Associations between soluble urokinase plasminogen activator receptor (suPAR) concentration and psychiatric disorders - A systematic review and meta-analysis.

BACKGROUND: There is some evidence of an association between inflammation in the pathogenesis of mental disorders. Soluble urokinase plasminogen activator receptor (suPAR) is a biomarker of chronic inflammation, which provides a more stable index of systemic inflammation than more widely used biomarkers. This review aims to synthesise studies that measured suPAR concentrations in individuals with a psychiatric disorder, to determine if these concentrations are altered in comparison to healthy participants. METHOD: Comprehensive literature searches from inception to October 2023 were conducted of five relevant databases (PubMed, Web of Science, Embase, Scopus, APA PsychInfo). Random-effects meta-analyses were performed to compare the standardised mean difference of blood suPAR levels (i.e. plasma or serum) for individuals with any psychiatric disorder relative to controls. Separate meta-analyses of suPAR levels were conducted for individuals with schizophrenia or other psychotic disorder and depressive disorder. Risk of bias was assessed using the Newcastle Ottawa Scale. Post-hoc sensitivity analyses included excluding studies at high risk of bias, and analyses of studies that measured suPAR concentrations either in serum or in plasma separately. RESULTS: The literature search identified 149 records. Ten full-text studies were screened for eligibility and 9 studies were included for review. Primary analyses revealed no significant difference in suPAR levels between individuals with any psychiatric disorder compared to controls (k = 7, SMD = 0.42, 95 % CI [-0.20, 1.04]). However, those with depressive disorder had elevated suPAR levels relative to controls (k = 3, SMD = 0.61, 95 % CI [0.34, 0.87]). Similarly, secondary analyses showed no evidence of a significant difference in suPAR levels in individuals with any psychiatric disorder when studies at high risk of bias were excluded (k = 6, SMD = 0.54, 95 % CI [-0.14, 1.22]), but elevated suPAR concentrations for those with schizophrenia or other psychotic disorder were found (k = 3, SMD = 0.98, 95 % CI [0.39, 1.58]). Furthermore, studies that analysed plasma suPAR concentrations found elevated plasma suPAR levels in individuals with any psychiatric disorder relative to controls (k = 5, SMD = 0.84, 95 % CI [0.38, 1.29]), while studies measuring serum suPAR levels in any psychiatric disorder did not find a difference (k = 2, SMD = -0.61, 95 % CI [-1.27, 0.04]). For plasma, elevated suPAR concentrations were also identified for those with schizophrenia or other psychotic disorder (k = 3, SMD = 0.98, 95 % CI [0.39, 1.58]). DISCUSSION: When studies measuring either only serum or only plasma suPAR were considered, no significant difference in suPAR levels were observed between psychiatric disorder groups, although significantly elevated suPAR levels were detected in those with moderate to severe depressive disorder. However, plasma suPAR levels were significantly elevated in those with any psychiatric disorder relative to controls, while no difference in serum samples was found. A similar finding was reported for schizophrenia or other psychotic disorder. The plasma findings suggest that chronic inflammatory dysregulation may contribute to the pathology of schizophrenia and depressive disorder. Future longitudinal studies are required to fully elucidate the role of this marker in the psychopathology of these disorders.

Comparing times of self-harm presentations to hospital emergency departments in children, adolescents, young adults and adults: a national registry study 2007-2019.

PURPOSE: The few studies that have explored self-harm presentation times at hospital emergency departments (EDs) - an important factor that can determine if a patient receives a mental health assessment - primarily focus on adult samples. This study examined the times of self-harm presentations to EDs, self-harm methods used, mental health assessments, and admission data across different age-groups. METHODS: Using data from the National Self-Harm Registry Ireland over a 13-year timeframe (2007-2019), this study compared times, days, seasons, methods of self-harm, and admission data for children (8-12 years), adolescents (13-17 years), young adults (18-25 years) and adults (> 25 years). RESULTS: The majority of the 152,474 self-harm presentations (78.6%) for all ages occurred out-of-hours (outside the standard working hours or in-hours times of 09:00-17:00, Monday-Friday). The four hours before midnight had the highest proportions of self-harm presentations for adolescents (27.9%) and adults (23.1%), whereas the four hours after midnight had the highest proportion of self-harm presentations for young adults (22.9%). The 16:00-midnight timeframe had highest proportion of self-harm presentations in children (52.3%). Higher proportions of patients received a mental health assessment in-hours compared to out-of-hours among young adults (78.2% vs. 73.3%) and adults (76.1% vs. 72.0%). Self-harm presentations were lowest during summer months in children and adolescents. DISCUSSION: Hospitals should ensure that adequate resources are available for individuals presenting with self-harm, especially in the case of overcrowded EDs, and protocols need to be designed for those presenting with self-harm due to intoxication. In line with national policy, protocols for patients presenting during out-of-hours should be designed that can incorporate services from allied health multidisciplinary teams, social work, addiction services and counselling organisations. Given the lower rates of self-harm during school holidays for children and adolescents, the school environment must be considered in the context of mental health and self-harm public health prevention interventions.

Longitudinal Trajectories of Plasma Polyunsaturated Fatty Acids and Associations With Psychosis Spectrum Outcomes in Early Adulthood.

BACKGROUND: Evidence supports associations between polyunsaturated fatty acids such as docosahexaenoic acid (DHA) and psychosis. However, polyunsaturated fatty acid trajectories in the general population have not been characterized, and associations with psychosis spectrum outcomes in early adulthood are unknown. METHODS: Plasma omega-6 to omega-3 ratio and DHA (expressed as percentage of total fatty acids) were measured by nuclear magnetic spectroscopy at 7, 15, 17, and 24 years of age in participants of ALSPAC (Avon Longitudinal Study of Parents and Children). Curvilinear growth mixture modeling evaluated body mass index-adjusted trajectories of both measures. Outcomes were assessed at 24 years. Psychotic experiences (PEs), at-risk mental state status, psychotic disorder, and number of PEs were assessed using the Psychosis-Like Symptoms interview (n = 3635; 2247 [61.8%] female). Negative symptoms score was measured using the Community Assessment of Psychic Experiences (n = 3484; 2161 [62.0%] female). Associations were adjusted for sex, ethnicity, parental social class, and cumulative smoking and alcohol use. RESULTS: Relative to stable average, the persistently high omega-6 to omega-3 ratio trajectory was associated with increased odds of PEs and psychotic disorder, but attenuated on adjustment for covariates (PEs adjusted odds ratio [aOR] = 1.63, 95% CI = 0.92-2.89; psychotic disorder aOR = 1.69, 95% CI = 0.71-4.07). This was also the case for persistently low DHA (PEs aOR = 1.42, 95% CI = 0.84-2.37; psychotic disorder aOR = 1.14, 95% CI = 0.49-2.67). Following adjustment, persistently high omega-6 to omega-3 ratio was associated with increased number of PEs (ß = 0.41, 95% CI = 0.05-0.78) and negative symptoms score (ß = 0.43, 95% CI = 0.14-0.72), as was persistently low DHA (number of PEs ß = 0.45, 95% CI = 0.14-0.76; negative symptoms ß = 0.35, 95% CI = 0.12-0.58). CONCLUSIONS: Optimization of polyunsaturated fatty acid status during development warrants further investigation in relation to psychotic symptoms in early adulthood.

Plasma complement and coagulation proteins as prognostic factors of negative symptoms: An analysis of the NAPLS 2 and 3 studies.

INTRODUCTION: Negative symptoms impact the quality of life of individuals with psychosis and current treatment options for negative symptoms have limited effectiveness. Previous studies have demonstrated that complement and coagulation pathway protein levels are related to later psychotic experiences, psychotic disorder, and functioning. However, the prognostic relationship between complement and coagulation proteins and negative symptoms is poorly characterised. METHODS: In the North American Prodrome Longitudinal Studies 2 and 3, negative symptoms in 431 individuals at clinical high-risk for psychosis (mean age: 18.2, SD 3.6; 42.5 % female) were measured at multiple visits over 2 years using the Scale of Psychosis-Risk Symptoms. Plasma proteins were quantified at baseline using mass spectrometry. Four factors were derived to represent levels of proteins involved in the activation or regulation of the complement or coagulation systems. The relationships between standardised protein group factors and serial measurements of negative symptoms over time were modelled using generalised least squares regression. Analyses were adjusted for baseline candidate prognostic factors: negative symptoms, positive symptoms, functioning, depressive symptoms, suicidal ideation, cannabis use, tobacco use, antipsychotic use, antidepressant use, age, and sex. RESULTS: Clinical and demographic prognostic factors of follow-up negative symptoms included negative, positive, and depressive symptoms, functioning, and age. Adjusting for all candidate prognostic factors, the complement regulators group and the coagulation regulators group were identified as prognostic factors of follow-up negative symptoms (ß: 0.501, 95 % CI: 0.160, 0.842; ß: 0.430, 95 % CI: 0.080, 0.780 respectively. The relationship between complement regulator levels and negative symptoms was also observed in NAPLS2 alone (ß: 0.501, 95 % CI: -0.037, 1.039) and NAPLS3 alone, additionally adjusting for BMI (ß: 0.442, 95 % CI: 0.127, 0.757). CONCLUSION: The results indicate that plasma complement and coagulation regulator levels are prognostic factors of negative symptoms, independent of clinical and demographic prognostic factors. These results suggest complement and coagulation regulator levels could have potential utility in informing treatment decisions for negative symptoms in individuals at risk.

Proteomic Biomarkers for the Prediction of Transition to Psychosis in Individuals at Clinical High Risk: A Multi-cohort Model Development Study.

Psychosis risk prediction is one of the leading challenges in psychiatry. Previous investigations have suggested that plasma proteomic data may be useful in accurately predicting transition to psychosis in individuals at clinical high risk (CHR). We hypothesized that an a priori-specified proteomic prediction model would have strong predictive accuracy for psychosis risk and aimed to replicate longitudinal associations between plasma proteins and transition to psychosis. This study used plasma samples from participants in 3 CHR cohorts: the North American Prodrome Longitudinal Studies 2 and 3, and the NEURAPRO randomized control trial (total n = 754). Plasma proteomic data were quantified using mass spectrometry. The primary outcome was transition to psychosis over the study follow-up period. Logistic regression models were internally validated, and optimism-corrected performance metrics derived with a bootstrap procedure. In the overall sample of CHR participants (age: 18.5, SD: 3.9; 51.9% male), 20.4% (n = 154) developed psychosis within 4.4 years. The a priori-specified model showed poor risk-prediction accuracy for the development of psychosis (C-statistic: 0.51 [95% CI: 0.50, 0.59], calibration slope: 0.45). At a group level, Complement C8B, C4B, C5, and leucine-rich α-2 glycoprotein 1 (LRG1) were associated with transition to psychosis but did not surpass correction for multiple comparisons. This study did not confirm the findings from a previous proteomic prediction model of transition from CHR to psychosis. Certain complement proteins may be weakly associated with transition at a group level. Previous findings, derived from small samples, should be interpreted with caution.

Differential expression of haptoglobin in individuals at clinical high risk of psychosis and its association with global functioning and clinical symptoms.

BACKGROUND: Immune dysregulation has been observed in patients with schizophrenia or first-episode psychosis, but few have examined dysregulation in those at clinical high-risk (CHR) for psychosis. The aim of this study was to examine whether the peripheral blood-based proteome was dysregulated in those with CHR. Secondly, we examined whether baseline dysregulation was related to current and future functioning and clinical symptoms. METHODS: We used data from participants of the North American Prodromal Longitudinal Studies (NAPLS) 2 and 3 (n = 715) who provided blood samples (Unaffected Comparison subjects (UC) n = 223 and CHR n = 483). Baseline proteomic data was quantified from plasma samples using mass spectrometry. Differential expression was examined between CHR and UC using logistic regression. Psychosocial functioning was measured using the Global Assessment of Functioning scale (GAF). Symptoms were measured using the subscale scores from the Scale of Psychosis-risk Symptoms; positive, negative, general, and disorganised. Three measures of each outcome were included: baseline, longest available follow-up (last follow-up) and most severe follow-up (MSF). Associations between the proteomic data, GAF and symptoms were assessed using ordinal regression. RESULTS: Of the 99 proteins quantified, six were differentially expressed between UC and CHR. However, only haptoglobin (HP) survived FDR-correction (OR:1.45, 95 %CI:1.23-1.69, padj = <0.001). HP was cross-sectionally and longitudinally associated with functioning and symptoms such that higher HP values were associated with poorer functioning and more severe symptoms. Results were evident after stringent adjustment and poorer functioning was observed in both NAPLS cohort separately. CONCLUSION: We demonstrate that elevated HP is robustly observed in those at CHR for psychosis, irrespective of transition to psychosis. HP is longitudinally associated with poorer functioning and greater symptom severity. These results agree with previous reports of increased HP gene expression in individuals at-risk for psychosis and with the dysfunction of the acute phase inflammatory response seen in psychotic disorders.

Measuring the impact of therapy on medication use: data-linkage study.

BACKGROUND: The psychological therapies service (PTS) in the Northern Health and Social Care Trust, in Northern Ireland, provides therapies to adults with moderate or severe mental health difficulties. Psychometric outcomes data are routinely collected to assess if a patient demonstrates significant improvement in their main presenting problem area following therapy. The wider impact of therapy is not fully measured in the outcomes database as this would be disproportionately burdensome for both patient and therapist. The present study, to our knowledge, is the first to use data linkage to link patient therapy outcomes data with prescriptions data. AIMS: To widen our understanding of patient medication use before and after therapy. METHOD: Using Health and Care Number as a unique identifier, the Psychological Therapies Service - Routine Outcome Measurement Database (n = 3625) and data from 72 500 controls were linked with data from the Enhanced Prescribing Database (EPD). The EPD data were sourced from the Honest Broker Service. RESULTS: Key findings from the study were: (a) the odds of PTS clients using antipsychotics in the year before therapy were 25 times greater compared with controls (odds ratio (OR) = 24.53, 95% CI 20.16-29.84); (b) in the 1st year post discharge, PTS clients who clinically improved post therapy discharge were more likely than 'non-engagers' and 'non-improvers' to come off antianxiety medication (OR = 0.61, 95%, CI 0.38-0.98); and (c) therapy did not have an impact on antidepressant use. CONCLUSIONS: The results highlight the need for discussion between therapy services, GPs and psychiatry about whether more engagement and collaboration is needed to plan phased reduction in medication.

Prognostic models predicting transition to psychotic disorder using blood-based biomarkers: a systematic review and critical appraisal.

Accumulating evidence suggests individuals with psychotic disorder show abnormalities in metabolic and inflammatory processes. Recently, several studies have employed blood-based predictors in models predicting transition to psychotic disorder in risk-enriched populations. A systematic review of the performance and methodology of prognostic models using blood-based biomarkers in the prediction of psychotic disorder from risk-enriched populations is warranted. Databases (PubMed, EMBASE and PsycINFO) were searched for eligible texts from 1998 to 15/05/2023, which detailed model development or validation studies. The checklist for Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies (CHARMS) was used to guide data extraction from eligible texts and the Prediction Model Risk of Bias Assessment Tool (PROBAST) was used to assess the risk of bias and applicability of the studies. A narrative synthesis of the included studies was performed. Seventeen eligible studies were identified: 16 eligible model development studies and one eligible model validation study. A wide range of biomarkers were assessed, including nucleic acids, proteins, metabolites, and lipids. The range of C-index (area under the curve) estimates reported for the models was 0.67-1.00. No studies assessed model calibration. According to PROBAST criteria, all studies were at high risk of bias in the analysis domain. While a wide range of potentially predictive biomarkers were identified in the included studies, most studies did not account for overfitting in model performance estimates, no studies assessed calibration, and all models were at high risk of bias according to PROBAST criteria. External validation of the models is needed to provide more accurate estimates of their performance. Future studies which follow the latest available methodological and reporting guidelines and adopt strategies to accommodate required sample sizes for model development or validation will clarify the value of including blood-based biomarkers in models predicting psychosis.

Associations between plasma inflammatory markers and psychotic disorder, depressive disorder and generalised anxiety disorder in early adulthood: A nested case-control study.

BACKGROUND: Low-grade inflammation may occur in association with several mental disorders of early adulthood, though associations with markers of chronic inflammation such as soluble urokinase plasminogen activator receptor (suPAR) are less well-established. We aimed to examine associations between acute and chronic inflammatory markers and mental disorders, as well as psychiatric co-morbidity, in young adults aged 24 years in the Avon Longitudinal Study of Parents and Children. METHODS: Included were 781 participants (of 4019 who attended at age 24 years) who completed psychiatric assessments and provided plasma samples. Of these, 377 met criteria for psychotic disorder, depressive disorder or generalised anxiety disorder and 404 did not. Plasma concentrations of IFN-γ, IL-6, IL-8, IL-10, TNF-α, CRP, sVCAM1, sICAM1, suPAR and alpha-2-macroglobulin were measured using immunoassays. Logistic regression compared standardised inflammatory marker levels in cases and controls. Negative binomial regression evaluated associations between inflammatory markers and co-morbidity (number of mental disorders). Models were adjusted for sex, body mass index, cigarette smoking, cannabis use and employment status, then additionally for childhood trauma. RESULTS: For psychotic disorder, there was evidence for associations with IL-6 (odds ratio[OR] 1.68, 95 %CI 1.20-2.34) and suPAR (OR 1.74, 95 %CI 1.17-2.58). There was weaker evidence for an association between suPAR and depressive disorder (OR 1.31, 95 %CI 1.05-1.62). There was little evidence for associations between inflammatory markers and generalised anxiety disorder. There was weak evidence for an association between suPAR and co-morbidity (ß 0.10, 95 %CI 0.01-0.19). There was little evidence for additional confounding by childhood trauma. CONCLUSIONS: There was evidence that 24-year-olds with psychotic disorder had raised plasma IL-6 and suPAR concentrations compared to controls. These findings have implications regarding the role of inflammation in mental disorders in early adulthood.

Association of Complement and Coagulation Pathway Proteins With Treatment Response in First-Episode Psychosis: A Longitudinal Analysis of the OPTiMiSE Clinical Trial.

BACKGROUND AND HYPOTHESIS: Treatment response to specific antipsychotic medications is difficult to predict on clinical grounds alone. The current study hypothesizes that the baseline complement pathway activity predicts the treatment response and investigates the relationship between baseline plasma biomarkers with treatment response to antipsychotic medications. STUDY DESIGN: Baseline plasma samples were collected from first episode of psychosis patients (n = 243) from a multi-center clinical trial. The participants were treated with amisulpride for 4 weeks. Levels of complement and coagulation proteins at baseline were measured using both data-dependent and data-independent mass spectrometry approaches. The primary outcome was remission status at 4 weeks and the secondary outcomes included change in psychotic and functional symptoms over the period of treatment. In addition, immunoassays were performed at baseline for complement C1R, as well as for activation markers C4a and sC5b-9. STUDY RESULTS: The plasma level of complement variant C4A was significantly associated with remission at 4 weeks. Moreover, higher levels of several complement and coagulation pathway proteins were associated with a reduction in psychotic symptoms and an improvement in functioning. Immunoassays showed an association of baseline levels of C1R and C4a as well as complement activation marker sC5b-9 levels with treatment response. CONCLUSION: The results demonstrated that the response to antipsychotic treatment might be related to pre-treatment levels of plasma complement and coagulation pathway proteins. This is consistent with independent evidence associating immune dysfunction with the pathophysiology of psychosis. Moreover, these results inform the development of novel therapeutic approaches that target the complement system for psychosis.

Evidence that complement and coagulation proteins are mediating the clinical response to omega-3 fatty acids: A mass spectrometry-based investigation in subjects at clinical high-risk for psychosis.

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.

Transdiagnostic inflammatory subgroups among psychiatric disorders and their relevance to role functioning: a nested case-control study of the ALSPAC cohort.

Individuals with psychotic disorders and depressive disorder exhibit altered concentrations of peripheral inflammatory markers. It has been suggested that clinical trials of anti-inflammatory therapies for psychiatric disorders should stratify patients by their inflammatory profile. Hence, we investigated whether different subgroups of individuals exist across psychiatric disorders, based on their inflammatory biomarker signatures. We measured the plasma concentrations of 17 inflammatory markers and receptors in 380 participants with psychotic disorder, depressive disorder or generalised anxiety disorder and 399 controls without psychiatric symptoms from the ALSPAC cohort at age 24. We employed a semi-supervised clustering algorithm, which discriminates multiple clusters of psychiatric disorder cases from controls. The best fit was for a two-cluster model of participants with psychiatric disorders (Adjusted Rand Index (ARI) = 0.52 ± 0.01) based on the inflammatory markers. Permutation analysis indicated the stability of the clustering solution performed better than chance (ARI = 0.43 ± 0.11; p < 0.001), and the clusters explained the inflammatory marker data better than a Gaussian distribution (p = 0.021). Cluster 2 exhibited marked increases in sTNFR1/2, suPAR, sCD93 and sIL-2RA, compared to cluster 1. Participants in the cluster exhibiting higher inflammation were less likely to be in employment, education or training, indicating poorer role functioning. This study found evidence for a novel pattern of inflammatory markers specific to psychiatric disorders and strongly associated with a transdiagnostic measure of illness severity. sTNFR1/2, suPAR, sCD93 and sIL-2RA could be used to stratify clinical trials of anti-inflammatory therapies for psychiatric disorders.

Plasma lipid alterations in young adults with psychotic experiences: A study from the Avon Longitudinal Study of Parents and Children cohort.

BACKGROUND: Psychotic experiences (PEs) are associated with an increased risk of future psychotic and non-psychotic mental disorders. The identification of biomarkers of PEs may provide insights regarding the underlying pathophysiology. METHODS: The current study applied targeted lipidomic approaches to compare plasma lipid profiles in participants from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort who did (n = 206) or did not (n = 206) have PEs when aged approximately 24 years. RESULTS: In total, 202 lipids including 8 lipid classes were measured by using ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS). Eight lipid clusters were generated. Thirteen individual lipids were nominally significantly higher in the PEs group compared to the control group. After correction for multiple comparisons, 9 lipids comprising 3 lysophosphatidylcholines (LPCs), 2 phosphatidylcholines (PCs) and 4 triacylglycerols (TGs) remained significant. In addition, PEs cases had increased levels of TGs and LPCs with a low double bond count. CONCLUSIONS: These findings indicate plasma lipidomic abnormalities in individuals experiencing PEs. The lipidomic profile measures could aid our understanding of the underlying pathophysiological mechanisms.

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.

Omega-3 fatty acid in ultra-high-risk psychosis: A systematic review based on functional outcome.

AIM: Among different types of poly unsaturated fatty acids, omega-3 fatty acids (FA) play a substantial role in brain development and functioning. This review was designed to evaluate and synthesize available evidence regarding omega-3 FAs and functional outcome in the ultra-high-risk (UHR) population. METHODS: An electronic search in PubMed, EMBASE, PSYCINFO and COCHRANE search engines has been performed for all articles published until January 2019. The studies that have data regarding omega-3 FAs and functional outcome in UHR population were included. RESULTS: Out of 397 nonduplicate citations, 19 articles met selection criteria. These articles were from four different primary studies, namely the Program of Rehabilitation and Therapy (PORT), the North American Prodromal Longitudinal Studies (NAPLS), Vienna High Risk study (VHR) and the NEURAPRO. The data from the NAPLS study found a positive correlation between functional improvement and frequency of dietary intake omega-3 FA. Moreover, among the erythrocyte omega-3 FA only eicosapentaenoic acid (EPA) showed a positive correlation with functional score. The VHR study found long-term improvement in functional outcome in omega-3 group compared to control, whereas such difference was noticed in the NEURAPRO. In the VHR study both omega-3 and omega-6 together predicted the functional improvement at 12 weeks. CONCLUSIONS: The number of studies available remains insufficient and more studies with standardized outcome measures in a clinically comparable UHR population would be of more value to understand the clinical benefits of omega-3 FA in the UHR population.

The association of plasma inflammatory markers with omega-3 fatty acids and their mediating role in psychotic symptoms and functioning: An analysis of the NEURAPRO clinical trial.

BACKGROUND: There is increasing evidence that dysregulation of polyunsaturated fatty acids (FAs) mediated membrane function plays a role in the pathophysiology of schizophrenia. Even though preclinical findings have supported the anti-inflammatory properties of omega-3 FAs on brain health, their biological roles as anti-inflammatory agents and their therapeutic role on clinical symptoms of psychosis risk are not well understood. In the current study, we investigated the relationship of erythrocyte omega-3 FAs with plasma immune markers in a clinical high risk for psychosis (CHR) sample. In addition, a mediation analysis was performed to examine whether previously reported associations between omega-3 FAs and clinical outcomes were mediated via plasma immune markers. Clinical outcomes for CHR participants in the NEURAPRO clinical trial were measured using the Brief Psychiatric Rating Scale (BPRS), Schedule for the Scale of Assessment of Negative Symptoms (SANS) and Social and Occupational Functioning Assessment Scale (SOFAS) scales. The erythrocyte omega-3 index [eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA)] and plasma concentrations of inflammatory markers were quantified at baseline (n = 268) and 6 month follow-up (n = 146) by gas chromatography and multiplex immunoassay, respectively. In linear regression models, the baseline plasma concentrations of Interleukin (IL)-15, Intercellular adhesion molecule (ICAM)-1 and Vascular cell adhesion molecule (VCAM)-1 were negatively associated with baseline omega-3 index. In addition, 6-month change in IL-12p40 and TNF-α showed a negative association with change in omega-3 index. In longitudinal analyses, the baseline and 6 month change in omega-3 index was negatively associated with VCAM-1 and TNF-α respectively at follow-up. Mediation analyses provided little evidence for mediating effects of plasma immune markers on the relationship between omega-3 FAs and clinical outcomes (psychotic symptoms and functioning) in CHR participants. Our results indicate a predominantly anti-inflammatory relationship of omega-3 FAs on plasma inflammatory status in CHR individuals, but this did not appear to convey clinical benefits at 6 month and 12 month follow-up. Both immune and non-immune biological effects of omega-3 FAs would be resourceful in understanding the clinical benefits of omega-3 FAs in CHR papulation.

Dysregulation of complement and coagulation pathways: emerging mechanisms in the development of psychosis.

Early identification and treatment significantly improve clinical outcomes of psychotic disorders. Recent studies identified protein components of the complement and coagulation systems as key pathways implicated in psychosis. These specific protein alterations are integral to the inflammatory response and can begin years before the onset of clinical symptoms of psychotic disorder. Critically, they have recently been shown to predict the transition from clinical high risk to first-episode psychosis, enabling stratification of individuals who are most likely to transition to psychotic disorder from those who are not. This reinforces the concept that the psychosis spectrum is likely a central nervous system manifestation of systemic changes and highlights the need to investigate plasma proteins as diagnostic or prognostic biomarkers and pathophysiological mediators. In this review, we integrate evidence of alterations in proteins belonging to the complement and coagulation protein systems, including the coagulation, anticoagulation, and fibrinolytic pathways and their dysregulation in psychosis, into a consolidated mechanism that could be integral to the progression and manifestation of psychosis. We consolidate the findings of altered blood proteins relevant for progression to psychotic disorders, using data from longitudinal studies of the general population in addition to clinical high-risk (CHR) individuals transitioning to psychotic disorder. These are compared to markers identified from first-episode psychosis and schizophrenia as well as other psychosis spectrum disorders. We propose the novel hypothesis that altered complement and coagulation plasma levels enhance their pathways' activating capacities, while low levels observed in key regulatory components contribute to excessive activation observed in patients. This hypothesis will require future testing through a range of experimental paradigms, and if upheld, complement and coagulation pathways or specific proteins could be useful diagnostic or prognostic tools and targets for early intervention and preventive strategies.

Associations between plasma fatty acid concentrations and schizophrenia: a two-sample Mendelian randomisation study.

BACKGROUND: Although studies suggest that concentrations of omega-3 and omega-6 fatty acids are lower in individuals with schizophrenia, evidence for beneficial effects of fatty acid supplementation is scarce. Therefore, in this study, we aimed to determine whether omega-3 and omega-6 fatty acid concentrations are causally related to schizophrenia. METHODS: We did a two-sample Mendelian randomisation study, using deidentified summary-level data that were publicly available. Exposure-outcome relationships were evaluated using the inverse variance weighted two-sample Mendelian randomisation method using results from genome-wide association studies (GWASs) of fatty acid concentrations and schizophrenia. GWAS results were available for European (fatty acids) and European and Asian (schizophrenia) ancestry samples. Overall age and gender information were not calculable from the summary-level GWAS results. Weighted median, weighted mode, and Mendelian randomisation Egger regression methods were used as sensitivity analyses. To address underlying mechanisms, further analyses were done using single instruments within the FADS gene cluster and ELOVL2 gene locus. FADS gene cluster and ELOVL2 gene causal effects on schizophrenia were calculated by dividing the single nucleotide polymorphism (SNP)-schizophrenia effect estimate by the SNP-fatty acid effect estimate with standard errors derived using the first term from a delta method expansion for the ratio estimate. Multivariable Mendelian randomisation was used to estimate direct effects of omega-3 fatty acids on schizophrenia, independent of omega-6 fatty acids, lipoproteins (ie, HDL and LDL), and triglycerides. FINDINGS: Mendelian randomisation analyses indicated that long-chain omega-3 and long-chain omega-6 fatty acid concentrations were associated with a lower risk of schizophrenia (eg, inverse variance weighted odds ratio [OR] 0·83 [95% CI 0·75-0·92] for docosahexaenoic acid). By contrast, there was weak evidence that short-chain omega-3 and short-chain omega-6 fatty acids were associated with an increased risk of schizophrenia (eg, inverse variance weighted OR 1·07 [95% CI 0·98-1·18] for α-linolenic acid). Effects were consistent across the sensitivity analyses and the FADS single-SNP analyses, suggesting that long-chain omega-3 and long-chain omega-6 fatty acid concentrations were associated with lower risk of schizophrenia (eg, OR 0·74 [95% CI 0·58-0·96] for docosahexaenoic acid) whereas short-chain omega-3 and short-chain omega-6 fatty acid concentrations were associated with an increased risk of schizophrenia (eg, OR 1·08 [95% CI 1·02-1·15] for α-linolenic acid). By contrast, estimates from the ELOVL2 single-SNP analyses were more imprecise and compatible with both risk-increasing and protective effects for each of the fatty acid measures. Multivariable Mendelian randomisation indicated that the protective effect of docosahexaenoic acid on schizophrenia persisted after conditioning on other lipids, although evidence was slightly weaker (multivariable inverse variance weighted OR 0·84 [95% CI 0·71-1·01]). INTERPRETATION: Our results are compatible with the protective effects of long-chain omega-3 and long-chain omega-6 fatty acids on schizophrenia, suggesting that people with schizophrenia might have difficulty converting short-chain polyunsaturated fatty acids to long-chain polyunsaturated fatty acids. Further studies are required to determine whether long-chain polyunsaturated fatty acid supplementation or diet enrichment might help prevent onset of schizophrenia. FUNDING: National Institute for Health Research Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol.