduction in PANSS score of ≥30% from baseline; a CGI-I score of 1 or 2 (much improved or improved); or reduction in PANSS score of ≥30% OR CGI-I score of 1 or 2. Functional response was defined as an increase in PSP total score of at least 10 points. The analyses were conducted using a mixed-model repeated measures [...]



T51. TREATMENT OF NEGATIVE SYMPTOMS OF SCHIZOPHRENIA WITH TRANSCRANIAL CURRENT STIMULATION (TDCS): RESULTS OF RANDOMIZED, DOUBLE-BLINDED, SHAM-CONTROLLED TRIAL

Sun, 01 Apr 2018 00:00:00 GMT

AbstractBackgroundThe negative symptoms of schizophrenia cause significant distress and impairment. The treatment of them is a challenge, with medications having none or little effect. So, new treatments are necessary for this condition. The aim of the study was to ascertain the efficacy of tDCS in treating negative symptoms of schizophreniaMethodsThis study was designed to be a randomized, sham-controlled, double-blinded trial using tDCS for the treatment of negative symptoms of schizophrenia. One-hundred (here we analyzed only 70% of the sample, the remaining will be presented at the meeting) patients will be enrolled and submitted to ten tDCS session over the left dorsolateral prefrontal cortex (anodal stimulation) and left temporo-parietal junction-left (cathodal stimulation), over 5 consecutive days, with 2 mA of current. Participants were assessed with clinical and neuropsychological tests before and after the intervention. The primary outcome was change (over time and across groups) in the scores of the Negative Subscale of Positive and Negative Symptoms Syndrome (PANSS). Our secondary outcomes consist of others scales as SANSS (Scale of Assessment of Negative Symptoms), Calgary and the AHRS (Auditory Hallucinations Rating Scale).ResultsFrom 70% of the sample the active tDCS was significantly superior to sham at endpoint at 6 weeks by negative sub scale of PANSS (mean difference, 3,5 points; SD=6.2; P<.05). The total PANSS and the hallucinations scale had no differen[...]



T52. N-ACETYL-CYSTEINE ADD-ON TREATMENT LEADS TO AN IMPROVEMENT OF FORNIX WHITE MATTER INTEGRITY IN EARLY PSYCHOSIS

Sun, 01 Apr 2018 00:00:00 GMT

AbstractBackgroundBeneficial effects of N-acetyl-cysteine (NAC) on negative symptoms in chronic schizophrenia have been reported in two studies. A recent study in early psychosis from our group, did not report significant improvement in negative symptoms (potentially linked to the modest baseline levels) but showed improvement in cognition (i.e. processing speed) and an increase in the brain antioxidant glutathione (GSH) levels, indicating good target engagement.1 Indeed, research in animal models highlights the critical role of redox regulation by brain GSH for white matter maturation and maintenance. Given the strong evidence of white matter (WM) alterations in schizophrenia as well as the current lack of etiological treatments, redox dysregulation is an interesting target. The current study aims at investigating the impact of NAC, a precursor of GSH, the main antioxidant in the brain, on WM integrity in patients in the early psychosis phase. We focused on the fornix bundle that has been shown to be impaired in an animal model of oxidative stress2 (i.e. impaired GSH synthesis) as well as in early psychosis patients.3MethodsWM diffusion properties were estimated using generalized fractional anisotropy (gFA) computed from diffusion spectrum imaging (DSI) brain scans acquired in patients who received either NAC (n=10; mean age=25.3 ± 5.7; males/females 9/1) or placebo (n=10; mean age=24.8 ± 7.9; males/females 5/5) as add-on treatment over 6-months. [...]



T53. USING ARTIFICIAL INTELLIGENCE PLATFORMS TO ENHANCE STUDY DESIGN IN SCHIZOPHRENIA TRIALS

Sun, 01 Apr 2018 00:00:00 GMT

AbstractBackgroundRemote patient monitoring is critical in ensuring optimal drug exposure. Between 30–50% of CNS trials fail because patients are not following the assigned protocol. It is estimated that non-adherence based on pharmacokinetic (PK) data is as high as 39% in schizophrenia trials. An AI platform that uses software algorithms on smartphones to visually and automatically confirm medication ingestion has been used extensively in schizophrenia trials, phases I-IV. Aggregated data demonstrate the feasibility of using the technology in patients with schizophrenia – where smartphone ownership is estimated to be well above 50% - and the potential value of enhancing study design through predictive data and statistical power.MethodsAggregated data were collected across seven schizophrenia studies; three trials are completed and four are ongoing. Protocols varied by geography, treatment duration, study design, inclusion/exclusion criteria, dosing regimens, and assessment frequency (US and global; six to 52 weeks’ treatment duration, lead-in or washout periods, ages 16–65 years, dosing QD or BID, 1–3 units per dose, inpatient and outpatient). Study subjects used the AI application for each dosing administration. In addition to tracking medication intake, the patient-facing interface also provided automated reminders, alarms, dosing windows, clinic visit scheduling, and protocol-specific dosing instructions. Stud[...]



T54. TAILOR – TAPERED DISCONTINUATION VERSUS MAINTENANCE THERAPY OF ANTIPSYCHOTIC MEDICATION IN PATIENTS WITH NEWLY DIAGNOSED SCHIZOPHRENIA SPECTRUM DISORDERS IN REMISSION OF PSYCHOTIC SYMPTOMS

Sun, 01 Apr 2018 00:00:00 GMT

AbstractBackgroundSchizophrenia spectrum disorders have major implications for the individuals, their families and society.Antipsychotic medication is the cornerstone in the treatment of psychotic symptoms and is effective in the reduction of psychotic symptoms and of relapse after remission of psychotic symptoms. This is the reason for recommending maintenance treatment with antipsychotic medication in national and international guidelines for the treatment of schizophrenia, one year after remission of psychotic symptoms in first episode psychosis.The aim of the study is to investigate the effect of tapered discontinuation versus maintenance therapy with antipsychotic medication in patients with newly diagnosed schizophrenia or persistent delusional disorder and with minimum three months remission of psychotic symptoms, and to find minimal effective dose of antipsychotic medication. Negative symptoms, cognitive impairments and the side effects of antipsychotic medication can cause a serious and long-term burden for patients and can reduce their quality of life. The TAILOR study will investigate these important aspects.MethodsThe study is a randomized multicenter single blinded clinical trial. The aim is to include 250 patients from the outpatient early intervention program, OPUS, a 2 years manualized psychiatric treatment programme. At baseline patients must have 3 months remission of psychotic [...]



T55. DRIVING ABILITIES IN CLINICALLY STABLE OUTPATIENTS WITH SCHIZOPHRENIA

Sun, 01 Apr 2018 00:00:00 GMT

AbstractBackgroundAccording to the UN convention of human rights, individual mobility is an important aspect for people suffering from chronic disease. Recent studies have shown that 30% of patients suffering from schizophrenia have a driving license for motorized vehicles, however, studies on driving abilities among this patient group are scarce. Accordingly, the current study investigates the parameters, which are relevant in this regard.MethodsIn this naturalistic study, stable patients, diagnosed with schizophrenia according to ICD-10, between 18 and 60 years of age, are recruited on an outpatient basis. They have to be clinically stable without hospitalization for at least 6 months and have to be on the same medication for at least 6 months. Psychopathology and extrapyramidal motor symptoms (EPS) are assessed by means of the Positive and Negative Syndrome Scale (PANSS) and the Modified Simpson-Angus Scale (MSAS), respectively. Driving abilities are investigated by means of a computerized test battery of the Wiener Testsystem, measuring visual perception, reactivity and stress tolerance, concentration, vigilance, and motor coordination.ResultsSo far, 42 outpatients suffering from schizophrenia, with a mean age of 42.7 ± 8.9 years and a mean duration of illness of 11.2 ± 5.5 years, have been included into the study. 52 % were male and the mean education was 14.4 ±[...]