Machine learning based prediction and the influence of complement - Coagulation pathway proteins on clinical outcome: Results from the NEURAPRO trial.

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 proteins (coagulation factor IX and complement C5) positively associated with the PSS score. Our study does not provide support for the utility of cytokines, proteomic or fatty acid data for prediction of functional outcomes in individuals at high-risk for psychosis. However, the association of complement protein levels with clinical outcome suggests a role for the complement system and the activity of its related pathway in the functional impairment and positive symptom severity of CHR patients.

Cross-sectional association of seafood consumption, polyunsaturated fatty acids and depressive symptoms in two Torres Strait communities.

Background Dietary intake of long-chain omega 3 (n-3) polyunsaturated fatty acids (LCPUFA) represents a putative modifiable risk factor for depression, and a high ratio of omega 6 (n-6) to n-3 LCPUFA is frequently observed in patients with major depressive disorder. Recent reports suggest that the availability of fish and seafood may be associated with lower depression rates. The aim of this study was to investigate associations of fish consumption and LCPUFA levels with depressive symptoms.Methods Participants for this cross-sectional study (n=206) were recruited at a community screening programme in two Torres Strait Islander communities (Mer and Waiben). Depressive symptoms were assessed with the adapted Patient Health Questionnaire-9 (aPHQ-9) and diet with a structured questionnaire. LCPUFA concentrations were measured with a capillary dried blood spot system (PUFAcoat). Logistic and quantile regression modelling was used to test the relationship between seafood consumption, membrane LCPUFAs and depression scores.Results A higher blood n-6/3 LCPUFA ratio was associated with moderate/severe depression scores across both study sites (OR=1.59 (95%CI 1.09-2.34), P = .017). Seafood consumption was higher and the proportion of participants with aPHQ-9 scores above the cut-off for depression was lower on Mer (n = 100) compared with Waiben (n = 106). Higher seafood consumption was associated with lower depression scores on Waiben (B = -0.57 (95%CI -0.98 - -0.16), P = .006) but not on Mer.Conclusions Our findings support an association of n-3 LCPUFA from natural sources with depressive symptoms. The availability of fresh seafood in the local diet may represent a protective factor for depression in this setting.

Broad clinical high-risk mental state (CHARMS): Methodology of a cohort study validating criteria for pluripotent risk.

AIM: The development of the ultra-high risk (UHR) criteria for psychosis created a new paradigm for the prevention research in psychiatry. Since (1) prevention research faces the challenge of achieving adequate statistical power when focusing on single low-incidence syndromes and (2) early clinical phenotypes are overlapping and non-specific, this study broadens the UHR state beyond psychosis as an outcome. The CHARMS (clinical high at-risk mental state) study aims to prospectively validate a set of trans-diagnostic criteria to identify help-seeking young people at risk of developing a range of serious mental illnesses. METHODS: This paper describes the methodology of the CHARMS study, which involves applying the CHARMS criteria to a cohort of help-seeking young people aged 12 to 25 attending youth mental health services in Melbourne. New referrals meeting the CHARMS criteria are allocated to the CHARMS+ group; referrals not meeting CHARMS threshold are allocated to CHARMS- group (control group); referrals meeting criteria for a full-threshold disorder are excluded. Transition status and clinical and functional outcomes are re-assessed at 6 and 12 months. CONCLUSIONS: This study will be the first to introduce and validate clinical criteria to identify a broader at-risk patient population, which may facilitate young people's access to clinical services and early treatment by reducing the reliance on "caseness" defined according to current diagnostic categories being required for service entry. These criteria may introduce a new, trans-diagnostic approach for understanding risk factors and pathogenic mechanisms that drive the onset of severe mental illness and the next generation of preventive intervention trials.

Can antipsychotic dose reduction lead to better functional recovery in first-episode psychosis? A randomized controlled-trial of antipsychotic dose reduction. The reduce trial: Study protocol.

Antipsychotic medication has been the mainstay of treatment for psychotic illnesses for over 60 years. This has been associated with improvements in positive psychotic symptoms and a reduction in relapse rates. However, there has been little improvement in functional outcomes for people with psychosis. At the same time there is increasing evidence that medications contribute to life shortening metabolic and cardiovascular illnesses. There is also uncertainty as to the role played by antipsychotic medication in brain volume changes. AIM: The primary aim of the study is, in a population of young people with first-episode psychosis, to compare functional outcomes between an antipsychotic dose reduction strategy with evidence-based intensive recovery treatment (EBIRT) group (DRS+) and an antipsychotic maintenance treatment with EBIRT group (AMTx+) at 24-months follow-up. METHODS: Our single-blind randomized controlled trial, within a specialist early psychosis treatment setting, will test the whether the DRS+ group leads to better vocational and social recovery than, the AMTx+ group over a 2-year period in 180 remitted first-episode psychosis patients. Additionally, we will examine the effect of DRS+ vs AMTx+ on physical health, brain volume and cognitive functioning. This study will also determine whether the group receiving DRS+ will be no worse off in terms of psychotic relapses over 2 years follow-up. RESULTS: This paper presents the protocol, rationale and hypotheses for this study which commenced recruitment in July 2017. CONCLUSION: This study will provide evidence as to whether an antipsychotic dose-reduction recovery treatment leads to improved functioning and safer outcomes in first-episode psychosis patients. In addition, it will be the first-controlled experiment of the effect of exposure to antipsychotic maintenance treatment on brain volume changes in this population.

In vivo imaging of oxidative stress and fronto-limbic white matter integrity in young adults with mood disorders.

Fronto-limbic connectivity is compromised in mood disorders, as reflected by impairments in white matter (WM) integrity revealed by diffusion tensor imaging. Although the underlying mechanisms remain unclear, disruption to normal myelination due to oxidative stress is thought to play a key role. We aimed to determine whether fronto-limbic WM integrity is compromised, and associated with in vivo antioxidant levels (indexed by glutathione; GSH), in young adults with unipolar depression (DEP) and bipolar (BD) disorders. Ninety-four patients with DEP, 76 with BD and 59 healthy controls (18-30 years) underwent diffusion tensor and proton magnetic resonance spectroscopy imaging. Fractional anisotropy (FA) was calculated from the cingulum bundle (cingulate, hippocampus), fornix, stria terminalis (ST) and uncinate fasciculus tracts. GSH concentration was measured in anterior cingulate cortex (ACC) and hippocampus (HIPP). Compared to controls, DEP showed significantly reduced FA in ST, whereas BD did not significantly differ in FA across the five tracts. There were significant positive correlations between ST-FA and HIPP-GSH across groups. Regression analysis revealed that having DEP or BD and reduced HIPP-GSH were significantly associated with reduced ST-FA. Similarly, decreased ST-FA was associated with poorer neuropsychological performance in conjunction with having DEP. Our findings suggest a structural disconnectivity specific to the limbic region of young adults with DEP. Decreased WM integrity was associated with depleted levels of hippocampal GSH suggesting that this particular disruption may be linked to oxidative stress at early stages of illness. Young adults with BD do not have the same degree of impairment.

Associations of obsessive-compulsive symptoms with clinical and neurocognitive features in schizophrenia according to stage of illness.

This study aimed to investigate the association of obsessive-compulsive symptoms with clinical and neurocognitive features in patients with schizophrenia. This study enrolled 163 people with schizophrenia who were receiving risperidone monotherapy. Comorbid obsessive-compulsive symptoms were assessed using the Yale-Brown Obsessive-Compulsive Scale, and subjects with a score ≥ 10 constituted the obsessive-compulsive symptom group (n=30, 18.4%). The learning index was significantly higher in patients with obsessive-compulsive symptoms than in those without such symptoms after adjusting for age, stage (early and chronic), duration of illness, and CDSS score. However, there was no significant interaction between obsessive-compulsive symptoms and stage of illness. Scores on Positive and Negative Syndrome Scale, Calgary Depression Scale for Schizophrenia, and Beck Depression Inventory were significantly higher in the obsessive-compulsive symptom group. In addition, the Subjective Well-being under Neuroleptic Treatment score was significantly lower in the obsessive-compulsive symptom group. In conclusion, comorbid obsessive-compulsive symptoms in patients with schizophrenia were associated with a higher learning ability without a significant interaction with stage of illness. However, schizophrenia patients with obsessive-compulsive symptoms had more severe psychotic and depressive symptoms and poorer quality of life.