Clinical High Risk Individuals Research Articles

Pre-pulse inhibition deficits in individuals at clinical high-risk for psychosis: A systematic review and meta-analysis.

Neurophysiological markers of schizophrenia may help identify individuals who are at an increased risk of developing psychosis. As an operational measure of sensorimotor gating, pre-pulse inhibition (PPI) deficit has been investigated in clinical high-risk (CHR) individuals. In this study, we performed a systematic review and meta-analysis of studies that investigated PPI in CHR individuals. Relevant studies published as of July 2019 were retrieved from the PubMed, Cochrane, Embase, PscyINFO, EBSCO and Chinese databases. PPI was evaluated by calculating the standard mean differences (SMDs) between CHR individuals and healthy controls (HC) in meta-analysis. Quality of studies was assessed using the Newcastle-Ottawa Scale. I2 index was used to assess heterogeneity and Egger's test was used to assess publication bias. Eight studies were found to be eligible. The meta-analysis included five studies with a combined study population of 184 CHR subjects and 161 HC. CHR individuals showed lower PPI levels compared to HC in 120 ms inter-stimulus interval or stimulus onset asynchrony paradigm (P=.491, SMD=-0.62). No significant heterogeneity was observed in 120 ms PPI paradigm (χ2 =3.41, P=.491, I2 =0.0%). CHR individuals had lower PPI level compared to HC in 120 ms paradigm, which were relatively stable and significant. The results indicate the presence of information processing and inhibitory problems prior to the development of full-blown psychosis. PPI may be clinically used as an objective indicator to supplement the understanding of CHR individuals.

Longitudinal Assessment and Functional Neuroimaging of Movement Variability Reveal Novel Insights Into Motor Dysfunction in Clinical High Risk for Psychosis.

Motor dysfunction in youth at clinical high risk (CHR) for psychosis is thought to reflect abnormal neurodevelopment within cortical-subcortical motor circuits and may be important for understanding clinical trajectories of CHR individuals. However, to date, our perspective of brain-behavior relationships has been informed solely by cross-sectional correlational studies linking behavior in the lab to brain structure or respective resting-state network connectivity. Here, we assess movement dysfunction from 2 perspectives: study 1 investigates the longitudinal progression of handwriting variability and positive symptoms in a sample of 91 CHR and healthy controls during a 12-month follow-up and study 2 involves a multiband functional magnetic resonance imaging task exploring the relationship between power grip force stability and motor network brain activation in a subset of participants. In study 1, we found that greater handwriting variability was a stable feature of CHR participants who experienced worse symptom progression. Study 2 results showed that CHR individuals had greater variability in their grip force and greater variability was related to decreased activation in the associative cortico-striatal network compared to controls. Motor variability may be a stable marker of vulnerability for psychosis risk and possible indicator of a vulnerable cortico-striatal brain network functioning in CHR participants, although the effects of antipsychotic medication should be considered.

Reductions in Complex Mismatch Negativity to Extra Tone Gestalt Pattern Deviance in First-Episode Schizophrenia.

Although “simple” mismatch negativity (sMMN) to stimulus parameter changes is robustly reduced in long-term schizophrenia (Sz), it is much less reduced in individuals at their first psychotic episode in the schizophrenia-spectrum (FESz). “Complex” MMN (cMMN) reflecting pre-attentive acoustic pattern analysis is also markedly reduced in Sz, but is little studied in FESz. The computational complexity of pattern analysis reflected in cMMN may more greatly stress auditory processing, providing a more sensitive measure of auditory processing deficits at first break. If so, cMMN would provide information about the underlying pathophysiology early in disease course, and may serve as a biomarker for pathology in the Sz prodrome. Twenty-two FESz individuals were compared to 22 volunteer healthy controls (HC) on sMMN and cMMN tasks. For sMMN, pitch- and duration-deviants were presented among standard repetitive tones. For cMMN, repeated groups of 3 identical tones were presented with occasional (14%) groups including an extra identical 4th tone deviant. FESz did not show reductions of pitch-deviant (Cohen's d = 0.08) or duration-deviant MMNs (d =-0.02), but showed large reduction in extra-tone cMMN (d = 0.83). Reduced cMMN was associated with poor social functioning. Reduction in cMMN but not in sMMNs in FESz suggests impairments in late perceptual pattern processing. cMMN is sensitive to subtle pathology and functioning early in disease course which may, in turn, impact social functioning. Future studies in clinical high risk individuals are needed to determine whether this putative biomarker of disease presence is sensitive to the prodromal stage of schizophrenia.

Real-world effectiveness of antipsychotic treatment in psychosis prevention in a 3-year cohort of 517 individuals at clinical high risk from the SHARP (ShangHai At Risk for Psychosis).

Antipsychotics are widely used for treating psychosis, but it is unclear whether they can also prevent psychosis. This study attempted a longitudinal evaluation of antipsychotics under real-world conditions in China to evaluate their effect on the rate of conversion to psychosis in individuals with a clinical high risk (CHR) of psychosis. A total of 517 CHR individuals were recruited between 2011 and 2016 and followed up for 3 years. Among these, 450 (87.0%) individuals completed follow-up, 108 (24.0%) showed conversion to psychosis and 309 (68.7%) received antipsychotics. The main outcome was conversion to psychosis. The sample was further stratified according to the severity of positive symptoms. Patients who did not receive antipsychotics showed a lower conversion rate than those who did (17.7% vs 26.9%; odds ratio [OR] = 0.660, 95% confidence interval [CI] = [0.442, 0.985], p = 0.035). In mild CHR cases, antipsychotic treatment was more likely to be associated with conversion to psychosis, compared with the no-antipsychotics group, with no such difference observed in severe CHR cases. Among those who received antipsychotics, monotherapy or low-dose treatment was associated with lower conversion rates. Our results did not favor any specific type of antipsychotics and suggested that a very small subgroup of CHR individuals with severe positive and general symptoms but mild negative symptoms may benefit from antipsychotic treatment. Administration of antipsychotics to CHR patients is potentially harmful with no preventive benefits. We do not recommend antipsychotic treatment for CHR individuals, which is practiced widely in China, and strongly advise caution if these drugs are used.

O6.6. MULTIMODAL PROGNOSIS OF NEGATIVE SYMPTOM SEVERITY IN INDIVIDUALS WITH INCREASED RISK OF DEVELOPING PSYCHOSIS

BackgroundPrecise prognosis of clinical outcomes in individuals at clinical high-risk (CHR) of developing psychosis is imperative to guide treatment selection. While much effort has been put into the prediction of transition to psychosis in CHR individuals, prognostic models focusing on negative symptom progression in this population are widely missing. This is a major oversight bearing in mind that 82% of CHR individuals exhibit at least one negative symptom in the moderate to severe range at first clinical presentation, whereas 54% still meet this criteria after 12 months. Negative symptoms are strong predictors of poor functional outcome irrespective of other symptoms such as depression or anxiety. Prognostic tools are therefore urgently required to track negative symptom progression in CHR individuals in order to guide early personalized interventions. Here, we applied machine-learning to multi-site data from five European countries with the aim of predicting negative symptoms of at least moderate severity 9-month after study inclusion.MethodsWe analyzed data from the ‘Personalized Prognostic Tools for Early Psychosis Management’ (PRONIA; www.pronia.eu) study, which consisted of 94 individuals at clinical high-risk of developing psychosis (CHR). Predictive models either included baseline level of negative symptoms, measured with the Structured Interview for Prodromal Syndromes, whole-brain gyrification pattern, or both to forecast negative symptoms of moderate severity or above in CHR individuals. Using data from the clinical and gyrification model, further sequential testing simulations were conducted to stratify CHR individuals into different risk groups. Lastly, we assessed the models’ ability to predict functional outcomes in CHR individuals.ResultsBaseline negative symptom severity alone predicted moderate to severe negative symptoms with a balanced accuracy (BAC) of 68%, whereas predictive models trained on gyrification measures achieved a BAC of 64%. Stacking the two modalities allowed for an increased BAC of 72%. Additional sequential testing simulations suggested, that CHR patients could be stratified into a high risk group with 83% probability of experiencing at least moderate negative symptoms at follow-up and a medium/low risk group with a risk ranging from 25 to 38%, when using the two models sequentially. Furthermore, the models trained to predict negative symptom severity from baseline symptoms were less predictive of role (60% BAC) and social (62% BAC) functioning at follow-up. However, the model trained on gyrification data also predicted role (74% BAC) and social (73% BAC) functioning later on. The stacking model predicted role, and social functioning with 64% BAC and 66% BAC respectively.DiscussionTo the best of our knowledge this is the first study using state-of-the-art predictive modelling to prospectively identify CHR subjects with negative symptoms in the moderate to above moderate severity range who potentially require further therapeutic consideration. While the predictive performance will need to be validated in other samples and may be improved by expanding the models with additional predictors, we believe that this pragmatic approach will help to stratify individual risk profiles and optimize personal interventions in the future.

S154. TOBACCO SMOKING AND CLINICAL HIGH RISK: A SYSTEMATIC REVIEW AND META-ANALYSIS OF THE EVIDENCE

BackgroundThere is converging evidence that youths at clinical high risk (CHR) are not only likely to develop the first episode of psychosis but also to develop poor physical outcomes. Some physical health risk factors - such as smoking - have been shown to increase the probability of a frank onset of psychosis in those at risk. A meta-analysis conducted in psychotic patients confirmed that daily tobacco use is associated with an increased risk of psychosis. A significant association between any attenuated psychotic symptoms (that characterize CHR state) and cigarette smoking has been recently shown in a study conducted in South London.Nowadays, it is not completely clear how these findings would translate to the CHR population but a better understanding of how physical health parameters could affect psychopathological outcomes could be beneficial for these vulnerable clinical populations. To shed light on the percentage of smokers in CHR populations, an updated systematic review and meta-analysis of the literature has been carried out. Our main aim was to test whether the probability of being a smoker was higher in the CHR subjects or in the control group.MethodsThe literature search was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. We systematically scrutinized from literature inception to 2019 the following on-line databases: Web of Science Core Collection, BIOSIS Citation Index, KCL-Korean Journal Database, MEDLINE, Russian Science Citation Index, SCiELO Citation Index.We have considered all the relevant studies reporting the smoking status in CHR subjects and in control groups.We used the odds ratio (OR) as effect size measure and data were pooled using a random effect approach.ResultsPreliminary data show that CHR individuals were more likely to use tobacco that matched healthy controls. Specifically, the overall OR of 2.016 (p<.001 95%CI=1.476–2.749) indicated a higher likelihood that CHR individuals would use tobacco compared to controls. Heterogeneity was not significant (I²=30.193 p=0.11). The visual inspection of funnel plots did not reveal a clear suggestion for publication bias and the Egger’s test was non-significant (p=0.10).DiscussionOur systematic review and meta-analysis suggest that is crucial to investigate physical health outcomes such as tobacco use as part of clinical practice in CHR services. Unfortunately, current CHR assessment tools are entirely based on the measurement of psychopathological features and do not include an assessment of these parameters on a regular basis.

T223. MULTIVARIATE PREDICTION OF FOLLOW UP SOCIAL AND OCCUPATIONAL OUTCOME IN CLINICAL HIGH-RISK INDIVIDUALS BASED ON GRAY MATTER VOLUMES AND HISTORY OF ENVIRONMENTAL ADVERSE EVENTS

BackgroundFunctional deficits associated with the Clinical High Risk (CHR) status very often lead to inability to attend school, unemployment, as well as social isolation, thus calling for predictors of individual functional outcomes which may facilitate the identification of people requiring care irrespective of transition to psychosis. Studies have revealed that a pattern of cortical and subcortical gray matter volumes (GMV) anomalies measured at baseline in CHR individuals could predict their functional abilities at follow up. Furthermore, literature is consistent in revealing the crucial role of several environmental adverse events in increasing the risk of developing either transition to psychosis, or a worse overall personal functioning. Therefore, the aim of this study is to employ machine learning to test the individual and combined ability of baseline GMV data and of history of environmental adverse events in predicting good vs. poor social and occupational outcome in CHR individuals at follow up.Methods92 CHR individuals recruited from the 7 discovery PRONIA sites were included in this project. Social and occupational impairment at follow up (9–12 months) were respectively measured through the Global Functioning: Social (GF:S) and Role (GF:R) scale, and CHR with a follow up rating of 7 or below were labeled as having a poor functional outcome. This way, we could separate our cohort in 52 poor outcome CHR and 40 good outcome CHR. GMV data were preprocessed following published procedures which allowed also to correct for site effects. The environmental classifier was built based on Childhood Trauma Questionnaire, Bullying Scale, and Premorbid Adjustment Scale (childhood, early adolescence, late adolescence and adulthood) scores. Raw scores have been normalized according to the psychometric properties of the healthy samples used for validating these questionnaires and scale, in order to obtain individual scores of deviation from the normative occurrence of adverse environmental events. GMV and environmental-based predictive models were independently trained and tested within a leave-site-out cross validation framework using a Support Vector Machine algorithm (LIBSVM) through the NeuroMiner software, and their predictions were subsequently combined through stacked generalization procedures.ResultsOur GMV-based model could predict follow up social outcome with 67.4% Balanced Accuracy (BAC) and significance (p=0.01), while it could not predict occupational outcome (46.6% BAC). On the other hand, our environmental-based model could discriminate both poor vs. good social and occupational outcomes at follow up with, respectively, 71% and 66.4% BACs, and significance (both p=0.0001). Specifically, the most reliable features in the environmental classifier were scores reflecting deviations from the normative values in childhood trauma and adult premorbid adjustment, for social outcome prediction, and in bullying experiences and late adolescence premorbid adjustment, for occupational outcome prediction. Only for social outcome prediction, stacked models outperformed individual classifiers’ predictions (74.3% BAC, p=0.0001).DiscussionEnvironmental features seem to be more accurate than GMV in predicting both social and occupational outcomes in CHR. Interestingly, the predictions of follow up social and occupational outcomes rely on different patterns of occurrence of specific environmental adverse events, thus providing novel insights about how environmental adjustment disabilities, bullying and traumatic premorbid experiences may impact on different bad outcomes associated with the CHR status.

S219. SINGLE-SUBJECT PREDICTION OF FUNCTIONAL OUTCOMES ACROSS DIAGNOSTIC GROUPS USING CLINICAL DATA

BackgroundPsychotic disorders are associated with serious deterioration in functioning even before the first psychotic episode. Also on clinical high risk (CHR) states of developing a first psychotic episode, several studies reported a decreased global functioning. In a considerable proportion of CHR individuals, functional deterioration remains even after (transient) remission of symptomatic risk indicators. Furthermore, deficits in functioning cause immense costs for the health care system and are often more debilitating for individuals than positive symptoms. However in the past, CHR research has mostly focused on clinical outcomes like transition. Prediction of functioning in CHR populations has received less attention. Therefore, the current study aims at predicting functioning in CHR individuals at a single subject level applying multi pattern recognition to clinical data. Patients with a first depressive episode who frequently have persistent functional deficits comparable to patients in the CHR state were investigated in addition.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 (MRI, clinical 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. 11 university centers in five European countries and in Australia (Munich, Basel, Birmingham, Cologne, Düsseldorf, Münster, Melbourne, Milan, Udine, Bari, Turku) 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.In the current study, we analysed data of 114 CHR and 106 ROD patients. Functioning was measured by the ‘Global Functioning: Social and Role’ Scales (GF S/R). In a repeated, nested cross validation framework we trained a l1-regularized SVM to predict good versus bad outcome. Multivariate pattern recognition analysis allowed to identify most predictive variables from a multitude of clinical, environmental as well as sociodemographic potential predictors assessed in PRONIA.ResultsBased on the 5 to 20 identified most predictive features, prediction models revealed a balanced accuracy (BAC) up to 77/72 for social functioning in CHR/ROD patients and up to 73/69 for role functioning. These models showed satisfying performance of BACs up to 69/63 for social functioning and 67/60 for role functioning in an independent test sample. As expected, prior functioning levels were identified as main predictive factor but also distinct protective and risk factors were selected into the prediction models.DiscussionResults suggest that especially prediction of the multi-faceted construct of role functioning could benefit from inclusion of a rich set of clinical variables.To the best of our knowledge this is the first study that has validated clinical prediction models of functioning in an independent test sample. Identification of predictive variables enables a much more efficient prognostic process. Moreover, understanding the mechanisms underlying functional decline and its illness related pattern might enable an improved definition of targets for intervention. Future research should aim at further maximisation of prediction accuracy and cross-centre generalisation capacity. In addition, other functioning outcomes as well as clinical outcomes need to be focused on.

M68. COGNITIVE IMPAIRMENT IN NEVER-TREATED SCHIZOPHRENIA SPECTRUM INDIVIDUALS

BackgroundCognitive impairment is a key feature of schizophrenia. While one recent study suggested that individuals with psychosis experience a progressive decline in certain cognitive domains during the first 10 years of their illness, other clinical and functional MRI-based studies have proposed that most cognitive deficits are present during the first episode and remain stable over time, possibly as a result of medication response. To examine the temporal nature of cognitive deficits in the schizophrenia spectrum, we examined cognition in never-medicated individuals at different stages of the illness.MethodsWe recruited three groups of patients: 1) individuals at clinical high-risk (CHR) for psychosis (n=87), 2) individuals experiencing their first-episode of a non-affective psychosis (FEP) (n=64) (defined by a duration of untreated psychosis < 74 weeks), and 3) individuals with chronic schizophrenia (n=40) (CSz – duration of untreated psychosis > 74 weeks). All three groups were antipsychotic-naïve. Patients with any comorbid disorders or current substance abuse disorders were excluded from this study. We also recruited matched healthy control subjects (n=102). All subjects were recruited at the Instituto Nacional de Neurología y Neurocirugía in Mexico City. The study was approved by the institutional review board. Adults provided written informed consent and minors provided assent with written consent provided by both parents. Cognition was assessed with the MATRICS Consensus Cognitive Battery. Differences between groups were analyzed using a repeated measures analysis of variance (RM-ANOVA) with cognitive domain as inter-subject factor and Bonferroni correction for post hoc pairwise comparisons. Statistical significance was set at p ≤ .05.ResultsSince age, gender, and parental education were significantly different between the groups, they were included as covariates in the RM-ANOVA. In this revised model, there was no main effect of age (p = 0.69) nor any interaction between age and any cognitive domain. Therefore, age was removed from the final model.We observed a significant main effect of group (p <.001); All patient groups were significantly impaired compared to the control group (CHR mean difference (MD) = 6.12; FEP MD = 16.46; CSz MD = 16.37; p <.001 in all cases), individuals with both FEP and CSz had significantly more cognitive impairment than the CHR group (FEP MD = 10.34; CSz MD = 10.25; p <.001 in both cases). No significant differences were observed between FEP and CSz groups (MD = .09, p >.99).We also found a significant group by cognitive domain interaction (p <.001). Namely, all patient groups were cognitively impaired compared to the control group, except in the Verbal and Visual Learning domains in which there were no significant differences between the control and CHR groups. No significant differences were found between the FEP and CSz groups in any domain. Moreover, the CHR group was not significantly different from the other clinical groups in the Social Cognition domain.Within the FEP and CSz groups, no significant correlations were observed between duration of untreated psychosis and any cognitive domain.DiscussionWe observed significant cognitive deficits since at-risk stages of the schizophrenia spectrum. Patients with FEP were as impaired as those with CSz, while cognitive functioning observed in CHR individuals was intermediate between controls and patients with syndromal psychosis. These results emphasize the importance of pre-syndromal detection and prediction of burgeoning psychotic illness. Future research on strategies to mitigate the decline in cognitive function between presyndromal and first-episode psychosis is warranted.

S65. THE ‘STRESS-SENSITIVE SELF’ IN PSYCHOSIS: A PILOT STUDY AMONG HEALTHY INDIVIDUALS OF A CHALLENGE (STRESS) TEST OF SELF-RELATED NEUROCOGNITIVE CAPACITIES

BackgroundDespite attempts to predict which clinical high risk (CHR) individuals will convert to schizophrenia (SCZ), current neurocognitive tests have yielded only modest results. Stress plays a pivotal role in the inception of psychotic symptoms. Accordingly, we have recently speculated that modest predictive success may be an outcome of the discrepancy between the neutral environment in which testing occurs and the stressful environments in which SCZ outbursts. According to this view, prediction of conversion to psychosis requires ‘stress’ tests analogous to those used in general medicine, such as examining cardiac activity under physical exertion. The purpose of this pilot study was to test this notion by developing and validating a ‘Stress-sensitive Self’ neurocognitive test. The focus on the self was chosen because disturbances of the basic self, such as impaired sense of agency (SoA) are central deficits in SCZ. We examined four hypotheses: (1) subjective ratings of stress will be associated with physiological markers of stress, (2) stress will impair judgments and metacognition of SoA, (3) the effect of stress on SoA will be related to the level of attenuated psychotic symptoms (APS), and (4) based on accumulating evidence relating cardiac signals to the bodily self, accuracy in SoA will be related to cardiac deceleration.MethodsTo test these hypotheses 14 healthy controls (HC) performed the ‘Virtual Hand’ (VH) task under two conditions; a neutral block and following a psychosocial stress induction in a ‘stress’ block. In the task they perform a movement with their hand, that is hidden from them, while on a monitor a VH is presented that performs the same movement. The movement is either presented synchronously or with temporal delays. Participants judge whether the VH’s movement is identical to their actual movement (i.e. agency question) and rate their confidence (i.e. metacognition question). Heart rate (HR) was continuously recorded. Presence and distress associated with APS were assessed via the brief version of the Prodromal Questionnaire (PQ-B).ResultsConsistent with our first hypothesis, HR variability captured subjective ratings of stress, and the two were strongly correlated (r = -.637, p = .014). Inconsistent with our second hypothesis, stress did not significantly alter sensitivity (d’) in recognition of the VH (F(1,12) < 1, p = .34). Moreover, it significantly improved, rather than impaired, metacognitive monitoring (i.e., the association between confidence judgments and the actual correctness of the answers) (F(1,12) = 10.64, p =.007, η²p = 0.47). Consistent with our third hypothesis, the beneficial effect of stress on metacognitive monitoring was smaller for HCs with high levels of APS, albeit not significantly so (r = -.28, p = .26). Finally, HR deceleration during VH presentation was significantly predictive of both SoA accuracy (F(1,12) = 13.3, p =.003, η²p = 0.53), and confidence in SoA judgments (F(1,12) = 10.64, p =.002, η²p = 0.52).DiscussionThe results of this pilot study provide mixed yet promising preliminary support for the notion of a ‘Stress-sensitive Self’ test’. More specifically, they suggest that mild stress improves metacognitive monitoring judgments of self-agency, whereas an opposite trend was observed for healthy participants that reported higher scores of APS. In addition, they provide preliminary evidence for a pre-reflexive implicit physiological mechanism supporting the basic self, a mechanism that may be disturbed in SCZ. Ongoing studies are examining CHR’s performance on the ‘Stress-sensitive Self’ test and replicating the current results in a larger sample of HCs.

T37. PREPULSE INHIBITION IN UNAFFECTED SIBLINGS OF SCHIZOPHRENIA AND CLINICAL-HIGH RISK WITHOUT FAMILY HISTORY OF PSYCHOSIS

BackgroundIt is reported that prepulse inhibition (PPI) deficiency of startle reflex in schizophrenia is associated with positive symptoms and is hereditary. In this study, the perceived spatial separation (PSS) induced-prepulse inhibition paradigm based on the priority effect effectively was used to explore PPI levels of genetically high-risk (GHR) of schizophrenia and clinical high risk (CHR) without family history of psychosisMethodsWe examined startle magnitude and PPI in38 CHR (No family history of psychosis), 28 GHR (Siblings or children of schizophrenia), and 44 healthy controls (HC). Modified acoustic PPI paradigm included PSS-PPI and perceived spatial co-location PPI (PSC-PPI) with inter-stimulus interval (ISI) of 60 or 120ms. The Structured Interview for Psychosis risk Syndromes (SIPS) and MATRICS Consensus Cognitive Battery (MCCB) was used to measure psychotic symptom and neuropsychological state of individualsResultsUsing gender, age, and smoking as covariates, Covariance analysis for modified PPI level results revealed that there were significant differences in PSSPPI60 (F = 6.25, p = 0.03) and PSSPI120 (F = 6.57, p = 0.03) paradigm between the three groups. Compared with HC, PSSPPI paradigm detected PPI defects of CHR individuals at 60ms ISI (F = 14.25, p ＜0.001) and 120ms ISI (F = 14.01, p ＜0.001). PPI deficiency was not detected in GHR individuals. PPI level in both groups were unrelated to demographics, clinical characteristics, and cognition. Using GLM analysis, the interaction between grouping and experimental paradigm had no significant effect on PPI level at 60ms (F = 1.88, P = 0.16) and 120ms (Z = 1.66, P = 0.19).DiscussionIt seems that mere heritability of psychosis is not enough to produce PPI defects, which may be related to the progression of psychosis

O5.6. ADVANCED DIFFUSION IMAGING IN PSYCHOSIS RISK: A CROSS-SECTIONAL AND LONGITUDINAL STUDY OF WHITE MATTER DEVELOPMENT

BackgroundStudies in individuals at clinical high risk (CHR) for psychosis provide a powerful means to predict outcomes and inform putative mechanisms underlying conversion to psychosis. In previous work, we applied advanced diffusion imaging methods to reveal that white matter pathology in a CHR population is characterized by cellular-specific changes in white matter, suggesting a preexisting neurodevelopmental anomaly. However, it remains unknown whether these deficits relate to clinical symptoms and/or conversion to frank psychosis. To address this gap, we examined cross-sectional and longitudinal white matter maturation in the largest imaging population of CHR individuals to date, obtained from the North American Prodrome Longitudinal Study (NAPLS-3).MethodsMulti-shell diffusion magnetic resonance imaging (MRI) data were collected across multiple timepoints (1–6 at ~2 month intervals) in 286 subjects (age range=12–32 years). These were 230 unmedicated CHR subjects, including 11% (n=25) who transitioned to psychosis (CHR-converters), as well as 56 age and sex-matched healthy controls. Raw diffusion signals were harmonized to remove scanner/site-induced effects, yielding a unified imaging dataset. Fractional anisotropy of cellular tissue (FAt) and the volume fraction of extracellular free-water (FW) were assessed in 12 major tracts from the IIT Human Brain Atlas (v.5.0). Linear mixed effects (LME) models were fitted to infer developmental trajectories of FAt and FW across age for CHR-converters, CHR-nonconverters and control groups, while accounting for the repeated measurements on each individual.ResultsThe rate at which FAt changed with age significantly differed between the three groups across commissural and association tracts (5 in total; p<0.05). In these tracts, FAt increased with age in controls (0.002% change per year) and in CHR-nonconverters, albeit at a slower rate (0.00074% per year). In contrast, FAt declined with age in CHR-converters at a rate that was significantly faster (-3.944% per year) than the rate of increase in the other two groups. By 25 years of age, FAt was significantly lower in both CHR groups compared to controls (p<0.05). With regard to FW, the rate of change significantly differed between CHR-converters and controls across the forceps major and the left inferior longitudinal and fronto‐occipital fasciculi (IFOF; 3 tracts in total; p<0.05). This was due to increased FW with age in the CHR-converters (0.0024% change per year) relative to controls (-0.0002% per year). Consequently, FW was significantly higher in CHR-converters compared to controls by 20 years of age (p<.05). With regard to symptoms, there was a significant impact of IFOF FW on positive symptom severity across CHR subjects, regardless of conversion status (t=2.37, p<0.05).DiscussionOur results revealed that clinical high-risk for psychosis is associated with cellular-specific alterations in white matter, regardless of conversion status. Only converters showed excess extracellular free-water, which involved tracts connecting occipital, posterior temporal, and orbito‐frontal areas. We also demonstrate a direct impact of free-water on positive symptomatology, collectively, suggesting that excess free-water may signal acute psychosis and its onset. This marker may be useful for patient selection for clinical trials and assessment of individuals with prodromal psychosis.

O1.1. ETRo: EVALUATION OF THE TREATMENT APPROACH “ROBIN” (STANDARDIZED MANUAL AND SMARTPHONE APP) FOR ADOLESCENTS WITH CLINICAL HIGH RISK FOR DEVELOPING A PSYCHOTIC DISORDER

BackgroundThe construct of a clinical high-risk (CHR) state of psychosis has been established to describe potentially prodromal symptoms which typically appear during adolescence and young adulthood. This is a very sensitive developmental period and the clinical high risk (CHR) is associated with increased functional impairment. However, there is a lack of research on age-appropriate treatment strategies for this vulnerable age group. To fill this gap, the experts from the specialized outpatient care unit for early intervention in psychosis at the Department of Child and Adolescent Psychiatry and Psychotherapy, Psychiatric University Hospital, of the University Zürich (CAPS), have developed the combined treatment program “Robin” (standardized manual and smartphone App). The therapy program is targeting at risk-symptoms and aims to improve of quality of life as well as daily functioning. The smartphone application “Robin Z” is an add-on treatment tool to support the patients between the sessions. While a number of trials with smartphone applications in therapy have shown promising effects with adult patient with psychosis, there is little known about using them in the therapy with minor patients. “Robin Z” is one of the first smartphone applications addressing adolescent patients with at risk- symptoms or full-blown psychotic symptoms. Since September 2017, the efficacy of this combined treatment approach is being evaluated with the systematic clinical intervention trial ETRo (Evaluation of the treatment approach “Robin“). The study has been registered at ClinicalTrials.gov (ClinicalTrials.gov Identifier: NCT03829527) and the study protocol has been published June 2019 in the journal “Frontiers in Psychiatry”.MethodsThe ETRo trial is a prospective, naturalistic, follow up study with a matched control design. Participants from a former early recognition study are included for the control condition (treatment as usual). For the intervention condition (16 weekly individual sessions + a minimum 4 family sessions), 30 help seeking CHR adolescents, aged 14–18, are being recruited. At-risk and comorbid symptoms, functioning, self-efficacy and quality of life are monitored at six time points (baseline, during the treatment period, immediately after intervention, and 6, 12, and 24 months later) and compared to the respective measures of the active control group.ResultsThe data from a pilot investigation showed, that “Robin” was accepted by clinicians and patients. Therefore, the authors hypothesize that the “Robin” will enhance the treatment engagement. Within the first 2 years of the systematic evaluation, 18 CHR individuals (61% female, mean age 16.1) have been included in the intervention condition. In Florence, the preliminary results and their implications will be presented. This will include baseline data of the first patients in the intervention group, the intraindividual changes in symptomatology and well-being after 6 months of treatment and data about the treatment satisfaction.Discussion“Robin” is a newly developed treatment approach for adolescents at clinical high risk (CHR) of developing a psychotic disorder combining a standardized treatment manual with a smartphone application. To the best of the author’s knowledge, this is the first controlled trial to test the efficacy of a specific early psychosis treatment in combination with a smartphone application for CHR adolescents. The results of the study are of clinical importance and expected to add essential information in the fields of eMental Health as well as in prevention and early intervention in psychosis.

Structure of positive psychotic symptoms in individuals at clinical high risk for psychosis.

Positive symptoms are a critical dimension of psychopathology in psychotic disorders and are used as a criterion for diagnosis across the psychosis continuum. Although initially considered as one dimension, there is evidence for multidimensionality within positive symptoms. The positive symptom structure has not been examined in individuals at clinical high risk (CHR) for psychosis. Knowledge of the dimensional structure of positive symptoms within CHR may contribute to our understanding of the aetiology and trajectory of this key facet of psychosis. Exploratory factor analysis (EFA) was conducted on the Prodromal Questionnaire-Brief for 183 individuals meeting CHR criteria. Internal consistency was examined to determine the hierarchical structure of the data and alternative models were compared. EFA revealed a three factor model, grouping in to: perceptual abnormalities, grandiose/unusual delusions and persecutory/thought delusions, with a general factor accounting for 56% of the variance. Confirmatory factor analysis showed that a hierarchical model was the best fit. One item referring to nihilistic thoughts did not load on any factor. There is a clear three-dimensional model, distinguishing perceptual abnormalities, and two subgroups of delusions in CHR individuals. The factors are similar to those found in psychotic disorders. The identification and comparison of symptomatic models is useful given the prominent role positive symptoms play in diagnosis, and is crucial to our understanding of the clinical progression of psychosis. This work may provide a useful tool for future studies examining correlations with varying symptom factors and disease progression in CHR.

Conversion to psychosis in adolescents and adults: similar proportions, different predictors.

Age effects may be important for improving models for the prediction of conversion to psychosis for individuals in the clinical high risk (CHR) state. This study aimed to explore whether adolescent CHR individuals (ages 9-17 years) differ significantly from adult CHR individuals (ages 18-45 years) in terms of conversion rates and predictors. Consecutive CHR individuals (N = 517) were assessed for demographic and clinical characteristics and followed up for 3 years. Individuals with CHR were classified as adolescent (n = 244) or adult (n = 273) groups. Age-specific prediction models of psychosis were generated separately using Cox regression. Similar conversion rates were found between age groups; 52 out of 216 (24.1%) adolescent CHR individuals and 55 out of 219 (25.1%) CHR adults converted to psychosis. The conversion outcome was best predicted by negative symptoms compared to other clinical variables in CHR adolescents (χ2 = 7.410, p = 0.006). In contrast, positive symptoms better predicted conversion in CHR adults (χ2 = 6.585, p = 0.01). Adolescent and adult CHR individuals may require a different approach to early identification and prediction. These results can inform the development of more precise prediction models based on age-specific approaches.

Delay discounting in youth at clinical high-risk for psychosis and adults with schizophrenia.

Schizophrenia (SZ) is typically preceded by a prodromal (i.e. pre-illness) period characterized by attenuated positive symptoms and declining functional outcome. Negative symptoms are prominent among individuals at clinical high-risk (CHR) for psychosis (i.e. those with prodromal syndromes) and highly predictive of conversion to illness. Mechanisms underlying negative symptoms in the CHR population are unclear. Two studies were conducted to evaluate whether abnormalities in a reward processing mechanism thought to be core to negative symptoms in SZ, value representation, also exist in CHR individuals and whether they are associated with negative symptoms transphasically. Study 1 included 33 individuals in the chronic phase of illness who have been diagnosed with schizophrenia or schizoaffective disorder (SZ) and 40 healthy controls (CN). Study 2 included 37 CHR participants and 45 CN. In both studies, participants completed the delay discounting (DD) task as a measure of value representation and the Brief Negative Symptom Scale was rated to measure negative symptoms. Results indicated that patients with SZ had steeper discounting rates than CN, indicating impairments in value representation. However, CHR participants were unimpaired on the DD task. In both studies, steeper discounting was associated with greater severity of negative symptoms. These findings suggest that deficits in value representation are associated with negative symptoms transphasically.

Stressor-Cortisol Concordance Among Individuals at Clinical High-Risk for Psychosis: Novel Findings from the NAPLS Cohort

Whilst elevations in basal cortisol levels have been reported among individuals at-risk for psychosis, the extent to which this represents hyperresponsivity of the hypothalamic-pituitary-adrenal (HPA) axis to psychosocial stressors encountered in the natural environment is currently unclear. We aimed to examine stressor-cortisol concordance among youth at clinical high-risk (CHR) for psychosis in the North American Prodrome Longitudinal Study 2 (NAPLS 2) and the relationship with clinical outcome. At baseline, CHR (N = 457) and healthy (N = 205) individuals provided salivary cortisol samples and completed daily stressor, life event, and childhood trauma measures. CHR youth were categorised as remitted, symptomatic, progression of positive symptoms, or psychosis conversion at the two-year follow-up. Within-group regression models tested associations between psychosocial stressors and cortisol; standardised beta coefficients (Stβ) were subsequently derived to enable within-group pooling of effect sizes across stressor types. After adjustment for potential confounders, all CHR subgroups reported greater exposure to life events and daily stressors, and more distress in relation to these events, relative to controls. All CHR groups were also more likely to experience childhood trauma; only CHR converters, however, were characterised by elevated basal cortisol. Daily stressor distress was significantly associated with cortisol in controls (β = 0.60, 95% CI: 0.12–1.08) and CHR youth who converted to psychosis (β = 0.91, 95% CI: 0.05–1.78). In controls only, life event exposure was associated with cortisol (β = 0.45, 95% CI: 0.08–0.83). When pooled across stressors, stressor-cortisol concordance was substantially higher among CHR converters (Stβ = 0.26, 95% CI: 0.07 to 0.44) relative to CHR progressed (Stβ = 0.02, 95% CI: -0.11 to 0.15), symptomatic (Stβ = 0.01, 95% CI: -0.11 to 0.12), and remitted groups (Stβ = 0.00, 95% CI: -0.13 to 0.13); however, unexpectedly, healthy controls showed intermediate levels of concordance (Stβ = 0.15, 95% CI: 0.05 to 0.26). In conclusion, whilst all CHR subgroups showed increased psychosocial stress exposure and distress relative to controls, only those who later converted to psychosis were characterised by significantly elevated basal cortisol levels. Moreover, only CHR converters showed a higher magnitude of stressor-cortisol concordance compared to controls, although confidence intervals overlapped considerably between these two groups. These findings do not support the notion that all individuals at CHR for psychosis show HPA hyperresponsiveness to psychosocial stressors. Instead, CHR individuals vary in their response to stressor exposure/distress, perhaps driven by genetic or other vulnerability factors.

Emotion Recognition and Adverse Childhood Experiences in Individuals at Clinical High Risk of Psychosis

To investigate the association between facial affect recognition (FAR) and type of adverse childhood experiences (ACEs) in a sample of clinical high risk (CHR) individuals and a matched sample of healthy controls (HCs). In total, 309 CHR individuals and 51 HC were recruited as part of an European Union-funded multicenter study (EU-GEI) and included in this work. During a 2-year follow-up period, 65 CHR participants made a transition to psychosis (CHR-T) and 279 did not (CHR-NT). FAR ability was measured using a computerized version of the Degraded Facial Affect Recognition (DFAR) task. ACEs were measured using the Childhood Experience of Care and Abuse Questionnaire, the Childhood Trauma Questionnaire, and the Bullying Questionnaire. Generalized regression models were used to investigate the relationship between ACE and FAR. Logistic regressions were used to investigate the relationship between FAR and psychotic transition. In CHR individuals, having experienced emotional abuse was associated with decreased total and neutral DFAR scores. CHR individuals who had experienced bullying performed better in the total DFAR and in the frightened condition. In HC and CHR, having experienced the death of a parent during childhood was associated with lower DFAR total score and lower neutral DFAR score, respectively. Analyses revealed a modest increase of transition risk with increasing mistakes from happy to angry faces. Adverse experiences in childhood seem to have a significant impact on emotional processing in adult life. This information could be helpful in a therapeutic setting where both difficulties in social interactions and adverse experiences are often addressed.

Individualized Diagnostic and Prognostic Models for Patients With Psychosis Risk Syndromes: A Meta-analytic View on the State of the Art

BackgroundThe clinical high risk (CHR) paradigm has facilitated research into the underpinnings of help-seeking individuals at risk for developing psychosis, aiming at predicting and possibly preventing transition to the overt disorder. Statistical methods such as machine learning and Cox regression have provided the methodological basis for this research by enabling the construction of diagnostic models (i.e., distinguishing CHR individuals from healthy individuals) and prognostic models (i.e., predicting a future outcome) based on different data modalities, including clinical, neurocognitive, and neurobiological data. However, their translation to clinical practice is still hindered by the high heterogeneity of both CHR populations and methodologies applied. MethodsWe systematically reviewed the literature on diagnostic and prognostic models built on Cox regression and machine learning. Furthermore, we conducted a meta-analysis on prediction performances investigating heterogeneity of methodological approaches and data modality. ResultsA total of 44 articles were included, covering 3707 individuals for prognostic studies and 1052 individuals for diagnostic studies (572 CHR patients and 480 healthy control subjects). CHR patients could be classified against healthy control subjects with 78% sensitivity and 77% specificity. Across prognostic models, sensitivity reached 67% and specificity reached 78%. Machine learning models outperformed those applying Cox regression by 10% sensitivity. There was a publication bias for prognostic studies yet no other moderator effects. ConclusionsOur results may be driven by substantial clinical and methodological heterogeneity currently affecting several aspects of the CHR field and limiting the clinical implementability of the proposed models. We discuss conceptual and methodological harmonization strategies to facilitate more reliable and generalizable models for future clinical practice.

Experiential negative symptoms are more predictive of real-life functional outcome than expressive negative symptoms in clinical high-risk states

BackgroundNegative symptoms are key features of psychosis-spectrum disorders linked to psychosis development and functional impairments. This study investigated the predictive strength of negative symptoms domains on multiple aspects of real-life functional outcome in individuals at clinical high-risk (CHR) for psychosis. MethodsA total of 146 UHR individuals were enrolled in a randomized, clinical trial (RCT), with this being analyses secondary to the RCT. The participants were assessed at baseline with the Scale for the Assessment of Negative Symptoms (SANS) encompassing the four domains of affect, alogia, avolition, and anhedonia. Functioning measures, encompassing overall-, social-, and role functioning, self-report social functioning, and quality of life, were obtained at 12-month follow-up. Regression analyses elucidated on the relationship between the four negative symptom domains and functional outcomes. ResultsAnhedonia and avolition were the aspects of negative symptoms most predictive of real-life functioning at 12-month follow-up explaining 7–20% of the variance on the outcome measures. Alogia was predictive of social functioning. These findings were maintained when controlling for the effect of neurocognition, antipsychotic medication, and depressive symptoms. DiscussionOur findings show experiential negative symptoms to predict multiple areas of real-life functioning and quality of life, while expressive negative symptoms exert a modest influence on the functional prognosis of CHR individuals. Experiential negative symptoms may therefore constitute an important treatment target in intervention approaches aimed at enhancing the functional outcome of CHR individuals.