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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 nâ =â 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% (nâ =â 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.
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Biomarcadores , Sintomas Prodrômicos , Proteômica , Transtornos Psicóticos , Humanos , Transtornos Psicóticos/sangue , Feminino , Masculino , Biomarcadores/sangue , Adulto Jovem , Adolescente , Adulto , Progressão da Doença , Estudos Longitudinais , RiscoRESUMO
BACKGROUND: The Collaborative Outcome study on Health and Functioning during Infection Times (COH-FIT; www.coh-fit.com) is an anonymous and global online survey measuring health and functioning during the COVID-19 pandemic. The aim of this study was to test concurrently the validity of COH-FIT items and the internal validity of the co-primary outcome, a composite psychopathology "P-score". METHODS: The COH-FIT survey has been translated into 30 languages (two blind forward-translations, consensus, one independent English back-translation, final harmonization). To measure mental health, 1-4 items ("COH-FIT items") were extracted from validated questionnaires (e.g. Patient Health Questionnaire 9). COH-FIT items measured anxiety, depressive, post-traumatic, obsessive-compulsive, bipolar and psychotic symptoms, as well as stress, sleep and concentration. COH-FIT Items which correlated r ≥ 0.5 with validated companion questionnaires, were initially retained. A P-score factor structure was then identified from these items using exploratory factor analysis (EFA) and confirmatory factor analyses (CFA) on data split into training and validation sets. Consistency of results across languages, gender and age was assessed. RESULTS: From >150,000 adult responses by May 6th, 2022, a subset of 22,456 completed both COH-FIT items and validated questionnaires. Concurrent validity was consistently demonstrated across different languages for COH-FIT items. CFA confirmed EFA results of five first-order factors (anxiety, depression, post-traumatic, psychotic, psychophysiologic symptoms) and revealed a single second-order factor P-score, with high internal reliability (ω = 0.95). Factor structure was consistent across age and sex. CONCLUSIONS: COH-FIT is a valid instrument to globally measure mental health during infection times. The P-score is a valid measure of multidimensional mental health.
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COVID-19 , Pandemias , Humanos , Adulto , Reprodutibilidade dos Testes , Inquéritos e Questionários , Avaliação de Resultados em Cuidados de Saúde , Análise Fatorial , PsicometriaRESUMO
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.
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Ácidos Graxos Ômega-3 , Transtornos Psicóticos , Humanos , Ácidos Graxos Ômega-3/uso terapêutico , Transtornos Psicóticos/tratamento farmacológico , Transtornos Psicóticos/metabolismo , Ácidos Graxos Insaturados , Proteínas do Sistema Complemento , Espectrometria de MassasRESUMO
BACKGROUND: Cognitive impairments are well-established features of psychotic disorders and are present when individuals are at ultra-high risk for psychosis. However, few interventions target cognitive functioning in this population. AIMS: To investigate whether omega-3 polyunsaturated fatty acid (n-3 PUFA) supplementation improves cognitive functioning among individuals at ultra-high risk for psychosis. METHOD: Data (N = 225) from an international, multi-site, randomised controlled trial (NEURAPRO) were analysed. Participants were given omega-3 supplementation (eicosapentaenoic acid and docosahexaenoic acid) or placebo over 6 months. Cognitive functioning was assessed with the Brief Assessment of Cognition in Schizophrenia (BACS). Mixed two-way analyses of variance were computed to compare the change in cognitive performance between omega-3 supplementation and placebo over 6 months. An additional biomarker analysis explored whether change in erythrocyte n-3 PUFA levels predicted change in cognitive performance. RESULTS: The placebo group showed a modest greater improvement over time than the omega-3 supplementation group for motor speed (ηp2 = 0.09) and BACS composite score (ηp2 = 0.21). After repeating the analyses without individuals who transitioned, motor speed was no longer significant (ηp2 = 0.02), but the composite score remained significant (ηp2 = 0.02). Change in erythrocyte n-3 PUFA levels did not predict change in cognitive performance over 6 months. CONCLUSIONS: We found no evidence to support the use of omega-3 supplementation to improve cognitive functioning in ultra-high risk individuals. The biomarker analysis suggests that this finding is unlikely to be attributed to poor adherence or consumption of non-trial n-3 PUFAs.
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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.
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Proteômica , Transtornos Psicóticos , Ensaios Clínicos como Assunto , Complemento C5 , Proteínas do Sistema Complemento , Citocinas , Ácidos Graxos , Humanos , Aprendizado de Máquina , Transtornos Psicóticos/diagnósticoRESUMO
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.
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Ácidos Graxos Ômega-3 , Transtornos Psicóticos , Biomarcadores , Ácidos Docosa-Hexaenoicos , Ácido Eicosapentaenoico , HumanosRESUMO
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.
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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.
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Causal interactions between specific psychiatric symptoms could contribute to the heterogenous clinical trajectories observed in early psychopathology. Current diagnostic approaches merge clinical manifestations that co-occur across subjects and could significantly hinder our understanding of clinical pathways connecting individual symptoms. Network analysis techniques have emerged as alternative approaches that could help shed light on the complex dynamics of early psychopathology. The present study attempts to address the two main limitations that have in our opinion hindered the application of network approaches in the clinical setting. Firstly, we show that a multi-layer network analysis approach, can move beyond a static view of psychopathology, by providing an intuitive characterization of the role of specific symptoms in contributing to clinical trajectories over time. Secondly, we show that a Graph-Signal-Processing approach, can exploit knowledge of longitudinal interactions between symptoms, to predict clinical trajectories at the level of the individual. We test our approaches in two independent samples of individuals with genetic and clinical vulnerability for developing psychosis. Novel network approaches can allow to embrace the dynamic complexity of early psychopathology and help pave the way towards a more a personalized approach to clinical care.
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Transtornos Psicóticos/fisiopatologia , Adulto , Feminino , Humanos , Estudos Longitudinais , Masculino , Medicina de PrecisãoRESUMO
Tourette syndrome (TS) is a neuropsychiatric disorder of complex genetic architecture involving multiple interacting genes. Here, we sought to elucidate the pathways that underlie the neurobiology of the disorder through genome-wide analysis. We analyzed genome-wide genotypic data of 3581 individuals with TS and 7682 ancestry-matched controls and investigated associations of TS with sets of genes that are expressed in particular cell types and operate in specific neuronal and glial functions. We employed a self-contained, set-based association method (SBA) as well as a competitive gene set method (MAGMA) using individual-level genotype data to perform a comprehensive investigation of the biological background of TS. Our SBA analysis identified three significant gene sets after Bonferroni correction, implicating ligand-gated ion channel signaling, lymphocytic, and cell adhesion and transsynaptic signaling processes. MAGMA analysis further supported the involvement of the cell adhesion and trans-synaptic signaling gene set. The lymphocytic gene set was driven by variants in FLT3, raising an intriguing hypothesis for the involvement of a neuroinflammatory element in TS pathogenesis. The indications of involvement of ligand-gated ion channel signaling reinforce the role of GABA in TS, while the association of cell adhesion and trans-synaptic signaling gene set provides additional support for the role of adhesion molecules in neuropsychiatric disorders. This study reinforces previous findings but also provides new insights into the neurobiology of TS.
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Síndrome de Tourette , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Neurônios , Síndrome de Tourette/genéticaRESUMO
PURPOSE: Migrant status is one of the most replicated and robust risk factors for developing a psychotic disorder. This study aimed to determine whether migrant status in people identified as Ultra-High Risk for Psychosis (UHR) was associated with risk of transitioning to a full-threshold psychotic disorder. METHODS: Hazard ratios for the risk of transition were calculated from five large UHR cohorts (n = 2166) and were used to conduct a meta-analysis using the generic inverse-variance method using a random-effects model. RESULTS: 2166 UHR young people, with a mean age of 19.1 years (SD ± 4.5) were included, of whom 221 (10.7%) were first-generation migrants. A total of 357 young people transitioned to psychosis over a median follow-up time of 417 days (I.Q.R.147-756 days), representing 17.0% of the cohort. The risk of transition to a full-threshold disorder was not increased for first-generation migrants, (HR = 1.08, 95% CI 0.62-1.89); however, there was a high level of heterogeneity between studies The hazard ratio for second-generation migrants to transition to a full-threshold psychotic disorder compared to the remainder of the native-born population was 1.03 (95% CI 0.70-1.51). CONCLUSIONS: This meta-analysis did not find a statistically significant association between migrant status and an increased risk for transition to a full-threshold psychotic disorder; however, several methodological issues could explain this finding. Further research should focus on examining the risk of specific migrant groups and also ensuring that migrant populations are adequately represented within UHR clinics.
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Transtornos Psicóticos , Migrantes , Adolescente , Adulto , Estudos de Coortes , Humanos , Modelos de Riscos Proporcionais , Escalas de Graduação Psiquiátrica , Transtornos Psicóticos/epidemiologia , Fatores de Risco , Adulto JovemRESUMO
BACKGROUND: Neurocognitive impairments are core early features of psychosis and are observed in those at ultra-high risk (UHR) for psychosis. The aim of the present study was to explore whether neurocognition is associated with polyunsaturated fatty acids (PUFAs), as has been observed in other clinical populations. METHOD: Erythrocyte levels of total omega-3-and omega-6 PUFAs the omega-3/omega-6 ratio, were measured in 265 UHR individuals. Six domains of neurocognition as well a Composite Score, were assessed using the Brief Assessment of Cognition in Schizophrenia. Pearson's correlations were used to assess the relationship between PUFAs and neurocognition. All analyses were controlled for tobacco smoking. RESULTS: Verbal Fluency correlated positively with eicosapentaenoic acid (P = .024) and alpha-linolenic acid (P = .01), and negatively with docosahexanoic acid (P = .007) and Working Memory positively correlated with omega-3/omega-6 ratio (P = .007). CONCLUSIONS: The current results provide support for a relationship between Verbal Fluency and omega-3 PUFAs in UHR. Further investigation is required to elucidate whether these biomarkers are useful as risk markers or in understanding the biological underpinning of neurocognitive impairment in this population.
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Ácidos Graxos Ômega-3 , Transtornos Psicóticos , Esquizofrenia , Adolescente , Cognição , Humanos , Memória de Curto PrazoRESUMO
[This corrects the article DOI: 10.3389/fpsyt.2019.00393.].
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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.
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Transtorno Depressivo Maior , Transtornos Psicóticos , Cognição , Depressão , Transtorno Depressivo Maior/complicações , Humanos , Testes Neuropsicológicos , Transtornos Psicóticos/complicaçõesRESUMO
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.
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Transtornos Psicóticos/psicologia , Adolescente , Adulto , Progressão da Doença , Feminino , Humanos , Masculino , Escalas de Graduação Psiquiátrica , Transtornos Psicóticos/diagnóstico , Índice de Gravidade de Doença , Adulto JovemRESUMO
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.
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Ácidos Graxos Ômega-3 , Transtornos Psicóticos , Adolescente , Biomarcadores , Ácidos Docosa-Hexaenoicos , Ácido Eicosapentaenoico , Humanos , Transtornos Psicóticos/tratamento farmacológicoRESUMO
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 (nâ¯=â¯285) with age-matched healthy controls (nâ¯=â¯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.
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Ácidos Graxos Ômega-3 , Transtornos Psicóticos , Ácidos Docosa-Hexaenoicos , Ácido Eicosapentaenoico , Eritrócitos , Ácidos Graxos , Humanos , FosfolipídeosRESUMO
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 840â¯mg EPA and 560â¯mg DHA per day) or placebo (paraffin oil) for 6â¯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 6â¯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 6â¯months of supplementation with placebo. N-3 supplementation for 6â¯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.
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Ácidos Graxos Ômega-3 , Transtornos Psicóticos , Suplementos Nutricionais , Ácidos Docosa-Hexaenoicos , Ácido Eicosapentaenoico , Ácidos Graxos , Humanos , FosfolipídeosRESUMO
Background: Deficiencies in membrane polyunsaturated fatty acids (PUFA) such as omega-3 (n-3) fatty acids are thought to contribute to the pathophysiological processes underlying psychotic disorders. Emerging evidence suggests that the levels of PUFA are related to clinical symptoms but significant heterogeneity exists between studies. Here, we investigated associations of membrane PUFA with clinical symptoms and functioning in a large sample of individuals at ultra-high risk (UHR) for psychosis. Methods: A total of 285 participants of the NEURAPRO clinical trial were investigated for erythrocyte PUFA levels, including the n-3 index, n-6/n-3 PUFA ratio, docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA). Severity of general psychopathology [Brief Psychiatric Rating Scale (BPRS)], psychotic symptoms (BPRS psychosis subscale), negative symptoms [Scale for the Assessment of Negative Symptoms (SANS)], manic symptoms [Young Mania Rating Scale (YMRS)], depressive symptoms [Montgomery Asberg Depression Rating Scale (MADRS)], and functioning [Social and Occupational Functioning Scale (SOFAS), Global Functioning Social (GF-S) and Role (GF-R) scales] were assessed concurrently. Partial correlation taking into account the effects of gender, age, and smoking was used to examine the relationship between PUFAs and symptoms severity. Results: The n-3 index negatively correlated with the severity of general psychopathology, psychotic symptoms, depressive symptoms, and manic symptoms. The n-6/n-3 PUFA ratio positively correlated with severity of psychotic and depressive symptoms. The n-3 PUFA DHA negatively correlated with the severity of general psychopathology, positive, manic, and depressive symptoms. EPA negatively correlated with manic symptoms. Nervonic acid, an n-9 monounsaturated fatty acid, positively correlated with general psychopathology, positive and negative symptoms, depressive symptoms, and manic symptoms. The long-chain saturated fatty acid tetracosanoic acid positively correlated with general psychopathology, positive, manic, and depressive symptoms. Conclusions: Partially consistent with a previous study, psychotic symptoms, depressive symptoms, and symptoms of mania were associated with several classes of FAs in the present study. These findings support the relevance of membrane fatty acids for the onset of psychotic symptoms and indicate that FAs should be further evaluated as biomarkers in the UHR for psychosis group. Clinical Trial Registration: ANZCTR, identifier: 12608000475347.
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OBJECTIVE: Tourette's syndrome is polygenic and highly heritable. Genome-wide association study (GWAS) approaches are useful for interrogating the genetic architecture and determinants of Tourette's syndrome and other tic disorders. The authors conducted a GWAS meta-analysis and probed aggregated Tourette's syndrome polygenic risk to test whether Tourette's and related tic disorders have an underlying shared genetic etiology and whether Tourette's polygenic risk scores correlate with worst-ever tic severity and may represent a potential predictor of disease severity. METHODS: GWAS meta-analysis, gene-based association, and genetic enrichment analyses were conducted in 4,819 Tourette's syndrome case subjects and 9,488 control subjects. Replication of top loci was conducted in an independent population-based sample (706 case subjects, 6,068 control subjects). Relationships between Tourette's polygenic risk scores (PRSs), other tic disorders, ascertainment, and tic severity were examined. RESULTS: GWAS and gene-based analyses identified one genome-wide significant locus within FLT3 on chromosome 13, rs2504235, although this association was not replicated in the population-based sample. Genetic variants spanning evolutionarily conserved regions significantly explained 92.4% of Tourette's syndrome heritability. Tourette's-associated genes were significantly preferentially expressed in dorsolateral prefrontal cortex. Tourette's PRS significantly predicted both Tourette's syndrome and tic spectrum disorders status in the population-based sample. Tourette's PRS also significantly correlated with worst-ever tic severity and was higher in case subjects with a family history of tics than in simplex case subjects. CONCLUSIONS: Modulation of gene expression through noncoding variants, particularly within cortico-striatal circuits, is implicated as a fundamental mechanism in Tourette's syndrome pathogenesis. At a genetic level, tic disorders represent a continuous spectrum of disease, supporting the unification of Tourette's syndrome and other tic disorders in future diagnostic schemata. Tourette's PRSs derived from sufficiently large samples may be useful in the future for predicting conversion of transient tics to chronic tic disorders, as well as tic persistence and lifetime tic severity.