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Preliminary evidence indicates beneficial effects of omega-3 polyunsaturated fatty acids (PUFAs) in early psychosis. The present study investigates the molecular mechanism of omega-3 PUFA-associated therapeutic effects in clinical high-risk (CHR) participants. Plasma samples of 126 CHR psychosis participants at baseline and 6-months follow-up were included. Plasma protein levels were quantified using mass spectrometry and erythrocyte omega-3 PUFA levels were quantified using gas chromatography. We examined the relationship between change in polyunsaturated PUFAs (between baseline and 6-month follow-up) and follow-up plasma proteins. Using mediation analysis, we investigated whether plasma proteins mediated the relationship between change in omega-3 PUFAs and clinical outcomes. A 6-months change in omega-3 PUFAs was associated with 24 plasma proteins at follow-up. Pathway analysis revealed the complement and coagulation pathway as the main biological pathway to be associated with change in omega-3 PUFAs. Moreover, complement and coagulation pathway proteins significantly mediated the relationship between change in omega-3 PUFAs and clinical outcome at follow-up. The inflammatory protein complement C5 and protein S100A9 negatively mediated the relationship between change in omega-3 PUFAs and positive symptom severity, while C5 positively mediated the relationship between change in omega-3 and functional outcome. The relationship between change in omega-3 PUFAs and cognition was positively mediated through coagulation factor V and complement protein C1QB. Our findings provide evidence for a longitudinal association of omega-3 PUFAs with complement and coagulation protein changes in the blood. Further, the results suggest that an increase in omega-3 PUFAs decreases symptom severity and improves cognition in the CHR state through modulating effects of complement and coagulation proteins.

This study examined whether distress in relation to attenuated psychotic symptoms (DAPS) is associated with clinical outcomes in an ultra-high risk (UHR) for psychosis sample. We also investigated whether DAPS is associated with cognitive style (attributional style and cognitive biases) and whether amount of psychosocial treatment provided is associated with reduction in DAPS. The study was a secondary analysis of the "Neurapro"clinical trial of omega-3 fatty acids. Three hundred and four UHR patients were recruited across 10 early intervention services. Data from baseline assessment, regular assessments over 12 months, and medium term follow-up (mean = 3.4 years) were used for analysis. Findings indicated: a positive association between DAPS assessed over time and transition to psychosis; a significant positive association between baseline and longitudinal DAPS and transdiagnostic clinical and functional outcomes; a significant positive association between baseline and longitudinal DAPS and nonremission of UHR status. There was no relationship between severity of DAPS and cognitive style. A greater amount of psychosocial treatment (cognitive-behavioral case management) was associated with an increase in DAPS scores. The study indicates that UHR patients who are more distressed by their attenuated psychotic symptoms are more likely to have a poorer clinical trajectory transdiagnostically. Assessment of DAPS may therefore function as a useful marker of risk for a range of poor outcomes. The findings underline the value of repeated assessment of variables and incorporation of dynamic change into predictive modeling. More research is required into mechanisms driving distress associated with symptoms and the possible bidirectional relationship between symptom severity and associated distress.

Understanding longitudinal cognitive performance in individuals at ultra-high risk for psychosis (UHR) is important for informing theoretical models and treatment. A vital step in this endeavor is to determine whether there are UHR subgroups that have similar patterns of cognitive change over time. The aims were to: i) identify latent class trajectories of cognitive performance over 12-months in UHR individuals, ii) identify baseline demographic and clinical predictors of the resulting classes, and iii) determine whether trajectory classes were associated with transition to psychosis or functional outcomes. Cognition was assessed using the Brief Assessment of Cognition in Schizophrenia (BACS) at baseline, 6- and 12-months (N = 288). Using Growth Mixture Modeling, a single unimpaired improving trajectory class was observed for motor function, speed of processing, verbal fluency, and BACS composite. A two-class solution was observed for executive function and working memory, showing one unimpaired and a second impaired class. A three-class solution was found for verbal learning and memory: unimpaired, mildly impaired, and initially extremely impaired, but improved ("caught up") to the level of the mildly impaired. IQ, omega-3 index, and premorbid adjustment were associated with class membership, whereas clinical variables (symptoms, substance use), including transition to psychosis, were not. Working memory and verbal learning and memory trajectory class membership was associated with functioning outcomes. These findings suggest there is no short-term progressive cognitive decline in help-seeking UHR individuals, including those who transition to psychosis. Screening of cognitive performance may be useful for identifying UHR individuals who may benefit from targeted cognitive interventions.

Background: Functional outcomes are important measures in the overall clinical course of psychosis and individuals at clinical high-risk (CHR), however, prediction of functional outcome remains difficult based on clinical information alone. In the first part of this study, we evaluated whether a combination of biological and clinical variables could predict future functional outcome in CHR individuals. The complement and coagulation pathways have previously been identified as being of relevance to the pathophysiology of psychosis and have been found to contribute to the prediction of clinical outcome in CHR participants. Hence, in the second part we extended the analysis to evaluate specifically the relationship of complement and coagulation proteins with psychotic symptoms and functional outcome in CHR. Materials and methods: We carried out plasma proteomics and measured plasma cytokine levels, and erythrocyte membrane fatty acid levels in a sub-sample (n = 158) from the NEURAPRO clinical trial at baseline and 6 months follow up. Functional outcome was measured using Social and Occupational Functional assessment Score (SOFAS) scale. Firstly, we used support vector machine learning techniques to develop predictive models for functional outcome at 12 months. Secondly, we developed linear regression models to understand the association between 6-month follow-up levels of complement and coagulation proteins with 6-month follow-up measures of positive symptoms summary (PSS) scores and functional outcome. Results and conclusion: A prediction model based on clinical and biological data including the plasma proteome, erythrocyte fatty acids and cytokines, poorly predicted functional outcome at 12 months follow-up in CHR participants. In linear regression models, four complement and coagulation proteins (coagulation protein X, Complement C1r subcomponent like protein, Complement C4A & Complement C5) indicated a significant association with functional outcome; and two

There is a growing recognition that psychiatric symptoms have the potential to causally interact with one another. Particularly in the earliest stages of psychopathology dynamic interactions between symptoms could contribute heterogeneous and cross-diagnostic clinical evolutions. Current clinical approaches attempt to merge clinical manifestations that co-occur across subjects and could therefore significantly hinder our understanding of clinical pathways connecting individual symptoms. Network approaches have the potential to shed light on the complex dynamics of early psychopathology. In the present manuscript we attempt to address 2 main limitations that have in our opinion hindered the application of network approaches in the clinical setting. The first limitation is that network analyses have mostly been applied to cross-sectional data, yielding results that often lack the intuitive interpretability of simpler categorical or dimensional approaches. Here we propose an approach based on multi-layer network analysis that offers an intuitive low-dimensional characterization of longitudinal pathways involved in the evolution of psychopathology, while conserving high-dimensional information on the role of specific symptoms. The second limitation is that network analyses typically characterize symptom connectivity at the level of a population, whereas clinical practice deals with symptom severity at the level of the individual. Here we propose an approach based on graph signal processing that exploits knowledge of network interactions between symptoms to predict longitudinal clinical evolution at the level of the individual. We test our approaches in two independent samples of individuals with genetic and clinical vulnerability for developing psychosis.

Aim: Several prediction models have been introduced to identify young people at greatest risk of transitioning to psychosis. To date, none has examined the possibility of developing a clinical prediction model of outcomes other than transition. The aims of this study were to examine the association between baseline clinical predictors and outcomes including, but not limited to, transition to psychosis in young people at risk for psychosis, and to develop a prediction model for these outcomes. Methods: Several evidence-based variables previously associated with transition to psychosis and some important clinical comorbidities experienced by ultra-high risk (UHR) individuals were identified in 202 UHR individuals. Secondary analysis of the Neurapro clinical trial were conducted to investigate the associations between these variables and favourable (remission and recovery) or unfavourable (transition to psychosis, no remission, any recurrence and relapse) clinical outcomes. Logistic regression, best subset selection, Akaike Information Criterion and receiver operating characteristic curves were used to seek the best prediction model for clinical outcomes from all combinations of possible predictors. Results: When considered individually, only higher general psychopathology levels (P =.023) was associated with the unfavourable outcomes. Prediction models suggest that general psychopathology and functioning are predictive of unfavourable outcomes. Conclusion: The predictive performance of the resulting models was modest and further research is needed. Nonetheless, when designing early intervention centres aiming to support individuals in the early phases of a mental disorder, the proper assessment of general psychopathology and functioning should be considered in order to inform interventions and length of care provided.

Omega-3 long chain polyunsaturated fatty acids (n-3 LCPUFA) are necessary for optimum mental health, with recent studies showing low n-3 LCPUFA in people at ultra-high risk (UHR) of developing psychosis. Furthermore, people at UHR of psychosis had increased erythrocyte sphingomyelin (SM) and reduced phosphatidylethanolamine (PE) concentrations as well as 27 erythrocyte phospholipid species that differed when compared to erythrocytes from age matched people not at UHR of psychosis. The aim of this analysis was to evaluate the effect of n-3 supplementation on the different erythrocyte lipid species (including SM and PE concentrations) in people at UHR of psychosis. Participants were randomly assigned to fish oil (containing 840 mg EPA and 560 mg DHA per day) or placebo (paraffin oil) for 6 months. Fasted blood samples were taken at baseline and post intervention. Mass spectrometry was used to analyse the molecular phospholipids and fatty acid composition of erythrocytes for both groups. The n-3 index was significantly increased from 3.0% to 4.12% after 6 months of receiving n-3 capsules. Fish oil capsules increased the phospholipid molecular species containing n-3 LCPUFA, and concomitant decreases in n-6 LCPUFA species. SM species did not show any significant changes in n-3 LCPUFA group however, three SM species (SM 16:0, SM 18:0, SM 18:1) significantly increased after 6 months of supplementation with placebo. N-3 supplementation for 6 months led to higher n-3 incorporation into erythrocytes, at the expense of n-6 PUFA across all phospholipid classes analyzed and may have prevented the increase in SM seen in the placebo group.

Neurocognitive impairments are well established in both ultra-high risk (UHR) for psychosis and major depressive disorder (MDD). Despite this understanding, investigation of neurocognitive deficits in UHR individuals with MDD and its association with MDD within this population, has been scarce. Hence, this study aimed to examine any differences in neurocognition at baseline between those with MDD at baseline and those with no history of MDD, as well as determine whether neurocognitive variables are significantly associated with meeting criteria for MDD at follow-up, while controlling for relevant clinical variables, within a UHR cohort. Data analysis was conducted on 207 participants whose baseline neurocognition was assessed using Brief Assessment of Cognition for Schizophrenia, as part of a trial of omega-3 fatty acids (NEURAPRO) for UHR individuals. While baseline MDD was the strongest predictor, poorer verbal memory and higher verbal fluency were significantly associated with MDD at 12 months (p =.04 and 0.026, respectively). Further, higher processing speed was significantly associated with MDD at medium-term follow-up (p =.047). These findings outline that neurocognitive skills were independently associated with meeting criteria for MDD at follow-up within UHR individuals, with novel findings of better verbal fluency and processing speed being linked to MDD outcomes. Hence, neurocognitive performance should be considered as a marker of risk for MDD outcomes and a target for management of MDD in UHR.

BACKGROUND: NEURAPRO was a multicenter, placebo-controlled trial of long-chain omega-3 polyunsaturated fatty acids (n-3 PUFAs) (fish oil) in 304 individuals at ultra-high risk for psychotic disorders. The study failed to show benefits of n-3 PUFAs over placebo. Although the randomized controlled trial design is placed at the top of the evidence hierarchy, this methodology has limitations in fish oil randomized controlled trials, as not only is the test agent present in the intervention group, but also n-3 fats are present in the diet and the body tissue of all participants.METHODS: Analysis of biomarker data (eicosapentaenoic acid [EPA], docosahexaenoic acid [DHA], n-3 index, EPA+DHA) collected as part of NEURAPRO was conducted on 218 participants with longitudinal biomarker data to determine if n-3 PUFAs measured in erythrocytes at baseline and month 6 predicted clinical outcomes.RESULTS: Increases of the n-3 index, EPA, and DHA predicted less severe psychopathology and better functioning at both follow-up time points. Higher baseline levels and increases of n-3 index also predicted overall clinical improvement at month 6 (n-3 index baseline: adjusted odds ratio [95% confidence interval (CI)] = 1.79 [1.30-2.48]; n-3 PUFA increase: adjusted odds ratio [95% CI] = 1.43 [1.16-1.76]) and at month 12 (n-3 index baseline: adjusted odds ratio [95% CI] = 2.60 [1.71-3.97]; n-3 PUFA increase: adjusted odds ratio [95% CI] = 1.36 [1.06-1.74]).CONCLUSIONS: These data suggest that n-3 PUFAs can exert therapeutic effects in ultra-high-risk individuals. This finding has implications for early intervention and treatment guidelines, as n-3 PUFA supplementation can easily and safely be used in a wide variety of settings, from primary care to specialist services.

The Ultra-High Risk (UHR) for psychosis group is known to be heterogeneous with diverse outcomes. This study aimed to: 1. Identify subclasses of UHR individuals based on trajectories of symptomatic and functional change over time, 2. Identify predictors of these trajectories. A sample of 304 UHR individuals participating in the Neurapro trial were followed over an average of 40 months. All participants received cognitive-behavioural case management (CBCM). Symptomatic and functional profiles were investigated using latent class growth analysis. Multinomial regression was employed to investigate predictors of classes. Identified trajectories showed mostly parallel slopes (i.e. improving symptoms/functioning over time), which were primarily distinct regarding the severity of symptomatology/level of functioning at baseline (i.e. the intercept). Higher symptomatic/lower functioning classes were predicted by higher substance use, older age, female gender, and lower cognitive functioning. No divergent trajectories were identified as all classes improved over time. This may reflect effective treatment through CBCM, natural illness course, or effective engagement with mental health services. Nonetheless, classes highest in symptoms/lowest in functioning still showed considerable impairment during follow-up, highlighting the need for targeted intervention in these subgroups. The study emphasizes the need for more clinical attention directed towards UHR patients being female or using substances.

[This corrects the article DOI: 10.3389/fpsyt.2019.00393.].

© 2019 People classified as ultra-high risk (UHR) of developing psychosis have reduced cellular membrane omega-3 and omega-6 polyunsaturated fatty acids (PUFA). We aimed to compare omega-3 index, fatty acids and molecular phospholipid species from erythrocytes of people with UHR (n = 285) with age-matched healthy controls (n = 120) assessed by mass spectrometry. Lower proportions of PUFA were observed in the UHR group compared to healthy controls; specifically, eicosapentaenoic acid (EPA) was 29.3% lower, docosahexaenoic acid (DHA) was 27.2% lower, arachidonic acid (AA) was 15.8% lower and the omega-3 index was 26.9% lower. The AA to EPA ratio was higher in the UHR group compared to the healthy group. Smoking status had no significant effect on PUFA levels in healthy or the UHR groups. BMI was associated with PUFA levels in the UHR group only and the statistical model only explains 2% of the variance of the PUFA levels. The proportion of nervonic acid was 64.4% higher in the UHR group compared to healthy controls. At a lipid class level, the UHR group had 16% higher concentrations of sphingomyelin (SM) and 46% lower concentrations phosphatidylethanolamine (PE) compared to healthy group. Of the 49 individual molecular phospholipids, twenty-seven phospholipid species were lower in the UHR group. In conclusion, there are clear differences in the proportions of erythrocyte fatty acids and phospholipids between UHR and healthy controls and UHR had higher concentrations of SM and lower concentrations of PE. These differences may represent a promising prodromal risk biomarker in the UHR population to aid clinical diagnosis.

© 2019 Omega-3 long chain polyunsaturated fatty acids (n-3 LCPUFA) are necessary for optimum mental health, with recent studies showing low n-3 LCPUFA in people at ultra-high risk (UHR) of developing psychosis. Furthermore, people at UHR of psychosis had increased erythrocyte sphingomyelin (SM) and reduced phosphatidylethanolamine (PE) concentrations as well as 27 erythrocyte phospholipid species that differed when compared to erythrocytes from age matched people not at UHR of psychosis. The aim of this analysis was to evaluate the effect of n-3 supplementation on the different erythrocyte lipid species (including SM and PE concentrations) in people at UHR of psychosis. Participants were randomly assigned to fish oil (containing 840 mg EPA and 560 mg DHA per day) or placebo (paraffin oil) for 6 months. Fasted blood samples were taken at baseline and post intervention. Mass spectrometry was used to analyse the molecular phospholipids and fatty acid composition of erythrocytes for both groups. The n-3 index was significantly increased from 3.0% to 4.12% after 6 months of receiving n-3 capsules. Fish oil capsules increased the phospholipid molecular species containing n-3 LCPUFA, and concomitant decreases in n-6 LCPUFA species. SM species did not show any significant changes in n-3 LCPUFA group however, three SM species (SM 16:0, SM 18:0, SM 18:1) significantly increased after 6 months of supplementation with placebo. N-3 supplementation for 6 months led to higher n-3 incorporation into erythrocytes, at the expense of n-6 PUFA across all phospholipid classes analyzed and may have prevented the increase in SM seen in the placebo group.

Background: Neurocognitive impairments experienced by individuals at ultra-high risk (UHR) for psychosis are potential predictors of outcome within this population, however there is inconsistency regarding the specific neurocognitive domains implicated. This study aimed to examine whether baseline neurocognition predicted transition to psychosis, or functional outcomes, at medium-term (mean = 3.4 years) follow-up, while controlling for other clinical/treatment variables associated with transition to psychosis. Method: Analysis of data collected as part of a multi-centre RCT of omega-3 fatty acids and cognitive-behavioural case management (NEURAPRO) for UHR individuals was conducted on the 294 participants (134 males, 160 females) who completed neurocognitive assessment (Brief Assessment of Cognition for Schizophrenia) at baseline. Transition to psychosis was determined using the Comprehensive Assessment of At-Risk Mental States (CAARMS), and functioning was measured with the Global Functioning: Social and Role Scales. Results: Mean baseline z-scores indicated that UHR participants performed a quarter to half a standard deviation below normative means in all domains (range mean z = −0.24 to −0.47), except for executive functioning (mean z = 0.16). After adjusting for covariates, poorer Executive (p = .010) and Motor (p = .030) functions were predictive of transition to psychosis. Processing Speed and Verbal Fluency were significant predictors of role functioning at 12 months (p = .004), and social functioning at medium-term follow-up (p = .015), respectively. Conclusions: Neurocognitive abilities are independent predictors of both transition to psychosis and functional outcomes within the UHR population. Further research is needed to determine the best combination of risk variables in UHR individuals for prediction of psychosis transition, functioning and other psychopathology outcomes.